1,698 research outputs found

    Growth inhibition of cytosolic Salmonella by caspase-1 and caspase-11 precedes host cell death

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    Sensing bacterial products in the cytosol of mammalian cells by NOD-like receptors leads to the activation of caspase-1 inflammasomes, and the production of the pro-inflammatory cytokines interleukin (IL)-18 and IL-1β. In addition, mouse caspase-11 (represented in humans by its orthologs, caspase-4 and caspase-5) detects cytosolic bacterial LPS directly. Activation of caspase-1 and caspase-11 initiates pyroptotic host cell death that releases potentially harmful bacteria from the nutrient-rich host cell cytosol into the extracellular environment. Here we use single cell analysis and time-lapse microscopy to identify a subpopulation of host cells, in which growth of cytosolic Salmonella Typhimurium is inhibited independently or prior to the onset of cell death. The enzymatic activities of caspase-1 and caspase-11 are required for growth inhibition in different cell types. Our results reveal that these proteases have important functions beyond the direct induction of pyroptosis and proinflammatory cytokine secretion in the control of growth and elimination of cytosolic bacteria

    A practical approach to estimate resting energy expenditure in frail elderly people

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    Objectives: Some prediction equations of resting energy expenditure (REE) are available and can be used in clinical wards to determine energy requirements of patients. The aim of the present study was to assess the accuracy of those equations in sick elderly patients, using the Bland & Altman methods with our database of 187 REE measurements.Design: The 3 equations tested were Harris & Benedict equation of 1919, WHO/FAO/UNU equation of 1985 and Fredrix et al. equation of 1990. In addition, three models developed from the present data were tested.Results: The present study shows that the Fredrix et al equation gave an accurate prediction of REE without significant bias along the whole range of REE. It also shows that under-weight sick elderly patients (BMI ≤ 21 kg/m2) had a greater weight-adjusted REE than their normal weight counterparts.Conclusion: A simple formula using a factor multiplying body weight, i.e. 22 kcal/kg/d in under-weight and 19 kcal/kg/d in normal weight sick elderly was accurate to predicting REE and bias was not influenced by the level of REE. This model included half of the group in the range of ±10% of the difference between predicted REE and measured REE, but the confidence interval of the bias was ±400 kcal/d. Conversely, the Harris & Benedict and WHO formulae did accurately predict REE

    An Unfinished Canvas: Allocating Funding and Instructional Time for Elementary Arts Education

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    An Unfinished Canvas found that California's elementary schools face unique challenges inproviding all students with sequential, standards-based arts education. In particular, elementary principals identified inadequate funding and insufficient instructional time as significant barriers to the provision of arts education. For this study, we sought to further understand the impact of funding and time on elementary arts education. To do so, we examined the allocation of funding and instructional time in 10 schools across five states (Kentucky, Massachusetts, Minnesota, New Jersey, and California)

    What do haematological cancer survivors want help with? A cross-sectional investigation of unmet supportive care needs

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    BACKGROUND: This study aimed to identify the most prevalent unmet needs of haematological cancer survivors. METHODS: Haematological cancer survivors aged 18–80 years at time of recruitment were selected from four Australian state cancer registries. Survivors completed the Survivor Unmet Needs Survey. The most frequently reported “high/very high” unmet needs items were identified, as well as characteristics associated with the three most prevalent “high/very high” unmet needs reported by haematological cancer survivors. RESULTS: A total of 715 eligible survivors returned a completed survey. “Dealing with feeling tired” (17%), was the most frequently endorsed “high/very high” unmet need. Seven out of the ten most frequently endorsed unmet needs related to emotional health. Higher levels of psychological distress (e.g., anxiety, depression and stress) and indicators of financial burden as a result of cancer (e.g., having used up savings and trouble meeting day-to-day expenses due to cancer) were consistently identified as characteristics associated with the three most prevalent “high/very high” unmet needs. CONCLUSIONS: A minority of haematological cancer survivors endorsed a “high/very high” unmet need on individual items. Additional emotional support may be needed by a minority of survivors. Survivors reporting high levels of psychological distress or those who experience increased financial burden as a result of their cancer diagnosis may be at risk of experiencing the most prevalent “high/very high” unmet needs identified by this study.This project was co-funded by beyondblue and Cancer Australia (Grant ID: 569290)

