Echocardiographic Changes and Long-Term Clinical Outcomes in Pediatric Patients With Pulmonary Arterial Hypertension Treated With Bosentan for 72 Weeks:A Post-hoc Analysis From the FUTURE 3 Study

FormUlation of bosenTan in pUlmonary arterial hypeRtEnsion (FUTURE) 3 was a 24-week open-label, prospective, and randomized phase 3 study that assessed the pharmacokinetics of bosentan 2 mg/kg b.i.d. or t.i.d. in children with pulmonary arterial hypertension (PAH). We report findings from a post-hoc analysis that explored the prognostic value of echocardiographic changes during FUTURE 3 in relation to clinical outcomes observed during the 24-week core study and 48-week extension. Patients aged ≥3 months to <12 years (n = 64) received oral doses of bosentan 2 mg/kg b.i.d. or t.i.d. (1:1) for 24 weeks, after which they were eligible to enter the extension with continued bosentan administration. Echocardiographic evaluations were performed at baseline, Week 12, and 24 of the core study via central reading, and analyzed post-hoc for correlation with clinical outcomes (time to PAH worsening, time to death, and vital status). Sixty-four patients were randomized in the core study [median (IQR) age 3.8 (1.7–7.8) years]; and 58 patients (90.6%) entered the 48-week extension. Most of the patients (68.8%) were receiving ≥1 PAH medication at baseline. Echocardiographic changes during the core study were small but with high variability. There were statistically significant associations at Week 24 between worsening of the parameters, systolic left ventricular eccentricity index (LVEIS) and E/A ratio mitral valve flow, and the outcomes of time to death and time to PAH worsening. Additional studies that utilize simple and reproducible echocardiographic assessments are needed to confirm these findings and subsequently identify potential treatment goals in pediatric PAH

Anderson localization in Bose-Einstein condensates

The understanding of disordered quantum systems is still far from being complete, despite many decades of research on a variety of physical systems. In this review we discuss how Bose-Einstein condensates of ultracold atoms in disordered potentials have opened a new window for studying fundamental phenomena related to disorder. In particular, we point our attention to recent experimental studies on Anderson localization and on the interplay of disorder and weak interactions. These realize a very promising starting point for a deeper understanding of the complex behaviour of interacting, disordered systems.Comment: 15 pages review, to appear in Reports on Progress in Physic

Neural networks and separation of Cosmic Microwave Background and astrophysical signals in sky maps

The Independent Component Analysis (ICA) algorithm is implemented as a neural network for separating signals of different origin in astrophysical sky maps. Due to its self-organizing capability, it works without prior assumptions on the signals, neither on their frequency scaling, nor on the signal maps themselves; instead, it learns directly from the input data how to separate the physical components, making use of their statistical independence. To test the capabilities of this approach, we apply the ICA algorithm on sky patches, taken from simulations and observations, at the microwave frequencies, that are going to be deeply explored in a few years on the whole sky, by the Microwave Anisotropy Probe (MAP) and by the {\sc Planck} Surveyor Satellite. The maps are at the frequencies of the Low Frequency Instrument (LFI) aboard the {\sc Planck} satellite (30, 44, 70 and 100 GHz), and contain simulated astrophysical radio sources, Cosmic Microwave Background (CMB) radiation, and Galactic diffuse emissions from thermal dust and synchrotron. We show that the ICA algorithm is able to recover each signal, with precision going from 10% for the Galactic components to percent for CMB; radio sources are almost completely recovered down to a flux limit corresponding to $0.7\sigma_{CMB}$, where $\sigma_{CMB}$ is the rms level of CMB fluctuations. The signal recovering possesses equal quality on all the scales larger then the pixel size. In addition, we show that the frequency scalings of the input signals can be partially inferred from the ICA outputs, at the percent precision for the dominant components, radio sources and CMB.Comment: 15 pages; 6 jpg and 1 ps figures. Final version to be published in MNRA

Physics–Dynamics Coupling in weather, climate and Earth system models: Challenges and recent progress

This is the final version. Available from American Meteorological Society via the DOI in this record.Numerical weather, climate, or Earth system models involve the coupling of components. At a broad level, these components can be classified as the resolved fluid dynamics, unresolved fluid dynamical aspects (i.e., those represented by physical parameterizations such as subgrid-scale mixing), and nonfluid dynamical aspects such as radiation and microphysical processes. Typically, each component is developed, at least initially, independently. Once development is mature, the components are coupled to deliver a model of the required complexity. The implementation of the coupling can have a significant impact on the model. As the error associated with each component decreases, the errors introduced by the coupling will eventually dominate. Hence, any improvement in one of the components is unlikely to improve the performance of the overall system. The challenges associated with combining the components to create a coherent model are here termed physics–dynamics coupling. The issue goes beyond the coupling between the parameterizations and the resolved fluid dynamics. This paper highlights recent progress and some of the current challenges. It focuses on three objectives: to illustrate the phenomenology of the coupling problem with references to examples in the literature, to show how the problem can be analyzed, and to create awareness of the issue across the disciplines and specializations. The topics addressed are different ways of advancing full models in time, approaches to understanding the role of the coupling and evaluation of approaches, coupling ocean and atmosphere models, thermodynamic compatibility between model components, and emerging issues such as those that arise as model resolutions increase and/or models use variable resolutions.Natural Environment Research Council (NERC)National Science FoundationDepartment of Energy Office of Biological and Environmental ResearchPacific Northwest National Laboratory (PNNL)DOE Office of Scienc

In vitro human growth hormone increases human chorionic gonadotropin and progesterone secretion by human placenta at term: evidence of a modulatory role by opioids

