Pruritus is a common feature in sheep infected with the BSE agent.

BACKGROUND: The variability in the clinical or pathological presentation of transmissible spongiform encephalopathies (TSEs) in sheep, such as scrapie and bovine spongiform encephalopathy (BSE), has been attributed to prion protein genotype, strain, breed, clinical duration, dose, route and type of inoculum and the age at infection. The study aimed to describe the clinical signs in sheep infected with the BSE agent throughout its clinical course to determine whether the clinical signs were as variable as described for classical scrapie in sheep. The clinical signs were compared to BSE-negative sheep to assess if disease-specific clinical markers exist. RESULTS: Forty-seven (34%) of 139 sheep, which comprised 123 challenged sheep and 16 undosed controls, were positive for BSE. Affected sheep belonged to five different breeds and three different genotypes (ARQ/ARQ, VRQ/VRQ and AHQ/AHQ). None of the controls or BSE exposed sheep with ARR alleles were positive. Pruritus was present in 41 (87%) BSE positive sheep; the remaining six were judged to be pre-clinically infected. Testing of the response to scratching along the dorsum of a sheep proved to be a good indicator of clinical disease with a test sensitivity of 85% and specificity of 98% and usually coincided with weight loss. Clinical signs that were displayed significantly earlier in BSE positive cases compared to negative cases were behavioural changes, pruritic behaviour, a positive scratch test, alopecia, skin lesions, teeth grinding, tremor, ataxia, loss of weight and loss of body condition. The frequency and severity of each specific clinical sign usually increased with the progression of disease over a period of 16-20 weeks. CONCLUSION: Our results suggest that BSE in sheep presents with relatively uniform clinical signs, with pruritus of increased severity and abnormalities in behaviour or movement as the disease progressed. Based on the studied sheep, these clinical features appear to be independent of breed, affected genotype, dose, route of inoculation and whether BSE was passed into sheep from cattle or from other sheep, suggesting that the clinical phenotype of BSE is influenced by the TSE strain more than by other factors. The clinical phenotype of BSE in the genotypes and breed studied was indistinguishable from that described for classical scrapie cases

Managing sustainable non-profit network organizations

We draw upon a case study conducted within a non-profit network organization to propose five dualities which are central to understanding effective management of non-profit networks. We then examine strategies that address these dualities, based on new approaches to leadership, performance measurement, governance, coaching and creative management of dualities

Physiological, perceptual, and technical responses to on-court tennis training on hard and clay courts

The aim of this study was to investigate the effect of court surface (clay vs. hard court) on technical, physiological, and perceptual responses to on-court tennis training. Four high-performance junior male players performed 2 identical training sessions on hard and clay courts, respectively. Sessions included both physical conditioning and technical elements as led by the coach. Each session was filmed for later notational analysis of stroke count and error rates. Furthermore, players wore a global positioning satellite device to measure distance covered during each session, while heart rate, countermovement jump distance, and capillary blood measures of metabolites were measured before, during, and after each session. Additionally, a respective coach and athlete rating of perceived exertion (RPE) were measured after each session. Total duration and distance covered during each session were comparable (p > 0.05; d 0.05; d 0.05; d > 0.90). Furthermore, large effects for increased heart rate, blood lactate, and RPE values were evident on clay compared with hard courts (p > 0.05; d > 0.90). Additionally, although player and coach RPE on hard courts were similar, there were large effects for coaches to underrate the RPE of players on clay courts (p > 0.05; d > 0.90). In conclusion, training on clay courts results in trends for increased heart rate, lactate, and RPE values, suggesting that sessions on clay courts tend towards higher physiological and perceptual loads than hard courts. Furthermore, coaches seem effective at rating player RPE on hard courts but may underrate the perceived exertion of sessions on clay courts. © 2013 National Strength and Conditioning Association

The International Mass Loading Service

The International Mass Loading Service computes four loadings: a) atmospheric pressure loading; b) land water storage loading; c) oceanic tidal loading; and d) non-tidal oceanic loading. The service provides to users the mass loading time series in three forms: 1) pre-computed time series for a list of 849 space geodesy stations; 2) pre-computed time series on the global 1deg x 1deg grid; and 3) on-demand Internet service for a list of stations and a time range specified by the user. The loading displacements are provided for the time period from 1979.01.01 through present, updated on an hourly basis, and have latencies 8-20 hours.Comment: 8 pages, 3 figures, to appear in the Proceedings of the Reference Frames for Applications in Geosciences Simposium, held in Luxemboug in October 201

STUDY OF THE POSSIBLE ANTIHYPERTENSIVE AND HYPOLIPIDEMIC EFFECTS OF AN HERBAL MIXTURE ON L-NAME-INDUCED HYPERTENSIVE RATS

