Elevated levels of inflammatory cytokines predict survival in idiopathic and familial pulmonary arterial hypertension

BACKGROUND: Inflammation is a feature of pulmonary arterial hypertension (PAH), and increased circulating levels of cytokines are reported in patients with PAH. However, to date, no information exists on the significance of elevated cytokines or their potential as biomarkers. We sought to determine the levels of a range of cytokines in PAH and to examine their impact on survival and relationship to hemodynamic indexes. METHODS AND RESULTS: We measured levels of serum cytokines (tumor necrosis factor-alpha, interferon-gamma and interleukin-1beta, -2, -4, -5, -6, -8, -10, -12p70, and -13) using ELISAs in idiopathic and heritable PAH patients (n=60). Concurrent clinical data included hemodynamics, 6-minute walk distance, and survival time from sampling to death or transplantation. Healthy volunteers served as control subjects (n=21). PAH patients had significantly higher levels of interleukin-1beta, -2, -4, -6, -8, -10, and -12p70 and tumor necrosis factor-alpha compared with healthy control subjects. Kaplan-Meier analysis showed that levels of interleukin-6, 8, 10, and 12p70 predicted survival in patients. For example, 5-year survival with interleukin-6 levels of >9 pg/mL was 30% compared with 63% for patients with levels < or = 9 pg/mL (P=0.008). In this PAH cohort, cytokine levels were superior to traditional markers of prognosis such as 6-minute walk distance and hemodynamics. CONCLUSIONS: This study illustrates dysregulation of a broad range of inflammatory mediators in idiopathic and familial PAH and demonstrates that cytokine levels have a previously unrecognized impact on patient survival. They may prove to be useful biomarkers and provide insight into the contribution of inflammation in PAH

XMM-Newton X-ray study of early type stars in the Carina OB1 association

&lt;p&gt;&lt;b&gt;Aims:&lt;/b&gt; X-ray properties of the stellar population in the Carina OB1 association are examined with special emphasis on early-type stars. Their spectral characteristics provide some clues to understanding the nature of X-ray formation mechanisms in the winds of single and binary early-type stars.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Methods:&lt;/b&gt; A timing and spectral analysis of five observations with XMM-Newton is performed using various statistical tests and thermal spectral models.&lt;/p&gt; &lt;p&gt;&lt;b&gt;Results:&lt;/b&gt; 235 point sources have been detected within the field of view. Several of these sources are probably pre-main sequence stars with characteristic short-term variability. Seven sources are possible background AGNs. Spectral analysis of twenty four sources of type OB and WR 25 was performed. We derived spectral parameters of the sources and their fluxes in three energy bands. Estimating the interstellar absorption for every source and the distance to the nebula, we derived X-ray luminosities of these stars and compared them to their bolometric luminosities. We discuss possible reasons for the fact that, on average, the observed X-ray properties of binary and single early type stars are not very different, and give several possible explanations.&lt;/p&gt

A Spectroscopic Survey of WNL Stars in the LMC: General Properties and Binary Status

We report the results of an intense, spectroscopic survey of all 41 late-type, nitrogen-rich Wolf-Rayet (WR) stars in the Large Magellanic Cloud (LMC) observable with ground-based telescopes. This survey concludes the decade-long effort of the Montr\'eal Massive Star Group to monitor every known WR star in the Magellanic Clouds except for the 6 crowded WNL stars in R136, which will be discussed elsewhere. The focus of our survey was to monitor the so-called WNL stars for radial-velocity (RV) variability in order to identify the short- to intermediate-period (P \la 200 days) binaries among them. Our results are in line with results of previous studies of other WR subtypes, and show that the binary frequency among LMC WNL stars is statistically consistent with that of WNL stars in the Milky Way. We have identified four previously unknown binaries, bringing the total number of known WNL binaries in the LMC to nine. Since it is very likely that none but one of the binaries are classical, helium-burning WNL stars, but rather superluminous, hence extremely massive, hydrogen-burning objects, our study has dramatically increased the number of known binaries harbouring such objects, and thus paved the way to determine their masses through model-independent, Keplerian orbits. It is expected that some of the stars in our binaries will be among the most massive known. With the binary status of each WR star now known, we also studied the photometric and X-ray properties of our program stars using archival MACHO photometry as well as Chandra and ROSAT data. We find that one of our presumably single WNL stars is among the X-ray brightest WR sources known. We also identify a binary candidate from its RV variability and X-ray luminosity which harbours the most luminous WR star known in the Local Group.Comment: 25 pages, 11 figures; accepted for MNRA

