Riociguat for the treatment of chronic thromboembolic pulmonary hypertension.

BACKGROUND: Riociguat, a member of a new class of compounds (soluble guanylate cyclase stimulators), has been shown in previous clinical studies to be beneficial in the treatment of chronic thromboembolic pulmonary hypertension. METHODS: In this phase 3, multicenter, randomized, double-blind, placebo-controlled study, we randomly assigned 261 patients with inoperable chronic thromboembolic pulmonary hypertension or persistent or recurrent pulmonary hypertension after pulmonary endarterectomy to receive placebo or riociguat. The primary end point was the change from baseline to the end of week 16 in the distance walked in 6 minutes. Secondary end points included changes from baseline in pulmonary vascular resistance, N-terminal pro-brain natriuretic peptide (NT-proBNP) level, World Health Organization (WHO) functional class, time to clinical worsening, Borg dyspnea score, quality-of-life variables, and safety. RESULTS: By week 16, the 6-minute walk distance had increased by a mean of 39 m in the riociguat group, as compared with a mean decrease of 6 m in the placebo group (least-squares mean difference, 46 m; 95% confidence interval [CI], 25 to 67; P<0.001). Pulmonary vascular resistance decreased by 226 dyn · sec · cm-5in the riociguat group and increased by 23 dyn · sec · cm-5in the placebo group (least-squares mean difference, -246 dyn · sec · cm-5; 95% CI, -303 to -190; P<0.001). Riociguat was also associated with significant improvements in the NT-proBNP level (P<0.001) and WHO functional class (P = 0.003). The most common serious adverse events were right ventricular failure (in 3% of patients in each group) and syncope (in 2% of the riociguat group and in 3% of the placebo group). CONCLUSIONS: Riociguat significantly improved exercise capacity and pulmonary vascular resistance in patients with chronic thromboembolic pulmonary hypertension. (Funded by Bayer HealthCare; CHEST-1 and CHEST-2 ClinicalTrials.gov numbers, NCT00855465 and NCT00910429, respectively.) Copyright © 2013 Massachusetts Medical Society

Impact of pump OSNR on noise figure for fiber-optical parametric amplifiers

Electrical measurements of the noise figure of a fiberoptical parametric amplifier are presented and compared with optical measurements. The transfer of pump noise by four-wave mixing was clearly demonstrated. A numerical model was developed to simulate the transfer of pump noise and validated by these measurements. Using this model, we determine, for practical systems, a minimum required pump optical signal-to-noise ratio of 65 dB

Impact of pump phase modulation on system performance of fibre-optical parametric amplifiers

Bit error rate induced in a parametric amplifier has been measured with a 10 Gbit=s line rate. It is shown experimentally that the phase modulation of the pump distorts the mark level of the channel and may cause system penalty. Different phase modulation schemes have been compared

Zero-dispersion Wavelength Mapping in Short Single-Mode Optical Fibers Using Parametric Amplification

We demonstrate a novel convenient nondestructive method based on optical parametric amplification that allows retrieval of the zero-dispersion wavelength map along a short optical fiber span with a high-spatial resolution. The improved resolution relies on the high sensitivity to the local longitudinal dispersion fluctuations of the parametric high-gain spectrum.Comment: 3 page

Impact of Holocene climate variability on lacustrine records and human settlements in South Greenland

International audienceDue to its sensitivity to climate changes, south Greenland is a particularly suitable area to study past global climate changes and their influence on locale Human settlements. A paleohydrological investigation was therefore carried out on two river-fed lakes: Lake Qallimiut and Little Kangerluluup, both located close to the Labrador Sea in the historic 5 farming center of Greenland. Two sediment cores (QAL-2011 and LKG-2011), spanning the last four millennia, were retrieved and showed similar thin laminae, described by high magnetic susceptibility and density, high titanium and TOC / TN atomic ratio, and coarse grain size. They are also characterized either by inverse grading followed by normal grading or by normal grading only and a prevalence of red amorphous particles 10 and lignocellulosic fragments, typical of flood deposits. Flood events showed similar trend in both records: they mainly occurred during cooler and wetter periods characterized by weaker Greenlandic paleo-temperatures, substantial glacier advances, and a high precipitation on the Greenlandic Ice Sheet and North Atlantic ice-rafting events. They can therefore be interpreted as a result of ice and 15 snow-melting episodes. They occurred especially during rapid climate changes (RCC) such as the Middle to Late Holocene transition around 2250 BC, the Sub-boreal/Sub-atlantic transition around 700 BC and the Little Ice Age (LIA) between AD 1300 and AD 1900, separated by cycles of 1500 years and driven by solar forcing. These global RCC revealed by QAL-2011 and LKG-2011 flood events may have influenced Human 20 settlements in south Greenland, especially the paleo-Eskimo cultures and the Norse settlement, and have been mainly responsible for their demise

