Assessment of the systemic effects of budesonide inhaled from Easyhaler®and from Turbuhaler®in healthy male volunteers

AbstractThe main objective of this study was to show dose-dependent equivalence in the systemic activity of budesonide 800 μ g day−1and 1600 μ g day−1delivered from either Easyhaler®or Turbuhaler®in healthy male subjects.This single-centre study was carried out according to a randomized, double-blind, double-dummy, five-way cross-over design over a 9-week period. All subjects received 1 week of treatment with the following, in randomized order, with a washout week between each treatment: budesonide Easyhaler®800 μ g day−1plus placebo Turbuhaler®; budesonide Easyhaler®1600 μ g day−1plus placebo Turbuhaler®; placebo Easyhaler®plus Pulmicort®Turbuhaler®800 μ g day−1; placebo Easyhaler®plus Pulmicort®Turbuhaler®1600 μ g day−1; placebo Easyhaler®plus placebo Turbuhaler®. The final inhalation of study drug was performed at the study centre, where blood and urine samples were collected.Fifteen subjects were recruited and all completed the study. Mean serum cortisol AUC0–20values (the primary outcome variable) were comparable for each device at the two dose levels, and met the defined criteria for equivalence (90% CI 0·8–1·25 for between-treatment difference). Budesonide 800 μ g day−1caused minimal suppression of serum cortisol AUC0-20values. Budesonide 1600 μ g day−1statistically significantly suppressed serum cortisol AUC0–20values compared with placebo. Mean morning serum cortisol values were within the reference range in all treatment groups. At a budesonide dose of 800 μ g day−1mean urine cortisol/creatinine ratio was statistically significantly higher with Easyhaler®than with Turbuhaler®, but there was no significant difference between the devices at the 1600 μ g day−1dose. Serum budesonide concentrations were equivalent for each device at both dose levels. Adverse drug reactions were infrequent and mild in nature and there were no clinically significant changes in laboratory safety variables.In conclusion, in healthy male volunteers, budesonide 800μ g day−1and 1600 μ g day−1inhaled from Easyhaler®had comparable systemic effects to the same doses inhaled via Turbuhaler®

Profiling filaments: comparing near-infrared extinction and submillimetre data in TMC-1

Interstellar filaments are an important part of star formation. To understand the structure of filaments, cross-section profiles are often fitted with Plummer profiles. This profiling is often done with submm studies, such as Herschel. It would be convenient if filament properties could also be studied using groundbased NIR data. We compare the filament profiles obtained by NIR extinction and submm observations to find out if reliable profiles can be derived using NIR data. We use J-, H-, and K-band data of a filament north of TMC-1 to derive an extinction map from colour excesses of background stars. We compare the Plummer profiles obtained from extinction maps with Herschel dust emission maps. We present 2 methods to estimate profiles from NIR: Plummer profile fits to median Av of stars or directly to the Av of individual stars. We compare the methods by simulations. In simulations extinction maps and the new methods give correct results to within ~10-20 for modest densities. Direct fit to data on individual stars gives more accurate results than extinction map, and can work in higher density. In profile fits to real observations, values of Plummer parameters are generally similar to within a factor of ~2. Although parameter values can vary significantly, estimates of filament mass usually remain accurate to within some tens of per cent. Our results for TMC-1 are in agreement with earlier results. High resolution NIR data give more details, but 2MASS data can be used to estimate profiles. NIR extinction can be used as an alternative to submm observations to profile filaments. Direct fits of stars can also be a valuable tool. Plummer profile parameters are not always well constrained, and caution should be taken when making fits. In the evaluation of Plummer parameters, one can use the independence of dust emission and NIR data and the difference in the shapes of the confidence regions.Comment: accepted to Astronomy & Astrophysics; abstract has been shortened for astrop

Dietary Intake, Serum Hormone Concentrations, Amenorrhea and Bone Mineral Density of Physique Athletes and Active Gym Enthusiasts