Why do hospital prescribers continue antibiotics when it is safe to stop? Results of a choice experiment survey

Background Deciding whether to discontinue antibiotics at early review is a cornerstone of hospital antimicrobial stewardship practice worldwide. In England, this approach is described in government guidance (‘Start Smart then Focus’). However, < 10% of hospital antibiotic prescriptions are discontinued at review, despite evidence that 20–30% could be discontinued safely. We aimed to quantify the relative importance of factors influencing prescriber decision-making at review. Methods We conducted an online choice experiment, a survey method to elicit preferences. Acute/general hospital prescribers in England were asked if they would continue or discontinue antibiotic treatment in 15 hypothetical scenarios. Scenarios were described according to six attributes, including patients’ presenting symptoms and whether discontinuation would conflict with local prescribing guidelines. Respondents’ choices were analysed using conditional logistic regression. Results One hundred respondents completed the survey. Respondents were more likely to continue antibiotics when discontinuation would ‘strongly conflict’ with local guidelines (average marginal effect (AME) on the probability of continuing + 0.194 (p < 0.001)), when presenting symptoms more clearly indicated antibiotics (AME of urinary tract infection symptoms + 0.173 (p < 0.001) versus unclear symptoms) and when patients had severe frailty/comorbidities (AME = + 0.101 (p < 0.001)). Respondents were less likely to continue antibiotics when under no external pressure to continue (AME = − 0.101 (p < 0.001)). Decisions were also influenced by the risks to patient health of continuing/discontinuing antibiotic treatment. Conclusions Guidelines that conflict with antibiotic discontinuation (e.g. pre-specify fixed durations) may discourage safe discontinuation at review. In contrast, guidelines conditional on patient factors/treatment response could help hospital prescribers discontinue antibiotics if diagnostic information suggesting they are no longer needed is available

Factors associated with informant-reported cognitive decline in older adults: a systemised literature review

Background Dementia diagnoses are typically made where there is a significant, progressive decline in cognitive functioning. Evidence of such decline is increasingly established through information provided by informants. However, some studies demonstrate that informant reports may not always be accurate and may be biased by extraneous factors. This review aimed to elucidate factors that have been identified as potentially having some influence on informant reports of cognitive decline. Method A search of PsychInfo, ASSIA, PubMed and Web of Science databases identified 13 peer-reviewed studies that met criteria for inclusion in the review. Results Reviewed studies provide some evidence for associations between informant-reported cognitive decline and demographic characteristics (patient age, education, ethnicity and informant gender), clinical factors (dementia severity, diagnosis, behavioural disturbance, everyday functioning) and psychological factors (patient depressive symptoms and neuroticism, informant psychological distress and burden). Several methodological limitations of the evidence base were identified. Conclusion Findings suggest that informant-reported cognitive decline may not always be wholly reliable in that information holds potential to be influenced by both patient and informant characteristics. Clinical and empirical implications are discussed

The underluminous Type Ia Supernova 2005bl and the class of objects similar to SN 1991bg

Optical observations of the Type Ia supernova (SN Ia) 2005bl in NGC 4070, obtained from -6 to +66 d with respect to the B-band maximum, are presented. The photometric evolution is characterised by rapidly-declining light curves and red colours at peak and soon thereafter. With M_B,max = -17.24 the SN is an underluminous SN Ia, similar to the peculiar SNe 1991bg and 1999by. This similarity also holds for the spectroscopic appearance, the only remarkable difference being the likely presence of carbon in pre-maximum spectra of SN 2005bl. A comparison study among underluminous SNe Ia is performed, based on a number of spectrophotometric parameters. Previously reported correlations of the light-curve decline rate with peak luminosity and R(Si) are confirmed, and a large range of post-maximum Si II lambda6355 velocity gradients is encountered. 1D synthetic spectra for SN 2005bl are presented, which confirm the presence of carbon and suggest an overall low burning efficiency with a significant amount of leftover unburned material. Also, the Fe content in pre-maximum spectra is very low, which may point to a low metallicity of the precursor. Implications for possible progenitor scenarios of underluminous SNe Ia are briefly discussed.Comment: 24 pages, 24 figures, accepted for publication in MNRA