Objective: Hypertension is a chronic medical condition. Diet can improve blood pressure control and decrease the risk of health complication.Methods: In this study, four plants: Roselle, Marjoram, Chamomile, and Doum were extracted by water. Equal portions of them were mixed. Lethaldose 50% of the mixture was assayed; the dose which did not cause any mortality was 266.94 mg/100 g body weight. Animals were classified into fivegroups: Negative control group, positive control group where hypertension was induced by L-name, two groups treated with two doses of the mixture,and a group treated with prazosin as a standard treatment. Treatment of hypertensive rats continued for 4 successive weeks.Results: Treatment with the mixture showed a significant reduction in blood pressure of hypertensive rats, as well as serum cholesterol, low-densitylipoprotein-cholesterol, and urea levels when compared to positive control group.Conclusion: The results obtained suggest that the aqueous extract is efficient as an antihypertensive and hypolipidemic agent.Keywords: Rats, Aqueous extract, Hypertension, Hyperlipidemia, L-name

Neuroprotection in a Novel Mouse Model of Multiple Sclerosis

The authors acknowledge the support of the Barts and the London Charity, the Multiple Sclerosis Society of Great Britain and Northern Ireland, the National Multiple Sclerosis Society, USA, notably the National Centre for the Replacement, Refinement & Reduction of Animals in Research, and the Wellcome Trust (grant no. 092539 to ZA). The siRNA was provided by Quark Pharmaceuticals. The funders and Quark Pharmaceuticals had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Elevated Paracellular Glucose Flux across Cystic Fibrosis Airway Epithelial Monolayers Is an Important Factor for Pseudomonas aeruginosa Growth.

People with cystic fibrosis (CF) who develop related diabetes (CFRD) have accelerated pulmonary decline, increased infection with antibiotic-resistant Pseudomonas aeruginosa and increased pulmonary exacerbations. We have previously shown that glucose concentrations are elevated in airway surface liquid (ASL) of people with CF, particularly in those with CFRD. We therefore explored the hypotheses that glucose homeostasis is altered in CF airway epithelia and that elevation of glucose flux into ASL drives increased bacterial growth, with an effect over and above other cystic fibrosis transmembrane conductance regulator (CFTR)-related ASL abnormalities. The aim of this study was to compare the mechanisms governing airway glucose homeostasis in CF and non-CF primary human bronchial epithelial (HBE) monolayers, under normal conditions and in the presence of Ps. aeruginosa filtrate. HBE-bacterial co-cultures were performed in the presence of 5 mM or 15 mM basolateral glucose to investigate how changes in blood glucose, such as those seen in CFRD, affects luminal Ps. aeruginosa growth. Calu-3 cell monolayers were used to evaluate the potential importance of glucose on Ps. aeruginosa growth, in comparison to other hallmarks of the CF ASL, namely mucus hyperviscosity and impaired CFTR-dependent fluid secretions. We show that elevation of basolateral glucose promotes the apical growth of Ps. aeruginosa on CF airway epithelial monolayers more than non-CF monolayers. Ps. aeruginosa secretions elicited more glucose flux across CF airway epithelial monolayers compared to non-CF monolayers which we propose increases glucose availability in ASL for bacterial growth. In addition, elevating basolateral glucose increased Ps. aeruginosa growth over and above any CFTR-dependent effects and the presence or absence of mucus in Calu-3 airway epithelia-bacteria co-cultures. Together these studies highlight the importance of glucose as an additional factor in promoting Ps. aeruginosa growth and respiratory infection in CF disease

Fructose transport-deficient Staphylococcus aureus reveals important role of epithelial glucose transporters in limiting sugar-driven bacterial growth in airway surface liquid.

Hyperglycaemia as a result of diabetes mellitus or acute illness is associated with increased susceptibility to respiratory infection with Staphylococcus aureus. Hyperglycaemia increases the concentration of glucose in airway surface liquid (ASL) and promotes the growth of S. aureus in vitro and in vivo. Whether elevation of other sugars in the blood, such as fructose, also results in increased concentrations in ASL is unknown and whether sugars in ASL are directly utilised by S. aureus for growth has not been investigated. We obtained mutant S. aureus JE2 strains with transposon disrupted sugar transport genes. NE768(fruA) exhibited restricted growth in 10 mM fructose. In H441 airway epithelial-bacterial co-culture, elevation of basolateral sugar concentration (5-20 mM) increased the apical growth of JE2. However, sugar-induced growth of NE768(fruA) was significantly less when basolateral fructose rather than glucose was elevated. This is the first experimental evidence to show that S. aureus directly utilises sugars present in the ASL for growth. Interestingly, JE2 growth was promoted less by glucose than fructose. Net transepithelial flux of D-glucose was lower than D-fructose. However, uptake of D-glucose was higher than D-fructose across both apical and basolateral membranes consistent with the presence of GLUT1/10 in the airway epithelium. Therefore, we propose that the preferential uptake of glucose (compared to fructose) limits its accumulation in ASL. Pre-treatment with metformin increased transepithelial resistance and reduced the sugar-dependent growth of S. aureus. Thus, epithelial paracellular permeability and glucose transport mechanisms are vital to maintain low glucose concentration in ASL and limit bacterial nutrient sources as a defence against infection

