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Genome-wide association studies (GWAS) have identified multiple associations with emphysema apicobasal distribution (EABD), but the biological functions of these variants are unknown. To characterize the functions of EABD-associated variants, we integrated GWAS results with 1) expression quantitative trait loci (eQTL) from the Genotype Tissue Expression (GTEx) project and subjects in the COPDGene (Genetic Epidemiology of COPD) study and 2) cell type epigenomic marks from the Roadmap Epigenomics project. On the basis of these analyses, we selected a variant near ACVR1B (activin A receptor type 1B) for functional validation. SNPs from 168 loci with P values less than 5 × 10(−5) in the largest GWAS meta-analysis of EABD were analyzed. Eighty-four loci overlapped eQTL, with 12 of these loci showing greater than 80% likelihood of harboring a single, shared GWAS and eQTL causal variant. Seventeen cell types were enriched for overlap between EABD loci and Roadmap Epigenomics marks (permutation P

Chronic respiratory failure describes a clinical state when the arterial Po2 breathing air is less than 8.0 kPa, which may or may not be associated with hypercapnia (defined as Pco2 more than 6.0 kPa (45 mm Hg)). Four processes cause arterial hypoxaemia due to inefficient pulmonary gas exchange—ventilation–perfusion (V/Q) mismatch, hypoventilation, diffusion limitation, and true shunt, with the most important of these being V/Q mismatching. The arterial CO2 is increased by inadequate alveolar ventilation and/or V/Q abnormality. A wide range of disorders can cause chronic respiratory failure, with the commonest being chronic obstructive pulmonary disease, interstitial lung diseases, chest wall and neuromuscular diseases, and morbid obesity.

We present measurements of the ionizing ultraviolet background (UVB) at z∼ 5–6 using the quasar proximity effect. The 15 quasars in our sample cover the range 4.6 5. The metagalactic hydrogen ionization rate, Γbkg, was determined by modelling the combined ionization field from the quasar and the UVB in the proximity zone on a pixel-by-pixel basis. The optical depths in the spectra were corrected for the expected effect of the quasar until the mean flux in the proximity region equalled that in the average Lyα forest, and from this we make a measurement of Γbkg. A number of systematic effects were tested using synthetic spectra. Noise in the flux was found to be the largest source of bias at z∼ 5, while uncertainties in the mean transmitted Lyα flux are responsible for the largest bias at z∼ 6. The impacts of large-scale overdensities and Lyman limit systems on Γbkgwere also investigated, but found to be small at z > 5. We find a decline in Γbkg with redshift, from log(Γbkg) =−12.15 ± 0.16 at z∼ 5 to log(Γbkg) =−12.84 ± 0.18 at z∼ 6 (1σ errors). Compared to UVB measurements at lower redshifts, our measurements suggest a drop of a factor of 5 in the H i photoionization rate between z∼ 4 and 6. The decline of Γbkg appears to be gradual, and we find no evidence for a sudden change in the UVB at any redshift that would indicate a rapid change in the attenuation length of ionizing photons. Combined with recent measurements of the evolution of the mean free path of ionizing photons, our results imply a decline in the emissivity of ionizing photons by roughly a factor of 2 from z∼ 5 to 6, albeit with significant uncertainty due to the measurement errors in both Γbkg and the mean free path.

Additional file 1. IPCRG scaling up activities.

The development of novel drugs for the treatment of chronic obstructive pulmonary disease (COPD) poses significant challenges. The mechanisms through which the chronic symptoms of COPD arise are poorly understood, making identification of potential therapeutic targets and in vivo evaluation of potential therapies extremely difficult. Despite these challenges, a unique approach of combined D 2 dopamine, β 2 -adrenoceptor agonism was identified as a valid potential target for the treatment of key COPD symptoms, the therapeutic potential of which was investigated in a series of pre-clinical evaluations. Subsequent clinical assessment has amassed a wealth of data from over 4000 patients, providing valuable insights into COPD, clinical trial design and the value of patient self-assessment tools.