Effect of hypoxia/reoxygenation on the cytokine-induced production of nitric oxide and superoxide anion in cultured osteoarthritic synoviocytes

SummaryObjectiveHypoxia/reoxygenation (H/R) is an important feature in the osteoarthritis (OA) physiopathology. Nitric oxide (NO) is a significant proinflammatory mediator in the inflamed synovium. The purpose of this study was to investigate the effects of H/R on inducible NO synthase (iNOS) activity and expression in OA synoviocytes. In addition we studied the relationship between nitrosative stress and NADPH oxidase (NOX) in such conditions.MethodsHuman cultured synoviocytes from OA patients were treated for 24 h with interleukin 1-β (IL-1β), tumour necrosis factor α (TNF-α) or neither; for the last 6 h, they were submitted to either normoxia or three periods of 1-h of hypoxia followed by 1-h of reoxygenation. NO metabolism (iNOS expression, nitrite and peroxynitrite measurements) was investigated. Furthermore, superoxide anion O2− production, NOX subunit expression and nitrosylation were also assessed.ResultsiNOS expression and nitrite (but not peroxynitrite) production were significantly increased under H/R conditions when compared with to normoxia (P < 0.05). H/R conditions decreased O2− production from ∼0.20 to ∼0.12 nmol min−1 mg proteins−1 (P < 0.05), while NOXs' subunit expression and p47-phox phosphorylation were increased. NOXs and p47-phox were dramatically nitrosylated under H/R conditions (P < 0.05 vs normoxia). Using NOS inhibitors under H/R conditions, p47-phox nitrosylation was prevented and O2− production was restored at normoxic levels (0.21 nmol min−1 mg of proteins−1).ConclusionsOur results provide evidence for an up-regulation of iNOS activity in OA synoviocytes under H/R conditions, associated to a down-regulation of NOX activity through nitrosylation. These findings highlight the importance of radical production to OA pathogenesis, and appraise the metabolic modifications of synovial cells under hypoxia

Determining the Physical Properties of the B Stars I. Methodology and First Results

We describe a new approach to fitting the UV-to-optical spectra of B stars to model atmospheres and present initial results. Using a sample of lightly reddened stars, we demonstrate that the Kurucz model atmospheres can produce excellent fits to either combined low dispersion IUE and optical photometry or HST FOS spectrophotometry, as long as the following conditions are fulfilled: 1) an extended grid of Kurucz models is employed, 2) the IUE NEWSIPS data are placed on the FOS absolute flux system using the Massa & Fitzpatrick (1999) transformation, and 3) all of the model parameters and the effects of interstellar extinction are solved for simultaneously. When these steps are taken, the temperatures, gravities, abundances and microturbulence velocities of lightly reddened B0-A0 V stars are determined to high precision. We also demonstrate that the same procedure can be used to fit the energy distributions of stars which are reddened by any UV extinction curve which can be expressed by the Fitzpatrick & Massa (1990) parameterization scheme. We present an initial set of results and verify our approach through comparisons with angular diameter measurements and the parameters derived for an eclipsing B star binary. We demonstrate that the metallicity derived from the ATLAS 9 fits to main sequence B stars is essentially the Fe abundance. We find that a near zero microturbulence velocity provides the best-fit to all but the hottest or most luminous stars (where it may become a surrogate for atmospheric expansion), and that the use of white dwarfs to calibrate UV spectrophotometry is valid.Comment: 17 pages, including 2 pages of Tables and 6 pages of Figures. Astrophysical Jounral, in pres

Clinical and molecular genetic features of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia

