Efficacy of azithromycin in severe asthma from the AMAZES randomised trial

Background:Low-dose azithromycin is an effective therapy for persistent asthma; however, its benefit in severe asthma is not defined. Methods:Participants with severe asthma were identified from the AMAZES randomised, placebo-controlled trial of long-term (48 weeks) low-dose azithromycin. Participants who met one of the following severe asthma definitions were included: 1) Global Initiative for Asthma step 4 treatment with poor asthma control (asthma control questionnaire score ≥0.75); 2) International Severe Asthma Registry definition; 3) American Thoracic Society and European Respiratory Society severe asthma definitions. The rate of total exacerbations was calculated for each subgroup and efficacy of azithromycin compared with placebo. Asthma-related quality of life was assessed before and after treatment along with adverse effects. Results:Azithromycin significantly reduced asthma exacerbations in each group. In patients meeting the American Thoracic Society and European Respiratory Society task force definition of severe asthma (n=211), the rate of exacerbations with treatment was 1.2 per person-year, which was significantly less than for placebo (2.01 per person-year), giving an incidence rate ratio (95% CI) of 0.63 (0.41, 0.96). The proportion of participants experiencing at least one asthma exacerbation was reduced by azithromycin from 64% to 49% (p=0.021). A similar beneficial treatment effect was seen in participants poorly controlled with Global Initiative for Asthma step 4 treatment and those with International Severe Asthma Registry-defined severe asthma. Azithromycin also significantly improved the quality of life in severe asthma (p<0.05). Treatment was well tolerated, with gastrointestinal symptoms being the main adverse effect. Conclusion:Long-term, low-dose azithromycin reduced asthma exacerbations and improved the quality of life in patients with severe asthma, regardless of how this was defined. These data support the addition of azithromycin as a treatment option for patients with severe asthma.Peter G. Gibson, Ian A. Yang, John W. Upham, Paul N. Reynolds, Sandra Hodge, Alan L. James ... et al

Multiple inflammasomes may regulate the interleukin-1-driven inflammation in protracted bacterial bronchitis

Protracted bacterial bronchitis (PBB) in young children is characterised by prolonged wet cough, prominent airway interleukin (IL)-1β expression and infection, often with nontypeable Haemophilus influenzae (NTHi). The mechanisms responsible for IL-1-driven inflammation in PBB are poorly understood. We hypothesised that the inflammation in PBB involves the NLRP3 and/or AIM2 inflammasome/IL-1β axis. Lung macrophages obtained from bronchoalveolar lavage (BAL), peripheral blood mononuclear cells (PBMCs), blood monocytes and monocyte-derived macrophages from patients with PBB and age-matched healthy controls were cultured in control medium or exposed to live NTHi. In healthy adult PBMCs, CD14+ monocytes contributed to 95% of total IL-1β-producing cells upon NTHi stimulation. Stimulation of PBB PBMCs with NTHi significantly increased IL-1β expression (p<0.001), but decreased NLRC4 expression (p<0.01). NTHi induced IL-1β secretion in PBMCs from both healthy controls and patients with recurrent PBB. This was inhibited by Z-YVAD-FMK (a caspase-1 selective inhibitor) and by MCC950 (a NLRP3 selective inhibitor). In PBB BAL macrophages inflammasome complexes were visualised as fluorescence specks of NLRP3 or AIM2 colocalised with cleaved caspase-1 and cleaved IL-1β. NTHi stimulation induced formation of specks of cleaved IL-1β, NLRP3 and AIM2 in PBMCs, blood monocytes and monocyte-derived macrophages. We conclude that both the NLRP3 and AIM2 inflammasomes probably drive the IL-1β-dominated inflammation in PBB.Alice C-H. Chen, Hai B. Tran, Yang Xi, Stephanie T. Yerkovich, Katherine J. Baines, Susan J. Pizzutto, Melanie Carroll, Avril A.B. Robertson, Matthew A. Cooper, Kate Schroder, Jodie L. Simpson, Peter G. Gibson, Greg Hodge, Ian B. Masters, Helen M. Buntain, Helen L. Petsky, Samantha J. Prime, Anne B. Chang, Sandra Hodge, and John W. Upha