It is a truth universally acknowledged that the simplest and most reliable way of assessing the function of the lungs is to make a spirometric measurement. Well, perhaps not universally acknowledged, but there is an increasing acceptance that the diagnosis of many lung diseases should involve a measurement of the functional capacity of the respiratory system and although this does not always tell us the whole truth 1, 2, it represents a substantial improvement on diagnostic criteria based solely on history examination and plain chest radiography. This is particularly true for diseases associated with airflow obstruction, such as chronic obstructive pulmonary disease (COPD), and those involving restriction of the lungs or chest wall, such as idiopathic pulmonary fibrosis or kyphoscoliosis. For doctors in primary care, the former is much more likely to be seen than the latter, and COPD along with bronchial asthma constitute the most frequent chronic respiratory diseases in this setting. While the importance of making an accurate diagnosis is not in doubt for patients with diabetes or chronic renal failure, we have been slow to adopt a similarly rigorous approach to respiratory conditions, especially COPD. Thanks to the efforts of many organisations, especially the European Respiratory Society (ERS) and the American Thoracic Society (ATS) 3, and also the Global Initiative for Chronic Obstructive Lung Disease (GOLD) programme 4, there is now a much wider appreciation of the need for objective diagnosis in common conditions such as COPD. As recent data from the Burden of Obstructive Lung Disease initiative has shown 5, this is a frequent and underappreciated problem, not only in developed European countries but particularly in many developing countries. One of our major tasks for the next decade will be to produce clear and consistent guidance as to how the relatively …

Background: Sleep apnoea syndrome (SAS), one of the main medical causes of excessive daytime sleepiness, has been shown to be a risk factor for traffic accidents. Treating SAS results in a normalized rate of traffic accidents. As part of the COST Action B-26, we looked at driving license regulations, and especially at its medical aspects in the European region. Methods: We obtained data from Transport Authorities in 25 countries (Austria, AT; Belgium, BE; Czech Republic, CZ; Denmark, DK; Estonia, EE; Finland, FI; France, FR; Germany, DE; Greece, GR; Hungary, HU; Ireland, IE; Italy, IT; Lithuania, LT; Luxembourg, LU; Malta, MT; Netherlands, NL; Norway, EC; Poland, PL; Portugal, PT; Slovakia, SK; Slovenia, SI; Spain, ES; Sweden, SE; Switzerland, CH; United Kingdom, UK). Results: Driving license regulations date from 1997 onwards. Excessive daytime sleepiness is mentioned in nine, whereas sleep apnoea syndrome is mentioned in 10 countries. A patient with untreated sleep apnoea is always considered unfit to drive. To recover the driving capacity, seven countries rely on a physician's medical certificate based on symptom control and compliance with therapy, whereas in two countries it is up to the patient to decide (on his doctor's advice) to drive again. Only FR requires a normalized electroencephalography (EEG)-based Maintenance of Wakefulness Test for professional drivers. Rare conditions (e.g., narcolepsy) are considered a driving safety risk more frequently than sleep apnoea syndrome. Conclusion: Despite the available scientific evidence, most countries in Europe do not include sleep apnoea syndrome or excessive daytime sleepiness among the specific medical conditions to be considered when judging whether or not a person is fit to drive. A unified European Directive seems desirable. (C) 2007 Elsevier B.V. All rights reserved.

A ship sinks at sea. The occupants are left floating in the ocean aided only by their life preservers and buoyant pieces of debris. Fortunately, a Coast-Guard cutter, attracted by an SOS sent from the sinking ship, arrives and saves the day. This is a rescue. Asthma is characterised by episodes of acutely worsening airflow, secondary to bronchospasm. An asthmatic, when exposed to a trigger, may develop acute bronchospasm, together with frightening and sometimes life-threatening symptoms. Rapid-acting bronchodilators, administered in a timely way, can reverse the bronchospasm, thus saving the day. This is termed “rescue” in asthma therapy. Acute episodes of asthma can be initiated by a variety of triggers ranging from cold air, cigarette smoke, dust, perfume and viral infections, to a variety of allergens including animal dander, insect and mite proteins, plant pollens and mould spores. An asthma attack can vary in severity, rate of onset and rate of resolution. Unexpected symptoms may be less dramatic and relatively mild and may commonly occur in some asthmatics. Unscheduled use of rapid-acting bronchodilators taken for acute symptom relief for all these various episodes is termed “rescue”. This use of rescue treatment has several utilities. Reserving the term rescue for severe “attacks” would require a definition of attacks, a daunting prospect. The concept also has mechanistic validity. The airway in the asthmatic with baseline conditions has its “normal” luminal diameter and airway tone. In response to a stimulus, airway tone acutely increases while airflow acutely decreases. Therefore, when the …

The development of novel drugs for the treatment of chronic obstructive pulmonary disease (COPD) poses significant challenges. The mechanisms through which the chronic symptoms of COPD arise are poorly understood, making identification of potential therapeutic targets and in vivo evaluation of potential therapies extremely difficult. Despite these challenges, a unique approach of combined D2 dopamine, beta2-adrenoceptor agonism was identified as a valid potential target for the treatment of key COPD symptoms, the therapeutic potential of which was investigated in a series of preclinical evaluations. Subsequent clinical assessment has amassed a wealth of data from over 4000 patients, providing valuable insights into COPD, clinical trial design and the value of patient self-assessment tools.