Can pain be self-managed?:Pain change in vulnerable participants to a health education programme

Chronic pain exerts a significant impact on the quality of life, giving rise to both physical and psycho-social vulnerabilities. It not only leads to direct costs associated with treatments, but also results in indirect costs due to the reduced productivity of affected individuals. Chronic conditions can be improved by reducing modifiable risk factors. Various educational programs, including the Chronic Disease Self-Management Programme (CDSMP), have demonstrated the advantages of enhancing patient empowerment and health literacy. Nevertheless, their efficacy in addressing pain symptoms has received limited attention, especially concerning vulnerable populations. This research aims to assess the effectiveness of the CDSMP in alleviating pain among socio-economically vulnerable participants with chronic conditions. By accounting for a wide range of variables, and using data from the EFFICHRONIC project (EU health programme), we investigated the changes in pain levels after the intervention, among 1070 participants from five European countries. Our analyses revealed a significant reduction in pain following the intervention. This finding supports the notion that training programs can effectively ameliorate pain and alleviate its impact on the quality of life, particularly in vulnerable populations. Younger participants, as well as those with higher education levels and individuals experiencing higher levels of pain at baseline, were more likely to experience a reduction in their pain levels. These findings underscore the importance of recognising the social determinants of health. The study was registered at ClinicalTrials.gov (ISRCTN70517103).</p

P2Y Receptors Sensitize Mouse and Human Colonic Nociceptors

Activation of visceral nociceptors by inflammatory mediators contributes to visceral hypersensitivity and abdominal pain associated with many gastrointestinal disorders. Purine and pyrimidine nucleotides (e.g., ATP and UTP) are strongly implicated in this process following their release from epithelial cells during mechanical stimulation of the gut, and from immune cells during inflammation. Actions of ATP are mediated through both ionotropic P2X receptors and metabotropic P2Y receptors. P2X receptor activation causes excitation of visceral afferents; however, the impact of P2Y receptor activation on visceral afferents innervating the gut is unclear. Here we investigate the effects of stimulating P2Y receptors in isolated mouse colonic sensory neurons, and visceral nociceptor fibers in mouse and human nerve-gut preparations. Additionally, we investigate the role of Na(v)1.9 in mediating murine responses. The application of UTP (P2Y(2) and P2Y(4) agonist) sensitized colonic sensory neurons by increasing action potential firing to current injection and depolarizing the membrane potential. The application of ADP (P2Y(1), P2Y(12), and P2Y(13) agonist) also increased action potential firing, an effect blocked by the selective P2Y(1) receptor antagonist MRS2500. UTP or ADP stimulated afferents, including mouse and human visceral nociceptors, in nerve-gut preparations. P2Y(1) and P2Y(2) transcripts were detected in 80% and 56% of retrogradely labeled colonic neurons, respectively. Na(v)1.9 transcripts colocalized in 86% of P2Y(1)-positive and 100% of P2Y(2)-positive colonic neurons, consistent with reduced afferent fiber responses to UTP and ADP in Na(v)1.9(−/−) mice. These data demonstrate that P2Y receptor activation stimulates mouse and human visceral nociceptors, highlighting P2Y-dependent mechanisms in the generation of visceral pain during gastrointestinal disease. SIGNIFICANCE STATEMENT Chronic visceral pain is a debilitating symptom of many gastrointestinal disorders. The activation of pain-sensing nerves located in the bowel wall and their sensitization to physiological stimuli, including bowel movements, underpins the development of such pain, and is associated with mediators released during disease. This work addresses the unstudied role of purine and pyrimidine nucleotides in modulating colonic nociceptors via P2Y receptors using a combination of electrophysiological recordings from human ex vivo samples and a detailed functional study in the mouse. This is the first report to identify colonic purinergic signaling as a function of P2Y receptor activation, in addition to established P2X receptor activity, and the results contribute to our understanding of the development of visceral pain during gastrointestinal disease