Chronic obstructive pulmonary disease (COPD) remains a major public health problem. It is the fourth leading cause of chronic morbidity and mortality in the United States, and is projected to rank fifth in 2020 in burden of disease worldwide, according to a study published by the World Bank/World Health Organization. Yet, COPD remains relatively unknown or ignored by the public as well as public health and government officials. In 1998, in an effort to bring more attention to COPD, its management, and its prevention, a committed group of scientists encouraged the U.S. National Heart, Lung, and Blood Institute and the World Health Organization to form the Global Initiative for Chronic Obstructive Lung Disease (GOLD). Among the important objectives of GOLD are to increase awareness of COPD and to help the millions of people who suffer from this disease and die prematurely of it or its complications. The first step in the GOLD program was to prepare a consensus report, Global Strategy for the Diagnosis, Management, and Prevention of COPD, published in 2001. The present, newly revised document follows the same format as the original consensus report, but has been updated to reflect the many publications on COPD that have appeared. GOLD national leaders, a network of international experts, have initiated investigations of the causes and prevalence of COPD in their countries, and developed innovative approaches for the dissemination and implementation of COPD management guidelines. We appreciate the enormous amount of work the GOLD national leaders have done on behalf of their patients with COPD. Despite the achievements in the 5 years since the GOLD report was originally published, considerable additional work is ahead of us if we are to control this major public health problem. The GOLD initiative will continue to bring COPD to the attention of governments, public health officials, health care workers, and the general public, but a concerted effort by all involved in health care will be necessary.

https://www.who.int/respiratory/copd/GOLD_WR_06.pdf

Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary.

Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease. NHLBI/WHO Global Initiative for Chronic Obstructive Lung Disease (GOLD) Workshop summary.

The discovery that mammalian cells have the ability to synthesize the free radical nitric oxide (NO) has stimulated an extraordinary impetus for scientific research in all the fields of biology and medicine. Since its early description as an endothelial-derived relaxing factor, NO has emerged as a fundamental signaling device regulating virtually every critical cellular function, as well as a potent mediator of cellular damage in a wide range of conditions. Recent evidence indicates that most of the cytotoxicity attributed to NO is rather due to peroxynitrite, produced from the diffusion-controlled reaction between NO and another free radical, the superoxide anion. Peroxynitrite interacts with lipids, DNA, and proteins via direct oxidative reactions or via indirect, radical-mediated mechanisms. These reactions trigger cellular responses ranging from subtle modulations of cell signaling to overwhelming oxidative injury, committing cells to necrosis or apoptosis. In vivo, peroxynitrite generation represents a crucial pathogenic mechanism in conditions such as stroke, myocardial infarction, chronic heart failure, diabetes, circulatory shock, chronic inflammatory diseases, cancer, and neurodegenerative disorders. Hence, novel pharmacological strategies aimed at removing peroxynitrite might represent powerful therapeutic tools in the future. Evidence supporting these novel roles of NO and peroxynitrite is presented in detail in this review.

/pdf/nitric-oxide-and-peroxynitrite-in-health-and-disease-3uuuqgfdcz.pdf

Nitric Oxide and Peroxynitrite in Health and Disease

The Task Force for the management of atrial fibrillation of the European Society of Cardiology (ESC)  

Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC  

Endorsed by the European Stroke Organisation (ESO)

/pdf/2016-esc-guidelines-for-the-management-of-atrial-ba0601yb9m.pdf

2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS

/pdf/2016-esc-guidelines-for-the-management-of-atrial-36b2cidm1x.pdf

2016 ESC Guidelines for the management of atrial fibrillation developed in collaboration with EACTS: The Task Force for the management of atrial fibrillation of the European Society of Cardiology (ESC). Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Endorsed by the European Stroke Organisation (ESO)

To identify airway pathologic abnormalities selectively associated with severe asthma, we examined 10 control subjects, 10 patients with intermittent asthma, 15 patients with mild-to-moderate persistent asthma, 15 patients with severe persistent asthma, and 10 patients with chronic obstructive pulmonary disease. Bronchial biopsies were assessed for epithelial integrity; subepithelial basement membrane (SBM) thickness; collagen type III deposition; eosinophil, neutrophil, and fibroblast numbers; mucous gland and airway smooth muscle (ASM) areas; SBM-ASM distance; ASM hypertrophy (increased cell size); and the expression of the contractile proteins alpha-actin, smooth muscle myosin heavy-chain isoforms, myosin light-chain kinase, and the phosphorylated form of the regulatory light chain of myosin. Neither mucosal eosinophilia nor neutrophilia, epithelial damage, or SBM thickness reflected asthma severity. In contrast, higher numbers of fibroblasts (p < 0.001), an increase in collagen type III deposition (p < 0.020), larger mucous gland (p < 0.040) and ASM (p < 0.001) areas, augmented ASM cell size (p < 0.001), and myosin light-chain kinase expression (p < 0.005) distinguished patients with severe persistent asthma from patients with milder disease or with chronic obstructive pulmonary disease. Stepwise multivariate regression analysis established that fibroblast numbers and ASM cell size were negatively associated with prebronchodilator and postbronchodilator FEV1 values in patients with asthma. We conclude that fibroblast accumulation and ASM hypertrophy in proximal airways are selective determinants of severe persistent asthma.

