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1.  Update in Chronic Obstructive Pulmonary Disease in 2010 
doi:10.1164/rccm.201102-0280UP
PMCID: PMC3114060  PMID: 21596833
2.  Update in Cystic Fibrosis 2005 
doi:10.1164/rccm.2601006
PMCID: PMC2662914  PMID: 16632633
3.  Update in Cystic Fibrosis 2006 
doi:10.1164/rccm.200701-160UP
PMCID: PMC2720114  PMID: 17405941
4.  Update in Acute Lung Injury and Critical Care 2010 
doi:10.1164/rccm.201102-0327UP
PMCID: PMC3114050  PMID: 21531954
5.  Update in Cystic Fibrosis 2007 
doi:10.1164/rccm.200801-069UP
PMCID: PMC2720148  PMID: 18460460
7.  Interstitial lung disease: raising the index of suspicion in primary care 
Interstitial lung disease (ILD) describes a group of diseases that cause progressive scarring of the lung tissue through inflammation and fibrosis. The most common form of ILD is idiopathic pulmonary fibrosis, which has a poor prognosis. ILD is rare and mainly a disease of the middle-aged and elderly. The symptoms of ILD—chronic dyspnoea and cough—are easily confused with the symptoms of more common diseases, particularly chronic obstructive pulmonary disease and heart failure. ILD is infrequently seen in primary care and a precise diagnosis of these disorders can be challenging for physicians who rarely encounter them. Confirming a diagnosis of ILD requires specialist expertise and review of a high-resolution computed tomography scan (HRCT). Primary care physicians (PCPs) play a key role in facilitating the diagnosis of ILD by referring patients with concerning symptoms to a pulmonologist and, in some cases, by ordering HRCTs. In our article, we highlight the importance of prompt diagnosis of ILD and describe the circumstances in which a PCP’s suspicion for ILD should be raised in a patient presenting with chronic dyspnoea on exertion, once more common causes of dyspnoea have been investigated and excluded.
doi:10.1038/npjpcrm.2014.54
PMCID: PMC4373409  PMID: 25208940
9.  Tidal Volume Reduction in Patients with Acute Lung Injury When Plateau Pressures Are Not High 
Use of a volume- and pressure-limited mechanical ventilation strategy improves clinical outcomes of patients with acute lung injury and acute respiratory distress syndrome (ALI/ARDS). However, the extent to which tidal volumes and inspiratory airway pressures should be reduced to optimize clinical outcomes is a controversial topic. This article addresses the question, “Is there a safe upper limit to inspiratory plateau pressure in patients with ALI/ARDS?” We reviewed data from animal models with and without preexisting lung injury, studies of normal human respiratory system mechanics, and the results of five clinical trials of lung-protective mechanical ventilation strategies. We also present an original analysis of data from the largest of the five clinical trials. The available data from each of these assessments do not support the commonly held view that inspiratory plateau pressures of 30 to 35 cm H2O are safe. We could not identify a safe upper limit for plateau pressures in patients with ALI/ARDS.
doi:10.1164/rccm.200501-048CP
PMCID: PMC2718413  PMID: 16081547
acute respiratory distress syndrome; acute lung injury; plateau; mechanical ventilation
12.  Good News for Lung Repair in Preterm Infants 
doi:10.1164/rccm.201303-0485ED
PMCID: PMC3734616  PMID: 23675712
15.  Update in Pulmonary Infections 2010 
doi:10.1164/rccm.201103-0381UP
PMCID: PMC3265274  PMID: 21765033
16.  Update in Asthma 2009 
doi:10.1164/rccm.201003-0321UP
PMCID: PMC3269238  PMID: 20516492
17.  Airway Smooth Muscle in Bronchial Tone, Inflammation, and Remodeling 
Airway smooth muscle (ASM) plays a pivotal role in modulating bronchomotor tone but also orchestrates and perpetuates airway inflammation and remodeling. Despite substantial research, there remain important unanswered questions. In 2006, the National Heart, Lung, and Blood Institute sponsored a workshop to define new directions in ASM biology. Important questions concerning the key functions of ASM include the following: Does developmental dysregulation of ASM function promote airway disease, what key signaling pathways in ASM evoke airway hyperresponsiveness in vivo, do alterations in ASM mass affect excitation–contraction coupling, and can ASM modulate airway inflammation and remodeling in a physiologically relevant manner? This workshop identified critical issues in ASM biology to delineate areas for scientific investigation in the identification of new therapeutic and diagnostic approaches in asthma, chronic obstructive pulmonary disease, and cystic fibrosis.
