Role of Platelet-Activating Factor and Hypoxia in Persistent Pulmonary Hypertension of the Newborn — Studies with Perinatal Pulmonary Vascular Smooth Muscle Cells

Platelet-activating factor (PAF) plays an important physiological role of maintaining a high vasomotor tone in fetal pulmonary circulation. At birth, endogenous vasodilators such as nitric oxide and prostacyclin are released and facilitate pulmonary vasodilation via cAMP-dependent protein kinase (cAMP/PKA) and cGMP-dependent protein kinase (cGMP/PKG) pathways. Interaction between the cyclic nucleotides and PAF receptor (PAFR)-mediated responses in pulmonary arterial smooth muscle is not well understood. To further understand the interactions of PAF-PAFR pathway and the cyclic nucleotides in ovine fetal pulmonary arterial smooth muscle cells (FPASMC), effects of cAMP and cGMP on PAFR-mediated responses in pulmonary arterial smooth muscle cells (PASMC) were studied. Ovine FPASMC were incubated with 10μM cAMP or cGMP in normoxia (5% CO2 in air, pO2~100 Torr) or hypoxia (2% O2, 5% CO2, pO2~30-40 Torr). Proteins were prepared and subjected to Western blotting. Effect of cell permeable cAMP and cGMP on PAFR binding was also studied and effect of cAMP on cell proliferation was also studied by RNAi to PKA-Cα. cAMP and cGMP significantly decreased PAFR binding and protein expression in normoxia and hypoxia, more so in hypoxia, when PAFR expression was usually high. PKA-Cα siRNA demonstrated that inhibition of PAFR-mediated responses by the cyclic nucleotides occurred through PKA. These data suggest that the normally high levels of cyclic nucleotides in the normoxic newborn pulmonary circulation assist in the downregulation of postnatal PAFR-mediated responses and that under hypoxic conditions, increasing the levels of cyclic nucleotides will abrogate PAF-mediated vasoconstriction thereby ameliorating PAF-induced persistent pulmonary hypertension of the newborn

Cross-sectional assessment of patient attitudes towards participation in clinical trials: does making results publicly available matter?

Previous studies have shown that a majority of patients cite altruistic motives, such as contributing to generalisable medical knowledge, as factors motivating clinical trial participation. We sought to examine the impact of making trial results publicly available on patients' willingness to participate in clinical research

A transgenic zebrafish model expressing KIT-D816V recapitulates features of aggressive systemic mastocytosis

Summary: Systemic mastocytosis (SM) is a rare myeloproliferative disease without curative therapy. Despite clinical variability, the majority of patients harbour a KIT-D816V mutation, but efforts to inhibit mutant KIT with tyrosine kinase inhibitors have been unsatisfactory, indicating a need for new preclinical approaches to identify alternative targets and novel therapies in this disease. Murine models to date have been limited and do not fully recapitulate the most aggressive forms of SM. We describe the generation of a transgenic zebrafish model expressing the human KIT-D816V mutation. Adult fish demonstrate a myeloproliferative disease phenotype, including features of aggressive SM in haematopoeitic tissues and high expression levels of endopeptidases, consistent with SM patients. Transgenic embryos demonstrate a cell-cycle phenotype with corresponding expression changes in genes associated with DNA maintenance and repair, such as reduced dnmt1. In addition, epcam was consistently downregulated in both transgenic adults and embryos. Decreased embryonic epcam expression was associated with reduced neuromast numbers, providing a robust in vivo phenotypic readout for chemical screening in KIT-D816V-induced disease. This study represents the first zebrafish model of a mast cell disease with an aggressive adult phenotype and embryonic markers that could be exploited to screen for novel agents in SM

Diagnosing and treating leprosy in a non-endemic setting in a national centre, London, United Kingdom 1995-2018