BACKGROUND: Most patients with familial primary pulmonary hypertension have defects in the gene for bone morphogenetic protein receptor II (BMPR2), a member of the transforming growth factor beta (TGF-beta) superfamily of receptors. Because patients with hereditary hemorrhagic telangiectasia may have lung disease that is indistinguishable from primary pulmonary hypertension, we investigated the genetic basis of lung disease in these patients. METHODS: We evaluated members of five kindreds plus one individual patient with hereditary hemorrhagic telangiectasia and identified 10 cases of pulmonary hypertension. In the two largest families, we used microsatellite markers to test for linkage to genes encoding TGF-beta-receptor proteins, including endoglin and activin-receptor-like kinase 1 (ALK1), and BMPR2. In subjects with hereditary hemorrhagic telangiectasia and pulmonary hypertension, we also scanned ALK1 and BMPR2 for mutations. RESULTS: We identified suggestive linkage of pulmonary hypertension with hereditary hemorrhagic telangiectasia on chromosome 12q13, a region that includes ALK1. We identified amino acid changes in activin-receptor-like kinase 1 that were inherited in subjects who had a disorder with clinical and histologic features indistinguishable from those of primary pulmonary hypertension. Immunohistochemical analysis in four subjects and one control showed pulmonary vascular endothelial expression of activin-receptor-like kinase 1 in normal and diseased pulmonary arteries. CONCLUSIONS: Pulmonary hypertension in association with hereditary hemorrhagic telangiectasia can involve mutations in ALK1. These mutations are associated with diverse effects, including the vascular dilatation characteristic of hereditary hemorrhagic telangiectasia and the occlusion of small pulmonary arteries that is typical of primary pulmonary hypertension

The long Galactic bar as seen by UKIDSS Galactic Plane Survey

Over the last decade there have been a series of results supporting the hypothesis of the existence of a long thin bar in the Milky Way with a half-length of 4.5 kpc and a position angle of around 45 deg. This is apparently a very different structure from the triaxial bulge of the Galaxy, which is thicker and shorter and dominates the star counts at |l|<10 deg. In this paper, we analyse the stellar distribution in the inner Galaxy to see if there is clear evidence for two triaxial or bar-like structures in the Milky Way. By using the red-clump population as a tracer of Galactic structure, we determine the apparent morphology of the inner Galaxy. Deeper and higher spatial resolution NIR photometry from the UKIDSS Galactic Plane Survey allows us to use in-plane data even at the innermost Galactic longitudes, a region where the source confusion is a dominant effect that makes it impossible to use other NIR databases such as 2MASS or TCS-CAIN. We show that results previously obtained with using the red-clump giants are confirmed with the in-plane data from UKIDSS GPS. There are two different structures coexisting in the inner Galactic plane: one with a position angle of 23.60+-2.19 deg that can be traced from the Galactic Centre up to l=10 deg (the Galactic bulge), and other with a larger position angle of 42.44+-2.14 deg, that ends around l=28 deg (the long Galactic bar).Comment: (8 pages, 14 figures, accepted for publication in A&A

Long-Term Safety, Tolerability and Survival in Patients with Pulmonary Arterial Hypertension Treated with Macitentan: Results from the SERAPHIN Open-Label Extension

Introduction: In SERAPHIN, a long-term, event-driven, double-blind randomised controlled trial in pulmonary arterial hypertension (PAH), macitentan 10&nbsp;mg significantly reduced the risk of morbidity/mortality compared with placebo. Its open-label extension study (SERAPHIN OL) further assessed long-term safety and tolerability of macitentan 10&nbsp;mg in PAH patients. Methods: Patients in SERAPHIN who completed the double-blind treatment period or experienced a morbidity event during the study could enter SERAPHIN OL. Patients received macitentan 10&nbsp;mg once daily, and safety and survival were assessed until end of treatment (+ 28&nbsp;days). Two overlapping sets were analysed for safety: (1) all patients in SERAPHIN OL (OL safety set); (2) patients randomised to macitentan 10&nbsp;mg in SERAPHIN (long-term safety/survival set). Survival was evaluated as an exploratory endpoint in the latter set. Results: Of 742 patients randomised in SERAPHIN, 550 (74.1%) entered SERAPHIN OL (OL safety set); 242 patients were randomised to macitentan 10&nbsp;mg in SERAPHIN (long-term safety/survival set). Median (min, max) exposure to macitentan 10&nbsp;mg was 40.1 (0.1, 130.5) months (2074.7 patient-years; OL safety set) and 54.7 (0.1, 141.3) months (1151.0 patient-years; long-term safety/survival set). Safety in both analysis sets was comparable to the known safety profile of macitentan. Kaplan-Meier survival estimates (95% CI) at 1, 5, 7 and 9&nbsp;years were 95.0% (91.3, 97.1), 73.3% (66.6, 78.9), 62.6% (54.6, 69.6) and 52.7% (43.6, 61.0), respectively (long-term safety/survival set; median follow-up: 5.9&nbsp;years). Conclusions: This analysis provides the longest follow-up for safety and survival published to date for any PAH therapy. The safety profile of macitentan 10&nbsp;mg over this extensive treatment period was in line with that observed in SERAPHIN. As the majority of patients were receiving other PAH therapy at macitentan initiation, our study provides additional insight into the long-term safety of macitentan, including as part of combination therapy. Trial Registration: ClinicalTrials.gov Identifiers: NCT00660179 and NCT00667823