doi:10.1164/rccm.200708-1217PP
PMCID: PMC2218850  PMID: 18006883
myocyte; signal transduction; force generation; migration; remodeling
18.  Activation of the Ubiquitin–Proteasome Pathway in the Diaphragm in Chronic Obstructive Pulmonary Disease 
Rationale: Studies show that the myosin content of the diaphragm in patients with mild to moderate chronic obstructive pulmonary disease (COPD) is reduced, compromising diaphragm contractile performance. The mechanisms for reduced contractile protein content are unknown. In the present study we hypothesized that the loss of contractile protein content is associated with activation of the ubiquitin–proteasome pathway in the diaphragm of patients with mild to moderate COPD.
Methods: Proteolytic activity of isolated 20S proteasomes was determined in diaphragm biopsies from patients with and without COPD (predicted mean FEV1, 66 and 93%, respectively). In addition, we determined 20S proteasome subunit C8 protein levels by means of Western blotting, ubiquitin-ligase mRNA levels by means of real-time polymerase chain reaction, and caspase-3 activity by determining the hydrolysis of fluorogenic substrates.
Results: The 20S proteasome activity was about threefold increased in the diaphragm of patients with COPD. C8 protein levels were not significantly different between COPD and non-COPD diaphragm, indicating increased specific activity of individual proteasomes, rather than an increased number of proteasomes. mRNA levels of the muscle-specific ubiquitin-ligase MAFbx were significantly higher in diaphragm from patients with COPD compared with patients without COPD. Caspase-3–mediated cleavage of actomyosin complexes is considered an initial step in muscle wasting, yielding fragments that can be degraded by the ubiquitin–proteasome pathway. In line with the increased ubiquitin–proteasome activity, caspase-3 activity was higher in diaphragm homogenates from patients with COPD.
Conclusions: The present study is the first to demonstrate increased activity of the ubiquitin–proteasome pathway in COPD diaphragm. Importantly, these changes occur in patients with only mild to moderate COPD (Global Initiative for Chronic Obstructive Lung Disease stage I/II).
doi:10.1164/rccm.200605-721OC
PMCID: PMC2648103  PMID: 16917114
caspase-3; chronic obstructive pulmonary disease; diaphragm function; myosin; proteolysis
19.  Fibroblast Foci Are Not Discrete Sites of Lung Injury or Repair 
Background: Usual interstitial pneumonia (UIP), the pathologic correlate of idiopathic pulmonary fibrosis, contains characteristic discrete areas of fibroblasts, myofibroblasts, and newly formed collagen, termed “fibroblast foci.” These lesions are argued to represent isolated sites of recurrent acute lung injury and suggested to be the mechanism of disease progression. We hypothesized that, rather than isolated, these lesions are part of an organized neoplasm.
Methods: Morphometric analysis of pentachrome-stained histologic sections of UIP was performed. Using point-counting technique on serial sections, fibroblast foci, arteries, and macrophage clusters were identified and we determined their individual “connectiveness” by estimating the Euler number. Two-dimensional micrographs were collated into a three-dimensional array from which a visual three-dimensional reconstruction could be constructed. Clonality analysis was performed using human androgen receptor gene methylation assay.
Results: Blood vessels show significant connectivity with a Euler number of 2, whereas macrophage clusters exhibited no connectivity. The fibroblast foci showed a high level of interconnection with Euler numbers ranging from 19 to 39. The computer generated three-dimensional models provide a visual confirmation of this connectiveness. Human androgen receptor gene methylation assay analysis of the foci showed balanced methylation consistent with polyclonality.