Background Leprosy is rare in the United Kingdom (UK), but migration from endemic countries results in new cases being diagnosed each year. We documented the clinical presentation of leprosy in a non-endemic setting. Methods Demographic and clinical data on all new cases of leprosy managed in the Leprosy Clinic at the Hospital for Tropical Diseases, London between 1995 and 2018 were analysed. Results 157 individuals with a median age of 34 (range 13-85) years were included. 67.5% were male. Patients came from 34 different countries and most contracted leprosy before migrating to the UK. Eighty-two (51.6%) acquired the infection in India, Sri Lanka, Bangladesh, Nepal and Pakistan. 30 patients (19.1%) acquired leprosy in Africa, including 11 from Nigeria. Seven patients were born in Europe; three acquired their leprosy infection in Africa, three in South East Asia, and one in Europe. The mean interval between arrival in the UK and symptom onset was 5.87 years (SD 10.33), the longest time to diagnosis was 20 years. Borderline tuberculoid leprosy (n=71, 42.0%), and lepromatous leprosy (n=,53 33.1%) were the commonest Ridley Jopling types. Dermatologists were the specialists diagnosing leprosy most often. Individuals were treated with World Health Organization recommended drug regimens (rifampicin, dapsone and clofazimine). Conclusion Leprosy is not a disease of travellers but develops after residence in an leprosy endemic area. The number of individuals from a leprosy endemic country reflect both the leprosy prevalence and the migration rates to the United Kingdom. There are challenges in diagnosing leprosy in non-endemic areas and clinicians need to recognise the symptoms and signs of leprosy

The clustering of galaxies in the SDSS-III Baryon Oscillation Spectroscopic Survey : baryon acoustic oscillations in the Data Releases 10 and 11 Galaxy samples

We present a one per cent measurement of the cosmic distance scale from the detections of the baryon acoustic oscillations (BAO) in the clustering of galaxies from the Baryon Oscillation Spectroscopic Survey, which is part of the Sloan Digital Sky Survey III. Our results come from the Data Release 11 (DR11) sample, containing nearly one million galaxies and covering approximately 8500 square degrees and the redshift range 0.2 < z < 0.7. We also compare these results with those from the publicly released DR9 and DR10 samples. Assuming a concordance Λ cold dark matter (ΛCDM) cosmological model, the DR11 sample covers a volume of 13 Gpc3 and is the largest region of the Universe ever surveyed at this density. We measure the correlation function and power spectrum, including density-field reconstruction of the BAO feature. The acoustic features are detected at a significance of over 7σ in both the correlation function and power spectrum. Fitting for the position of the acoustic features measures the distance relative to the sound horizon at the drag epoch, rd, which has a value of rd,fid = 149.28 Mpc in our fiducial cosmology. We find DV = (1264 ± 25 Mpc)(rd/rd,fid) at z = 0.32 and DV = (2056 ± 20 Mpc)(rd/rd,fid) at z = 0.57. At 1.0 per cent, this latter measure is the most precise distance constraint ever obtained from a galaxy survey. Separating the clustering along and transverse to the line of sight yields measurements at z = 0.57 of DA = (1421 ± 20 Mpc)(rd/rd,fid) and H = (96.8 ± 3.4 km s−1 Mpc−1)(rd,fid/rd). Our measurements of the distance scale are in good agreement with previous BAO measurements and with the predictions from cosmic microwave background data for a spatially flat CDM model with a cosmological constant.Publisher PDFPeer reviewe

The importance of socio-economic context for social marketing models for improving reproductive health: Evidence from 555 years of program experience

BACKGROUND: Over the past two decades, social marketing programs have become an important element of the national family planning and HIV prevention strategy in several developing countries. As yet, there has not been any comprehensive empirical assessment to determine which of several social marketing models is most effective for a given socio-economic context. Such an assessment is urgently needed to inform the design of future social marketing programs, and to avoid that programs are designed using an ineffective model. METHODS: This study addresses this issue using a database of annual statistics about reproductive health oriented social marketing programs in over 70 countries. In total, the database covers 555 years of program experience with social marketing programs that distribute and promote the use of oral contraceptives and condoms. Specifically, our analysis assesses to what extent the model used by different reproductive health social marketing programs has varied across different socio-economic contexts. We then use random effects regression to test in which socio-economic context each of the models is most successful at increasing use of socially marketed oral contraceptives and condoms. RESULTS: The results show that there has been a tendency to design reproductive health social marketing program with a management structure that matches the local context. However, the evidence also shows that this has not always been the case. While socio-economic context clearly influences the effectiveness of some of the social marketing models, program maturity and the size of the target population appear equally important. CONCLUSIONS: To maximize the effectiveness of future social marketing programs, it is essential that more effort is devoted to ensuring that such programs are designed using the model or approach that is most suitable for the local context

