797 research outputs found
The use of combination therapy in pulmonary arterial hypertension: new developments
There is a strong clinical rationale for combination therapy in pulmonary arterial hypertension (PAH), as several pathological pathways have been implicated in its pathogenesis and no single agent has yet been shown to deliver completely satisfactory results. Registry data indicate that use of combination therapy is in fact common in existing clinical practice, even though support has been largely empirical or derived from small-scale observational studies. Data from large, adequately powered, randomised controlled trials of combination therapy in PAH are now emerging and suggest that combination therapy may be clinically beneficial. Studies of bosentan in combination with prostanoids and phosphodiesterase (PDE)-5 inhibitors show consistent evidence of improvements in exercise capacity compared with placebo. Similar improvements have been observed with PDE-5 inhibitors in combination with prostanoids. The appropriate timing of combination therapy requires further evaluation but goal-oriented therapy using combinations of oral and inhaled drugs has been shown to provide acceptable long-term results in patients with advanced PAH. Monitoring should be performed regularly and be based on repeatable, noninvasive, measurable parameters that have prognostic value
Pulmonary hypertension, how to diagnose and who to treat?
# The Author(s) 2011. This article is published with open access at Springerlink.com Pulmonary arterial hypertension is a fatal disease with an estimated survival rate of only 50 % after 5 years [1]. Over the last years, knowledge in the field of pulmonary hypertension has grown consistently and significantly. New diagnostic tools, as well as the efficacy of new medications and drug combinations, have been described. How to define and diagnose pulmonary arterial hypertension is the first important issue. Should echocardiography be the method of choice? It is easy to access, cheap and noninvasive. However, the cut-off values are debatable. In the ESC guidelines of 2009 [2] an estimated peak pulmonary artery pressure of>50 mmHg is stated as ‘pulmonary hypertension is likely’, while a PAP of 37–50 is defined as ‘possible PH’. However, the gold standard remains heart catheterisation. Now the definition is made using a mean pulmonary artery pressure of 25 mmHg or more. Age and gender seem to have an important impact on the incidence and severity of PH. For instance, female patients with an atrial septal defect do present with pulmonary hypertension, while in male ASD patients pulmonary hypertension is seldom if ever seen. In order to simplify the clinical management of patients, the classification of pulmonary hypertension was changed in 2009 [3]. Pre-capillary PH is defined as a wedge pressure <15 mmHg and can be divided into pulmonary arterial hypertension, PH due to lung disease, chronic thromboembolic PH or PH with unclear and/or multifactorial mechanisms. Post-capillary PH is defined as a wedge pressure above 15 mmHg and is due to left-sided heart disease. Who should be screened for pulmonary hypertension? Should all patients undergoing non-cardiac surgery b
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
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
Treprostinil increases the number and angiogenic potential of endothelial progenitor cells in children with pulmonary hypertension
Background Pulmonary vasodilators in general and prostacyclin therapy in particular, have markedly improved the outcome of patients with pulmonary arterial hypertension (PAH). As endothelial dysfunction is a key feature of PAH, and as endothelial progenitor cells (EPC) may contribute to vascular repair in PAH, we suspected that prostacyclin therapy might enhance EPC numbers and functions. In the present study, objectives were to determine whether EPC may contribute to vasodilator treatment efficacy in PAH. Methods We quantified CD34+ cells, CFU-Hill and ECFC (endothelial colony forming cells) in peripheral blood from children with idiopathic PAH (n = 27) or PAH secondary to congenital heart disease (n = 52). CD34+ were enumerated by flow cytometry, CFU-Hill and ECFC by a culture assay. ECFC grown ex vivo were tested for their angiogenic capacities before and after prostacyclin analog therapy (subcutaneous treprostinil). Results ECFC counts were significantly enhanced in the 8 children treated with treprostinil, while no change was observed in children receiving oral therapy with endothelin antagonists and/or PDE5 inhibitors. CD34+ cell and CFU-Hill counts were unaffected. ECFC from patients treated with treprostinil had a hyperproliferative phenotype and showed enhanced angiogenic potential in a nude mouse preclinical model of limb ischemia. Conclusions ECFC may partly mediate the clinical benefits of prostanoids in pulmonary arterial hypertension
Haemodynamic definitions and updated clinical classification of pulmonary hypertension.
