335 research outputs found

    Interleukin-1Ī² sequesters hypoxia inducible factor 2Ī± to the primary cilium.

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    BACKGROUND: The primary cilium coordinates signalling in development, health and disease. Previously we have shown that the cilium is essential for the anabolic response to loading and the inflammatory response to interleukin-1Ī² (IL-1Ī²). We have also shown the primary cilium elongates in response to IL-1Ī² exposure. Both anabolic phenotype and inflammatory pathology are proposed to be dependent on hypoxia-inducible factor 2 alpha (HIF-2Ī±). The present study tests the hypothesis that an association exists between the primary cilium and HIFs in inflammatory signalling. RESULTS: Here we show, in articular chondrocytes, that IL-1Ī²-induces primary cilia elongation with alterations to cilia trafficking of arl13b. This elongation is associated with a transient increase in HIF-2Ī± expression and accumulation in the primary cilium. Prolyl hydroxylase inhibition results in primary cilia elongation also associated with accumulation of HIF-2Ī± in the ciliary base and axoneme. This recruitment and the associated cilia elongation is not inhibited by blockade of HIFĪ± transcription activity or rescue of basal HIF-2Ī± expression. Hypomorphic mutation to intraflagellar transport protein IFT88 results in limited ciliogenesis. This is associated with increased HIF-2Ī± expression and inhibited response to prolyl hydroxylase inhibition. CONCLUSIONS: These findings suggest that ciliary sequestration of HIF-2Ī± provides negative regulation of HIF-2Ī± expression and potentially activity. This study indicates, for the first time, that the primary cilium regulates HIF signalling during inflammation

    Detection of the pairwise kinematic Sunyaev-Zel'dovich effect with BOSS DR11 and the Atacama Cosmology Telescope

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    We present a new measurement of the kinematic Sunyaev-Zeldovich effect using data from the Atacama Cosmology Telescope (ACT) and the Baryon Oscillation Spectroscopic Survey (BOSS). Using 600 square degrees of overlapping sky area, we evaluate the mean pairwise baryon momentum associated with the positions of 50,000 bright galaxies in the BOSS DR11 Large Scale Structure catalog. A non-zero signal arises from the large-scale motions of halos containing the sample galaxies. The data fits an analytical signal model well, with the optical depth to microwave photon scattering as a free parameter determining the overall signal amplitude. We estimate the covariance matrix of the mean pairwise momentum as a function of galaxy separation, using microwave sky simulations, jackknife evaluation, and bootstrap estimates. The most conservative simulation-based errors give signal-to-noise estimates between 3.6 and 4.1 for varying galaxy luminosity cuts. We discuss how the other error determinations can lead to higher signal-to-noise values, and consider the impact of several possible systematic errors. Estimates of the optical depth from the average thermal Sunyaev-Zeldovich signal at the sample galaxy positions are broadly consistent with those obtained from the mean pairwise momentum signal.Comment: 15 pages, 8 figures, 2 table

    Circulating markers of arterial thrombosis and late-stage age-related macular degeneration: a case-control study.

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    PURPOSE: The aim of this study was to examine the relation of late-stage age-related macular degeneration (AMD) with markers of systemic atherothrombosis. METHODS: A hospital-based case-control study of AMD was undertaken in London, UK. Cases of AMD (n=81) and controls (n=77) were group matched for age and sex. Standard protocols were used for colour fundus photography and to classify AMD; physical examination included height, weight, history of or treatment for vascular-related diseases and smoking status. Blood samples were taken for measurement of fibrinogen, factor VIIc (FVIIc), factor VIIIc, prothrombin fragment F1.2 (F1.2), tissue plasminogen activator, and von Willebrand factor. Odds ratios from logistic regression analyses of each atherothrombotic marker with AMD were adjusted for age, sex, and established cardiovascular disease risk factors, including smoking, blood pressure, body mass index, and total cholesterol. RESULTS: After adjustment FVIIc and possibly F1.2 were inversely associated with the risk of AMD; per 1 standard deviation increase in these markers the odds ratio were, respectively, 0.62 (95% confidence interval 0.40, 0.95) and 0.71 (0.46, 1.09). None of the other atherothrombotic risk factors appeared to be related to AMD status. There was weak evidence that aspirin is associated with a lower risk of AMD. CONCLUSIONS: This study does not provide strong evidence of associations between AMD and systematic markers of arterial thrombosis, but the potential effects of FVIIc, and F1.2 are worthy of further investigation

    Identity-by-descent estimation with population- and pedigree-based imputation in admixed family data

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    BACKGROUND: In the past few years, imputation approaches have been mainly used in population-based designs of genome-wide association studies, although both family- and population-based imputation methods have been proposed. With the recent surge of family-based designs, family-based imputation has become more important. Imputation methods for both designs are based on identity-by-descent (IBD) information. Apart from imputation, the use of IBD information is also common for several types of genetic analysis, including pedigree-based linkage analysis. METHODS: We compared the performance of several family- and population-based imputation methods in large pedigrees provided by Genetic Analysis Workshop 19 (GAW19). We also evaluated the performance of a new IBD mapping approach that we propose, which combines IBD information from known pedigrees with information from unrelated individuals. RESULTS: Different combinations of the imputation methods have varied imputation accuracies. Moreover, we showed gains from the use of both known pedigrees and unrelated individuals with our IBD mapping approach over the use of known pedigrees only. CONCLUSIONS: Our results represent accuracies of different combinations of imputation methods that may be useful for data sets similar to the GAW19 pedigree data. Our IBD mapping approach, which uses both known pedigree and unrelated individuals, performed better than classical linkage analysis