The state of the Martian climate

60°N was +2.0°C, relative to the 1981–2010 average value (Fig. 5.1). This marks a new high for the record. The average annual surface air temperature (SAT) anomaly for 2016 for land stations north of starting in 1900, and is a significant increase over the previous highest value of +1.2°C, which was observed in 2007, 2011, and 2015. Average global annual temperatures also showed record values in 2015 and 2016. Currently, the Arctic is warming at more than twice the rate of lower latitudes

The Baryon Oscillation Spectroscopic Survey of SDSS-III

The Baryon Oscillation Spectroscopic Survey (BOSS) is designed to measure the scale of baryon acoustic oscillations (BAO) in the clustering of matter over a larger volume than the combined efforts of all previous spectroscopic surveys of large scale structure. BOSS uses 1.5 million luminous galaxies as faint as i=19.9 over 10,000 square degrees to measure BAO to redshifts z<0.7. Observations of neutral hydrogen in the Lyman alpha forest in more than 150,000 quasar spectra (g<22) will constrain BAO over the redshift range 2.15<z<3.5. Early results from BOSS include the first detection of the large-scale three-dimensional clustering of the Lyman alpha forest and a strong detection from the Data Release 9 data set of the BAO in the clustering of massive galaxies at an effective redshift z = 0.57. We project that BOSS will yield measurements of the angular diameter distance D_A to an accuracy of 1.0% at redshifts z=0.3 and z=0.57 and measurements of H(z) to 1.8% and 1.7% at the same redshifts. Forecasts for Lyman alpha forest constraints predict a measurement of an overall dilation factor that scales the highly degenerate D_A(z) and H^{-1}(z) parameters to an accuracy of 1.9% at z~2.5 when the survey is complete. Here, we provide an overview of the selection of spectroscopic targets, planning of observations, and analysis of data and data quality of BOSS.Comment: 49 pages, 16 figures, accepted by A

The Ninth Data Release of the Sloan Digital Sky Survey: First Spectroscopic Data from the SDSS-III Baryon Oscillation Spectroscopic Survey

The Sloan Digital Sky Survey III (SDSS-III) presents the first spectroscopic data from the Baryon Oscillation Spectroscopic Survey (BOSS). This ninth data release (DR9) of the SDSS project includes 535,995 new galaxy spectra (median z=0.52), 102,100 new quasar spectra (median z=2.32), and 90,897 new stellar spectra, along with the data presented in previous data releases. These spectra were obtained with the new BOSS spectrograph and were taken between 2009 December and 2011 July. In addition, the stellar parameters pipeline, which determines radial velocities, surface temperatures, surface gravities, and metallicities of stars, has been updated and refined with improvements in temperature estimates for stars with T_eff<5000 K and in metallicity estimates for stars with [Fe/H]>-0.5. DR9 includes new stellar parameters for all stars presented in DR8, including stars from SDSS-I and II, as well as those observed as part of the SDSS-III Sloan Extension for Galactic Understanding and Exploration-2 (SEGUE-2). The astrometry error introduced in the DR8 imaging catalogs has been corrected in the DR9 data products. The next data release for SDSS-III will be in Summer 2013, which will present the first data from the Apache Point Observatory Galactic Evolution Experiment (APOGEE) along with another year of data from BOSS, followed by the final SDSS-III data release in December 2014.Comment: 9 figures; 2 tables. Submitted to ApJS. DR9 is available at http://www.sdss3.org/dr