Since the 1st World Symposium on Pulmonary Hypertension (WSPH) in 1973, pulmonary hypertension (PH) has been arbitrarily defined as mean pulmonary arterial pressure (mPAP) ≥25 mmHg at rest, measured by right heart catheterisation. Recent data from normal subjects has shown that normal mPAP was 14.0±3.3 mmHg. Two standard deviations above this mean value would suggest mPAP >20 mmHg as above the upper limit of normal (above the 97.5th percentile). This definition is no longer arbitrary, but based on a scientific approach. However, this abnormal elevation of mPAP is not sufficient to define pulmonary vascular disease as it can be due to an increase in cardiac output or pulmonary arterial wedge pressure. Thus, this 6th WSPH Task Force proposes to include pulmonary vascular resistance ≥3 Wood Units in the definition of all forms of pre-capillary PH associated with mPAP >20 mmHg. Prospective trials are required to determine whether this PH population might benefit from specific management.Regarding clinical classification, the main Task Force changes were the inclusion in group 1 of a subgroup "pulmonary arterial hypertension (PAH) long-term responders to calcium channel blockers", due to the specific prognostic and management of these patients, and a subgroup "PAH with overt features of venous/capillaries (pulmonary veno-occlusive disease/pulmonary capillary haemangiomatosis) involvement", due to evidence suggesting a continuum between arterial, capillary and vein involvement in PAH
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 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 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 mg once daily, and safety and survival were assessed until end of treatment (+ 28 days). Two overlapping sets were analysed for safety: (1) all patients in SERAPHIN OL (OL safety set); (2) patients randomised to macitentan 10 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 mg in SERAPHIN (long-term safety/survival set). Median (min, max) exposure to macitentan 10 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 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 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 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
Bridging the gap between low and high mass dwarf galaxies
While the dark matter content within the most massive giant and smallest
dwarf galaxies has been probed -- spanning a range of over one million in mass
-- an important observational gap remains for galaxies of intermediate mass.
This gap covers K band magnitudes of approximately -16 > M_K > -18 (for which
dwarf galaxies have B--K ~ 2). On the high mass side of the gap are dwarf
elliptical (dE) galaxies, that are dominated by stars in their inner regions.
While the low mass side includes dwarf spheroidal (dSph) galaxies that are dark
matter-dominated and ultra compact dwarf (UCD) objects that are star-dominated.
Evolutionary pathways across the gap have been suggested but remain largely
untested because the `gap' galaxies are faint, making dynamical measurements
very challenging. With long exposures on the Keck telescope using the ESI
instrument we have succeeded in bridging this gap by measuring the dynamical
mass for five dwarf galaxies with M_K ~ -17.5 (M_B ~ --15.5). With the
exception of our brightest dwarf galaxy, they possess relatively flat velocity
dispersion profiles of around 20 km/s. By examining their 2D scaling relations
and 3D fundamental manifold, we found that the sizes and velocity dispersions
of these gap galaxies reveal continuous trends from dE to dSph galaxies. We
conclude that low-luminosity dwarf elliptical galaxies are dominated by stars,
not by dark matter, within their half light radii. This finding can be
understood if internal feedback processes are operating most efficiently in gap
galaxies, gravitationally heating the centrally-located dark matter to larger
radii. Whereas external environmental processes, which can strip away stars,
have a greater influence on dSph galaxies resulting in their higher dark matter
fractions. Abridged.Comment: 20 pages, includes 12 figures, accepted for publication in MNRA
Adiabatic compression and indirect detection of supersymmetric dark matter
Recent developments in the modelling of the dark matter distribution in our
Galaxy point out the necessity to consider some physical processes to satisfy
observational data. In particular, models with adiabatic compression, which
include the effect of the baryonic gas in the halo, increase significantly the
dark matter density in the central region of the Milky Way. On the other hand,
the non-universality in scalar and gaugino sectors of supergravity models can
also increase significantly the neutralino annihilation cross section. We show
that the combination of both effects gives rise to a gamma-ray flux arising
from the Galactic Center largely reachable by future experiments like GLAST. We
also analyse in this framework the EGRET excess data above 1 GeV, as well as
the recent data from CANGAROO and HESS. The analysis has been carried out
imposing the most recent experimental constraints, such as the lower bound on
the Higgs mass, the \bsg branching ratio, and the muon . In addition, the
recently improved upper bound on has also been taken
into account. The astrophysical (WMAP) bounds on the dark matter density have
also been imposed on the theoretical computation of the relic neutralino
density through thermal production.Comment: 32 pages, 11 figures, final version to appear in JCA
- …