1,169 research outputs found

    Sialylation on O-linked glycans protects von Willebrand factor from macrophage galactose lectin mediated clearance

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    Terminal sialylation determines the plasma half-life of von Willebrand factor (VWF). A role for macrophage galactose lectin (MGL) in regulating hyposialylated VWF clearance has recently been proposed. In this study, we showed that MGL influences physiological plasma VWF clearance. MGL inhibition was associated with a significantly extended mean residence time and 3-fold increase in endogenous plasma VWF antigen levels (P<0.05). Using a series of VWF truncations, we further demonstrated that the A1 domain of VWF is predominantly responsible for enabling the MGL interaction. Binding of both full-length and VWF-A1-A2-A3 to MGL was significantly enhanced in the presence of ristocetin (P<0.05), suggesting that the MGL-binding site in A1 is not fully accessible in globular VWF. Additional studies using different VWF glycoforms demonstrated that VWF O-linked glycans, clustered at either end of the A1 domain, play a key role in protecting VWF against MGLmediated clearance. Reduced sialylation has been associated with pathological, increased clearance of VWF in patients with von Willebrand disease. Herein, we demonstrate that specific loss of α2-3 linked sialylation from O-glycans results in markedly increased MGL-binding in vitro, and markedly enhanced MGL-mediated clearance of VWF in vivo. Our data further show that the asialoglycoprotein receptor (ASGPR) does not have a significant role in mediating the increased clearance of VWF following loss of O-sialylation. Conversely however, we observed that loss of N-linked sialylation from VWF drives enhanced circulatory clearance predominantly via the ASGPR. Collectively, our data support the hypothesis that in addition to regulating physiological VWF clearance, the MGL receptor works in tandem with ASGPR to modulate enhanced clearance of aberrantly sialylated VWF in the pathogenesis of von Willebrand disease

    Serum N-Glycosylation RPLC-FD-MS Assay to Assess Colorectal Cancer Surgical Interventions.

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    A newly developed analytical strategy was applied to profile the total serum N-glycome of 64 colorectal cancer (CRC) patients before and after surgical intervention. In this cohort, it was previously found that serum N-glycome alterations in CRC were associated with patient survival. Here, fluorescent labeling of serum N-glycans was applied using procainamide and followed by sialic acid derivatization specific for α2,6- and α2,3-linkage types via ethyl esterification and amidation, respectively. This strategy allowed efficient separation of specific positional isomers on reversed-phase liquid chromatography-fluorescence detection-mass spectrometry (RPLC-FD-MS) and complemented the previous glycomics data based on matrix-assisted laser desorption/ionization (MALDI)-MS that did not include such separations. The results from comparing pre-operative CRC to post-operative samples were in agreement with studies that identified a decrease in di-antennary structures with core fucosylation and an increase in sialylated tri- and tetra-antennary N-glycans in CRC patient sera. Pre-operative abundances of N-glycans showed good performance for the classification of adenocarcinoma and led to the revisit of the previous MALDI-MS dataset with regard to histological and clinical data. This strategy has the potential to monitor patient profiles before, during, and after clinical events such as treatment, therapy, or surgery and should also be further explored. </p

    Transitions at the end of life for older adults - patient, carer and professional perspectives