Effects of Explosion Asymmetry and Viewing Angle on the Type Ia Supernova Color and Luminosity Calibration

Phenomenological relations exist between the peak luminosity and other observables of type Ia supernovae (SNe~Ia), that allow one to standardize their peak luminosities. However, several issues are yet to be clarified: SNe~Ia show color variations after the standardization. Also, individual SNe~Ia can show residuals in their standardized peak absolute magnitude at the level of $\sim 0.15$ mag. In this paper, we explore how the color and luminosity residual are related to the wavelength shift of nebular emission lines observed at \gsim 150 days after maximum light. A sample of 11 SNe Ia which likely suffer from little host extinction indicates a correlation ($3.3\sigma$) between the peak $B-V$ color and the late-time emission-line shift. Furthermore, a nearly identical relation applies for a larger sample in which only three SNe with B-V \gsim 0.2 mag are excluded. Following the interpretation that the late-time emission-line shift is a tracer of the viewing direction from which an off-centre explosion is observed, we suggest that the viewing direction is a dominant factor controlling the SN color and that a large part of the color variations is intrinsic, rather than due to the host extinction. We also investigate a relation between the peak luminosity residuals and the wavelength shift in nebular emission lines in a sample of 20 SNe. We thereby found a hint of a correlation (at $\sim 1.6 \sigma$ level). The confirmation of this will require a future sample of SNe with more accurate distance estimates. Radiation transfer simulations for a toy explosion model where different viewing angles cause the late-time emission-line shift are presented, predicting a strong correlation between the color and shift, and a weaker one for the luminosity residual.Comment: Accepted by Monthly Notices of the Royal Astronomical Society. 22 pages, 20 figures and 7 tabels (including appendix

The VLT-FLAMES Tarantula Survey

Context. The Tarantula region in the Large Magellanic Cloud (LMC) contains the richest population of spatially resolved massive O-type stars known so far. This unmatched sample offers an opportunity to test models describing their main-sequence evolution and mass-loss properties. Aims. Using ground-based optical spectroscopy obtained in the framework of the VLT-FLAMES Tarantula Survey (VFTS), we aim to determine stellar, photospheric and wind properties of 72 presumably single O-type giants, bright giants and supergiants and to confront them with predictions of stellar evolution and of line-driven mass-loss theories. Methods. We apply an automated method for quantitative spectroscopic analysis of O stars combining the non-LTE stellar atmosphere model fastwind with the genetic fitting algorithm pikaia to determine the following stellar properties: effective temperature, surface gravity, mass-loss rate, helium abundance, and projected rotational velocity. The latter has been constrained without taking into account the contribution from macro-turbulent motions to the line broadening. Results. We present empirical effective temperature versus spectral subtype calibrations at LMC-metallicity for giants and supergiants. The calibration for giants shows a +1kK offset compared to similar Galactic calibrations; a shift of the same magnitude has been reported for dwarfs. The supergiant calibrations, though only based on a handful of stars, do not seem to indicate such an offset. The presence of a strong upturn at spectral type O3 and earlier can also not be confirmed by our data. In the spectroscopic and classical Hertzsprung-Russell diagrams, our sample O stars are found to occupy the region predicted to be the core hydrogen-burning phase by state-of-the-art models. For stars initially more massive than approximately 60 M⊙, the giant phase already appears relatively early on in the evolution; the supergiant phase develops later. Bright giants, however, are not systematically positioned between giants and supergiants at Minit ≳ 25 M⊙. At masses below 60 M⊙, the dwarf phase clearly precedes the giant and supergiant phases; however this behavior seems to break down at Minit ≲ 18 M⊙. Here, stars classified as late O III and II stars occupy the region where O9.5-9.7 V stars are expected, but where few such late O V stars are actually seen. Though we can not exclude that these stars represent a physically distinct group, this behavior may reflect an intricacy in the luminosity classification at late O spectral subtype. Indeed, on the basis of a secondary classification criterion, the relative strength of Si iv to He i absorption lines, these stars would have been assigned a luminosity class IV or V. Except for five stars, the helium abundance of our sample stars is in agreement with the initial LMC composition. This outcome is independent of their projected spin rates. The aforementioned five stars present moderate projected rotational velocities (i.e., νesini < 200kms-1) and hence do not agree with current predictions of rotational mixing in main-sequence stars. They may potentially reveal other physics not included in the models such as binary-interaction effects. Adopting theoretical results for the wind velocity law, we find modified wind momenta for LMC stars that are ~0.3 dex higher than earlier results. For stars brighter than 105 L⊙, that is, in the regime of strong stellar winds, the measured (unclumped) mass-loss rates could be considered to be in agreement with line-driven wind predictions if the clump volume filling factors were fV ~ 1/8 to 1/6