As the diet, hormones, amenorrhea, and bone mineral density (BMD) of physique athletes (PA) and gym enthusiasts (GE) are little-explored, we studied those in 69 females (50 PA, 19 GE) and 20 males (11 PA, 9 GE). Energy availability (EA, kcal·kgFFM−1·d−1 in DXA) in female and male PA was ~41.3 and ~37.2, and in GE ~39.4 and ~35.3, respectively. Low EA (LEA) was found in 10% and 26% of female PA and GE, respectively, and in 11% of male GE. In PA, daily protein intake (g/kg body mass) was ~2.9–3.0, whereas carbohydrate and fat intakes were ~3.6–4.3 and ~0.8–1.0, respectively. PA had higher protein and carbohydrate and lower fat intakes than GE (p < 0.05). Estradiol, testosterone, IGF-1, insulin, leptin, TSH, T4, T3, cortisol, or BMD did not differ between PA and GE. Serum IGF-1 and leptin were explained 6% and 7%, respectively, by EA. In non-users of hormonal contraceptives, amenorrhea was found only in PA (27%) and was associated with lower fat percentage, but not EA, BMD, or hormones. In conclusion, off-season dietary intakes, hormone levels, and BMD meet the recommendations in most of the PA and GE. Maintaining too-low body fat during the off-season may predispose to menstrual disturbances

Dietary Intake, Serum Hormone Concentrations, Amenorrhea and Bone Mineral Density of Physique Athletes and Active Gym Enthusiasts

As the diet, hormones, amenorrhea, and bone mineral density (BMD) of physique athletes (PA) and gym enthusiasts (GE) are little-explored, we studied those in 69 females (50 PA, 19 GE) and 20 males (11 PA, 9 GE). Energy availability (EA, kcal·kgFFM−1·d−1 in DXA) in female and male PA was ~41.3 and ~37.2, and in GE ~39.4 and ~35.3, respectively. Low EA (LEA) was found in 10% and 26% of female PA and GE, respectively, and in 11% of male GE. In PA, daily protein intake (g/kg body mass) was ~2.9–3.0, whereas carbohydrate and fat intakes were ~3.6–4.3 and ~0.8–1.0, respectively. PA had higher protein and carbohydrate and lower fat intakes than GE (p < 0.05). Estradiol, testosterone, IGF-1, insulin, leptin, TSH, T4, T3, cortisol, or BMD did not differ between PA and GE. Serum IGF-1 and leptin were explained 6% and 7%, respectively, by EA. In non-users of hormonal contraceptives, amenorrhea was found only in PA (27%) and was associated with lower fat percentage, but not EA, BMD, or hormones. In conclusion, off-season dietary intakes, hormone levels, and BMD meet the recommendations in most of the PA and GE. Maintaining too-low body fat during the off-season may predispose to menstrual disturbances

Multiwavelength study of the high-latitude cloud L1642: chain of star formation

L1642 is one of the two high galactic latitude (|b| > 30deg) clouds confirmed to have active star formation. We examine the properties of this cloud, especially the large-scale structure, dust properties, and compact sources in different stages of star formation. We present high-resolution far-infrared and submm observations with the Herschel and AKARI satellites and mm observations with the AzTEC/ASTE telescope, which we combined with archive data from near- and mid-infrared (2MASS, WISE) to mm observations (Planck). The Herschel observations, combined with other data, show a sequence of objects from a cold clump to young stellar objects at different evolutionary stages. Source B-3 (2MASS J04351455-1414468) appears to be a YSO forming inside the L1642 cloud, instead of a foreground brown dwarf, as previously classified. Herschel data reveal striation in the diffuse dust emission around L1642. The western region shows striation towards NE and has a steeper column density gradient on its southern side. The densest central region has a bow-shock like structure showing compression from the west and a filamentary tail extending towards east. The differences suggest that these may be spatially distinct structures, aligned only in projection. We derive values of the dust emission cross-section per H nucleon for different regions of the cloud. Modified black-body fits to the spectral energy distribution of Herschel and Planck data give emissivity spectral index beta values 1.8-2.0 for the different regions. The compact sources have lower beta values and show an anticorrelation between T and beta. Markov chain Monte Carlo calculations demonstrate the strong anticorrelation between beta and T errors and the importance of mm Planck data in constraining the estimates. L1642 reveals a more complex structure and sequence of star formation than previously known.Comment: 22 pages, 18 figures, accepted to Astronomy & Astrophysics; abstract shortened and figures reduced for astrop