    How a Diverse Research Ecosystem Has Generated New Rehabilitation Technologies: Review of NIDILRRā€™s Rehabilitation Engineering Research Centers

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    Over 50 million United States citizens (1 in 6 people in the US) have a developmental, acquired, or degenerative disability. The average US citizen can expect to live 20% of his or her life with a disability. Rehabilitation technologies play a major role in improving the quality of life for people with a disability, yet widespread and highly challenging needs remain. Within the US, a major effort aimed at the creation and evaluation of rehabilitation technology has been the Rehabilitation Engineering Research Centers (RERCs) sponsored by the National Institute on Disability, Independent Living, and Rehabilitation Research. As envisioned at their conception by a panel of the National Academy of Science in 1970, these centers were intended to take a ā€œtotal approach to rehabilitationā€, combining medicine, engineering, and related science, to improve the quality of life of individuals with a disability. Here, we review the scope, achievements, and ongoing projects of an unbiased sample of 19 currently active or recently terminated RERCs. Specifically, for each center, we briefly explain the needs it targets, summarize key historical advances, identify emerging innovations, and consider future directions. Our assessment from this review is that the RERC program indeed involves a multidisciplinary approach, with 36 professional fields involved, although 70% of research and development staff are in engineering fields, 23% in clinical fields, and only 7% in basic science fields; significantly, 11% of the professional staff have a disability related to their research. We observe that the RERC program has substantially diversified the scope of its work since the 1970ā€™s, addressing more types of disabilities using more technologies, and, in particular, often now focusing on information technologies. RERC work also now often views users as integrated into an interdependent society through technologies that both people with and without disabilities co-use (such as the internet, wireless communication, and architecture). In addition, RERC research has evolved to view users as able at improving outcomes through learning, exercise, and plasticity (rather than being static), which can be optimally timed. We provide examples of rehabilitation technology innovation produced by the RERCs that illustrate this increasingly diversifying scope and evolving perspective. We conclude by discussing growth opportunities and possible future directions of the RERC program

    Is short-term-variation of fetal-heart-rate a better predictor of fetal acidaemia in labour? A feasibility study

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    Background Continuous intrapartum fetal monitoring is challenging and its clinical benefits are debated. The project evaluated whether short-term-variation (STV) and other computerised fetal heart rate (FHR) parameters (baseline FHR, long-term-variation, accelerations and decelerations) predicted acidaemia at birth. The aims of the study were to assess the changes in FHR pattern during labour and determine the feasibility of undertaking a definitive trial by reporting the practicalities of using the monitoring device, participant recruitment, data collection and staff training. Methods 200 high-risk women carrying a term singleton, non-anomalous fetus, requiring continuous FHR monitoring in labour were consented to participate from the Jessop Wing maternity unit, Sheffield, UK. The trans-abdominal fetal ECG monitor was placed as per clinical protocol. During the monitoring session, clinicians were blinded to the computerised FHR parameters. We analysed the last hour of the FHR and its ability to predict umbilical arterial blood pH <7.20 using receiver operator characteristics (ROC) curves. Results Of 200 women, 137 cases were excluded as either the monitor did not work from the onset of labour (n = 30), clinical staff did not return or used the monitor on another patient (n = 37), umbilical cord blood not obtained (n = 25), FHR data not recorded within an hour of birth (n = 34) and other reasons (n = 11). In 63 cases included in the final analysis, the computer-derived FHR parameters did not show significant correlation with umbilical artery cord pH <7.20. Labour was associated with a significant increase in short and long term variation of FHR and number of deceleration (P<0.001). However, baseline FHR decreased significantly before delivery (P<0.001). Conclusions The project encountered a number of challenges, with learning points crucial to informing the design of a large study to evaluate the potential place of intrapartum computerised FHR parameters, using abdominal fetal ECG monitor before its clinical utility and more widespread adoption can be ascertained

    Food choices and practices during pregnancy of immigrant women with high-risk pregnancies in Canada: a pilot study

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    Background: Immigrant women may be regarded as a vulnerable population with respect to access and navigation of maternity care services. They may encounter difficulties when accessing culturally safe and appropriate maternity care, which may be further exacerbated by language difficulties and discriminatory practices or attitudes. The project aimed to understand ethnocultural food and health practices and how these intersect in a particular social context of cultural adaptation and adjustment in order to improve the care-giving capacities of health practitioners working in multicultural perinatal clinics. Methods: This four-phase study employed a case study design allowing for multiple means of data collection and different units of analysis. Phase one consists of a scoping review of the literature. Phases two and three incorporate pictorial representations of food choices with semi-structured photo-elicited interviews. This study was undertaken at a Prenatal and Obstetric Clinic, in an urban Canadian city. In phase four, the research team will inform the development of culturally appropriate visual tools for health promotion. Results: Five themes were identified: (a) Perceptions of Health, (b) Social Support (c) Antenatal Foods (d) Postnatal Foods and (e) Role of Health Education. These themes provide practitioners with an understanding of the cultural differences that affect womenā€™s dietary choices during pregnancy. The project identified building collaborations between practitioners and families of pregnant immigrant women to be of utmost importance in supporting healthy pregnancies, along with facilitating social support for pregnant and breastfeeding mothers. Conclusion: In a multicultural society that contemporary Canada is, it is challenging for health practitioners to understand various ethnocultural dietary norms and practices. Practitioners need to be aware of customary practices of the ethnocultural groups that they work with, while simultaneously recognizing the variation withinā€”not everyone follows customary practices, individuals may pick and choose which customary guidelines they follow. What women choose to eat is also influenced by their own experiences, access to particular foods, socioeconomic status, family context, and so on. The pilot study demonstrated the efficacy of the employed research strategies and we subsequently acquired funding for a national study
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