Conclusions: The fibroblast foci of UIP are the leading edge of a complex reticulum that is highly interconnected and extends from the pleura into the underlying parenchyma. It is a reactive, rather than a malignant, process.
doi:10.1164/rccm.200602-205OC
PMCID: PMC2648056  PMID: 16799077
fibroblast foci; fibroblast reticulum; idiopathic pulmonary fibrosis; usual interstitial pneumonia
20.  Oxidative Stress in Pulmonary Fibrosis 
Idiopathic ulmonary fibrosis (histopathology of usual interstitial pneumonia) is a progressive lung disease of unknown etiology. No treatment has been shown to improve the prognosis of the patients with this disease. Recent evidence, including the observations that the patients with idiopathic pulmonary fibrosis have higher levels of oxidant stress than control patients, and a recent multicenter European study examining the effect of the antioxidant N-acetylcysteine on the progression of idiopathic pulmonary fibrosis suggest that the cellular redox state may play a significant role in the progression of this disease. These complex mechanisms include activation of growth factors as well as regulation of matrix metalloproteinases and protease inhibitors. Potential future approaches for the therapy of interstitial pulmonary fibrosis may involve synthetic agents able to modulate cellular redox state. Investigation into therapeutic approaches to inhibit oxidant-mediated reactions in the initiation and progression of pulmonary fibrosis may provide hope for the future treatment of this disease.
doi:10.1164/rccm.200501-017PP
PMCID: PMC2718525  PMID: 15894605
antioxidant; idiopathic pulmonary fibrosis; oxidant; radical
21.  Prognostic Value of Bronchiolitis Obliterans Syndrome Stage 0-p in Single-Lung Transplant Recipients 
Rationale: Early diagnosis of bronchiolitis obliterans syndrome (BOS) is critical in understanding pathogenesis and devising therapeutic trials. Although potential-BOS stage (BOS 0-p), encompassing early changes in FEV1 and forced expiratory flow, midexpiratory phase (FEF25–75%), has been proposed, there is a paucity of data validating its utility in single-lung transplantation. Objective: The aim of this study was to define the predictive ability of BOS 0-p in single-lung transplantation. Methods: We retrospectively analyzed spirometric data for 197 single-lung recipients. Sensitivity, specificity, and positive predictive value of BOS 0-p were examined over time using Kaplan-Meier methodology. Results: BOS 0-p FEV1 was associated with higher sensitivity, specificity, and positive predictive value than the FEF25–75% criterion over different time periods investigated. The probability of testing positive for BOS 0-p FEV1 in patients with BOS (sensitivity) was 71% at 2 years before the onset of BOS. The probability of being free from development of BOS 0-p FEV1 in patients free of BOS at follow-up (specificity) was 93% within the last year. Of patients who met the BOS 0-p FEV1 criterion, 81% developed BOS or died within 3 years. The specificity and positive predictive value curves for the BOS 0-p FEV1 were significantly different between patients with underlying restrictive versus obstructive physiology (p = 0.05 and 0.01, respectively). Conclusion: The FEV1 criterion for BOS 0-p provides useful predictive information regarding the risk of development of BOS or death in single-lung recipients. The predictive value of this criterion is higher in patients with underlying restriction and is superior to the FEF25–75% criterion.
doi:10.1164/rccm.200501-097OC
PMCID: PMC2718475  PMID: 15894603
bronchiolitis obliterans syndrome; diagnosis; lung transplantation; staging
22.  Lung Volume and Continuous Positive Airway Pressure Requirements in Obstructive Sleep Apnea 
Previous studies have demonstrated that lung volume during wakefulness influences upper airway size and resistance, particularly in patients with sleep apnea. We sought to determine the influence of lung volume on the level of continuous positive airway pressure (CPAP) required to prevent flow limitation during non-REM sleep in subjects with sleep apnea. Seventeen subjects (apnea–hypopnea index, 42.6 ± 6.2 [SEM]) were studied during stable non-REM sleep in a rigid head-out shell equipped with a positive/negative pressure attachment for manipulation of extrathoracic pressure. An epiglottic pressure catheter plus a mask/pneumotachometer were used to assess flow limitation. When lung volume was increased by 1,035 ± 22 ml, the CPAP level could be decreased from 11.9 ± 0.7 to 4.8 ± 0.7 cm H2O (p < 0.001) without flow limitation. The decreased CPAP at the same negative extrathoracic pressure yielded a final lung volume increase of 421 ± 36 ml above the initial value. Conversely, when lung volume was reduced by 732 ± 74 ml (n = 8), the CPAP level had to be increased from 11.9 ± 0.7 to 17.1 ± 1.0 cm H2O (p < 0.001) to prevent flow limitation, with a final lung volume decrease of 567 ± 78 ml. These results demonstrate that relatively small changes in lung volume have an important effect on the upper airway in subjects with sleep apnea during non-REM sleep.