Fatty Acid Fingerprints and Hyaluronic Acid in Extracellular Vesicles from Proliferating Human Fibroblast-like Synoviocytes

Extracellular vesicles (EVs) function as conveyors of fatty acids (FAs) and other bioactive lipids and can modulate the gene expression and behavior of target cells. EV lipid composition influences the fluidity and stability of EV membranes and reflects the availability of lipid mediator precursors. Fibroblast-like synoviocytes (FLSs) secrete EVs that transport hyaluronic acid (HA). FLSs play a central role in inflammation, pannus formation, and cartilage degradation in joint diseases, and EVs have recently emerged as potential mediators of these effects. The aim of the present study was to follow temporal changes in HA and EV secretion by normal FLSs, and to characterize the FA profiles of FLSs and EVs during proliferation. The methods used included nanoparticle tracking analysis, confocal laser scanning microscopy, sandwich-type enzyme-linked sorbent assay, quantitative PCR, and gas chromatography. The expression of hyaluronan synthases 1–3 in FLSs and HA concentrations in conditioned media decreased during cell proliferation. This was associated with elevated proportions of 20:4n-6 and total n-6 polyunsaturated FAs (PUFAs) in high-density cells, reductions in n-3/n-6 PUFA ratios, and up-regulation of cluster of differentiation 44, tumor necrosis factor α, peroxisome proliferator-activated receptor (PPAR)-α, and PPAR-γ. Compared to the parent FLSs, 16:0, 18:0, and 18:1n-9 were enriched in the EV fraction. EV counts decreased during cell growth, and 18:2n-6 in EVs correlated with the cell count. To conclude, FLS proliferation was featured by increased 20:4n-6 proportions and reduced n-3/n-6 PUFA ratios, and FAs with a low degree of unsaturation were selectively transferred from FLSs into EVs. These FA modifications have the potential to affect membrane fluidity, biosynthesis of lipid mediators, and inflammatory processes in joints, and could eventually provide tools for translational studies to counteract cartilage degradation in inflammatory joint diseases

Far-Infrared to Millimeter Astrophysical Dust Emission. II: Comparison of the Two-Level Systems (TLS) model with Astronomical Data

In a previous paper we proposed a new model for the emission by amorphous astronomical dust grains, based on solid-state physics. The model uses a description of the Disordered Charge Distribution (DCD) combined with the presence of Two-Level Systems (TLS) defects in the amorphous solid composing the grains. The goal of this paper is to confront this new model to astronomical observations of different Galactic environments in the FIR/submm, in order to derive a set of canonical model parameters to be used as a Galactic reference to be compared to in future Galactic and extragalactic studies. We confront the TLS model with existing astronomical data. We consider the average emission spectrum at high latitudes in our Galaxy as measured with FIRAS and WMAP, as well as the emission from Galactic compact sources observed with Archeops, for which an inverse relationship between the dust temperature and the emissivity spectral index has been evidenced. We show that, unlike models previously proposed which often invoke two dust components at different temperatures, the TLS model successfully reproduces both the shape of the Galactic SED and its evolution with temperature as observed in the Archeops data. The best TLS model parameters indicate a charge coherence length of \simeq 13 nm and other model parameters in broad agreement with expectations from laboratory studies of dust analogs. We conclude that the millimeter excess emission, which is often attributed to the presence of very cold dust in the diffuse ISM, is likely caused solely by TLS emission in disordered amorphous dust grains. We discuss the implications of the new model, in terms of mass determinations from millimeter continuum observations and the expected variations of the emissivity spectral index with wavelength and dust temperature. The implications for the analysis of the Herschel and Planck satellite data are discussed.Comment: Accepted for publication in A&A (16 pages, 9 figures, 6 tables