The IMF in Starbursts

The history of the IMF in starburst regions is reviewed. The IMFs are no longer believed to be top-heavy, although some superstar clusters, whether in starburst regions or not, could be. General observations of the IMF are discussed to put the starburst results in perspective. Observed IMF variations seem to suggest that the IMF varies a little with environment in the sense that denser and more massive clusters produce more massive stars, and perhaps more brown dwarfs too, compared to intermediate mass stars.Comment: 8 pages, to be published in ``Starbursts: from 30 Doradus to Lyman Break Galaxies,'' held at Institute of Astronomy, Cambridge University, UK, September 6-10, 2004. Kluwer Academic Publishers, edited by Richard de Grijs and Rosa M. Gonzalez Delgad

Consensus guidelines for the definition, detection and interpretation of immunogenic cell death.

Cells succumbing to stress via regulated cell death (RCD) can initiate an adaptive immune response associated with immunological memory, provided they display sufficient antigenicity and adjuvanticity. Moreover, multiple intracellular and microenvironmental features determine the propensity of RCD to drive adaptive immunity. Here, we provide an updated operational definition of immunogenic cell death (ICD), discuss the key factors that dictate the ability of dying cells to drive an adaptive immune response, summarize experimental assays that are currently available for the assessment of ICD in vitro and in vivo, and formulate guidelines for their interpretation

Cluster Density and the IMF

Observed variations in the IMF are reviewed with an emphasis on environmental density. The remote field IMF studied in the LMC by several authors is clearly steeper than most cluster IMFs, which have slopes close to the Salpeter value. Local field regions of star formation, like Taurus, may have relatively steep IMFs too. Very dense and massive clusters, like super star clusters, could have flatter IMFs, or inner-truncated IMFs. We propose that these variations are the result of three distinct processes during star formation that affect the mass function in different ways depending on mass range. At solar to intermediate stellar masses, gas processes involving thermal pressure and supersonic turbulence determine the basic scale for stellar mass, starting with the observed pre-stellar condensations, and they define the mass function from several tenths to several solar masses. Brown dwarfs require extraordinarily high pressures for fragmentation from the gas, and presumably form inside the pre-stellar condensations during mutual collisions, secondary fragmentations, or in disks. High mass stars form in excess of the numbers expected from pure turbulent fragmentation as pre-stellar condensations coalesce and accrete with an enhanced gravitational cross section. Variations in the interaction rate, interaction strength, and accretion rate among the primary fragments formed by turbulence lead to variations in the relative proportions of brown dwarfs, solar to intermediate mass stars, and high mass stars.Comment: 14 pages, 3 figures, to be published in ``IMF@50: A Fest-Colloquium in honor of Edwin E. Salpeter,'' held at Abbazia di Spineto, Siena, Italy, May 16-20, 2004. Kluwer Academic Publishers; edited by E. Corbelli, F. Palla, and H. Zinnecke

A joint Fermi-GBM and Swift-BAT analysis of gravitational-wave candidates from the third gravitational-wave observing run

We present Fermi Gamma-ray Burst Monitor (Fermi-GBM) and Swift Burst Alert Telescope (Swift-BAT) searches for gamma-ray/X-ray counterparts to gravitational-wave (GW) candidate events identified during the third observing run of the Advanced LIGO and Advanced Virgo detectors. Using Fermi-GBM onboard triggers and subthreshold gamma-ray burst (GRB) candidates found in the Fermi-GBM ground analyses, the Targeted Search and the Untargeted Search, we investigate whether there are any coincident GRBs associated with the GWs. We also search the Swift-BAT rate data around the GW times to determine whether a GRB counterpart is present. No counterparts are found. Using both the Fermi-GBM Targeted Search and the Swift-BAT search, we calculate flux upper limits and present joint upper limits on the gamma-ray luminosity of each GW. Given these limits, we constrain theoretical models for the emission of gamma rays from binary black hole mergers