955 research outputs found

    The early life microbiota protects neonatal mice from pathological small intestinal epithelial cell shedding

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    The early life gut microbiota plays a crucial role in regulating and maintaining the intestinal barrier, with disturbances in these communities linked to dysregulated renewal and replenishment of intestinal epithelial cells. Here we sought to determine pathological cell shedding outcomes throughout the postnatal developmental period, and which host and microbial factors mediate these responses. Surprisingly, neonatal mice (Day 14 and 21) were highly refractory to induction of cell shedding after intraperitoneal administration of liposaccharide (LPS), with Day 29 mice showing strong pathological responses, more similar to those observed in adult mice. These differential responses were not linked to defects in the cellular mechanisms and pathways known to regulate cell shedding responses. When we profiled microbiota and metabolites, we observed significant alterations. Neonatal mice had high relative abundances of Streptococcus, Escherichia, and Enterococcus and increased primary bile acids. In contrast, older mice were dominated by Candidatus Arthromitus, Alistipes, and Lachnoclostridium, and had increased concentrations of SCFAs and methyamines. Antibiotic treatment of neonates restored LPS-induced small intestinal cell shedding, whereas adult fecal microbiota transplant alone had no effect. Our findings further support the importance of the early life window for microbiota-epithelial interactions in the presence of inflammatory stimuli and highlights areas for further investigation

    Geo‐Hydromorphological Assessment of Europe’s Southernmost Blanket Bogs

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    Blanket bogs are a globally rare type of ombrotrophic peatland internationally recognised for long‐term terrestrial carbon storage, the potential to serve as carbon sinks, habitat provision and for their palaeoenvironmental archive. This habitat is protected in the European Union under the Habitats Directive (92/43/EEC), but a number of blanket bogs located in the Cantabrian Mountains (northern Spain), representing the southernmost known edge‐of‐range for this habitat in Europe, are currently not recognised and are at increased threat of loss. Using climatic data, topography, aerial photography and peat depth surveys, this study has identified ten new areas of blanket bog located between the administrative regions of Cantabria and Castilla y LeĂłn. Peat depth data and topography were used to provide a detailed geomorphological description and hydromorphological classification (mesotope units) of these currently unrecognised areas of blanket bog. Maximum peat depth measured across the ten sites ranged from 1.61 m to 3.78 m covering a total area of 18.6 ha of blanket bog (> 40 cm peat depth). The volume of peat accumulated across the sites was determined to be more than 216,000 m3 and is estimated to hold 19.89 ± 3.51kt C. Twenty‐four individual hydrological mesotope units were described indicating a diverse assemblage of blanket bogs in this region. The peatlands identified in this research extend the known limit of blanket bogs in Europe farther south than previously recorded and combined with four other unprotected blanket bogs recently identified in the Cantabrian Mountains, these peatlands represent 10.5% of blanket bog currently recognised and protected in Spain. The range of anthropogenic pressures currently acting on peatlands in the Cantabrian Mountains indicates that without protection these important landforms and carbon stored may be lost. An urgent update of European peatland inventories is thus required to preserve these valuable carbon stores and potential carbon sinks

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

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    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

    Susceptibility of hamsters to clostridium difficile isolates of differing toxinotype

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    Clostridium difficile is the most commonly associated cause of antibiotic associated disease (AAD), which caused ~21,000 cases of AAD in 2011 in the U.K. alone. The golden Syrian hamster model of CDI is an acute model displaying many of the clinical features of C. difficile disease. Using this model we characterised three clinical strains of C. difficile, all differing in toxinotype; CD1342 (PaLoc negative), M68 (toxinotype VIII) and BI-7 (toxinotype III). The naturally occurring non-toxic strain colonised all hamsters within 1-day post challenge (d.p.c.) with high-levels of spores being shed in the faeces of animals that appeared well throughout the entire experiment. However, some changes including increased neutrophil influx and unclotted red blood cells were observed at early time points despite the fact that the known C. difficile toxins (TcdA, TcdB and CDT) are absent from the genome. In contrast, hamsters challenged with strain M68 resulted in a 45% mortality rate, with those that survived challenge remaining highly colonised. It is currently unclear why some hamsters survive infection, as bacterial and toxin levels and histology scores were similar to those culled at a similar time-point. Hamsters challenged with strain BI-7 resulted in a rapid fatal infection in 100% of the hamsters approximately 26 hr post challenge. Severe caecal pathology, including transmural neutrophil infiltrates and extensive submucosal damage correlated with high levels of toxin measured in gut filtrates ex vivo. These data describes the infection kinetics and disease outcomes of 3 clinical C. difficile isolates differing in toxin carriage and provides additional insights to the role of each toxin in disease progression

    Rethinking the patient: using Burden of Treatment Theory to understand the changing dynamics of illness

