331 research outputs found

    MEK 1 inhibition and bleeding in hereditary haemorrhagic telangiectasia

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    Evaluating active travel and health economic impacts of small streetscape schemes: An exploratory study in London

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    Abstract Introduction This article proposes a low-cost approach that transport authorities can use to evaluate small-scale active travel interventions, including estimating health economic benefits from uptake of walking and/or cycling. Methods The method combines post-intervention intercept surveys with the re-use of routinely collected count data. While inferior to more robust, longitudinal methods, the approach represents good value use of primary and secondary data at a far lower cost, for interventions unlikely otherwise to be evaluated at all. It makes use of government-supported tools that estimate physical activity health benefits from increased active travel. Findings The article describes an example in which a residential street was closed to through motor traffic, which led to a decline of 90% in motor traffic volume and uplift in pedestrian and cycle counts. This example is exploratory in nature due to sample size (124 respondents). The intercept survey of pedestrians and cyclists found uplift in perceived quality of the local environment across various indicators. Results suggested that around a third of the increase in pedestrian and cycle counts post-scheme represents new journeys, mainly via mode shift, with most of the remaining two-thirds being diverted journeys. This information is used alongside the before-and-after count data to estimate new cycling and walking trips induced by the route improvement. Finally, the article estimates the health economic benefit resulting from increased physical activity, of approximately £500,000 over 20 years. Conclusions The article demonstrates a method for estimating active traveluptake and associated health benefits for smaller schemes. If applied over a number of schemes, the results could then be used to create an evidence base that could be used in assessing possible benefits of future schemes

    Economic value of ecosystem services, minerals and oil in a melting Arctic: a preliminary assessment

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    The Arctic region is composed of unique marine and terrestrial ecosystems that provide a range of services to local and global populations. However, Arctic sea-ice and permafrost is melting at an unprecedented rate, threatening many of these ecosystems and the services they provide. This short communication provides a preliminary assessment of the quantity, distribution and economic value of key ecosystem services as well as geological resources such as oil and minerals provided by Arctic ecosystems to beneficiaries in the Arctic region and globally. Using biophysical and economic data from existing studies, preliminary estimates indicate that the Arctic currently provides about 281 billion per year (in 2016 US$) in terms of food, mineral extraction, oil production, tourism, hunting, existence values and climate regulation. However, given predictions of ice-free summers by 2037, many of the ecosystem services may be lost. We hope that this communication stimulates discussion among policy-makers regarding the value of ecosystem services and such geological resources as minerals and oil provided by the Arctic region, and the potential ecosystem losses resulting from Arctic melt, so as to motivate decisions vis a vis climate change mitigation before Arctic ice disappears completely

    Investigating users’ perspectives on the development of bike-sharing in Shanghai

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    High levels of car dependence have caused tremendous challenges for sustainable transport development. Transport planners, therefore, seek ways of replacing motor vehicles, as well as increasing the proportion of active travel. The bike-sharing scheme can be seen as an effective way of doing so, particularly in Asian cities. The aim of this paper is to investigate users’ perspectives on the development of bike-sharing using Shanghai as an example. Semi-structured interviews are used to examine the main factors motivating and impeding the development of the bike-sharing scheme in Shanghai. Our findings show that convenience, saving time and financial savings are the major motivations; whereas problems with bicycles being poorly maintained and abused by users, operational issues, financial issues and an unsuitable business model are the major obstacles. In addition, the findings also suggest that a public and private partnership could be the best option for running a sustainable bike-sharing scheme with clear areas of responsibility. Financial incentives, a bicycle-friendly infrastructure, regular operational management and supportive policies should be prioritised. In order to achieve the targets set by the Shanghai Master Plan 2035, transport planners and policymakers should integrate the bike-sharing scheme within the wider active travel system

    A Novel BMPR2 Mutation Associated with Pulmonary Arterial Hypertension in an Octogenarian

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    We describe the case of an 83-year-old man with a family history of pulmonary hypertension (PH) who presented with severe pulmonary arterial hypertension (PAH) and later tested positive for a novel bone morphogenetic protein receptor 2 (BMPR2) gene mutation. To our knowledge, this may be the oldest reported patient with PAH in whom a BMPR2 mutation was initially identified

    Pulmonary Arterial Hypertension: A Current Perspective on Established and Emerging Molecular Genetic Defects.