https://www.atsjournals.org/doi/pdf/10.1164/rccm.200209-1030OC

Airway Structural Alterations Selectively Associated with Severe Asthma

The effects of the administration of 100% oxygen on minute ventilation (VE) and arterial blood gases were studied in patients with chronic obstructive pulmonary disease during acute respiratory failure. The administration of O2 resulted in an early decrease in VE, which averaged 18% +/- 2 SE of the control VE, and was due to a decrease in both tidal volume (VT) and respiratory frequency (f). This was followed by a slow increase in VE, such that after 15 min of breathing O2, VE rose to 93 +/- 6% of the control room air value, with both VT and f similar to control values. Despite the small difference between VE while breathing room air and that at the fifteenth minute of O2 inhalation, PaCO2 increased by 23 +/- 5 mmHg, and no significant correlation was found between the changes in VE and PaCO2. By the fifteenth minute of O2 inhalation the PaO2 averaged 225 +/- 23 mmHg, and it was concluded that despite the removal of the hypoxic stimulus of O2 inhalation, the activity of the respiratory muscles remained great enough to maintain VE at nearly the same degree as that while breathing room air. Consequently, the changes in PaCO2 after the administration of O2 were mainly due to increased inhomogeneity of VA/Q distribution within the lungs.

Effects of the administration of O2 on ventilation and blood gases in patients with chronic obstructive pulmonary disease during acute respiratory failure.

In an attempt to explain the clinical efficacy of aminophylline, we studied its effect on diaphragmatic function in eight normal subjects. The relation between the electrical activity of the diaphragm and the pressure generated by the diaphragm was assessed during voluntary contractions before and after aminophylline infusion. Aminophylline shifted the electrical activity/pressure curve to the left; the pressure at a given electrical activity increased an average of 15 per cent (P less than 0.001). In four subjects, pressure was also measured during stimulation of the phrenic nerve at various frequencies before and after diaphragmatic fatigue was produced by resistive breathing, with and without aminophylline infusion. Pressure increased after fatigue at all stimulation frequencies with aminophylline, as compared with the pressure after identical fatigue runs at the same stimulation frequencies without aminophylline. The mean plasma aminophylline concentration associated with these responses was 13 +/- 0.9 mg per liter. We conclude that aminophylline improves the diaphragm's contractility and renders it less susceptible to fatigue.

https://www.nejm.org/doi/pdf/10.1056/NEJM198107303050503?listPDF=true

Aminophylline Improves Diaphragmatic Contractility

Background Although asthma and rhinitis often occur together, the reason for this common comorbidity is still a matter of debate. Objective We sought to assess whether the coexistence of asthma and rhinitis could be explained by common risk factors. Methods International cross-sectional study of representative samples of young adults, who completed a detailed questionnaire and underwent lung function tests, bronchoprovocation challenge, IgE measurements, and skin prick tests. Results In all countries, asthma and bronchial hyperreactivity were more frequent in subjects with rhinitis than in those without (odds ratio [OR], 6.63; 95% CI, 5.44-8.08; and OR, 3.02 95% CI, 2.66-3.43, respectively). Seventy-four percent to 81% of subjects with asthma reported rhinitis, depending on sensitization to specific allergens. Conversely, the risk of asthma increased from 2.0% in subjects without rhinitis to 6.7% in subjects with rhinitis only when exposed to pollen, 11.9% in subjects with rhinitis when exposed to animals, and 18.8% in subjects with rhinitis either when exposed to pollen or to animals. The association between rhinitis and asthma remained significant after adjustment for total IgE, parental history of asthma, and allergen sensitization (OR, 3.41; 95% CI, 2.75-4.2 suggesting that the coexistence of asthma and rhinitis is not solely due to atopic predisposition to these 2 diseases. Conclusions Although there were some variations in the association between asthma and rhinitis according to sensitization to individual allergens, the strong association between asthma and rhinitis was not fully explained by shared risk factors, including atopy. Our findings are consistent with the hypothesis that rhinitis might increase the risk of asthma.

https://www.jacionline.org/article/S0091-6749(03)02447-3/pdf

Michel Aubier

Papers

Airway Structural Alterations Selectively Associated with Severe Asthma

Effects of the administration of O2 on ventilation and blood gases in patients with chronic obstructive pulmonary disease during acute respiratory failure.

Aminophylline Improves Diaphragmatic Contractility

Association between asthma and rhinitis according to atopic sensitization in a population-based study.

Myocardial cell death in fibrillating and dilated human right atria.