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    <b>Background</b> In this article we outline Burden of Treatment Theory, a new model of the relationship between sick people, their social networks, and healthcare services. Health services face the challenge of growing populations with long-term and life-limiting conditions, they have responded to this by delegating to sick people and their networks routine work aimed at managing symptoms, and at retarding - and sometimes preventing - disease progression. This is the new proactive work of patient-hood for which patients are increasingly accountable: founded on ideas about self-care, self-empowerment, and self-actualization, and on new technologies and treatment modalities which can be shifted from the clinic into the community. These place new demands on sick people, which they may experience as burdens of treatment.<p></p> <b>Discussion</b> As the burdens accumulate some patients are overwhelmed, and the consequences are likely to be poor healthcare outcomes for individual patients, increasing strain on caregivers, and rising demand and costs of healthcare services. In the face of these challenges we need to better understand the resources that patients draw upon as they respond to the demands of both burdens of illness and burdens of treatment, and the ways that resources interact with healthcare utilization.<p></p> <b>Summary</b> Burden of Treatment Theory is oriented to understanding how capacity for action interacts with the work that stems from healthcare. Burden of Treatment Theory is a structural model that focuses on the work that patients and their networks do. It thus helps us understand variations in healthcare utilization and adherence in different healthcare settings and clinical contexts

    Challenges Associated with Estimating Utility in Wet Age-Related Macular Degeneration : A Novel Regression Analysis to Capture the Bilateral Nature of the Disease

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    INTRODUCTION: The estimation of utility values for the economic evaluation of therapies for wet age-related macular degeneration (AMD) is a particular challenge. Previous economic models in wet AMD have been criticized for failing to capture the bilateral nature of wet AMD by modelling visual acuity (VA) and utility values associated with the better-seeing eye only. METHODS: Here we present a de novo regression analysis using generalized estimating equations (GEE) applied to a previous dataset of time trade-off (TTO)-derived utility values from a sample of the UK population that wore contact lenses to simulate visual deterioration in wet AMD. This analysis allows utility values to be estimated as a function of VA in both the better-seeing eye (BSE) and worse-seeing eye (WSE). RESULTS: VAs in both the BSE and WSE were found to be statistically significant (p < 0.05) when regressed separately. When included without an interaction term, only the coefficient for VA in the BSE was significant (p = 0.04), but when an interaction term between VA in the BSE and WSE was included, only the constant term (mean TTO utility value) was significant, potentially a result of the collinearity between the VA of the two eyes. The lack of both formal model fit statistics from the GEE approach and theoretical knowledge to support the superiority of one model over another make it difficult to select the best model. CONCLUSION: Limitations of this analysis arise from the potential influence of collinearity between the VA of both eyes, and the use of contact lenses to reflect VA states to obtain the original dataset. Whilst further research is required to elicit more accurate utility values for wet AMD, this novel regression analysis provides a possible source of utility values to allow future economic models to capture the quality of life impact of changes in VA in both eyes. FUNDING: Novartis Pharmaceuticals UK Limited

    Potential climatic transitions with profound impact on Europe

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    We discuss potential transitions of six climatic subsystems with large-scale impact on Europe, sometimes denoted as tipping elements. These are the ice sheets on Greenland and West Antarctica, the Atlantic thermohaline circulation, Arctic sea ice, Alpine glaciers and northern hemisphere stratospheric ozone. Each system is represented by co-authors actively publishing in the corresponding field. For each subsystem we summarize the mechanism of a potential transition in a warmer climate along with its impact on Europe and assess the likelihood for such a transition based on published scientific literature. As a summary, the ‘tipping’ potential for each system is provided as a function of global mean temperature increase which required some subjective interpretation of scientific facts by the authors and should be considered as a snapshot of our current understanding. <br/

    Geography, private costs and uptake of screening for abdominal aortic aneurysm in a remote rural area

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    BACKGROUND: The relationship between geographical location, private costs, health provider costs and uptake of health screening is unclear. This paper examines these relationships in a screening programme for abdominal aortic aneurysm in the Highlands and Western Isles of Scotland, a rural and remote area of over 10,000 square miles. METHODS: Men aged 65–74 (n = 9323) were invited to attend screening at 51 locations in 50 settlements. Effects of geography, deprivation and age on uptake were examined. Among 8,355 attendees, 8,292 completed a questionnaire detailing mode of travel and costs incurred, time travelled, whether accompanied, whether dependants were cared for, and what they would have been doing if not attending screening, thus allowing private costs to be calculated. Health provider (NHS) costs were also determined. Data were analysed by deprivation categories, using the Scottish Indices of Deprivation (2003), and by settlement type ranging from urban to very remote rural. RESULTS: Uptake of screening was high in all settlement types (mean 89.6%, range 87.4 – 92.6%). Non-attendees were more deprived in terms of income, employment, education and health but there was no significant difference between non-attendees and attendees in terms of geographical access to services. Age was similar in both groups. The highest private costs (median £7.29 per man) and NHS screening costs (£18.27 per man invited) were observed in very remote rural areas. Corresponding values for all subjects were: private cost £4.34 and NHS cost £15.72 per man invited. CONCLUSION: Uptake of screening for abdominal aortic aneurysm in this remote and rural setting was high in comparison with previous studies, and this applied across all settlement types. Geographical location did not affect uptake, most likely due to the outreach approach adopted. Private and NHS costs were highest in very remote settings but still compared favourably with other published studies
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