doi:10.1164/rccm.200404-552OC
PMCID: PMC2718445  PMID: 15817803
airflow limitation; continuous positive airway pressure; lung volume; sleep apnea; upper airway
23.  ENDOTOXIN EXPOSURE IS A RISK FACTOR FOR ASTHMA: THE NATIONAL SURVEY OF ENDOTOXIN IN U.S. HOUSING 
Background: While research has shown that early life exposure to household endotoxin protects against development of allergies, studies are less clear on the relationship between household endotoxin exposure and prevalence of wheezing and asthma. We assayed 2552 house dust samples in a representative nationwide sample to explore relationships between endotoxin exposures and risk factors for asthma, asthma symptoms and medication use.
Methods: House dust was vacuum-sampled from five locations within homes and assayed for endotoxin. Health, demographic and housing information was assessed through questionnaire and on-site evaluation of 2456 residents of 831 homes selected to represent the demographics of the U.S.
Results: Endotoxin concentration (EU/mg) and load (EU/m2) were highly correlated (r=0.73-0.79). Geometric mean endotoxin concentrations were (in EU/mg): bedroom floors: 35.3 (5th-95thpercentile: 5.0-260); bedding: 18.7 (2.0-142); family room floors: 63.9 (11.5-331); sofas: 44.8 (6.4-240); kitchen floors: 80.5 (9.8-512). Multivariate analysis demonstrated significant relationships between increasing endotoxin levels and diagnosed asthma, asthma symptoms in the past year, current use of asthma medications, and wheezing among residents of the homes. These relationships were strongest for bedroom floor and bedding dust and were observed in adults only. Modeling the joint effect of bedding and bedroom floor endotoxin on recent asthma symptoms yielded an adjusted odds ratio of 2.83 (95%CI: 1.01-7.87). When stratified by allergy status, allergic subjects with higher endotoxin exposure were no more likely to have diagnosed asthma or asthma symptoms than non-allergic subjects.
Conclusion: This study demonstrates that household endotoxin exposure is a significant risk factor for increased asthma prevalence.
doi:10.1164/rccm.200505-758OC
PMCID: PMC1379232  PMID: 16141442
Wheeze; Airways Inflammation; House Dust; Lipopolysaccharide
24.  Ozone, Fine Particulate Matter, and Chronic Lower Respiratory Disease Mortality in the United States 
Rationale
Short-term effects of air pollution exposure on respiratory disease mortality are well established. However, few studies have examined the effects of long-term exposure, and among those that have, results are inconsistent.
Objectives
To evaluate long-term association between ambient ozone, fine particulate matter (PM2.5, particles with an aerodynamic diameter of 2.5 µm or less), and chronic lower respiratory disease (CLRD) mortality in the contiguous United States.
Methods
We fit Bayesian hierarchical spatial Poisson models, adjusting for five county-level covariates (percentage of adults aged ≥65 years, poverty, lifetime smoking, obesity, and temperature), with random effects at state and county levels to account for spatial heterogeneity and spatial dependence.
Measurements and Main Results
We derived county-level average daily concentration levels for ambient ozone and PM2.5 for 2001–2008 from the U.S. Environmental Protection Agency’s down-scaled estimates and obtained 2007–2008 CLRD deaths from the National Center for Health Statistics. Exposure to ambient ozone was associated with an increased rate of CLRD deaths, with a rate ratio of 1.05 (95% credible interval, 1.01–1.09) per 5-ppb increase in ozone; the association between ambient PM2.5 and CLRD mortality was positive but statistically insignificant (rate ratio, 1.07; 95% credible interval, 0.99–1.14).
Conclusions
This study links air pollution exposure data with CLRD mortality for all 3,109 contiguous U.S. counties. Ambient ozone may be associated with an increased rate of death from CLRD in the contiguous United States. Although we adjusted for selected county-level covariates and unobserved influences through Bayesian hierarchical spatial modeling, the possibility of ecologic bias remains.
doi:10.1164/rccm.201410-1852OC
PMCID: PMC4937454  PMID: 26017067
air pollution; chronic lower respiratory disease mortality; Bayesian hierarchical spatial models

Résultats 1-25 (1640)