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    BackgroundThe end of life may be a time of high service utilisation for older adults. Transitions between care settings occur frequently, but may produce little improvement in symptom control or quality of life for patients. Ensuring that patients experience co-ordinated care, and moves occur because of individual needs rather than system imperatives, is crucial to patients’ well-being and to containing health-care costs.ObjectiveThe aim of this study was to understand the experiences, influences and consequences of transitions between settings for older adults at the end of life. Three conditions were the focus of study, chosen to represent differing disease trajectories.SettingEngland.ParticipantsThirty patients aged over 75 years, in their last year of life, diagnosed with heart failure, lung cancer and stroke; 118 caregivers of decedents aged 66–98 years, who had died with heart failure, lung cancer, stroke, chronic obstructive pulmonary disease or selected other cancers; and 43 providers and commissioners of services in primary care, hospital, hospice, social care and ambulance services.Design and methodsThis was a mixed-methods study, composed of four parts: (1) in-depth interviews with older adults; (2) qualitative interviews and structured questionnaire with bereaved carers of older adult decedents; (3) telephone interviews with care commissioners and providers using case scenarios derived from the interviews with carers; and (4) analysis of linked Hospital Episode Statistics (HES) and mortality data relating to hospital admissions for heart failure and lung cancer in England 2001–10.ResultsTransitions between care settings in the last year of life were a common component of end-of-life care across all the data sets that made up this study, and many moves were made shortly before death. Patients’ and carers’ experiences of transitions were of a disjointed system in which organisational processes were prioritised over individual needs. In many cases, the family carer was the co-ordinator and provider of care at home, excluded from participation in institutional care but lacking the information and support to extend their role with confidence. The general practitioner (GP) was a valued, central figure in end-of-life care across settings, though other disciplines were critical of GPs’ expertise and adherence to guidelines. Out-of-hours services and care homes were identified by many as contributors to unnecessary transitions. Good relationships and communication between professionals in different settings and sectors was recognised by families as one of the most important influences on transitions but this was rarely acknowledged by staff.ConclusionsDevelopment of a shared understanding of professional and carer roles in end-of-life transitions may be one of the most effective ways of improving patients’ experiences. Patients and carers manage many aspects of end-of-life care for themselves. Identifying ways to extend their skills and strengthen their voices, particularly in hospital settings, would be welcomed and may reduce unnecessary end-of-life transitions. Why the experiences of carers appear to have changed little, despite the implementation of a range of relevant policies, is an important question that has not been answered. Recommendations for future research include the relationship between policy interventions and the experiences of end-of-life carers; identification of ways to harmonise understanding of the carers’ role and strengthen their voice, particularly in hospital settings; identification of ways to reduce the influence of interprofessional tensions in end-of-life care; and development of interventions to enhance patients’ experiences across transitions.FundingThe National Institute for Health Research Health Services and Delivery Research programme

    A WISE View of Star Formation in Local Galaxy Clusters

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    We present results from a systematic study of star formation in local galaxy clusters using 22 micron data from the Wide-field Infrared Survey Explorer (WISE). The 69 systems in our sample are drawn from the Cluster Infall Regions Survey (CIRS), and all have robust mass determinations. The all-sky WISE data enables us to quantify the amount of star formation, as traced by 22 micron, as a function of radius well beyond R200, and investigate the dependence of total star formation rate upon cluster mass. We find that the fraction of star-forming galaxies increases with cluster radius but remains below the field value even at 3 R200. We also find that there is no strong correlation between the mass-normalized total specific star formation rate and cluster mass, indicating that the mass of the host cluster does not strongly influence the total star formation rate of cluster members.Comment: Accepted for publication in the Astrophysical Journal, 10 pages, 5 figure

    Research priorities for fertility and conception research as identified by multidisciplinary health care practitioners and researchers

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    The Robinson Research Institute of the University of Adelaide convened a multidisciplinary group of n = 33 clinicians, researchers and representatives of government organisations on the 2 October 2014 for a workshop entitled "Promoting fertility and healthy conception. How do we generate greater reproductive health awareness?" The key aim of the workshop was to assess the body of knowledge that informs clinical practice and government policy, and to identify questions and additional information needed by health practitioners and government representatives working in the field of reproductive health and to frame future research and policy. The workshop identified topics that fell mostly into three categories: lifestyle-related, societal and biological factors. The lifestyle topics included nutrition and diet, exercise, obesity, shift work and other factors deemed to be modifiable at the level of the individual. The societal topics included discussions of matters that are structural, and resistant to change by individuals, including specific ethical issues, social disadvantage, government and educational policies. The biological factors are intrinsic physical states of the individual, and included many factors where there is a dense body of scientific knowledge which may not be readily accessible in less academic language. This workshop thus provided an opportunity to identify further actions that could be undertaken to meet the needs of diverse organisations and groups of professionals with an interest in human fertility. Since so many factors in our social and biological environment can impact fertility and preconception health, it is imperative to involve many disciplines or levels of government or societal organisations that have not traditionally been involved in this area.Lisa J. Moran, Laura Spencer, Darryl L. Russell, Mary Louise Hull, Sarah A. Robertson, Tamara J. Varcoe, Michael J. Davies, Hannah M. Brown, Raymond J. Rodger

    Murray Valley encephalitis virus surveillance and control initiatives in Australia.