Accuracy of core mass estimates in simulated observations of dust emission

We study the reliability of mass estimates obtained for molecular cloud cores using sub-millimetre and infrared dust emission. We use magnetohydrodynamic simulations and radiative transfer to produce synthetic observations with spatial resolution and noise levels typical of Herschel surveys. We estimate dust colour temperatures using different pairs of intensities, calculate column densities and compare the estimated masses with the true values. We compare these results to the case when all five Herschel wavelengths are available. We investigate the effects of spatial variations of dust properties and the influence of embedded heating sources. Wrong assumptions of dust opacity and its spectral index beta can cause significant systematic errors in mass estimates. These are mainly multiplicative and leave the slope of the mass spectrum intact, unless cores with very high optical depth are included. Temperature variations bias colour temperature estimates and, in quiescent cores with optical depths higher than for normal stable cores, masses can be underestimated by up to one order of magnitude. When heated by internal radiation sources the observations recover the true mass spectra. The shape, although not the position, of the mass spectrum is reliable against observational errors and biases introduced in the analysis. This changes only if the cores have optical depths much higher than expected for basic hydrostatic equilibrium conditions. Observations underestimate the value of beta whenever there are temperature variations along the line of sight. A bias can also be observed when the true beta varies with wavelength. Internal heating sources produce an inverse correlation between colour temperature and beta that may be difficult to separate from any intrinsic beta(T) relation of the dust grains. This suggests caution when interpreting the observed mass spectra and the spectral indices.Comment: Revised version, 17 pages, 17 figures, submitted to A&

Oxazinomycin arrests RNA polymerase at the polythymidine sequences

Oxazinomycin is a C-nucleoside antibiotic that is produced by Streptomyces hygroscopicus and closely resembles uridine. Here, we show that the oxazinomycin triphosphate is a good substrate for bacterial and eukaryotic RNA polymerases (RNAPs) and that a single incorporated oxazinomycin is rapidly extended by the next nucleotide. However, the incorporation of several successive oxazinomycins or a single oxazinomycin in a certain sequence context arrested a fraction of the transcribing RNAP. The addition of Gre RNA cleavage factors eliminated the transcriptional arrest at a single oxazinomycin and shortened the nascent RNAs arrested at the polythymidine sequences suggesting that the transcriptional arrest was caused by backtracking of RNAP along the DNA template. We further demonstrate that the ubiquitous C-nucleoside pseudouridine is also a good substrate for RNA polymerases in a triphosphorylated form but does not inhibit transcription of the polythymidine sequences. Our results collectively suggest that oxazinomycin functions as a Trojan horse substrate and its inhibitory effect is attributable to the oxygen atom in the position corresponding to carbon five of the uracil ring

Galactic cold cores VIII. Filament formation and evolution : Filament properties in context with evolutionary models

Context. The onset of star formation is intimately linked with the presence of massive unstable filamentary structures. These filaments are therefore key for theoretical models that aim to reproduce the observed characteristics of the star formation process in the Galaxy. Aims. As part of the filament study carried out by the Herschel Galactic Cold Cores Key Programme, here we study and discuss the filament properties presented in GCC VII (Paper I) in context with theoretical models of filament formation and evolution. Methods. A conservatively selected sample of filaments located at a distance D <500 pc was extracted from the GCC fields with the getfilaments algorithm. The physical structure of the filaments was quantified according to two main components: the central (Gaussian) region of the filament (core component), and the power-law-like region dominating the filament column density profile at larger radii (wing component). The properties and behaviour of these components relative to the total linear mass density of the filament and the column density of its environment were compared with the predictions from theoretical models describing the evolution of filaments under gravity-dominated conditions. Results. The feasibility of a transition from a subcritical to supercritical state by accretion at any given time is dependent on the combined effect of filament intrinsic properties and environmental conditions. Reasonably self-gravitating (high M-line,M-core) filaments in dense environments (Av greater than or similar to 3 mag) can become supercritical on timescales of t similar to 1 Myr by accreting mass at constant or decreasing width. The trend of increasing M-line,M-tot (M-line,M-core and M-line,M-wing) and ridge A(v) with background for the filament population also indicates that the precursors of star-forming filaments evolve coevally with their environment. The simultaneous increase of environment and filament Av explains the observed association between dense environments and high Mlille,co values, and it argues against filaments remaining in constant single-pressure equilibrium states. The simultaneous growth of filament and background in locations with efficient mass assembly, predicted in numerical models of filaments in collapsing clouds, presents a suitable scenario for the fulfillment of the combined filament mass-environment criterium that is in quantitative agreement with Herschel observations.Peer reviewe