    Peribiliary glands are key in regeneration of the human biliary epithelium after severe bile duct injury

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    Peribiliary glands (PBG) are a source of stem/progenitor cells organized in a cellular network encircling large bile ducts. Severe cholangiopathy with loss of luminal biliary epithelium has been proposed to activate PBG, resulting in cell proliferation and differentiation to restore biliary epithelial integrity. However, formal evidence for this concept in human livers is lacking. We, therefore, developed a novel ex vivo model using precision-cut slices of extrahepatic human bile ducts obtained from discarded donor livers, providing an intact anatomical organization of cell structures, to study spatiotemporal differentiation and migration of PBG cells after severe biliary injury. Post-ischemic bile duct slices were incubated in oxygenated culture medium for up to a week. At baseline, severe tissue injury was evident with loss of luminal epithelial lining and mural stroma necrosis. In contrast, PBG remained relatively well preserved and different reactions of PBG were noted, including PBG dilatation, cell proliferation and maturation. Proliferation of PBG cells increased after 24 h of oxygenated incubation, reaching a peak after 72 h. Proliferation of PBG cells was paralleled by a reduction in PBG apoptosis and differentiation from a primitive and pluripotent (Nanog+/Sox9+) to a mature (CFTR+/secretin receptor+) and activated phenotype (increased expression of HIF-1α, Glut-1, and VEGF-A). Migration of proliferating PBG cells in our ex vivo model was unorganized, but resulted in generation of epithelial monolayers at stromal surfaces. CONCLUSION: Human PBG contain biliary progenitor cells and are able to respond to bile duct epithelial loss with proliferation, differentiation, and maturation to restore epithelial integrity. The ex vivo spatiotemporal behaviour of human PBG cells provides evidence for a pivotal role of PBG in biliary regeneration after severe injury. This article is protected by copyright. All rights reserved

    Imaging muscle as a potential biomarker of denervation in motor neuron disease

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    Objective To assess clinical, electrophysiological and whole-body muscle MRI measurements of progression in patients with motor neuron disease (MND), as tools for future clinical trials, and to probe pathophysiological mechanisms in vivo. Methods A prospective longitudinal observational clinico-electrophysiological and radiological cohort study was performed. Twenty-nine MND patients and 22 age and gender-matched healthy controls were assessed with clinical measures, electrophysiological motor unit number index (MUNIX) and T2-weighted whole-body muscle MRI, at first clinic presentation and four months later. Between-group differences and associations were assessed using age and gender-adjusted multivariable regression models. Within-subject longitudinal changes were assessed using paired t-tests. Patterns of disease spread were modelled using mixed-effects multivariable regression, assessing associations between muscle relative T2 signal and anatomical adjacency to site of clinical onset. Results MND patients had 30% higher relative T2 muscle signal than controls at baseline (all-regions mean, 95%CI 15%, 45%, p<0.001). Higher T2 signal was associated with greater overall disability (coefficient -0.009, 95%CI -0.017, -0.001, p=0.023), and with clinical weakness and lower MUNIX in multiple individual muscles. Relative T2 signal in bilateral tibialis anterior increased over four months in MND patients (right: 10.2%, 95%CI 2.0%, 18.4%, p=0.017; left: 14.1%, 95%CI 3.4%, 24.9%, p=0.013). Anatomically contiguous disease spread on MRI was not apparent in this model. Conclusions Whole-body muscle MRI offers a new approach to objective assessment of denervation over short timescales in MND, and enables investigation of patterns of disease spread in vivo. Muscles inaccessible to conventional clinical and electrophysiological assessment may be investigated using this methodology
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