We examined the in vitro effect of human growth hormone (hGH) on hormone placental production and the modulation by opioids of this function. Small placental fragments from 12 term placentas were incubated at 37 degrees C in a 95% air and 5% CO2 atmosphere for 4 h with various concentrations of hGH (1-1000 ng/ml) or naloxone (3-500 ng/ml). Both hGH and naloxone increased the concentrations of human chorionic gonadotropin (hCG) and progesterone in the media. The effect of the hGH was dose-dependent and statistically significant at 10 ng/ml, while naloxone was able to increase hCG and progesterone production only at the highest doses (250-500 ng/ml). The concomitant treatment with ineffective doses of naloxone and hGH was able to enhance hCG and progesterone secretion reaching levels similar to those obtained with the highest doses of hGH alone. High naloxone concentrations significantly decreased both hCG and progesterone secretion induced by high doses of hGH. This study confirms the relevance of growth hormone in sustaining placental endocrine activities and indicates an effect of opioids in modulating these function

A high fat breakfast attenuates the suppression of appetite and acylated ghrelin during exercise at simulated altitude.

High-altitude exposure induces a negative energy balance by increasing resting energy expenditure and decreasing energy intake. This diminished energy intake is likely caused by altitude-induced anorexia and can have detrimental effects for those travelling to high-altitude. We aimed to investigate whether altering the macronutrient composition of breakfast could attenuate altitude-induced anorexia and augment energy intake at high-altitude. Twelve healthy men (aged 26 (8) years, body mass index 23.9 (2.7) kg·m(-2)) completed two, 305min experimental trials at 4300m simulated altitude (~11.7% O2). After an overnight fast, participants entered a normobaric hypoxic chamber and rested for one hour, before receiving either a high fat (HF; 60% fat, 25% carbohydrate) or an isocaloric high carbohydrate (HC; 60% carbohydrate, 25% fat) breakfast. One hour after breakfast, participants performed 60min of treadmill walking at 50% of relative V̇O2max. An ad-libitum buffet meal was consumed 1h 30min after exercise. Appetite perceptions, blood samples and substrate oxidation rates were measured throughout. A significantly higher area under the curve for composite appetite score was observed during exercise in HF (40 (12) mm·h(-1)) compared with HC (30 (17) mm·h(-1), P=0.036). During exercise, lower insulin concentrations (P=0.013) and elevated acylated ghrelin concentrations (P=0.048) were observed in HF compared with HC. After exercise there was no significant difference in composite appetite score (P=0.356), acylated ghrelin (P=0.229) or insulin (P=0.513) between conditions. Energy intake at the buffet did not significantly differ between conditions (P=0.384). A HF breakfast attenuated appetite suppression during exercise at 4300m simulated altitude, however ad-libitum energy intake did not increase

Grape-Derived Polyphenols Improve Aging-Related Endothelial Dysfunction in Rat Mesenteric Artery: Role of Oxidative Stress and the Angiotensin System

Aging is characterized by the development of an endothelial dysfunction, which affects both the nitric oxide (NO)- and the endothelium-derived hyperpolarizing factor (EDHF)-mediated relaxations, associated with vascular oxidative stress and the activation of the angiotensin system. This study investigated whether red wine polyphenols (RWPs), antioxidants and potent stimulators of NO- and EDHF-mediated relaxations improve aging-related endothelial dysfunction, and, if so, examined the underlying mechanism. Mesenteric artery reactivity was determined in organ chambers, vascular oxidative stress by dihydroethidine and MitoSOX staining, and expression of target proteins by immunohistochemical staining. Control young rats (16 weeks) received solvent (ethanol, 3% v/v), and middle-aged rats (46 weeks) either solvent or RWPs (100 mg/kg/day) in the drinking water. The acetylcholine-induced endothelium-dependent NO component was slightly reduced whereas the EDHF component was markedly blunted in rings of middle-aged rats compared to young rats. The endothelial dysfunction was associated with oxidative stress, an upregulation of angiotensin II and AT1 receptors and a down-regulation of SKCa, IKCa, and angiotensin converting enzyme. Intake of RWPs for either one or two weeks improved the NO and the EDHF components of the relaxation, and normalized oxidative stress, the expression of SKCa, IKCa and the components of the angiotensin system. The protective effect of the 2-week RWPs treatment persisted for one and two weeks following stopping intake of RWPs. Thus, intake of RWPs caused a persistent improvement of the endothelial function, particularly the EDHF component, in middle-aged rats and this effect seems to involve the normalization of the expression of SKCa, IKCa and the angiotensin system

Determining Signalling Nodes for Apoptosis by a Genetic High-Throughput Screen

With the ever-increasing information emerging from the various sequencing and gene annotation projects, there is an urgent need to elucidate the cellular functions of the newly discovered genes. The genetically regulated cell suicide of apoptosis is especially suitable for such endeavours as it is governed by a vast number of factors.We have set up a high-throughput screen in 96-well microtiter plates for genes that induce apoptosis upon their individual transfection into human cells. Upon screening approximately 100,000 cDNA clones we determined 74 genes that initiate this cellular suicide programme. A thorough bioinformatics analysis of these genes revealed that 91% are novel apoptosis regulators. Careful sequence analysis and functional annotation showed that the apoptosis factors exhibit a distinct functional distribution that distinguishes the cell death process from other signalling pathways. While only a minority of classic signal transducers were determined, a substantial number of the genes fall into the transporter- and enzyme-category. The apoptosis factors are distributed throughout all cellular organelles and many signalling circuits, but one distinct signalling pathway connects at least some of the isolated genes. Comparisons with microarray data suggest that several genes are dysregulated in specific types of cancers and degenerative diseases.Many unknown genes for cell death were revealed through our screen, supporting the enormous complexity of cell death regulation. Our results will serve as a repository for other researchers working with genomics data related to apoptosis or for those seeking to reveal novel signalling pathways for cell suicide