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    Mechanisms for monitoring Murray Valley encephalitis (MVE) virus activity include surveillance of human cases, surveillance for activity in sentinel animals, monitoring of mosquito vectors and monitoring of weather conditions. The monitoring of human cases is only one possible trigger for public health action and the additional surveillance systems are used in concert to signal the risk of human disease, often before the appearance of human cases. Mosquito vector surveillance includes mosquito trapping for speciation and enumeration of mosquitoes to monitor population sizes and relative composition. Virus isolation from mosquitoes can also be undertaken. Monitoring of weather conditions and vector surveillance determines whether there is a potential for MVE activity to occur. Virus isolation from trapped mosquitoes is necessary to define whether MVE is actually present, but is difficult to deliver in a timely fashion in some jurisdictions. Monitoring of sentinel animals indicates whether MVE transmission to vertebrates is actually occurring. Meteorological surveillance can assist in the prediction of potential MVE virus activity by signalling conditions that have been associated with outbreaks of Murray Valley encephalitis in humans in the past. Predictive models of MVE virus activity for south-eastern Australia have been developed, but due to the infrequency of outbreaks, are yet to be demonstrated as useful for the forecasting of major outbreaks. Surveillance mechanisms vary across the jurisdictions. Surveillance of human disease occurs in all States and Territories by reporting of cases to health authorities. Sentinel flocks of chickens are maintained in 4 jurisdictions (Western Australia, the Northern Territory, Victoria and New South Wales) with collaborations between Western Australia and the Northern Territory. Mosquito monitoring complements the surveillance of sentinel animals in these jurisdictions. In addition, other mosquito monitoring programs exist in other States (including South Australia and Queensland). Public health control measures may include advice to the general public and mosquito management programs to reduce the numbers of both mosquito larvae and adult vectors. Strategic plans for public health action in the event of MVE virus activity are currently developed or being developed in New South Wales, the Northern Territory, South Australia, Western Australia and Victoria. A southern tri-State agreement exists between health departments of New South Wales, Victoria and South Australia and the Commonwealth Department of Health and Aged Care. All partners have agreed to co-operate and provide assistance in predicting and combatting outbreaks of mosquito-borne disease in south-eastern Australia. The newly formed National Arbovirus Advisory Committee is a working party providing advice to the Communicable Diseases Network Australia on arbovirus surveillance and control. Recommendations for further enhancement of national surveillance for Murray Valley encephalitis are described

    Patterns and Drivers of UV Absorbing Chromophoric Dissolved Organic Matter in the Euphotic Layer of the Open Ocean

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    The global distribution of chromophoric dissolved organic matter (CDOM) in the euphotic layer of the Atlantic, Indian, and Pacific oceans (between 35 N and 40 S) was analyzed by absorption spectroscopy during the Malaspina 2010 circumnavigation. Absorption coefficients at 254 nm (a254) and 325 nm (a325), indices (a254/a365) and spectral slopes (between 275 and 295 nm, S275--295) were calculated from the dissolved fraction of the UV absorption spectra to describe the amount and quality of CDOM. Generalized Additive Models (GAMs) were applied to evaluate the relevance of physical and biogeochemical drivers for the variability of CDOM. Besides the low CDOM values, a first division of our data following the Longhurst’s biogeographic classification showed significant differences in CDOM levels among provinces. The lowest values of a254 and a325 were found in the oligotrophic gyres, particularly in the Indian Ocean, and the highest in the upwelling areas, particularly in the Equatorial Pacific. Opposite distributions were obtained for S275--295 and a254/a365, indicative of higher photobleaching in the gyres. The GAM analysis also shows that a254/a365 and S275--295 exhibited inverse relationships with solar radiation, indicating that the biological production of CDOM counteracts photodegradation as solar radiation increases. In summary, whereas photobleaching dictates the vertical distribution of CDOM, Chl a explains the CDOM differences among the photic layer of the tropical and subtropical ocean provinces visited during the circumnavigation.This study was funded by the Ingenio-Consolider project Malaspina 2010 Circumnavigation Expedition (MICINN CSD2008-00077). FI and JO were supported by a fellowship from the “Junta para la Ampliación de Estudios” (JAE-preDOC and JAE-postDOC programs 2011, respectively) from the CSIC

    Primary myoepithelial carcinoma of the lung: a rare entity treated with parenchymal sparing resection

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    Primary lung myoepithelial carcinomas are rare neoplasms arising from the salivary glands of the respiratory epithelium. Given the rare occurrences and reports of these tumors, appropriate recommendations for resection are difficult to formulate. Although classified as low-grade neoplasms, these tumors have a significant rate of recurrence and distant metastasis
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