Transcriptional Analysis of Murine Macrophages Infected with Different Toxoplasma Strains Identifies Novel Regulation of Host Signaling Pathways

Most isolates of Toxoplasma from Europe and North America fall into one of three genetically distinct clonal lineages, the type I, II and III lineages. However, in South America these strains are rarely isolated and instead a great variety of other strains are found. T. gondii strains differ widely in a number of phenotypes in mice, such as virulence, persistence, oral infectivity, migratory capacity, induction of cytokine expression and modulation of host gene expression. The outcome of toxoplasmosis in patients is also variable and we hypothesize that, besides host and environmental factors, the genotype of the parasite strain plays a major role. The molecular basis for these differences in pathogenesis, especially in strains other than the clonal lineages, remains largely unexplored. Macrophages play an essential role in the early immune response against T. gondii and are also the cell type preferentially infected in vivo. To determine if non-canonical Toxoplasma strains have unique interactions with the host cell, we infected murine macrophages with 29 different Toxoplasma strains, representing global diversity, and used RNA-sequencing to determine host and parasite transcriptomes. We identified large differences between strains in the expression level of known parasite effectors and large chromosomal structural variation in some strains. We also identified novel strain-specifically regulated host pathways, including the regulation of the type I interferon response by some atypical strains. IFNβ production by infected cells was associated with parasite killing, independent of interferon gamma activation, and dependent on endosomal Toll-like receptors in macrophages and the cytoplasmic receptor retinoic acid-inducible gene 1 (RIG-I) in fibroblasts.National Institutes of Health (U.S.) (R01-AI080621)New England Regional Center of Excellence for Biodefense and Emerging Infectious Diseases (Developmental Grant AIO57159)Pew Charitable Trusts (Biomedical Scholars Program)Robert A. Swanson Career Development awardThe Knights Templar Eye Foundation, Inc.Pre-Doctoral Grant in the Biological Sciences (5-T32-GM007287-33)Cleo and Paul Schimmel Foundatio

The relation between the most-massive star and its parental star cluster mass

We present a thorough literature study of the most-massive star, m_max, in several young star clusters in order to assess whether or not star clusters are populated from the stellar initial mass function (IMF) by random sampling over the mass range 0.01 < m < 150 M_sol without being constrained by the cluster mass, M_ecl. The data reveal a partition of the sample into lowest mass objects (M_ecl < 10^2 M_sol), moderate mass clusters (10^2 M_sol < M_ecl < 10^3 M_sol) and rich clusters above 10^3 M_sol. Additionally, there is a plateau of a constant maximal star mass (m_max ~ 25 M_sol) for clusters with masses between 10^3 M_sol and 4 10^3 M_sol. Statistical tests of this data set reveal that the hypothesis of random sampling from the IMF between 0.01 and 150 M_sol is highly unlikely for star clusters more massive than 10^2 M_sol with a probability of p ~ 2 10^-7 for the objects with M_ecl between 10^2 M_sol and 10^3 M_sol and p ~ 3 10^-9 for the more massive star clusters. Also, the spread of m_max values at a given M_ecl is smaller than expected from random sampling. We suggest that the basic physical process able to explain this dependence of stellar inventory of a star cluster on its mass may be the interplay between stellar feedback and the binding energy of the cluster-forming molecular cloud core. Given these results, it would follow that an integrated galactic initial mass function (IGIMF) sampled from such clusters would automatically be steeper in comparison to the IMF within individual star clusters.Comment: 26 pages, 13 figures, 3 tables, accepted for publication in MNRA