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    Pulmonary arterial hypertension (PAH) is an often fatal disorder resulting from several causes including heterogeneous genetic defects. While mutations in the bone morphogenetic protein receptor type II (BMPR2) gene are the single most common causal factor for hereditary cases, pathogenic mutations have been observed in approximately 25% of idiopathic PAH patients without a prior family history of disease. Additional defects of the transforming growth factor beta pathway have been implicated in disease pathogenesis. Specifically, studies have confirmed activin A receptor type II-like 1 (ACVRL1), endoglin (ENG), and members of the SMAD family as contributing to PAH both with and without associated clinical phenotypes. Most recently, next-generation sequencing has identified novel, rare genetic variation implicated in the PAH disease spectrum. Of importance, several identified genetic factors converge on related pathways and provide significant insight into the development, maintenance, and pathogenetic transformation of the pulmonary vascular bed. Together, these analyses represent the largest comprehensive compilation of BMPR2 and associated genetic risk factors for PAH, comprising known and novel variation. Additionally, with the inclusion of an allelic series of locus-specific variation in BMPR2, these data provide a key resource in data interpretation and development of contemporary therapeutic and diagnostic tools

    Truncating and missense BMPR2 mutations differentially affect the severity of heritable pulmonary arterial hypertension

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    <p>Abstract</p> <p>Background</p> <p>Autosomal dominant inheritance of germline mutations in the bone morphogenetic protein receptor type 2 (<it>BMPR2</it>) gene are a major risk factor for pulmonary arterial hypertension (PAH). While previous studies demonstrated a difference in severity between <it>BMPR2 </it>mutation carriers and noncarriers, it is likely disease severity is not equal among <it>BMPR2 </it>mutations. We hypothesized that patients with missense <it>BMPR2 </it>mutations have more severe disease than those with truncating mutations.</p> <p>Methods</p> <p>Testing for <it>BMPR2 </it>mutations was performed in 169 patients with PAH (125 with a family history of PAH and 44 with sporadic disease). Of the 106 patients with a detectable <it>BMPR2 </it>mutation, lymphocytes were available in 96 to functionally assess the nonsense-mediated decay pathway of RNA surveillance. Phenotypic characteristics were compared between <it>BMPR2 </it>mutation carriers and noncarriers, as well as between those carriers with a missense versus truncating mutation.</p> <p>Results</p> <p>While there was a statistically significant difference in age at diagnosis between carriers and noncarriers, subgroup analysis revealed this to be the case only for females. Among carriers, there was no difference in age at diagnosis, death, or survival according to exonic location of the <it>BMPR2 </it>mutation. However, patients with missense mutations had statistically significant younger ages at diagnosis and death, as well as shorter survival from diagnosis to death or lung transplantation than those with truncating mutations. Consistent with this data, the majority of missense mutations were penetrant prior to age 36 years, while the majority of truncating mutations were penetrant after age 36 years.</p> <p>Conclusion</p> <p>In this cohort, <it>BMPR2 </it>mutation carriers have more severe PAH disease than noncarriers, but this is only the case for females. Among carriers, patients with missense mutations that escape nonsense-mediated decay have more severe disease than those with truncating mutations. These findings suggest that treatment and prevention strategies directed specifically at <it>BMPR2 </it>pathway defects may need to vary according to the type of mutation.</p

    Gene expression profiling associated with the progression to poorly differentiated thyroid carcinomas

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    Poorly differentiated thyroid carcinomas (PDTC) represent a heterogeneous, aggressive entity, presenting features that suggest a progression from well-differentiated carcinomas. To elucidate the mechanisms underlying such progression and identify novel therapeutic targets, we assessed the genome-wide expression in normal and tumour thyroid tissues.info:eu-repo/semantics/publishe

    Downregulated parafibromin expression is a promising marker for pathogenesis, invasion, metastasis and prognosis of gastric carcinomas

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    Parafibromin is a protein encoded by the hyperparathyroidism 2 oncosuppressor gene and its downregulated expression is involved in pathogenesis of parathyroid carcinomas. To clarify the roles of parafibromin expression in tumourigenesis and progression of gastric carcinomas, it was examined by immunohistochemistry (IHC) on tissue microarray containing gastric carcinomas (n = 508), adenomas (n = 45) and gastritis (n = 49) with a comparison of its expression with clinicopathological parametres of carcinomas. Gastric carcinoma cell lines (MKN28, AGS, MKN45, KATO-III and HGC-27) were studied for parafibromin expression by IHC and western blot. Parafibromin expression was localised in the nucleus of gastric epithelial cells, adenoma, carcinoma cells and cell lines. Its expression was gradually decreased from gastritis to gastric carcinoma, through gastric adenomas (p < 0.05) and inversely correlated with tumour size, depth of invasion, lymphatic invasion, lymph node metastasis and Union Internationale Contre le Cancer (UICC) staging (p < 0.05) but not with sex or venous invasion (p > 0.05). Parafibromin was strongly expressed in older carcinoma patients compared with younger ones (p < 0.05). There was stronger positivity of parafibromin in intestinal-type than diffuse-type carcinomas (p < 0.05). Univariate analysis indicated cumulative survival rate of patients with positive parafibromin expression to be higher than without its expression (p < 0.05). Multivariate analysis showed that age, tumour size, depth of invasion, lymphatic invasion, lymph node metastasis, UICC staging and Lauren’s classification but not sex, venous invasion or parafibromin expression were independent prognostic factors for carcinomas(p < 0.05). Downregulated parafibromin expression possibly contributed to pathogenesis, growth, invasion and metastasis of gastric carcinomas. It was considered as a promising marker to indicate the aggressive behaviours and prognosis of gastric carcinomas
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