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1.  Rifampicin Reduces Susceptibility to Ofloxacin in Rifampicin-resistant Mycobacterium tuberculosis through Efflux 
Rationale
Central dogma suggests that rifampicin resistance in Mycobacterium tuberculosis develops solely through rpoB gene mutations.
Objective
To determine whether rifampicin induces efflux pumps activation in rifampicin resistant M. tuberculosis strains thereby defining rifampicin resistance levels and reducing ofloxacin susceptibility.
Methods
Rifampicin and/or ofloxacin minimum inhibitory concentrations (MICs) were determined in rifampicin resistant strains by culture in BACTEC 12B medium. Verapamil and reserpine were included to determine their effect on rifampicin and ofloxacin susceptibility. RT-qPCR was applied to assess expression of efflux pump/transporter genes after rifampicin exposure. To determine whether verapamil could restore susceptibility to first-line drugs, BALB/c mice were infected with a MDR-TB strain and treated with first-line drugs with/without verapamil.
Measurements and Main Findings
Rifampicin MICs varied independently of rpoB mutation and genetic background. Addition reserpine and verapamil significantly restored rifampicin susceptibility (p = 0.0000). RT-qPCR demonstrated that rifampicin induced differential expression of efflux/transporter genes in MDR-TB isolates. Incubation of rifampicin mono-resistant strains in rifampicin (2 μg/ml) for 7 days induced ofloxacin resistance (MIC> 2 μg/ml) in strains with an rpoB531 mutation. Ofloxacin susceptibility was restored by exposure to efflux pump inhibitors. Studies in BALB/c mice showed that verapamil in combination with first-line drugs significantly reduced pulmonary CFUs after 1 and 2 months treatment (p < 0.05).
Conclusion
Exposure of rifampicin resistant M. tuberculosis strains to rifampicin can potentially compromise the efficacy of the second-line treatment regimens containing ofloxacin, thereby emphasising the need for rapid diagnostics to guide treatment. Efflux pump inhibitors have the potential to improve the efficacy of anti-tuberculosis drug treatment.
doi:10.1164/rccm.201011-1924OC
PMCID: PMC3698754  PMID: 21512166
Mycobacterium tuberculosis; drug resistance; rifampicin; efflux pumps; cross resistance
2.  Gastroesophageal Reflux Therapy Is Associated with Longer Survival in Patients with Idiopathic Pulmonary Fibrosis 
Rationale: Gastroesophageal reflux (GER) is highly prevalent in patients with idiopathic pulmonary fibrosis (IPF). Chronic microaspiration secondary to GER may play a role in the pathogenesis and natural history of IPF.
Objectives: To investigate the relationship between GER-related variables and survival time in patients with IPF.
Methods: Regression analysis was used to investigate the relationship between GER-related variables and survival time in a retrospectively identified cohort of patients with well-characterized IPF from two academic medical centers.
Measurements and Main Results: Two hundred four patients were identified for inclusion. GER-related variables were common in this cohort: reported symptoms of GER (34%), a history of GER disease (45%), reported use of GER medications (47%), and Nissen fundoplication (5%). These GER-related variables were significantly associated with longer survival time on unadjusted analysis. After adjustment, the use of GER medications was an independent predictor of longer survival time. In addition, the use of gastroesophageal reflux medications was associated with a lower radiologic fibrosis score. These findings were present regardless of center.
Conclusions: The reported use of GER medications is associated with decreased radiologic fibrosis and is an independent predictor of longer survival time in patients with IPF. These findings further support the hypothesis that GER and chronic microaspiration may play important roles in the pathobiology of IPF.
doi:10.1164/rccm.201101-0138OC
PMCID: PMC3262030  PMID: 21700909
pulmonary fibrosis; respiratory aspiration; idiopathic interstitial pneumonia; survival
3.  Altered MicroRNA Processing in Heritable Pulmonary Arterial Hypertension 
Rationale: Heritable pulmonary arterial hypertension (HPAH) is primarily caused by mutations of the bone morphogenetic protein (BMP) type-II receptor (BMPR2). Recent identification of mutations in the downstream mediator Smad-8 (gene, SMAD9) was surprising, because loss of Smad-8 function in canonical BMP signaling is largely compensated by Smad-1 and -5. We therefore hypothesized that noncanonical pathways may play an important role in PAH.
Objectives: To determine whether HPAH mutations disrupt noncanonical Smad-mediated microRNA (miR) processing.
Methods: Expression of miR-21, miR-27a, and miR-100 was studied in pulmonary artery endothelial (PAEC) and pulmonary artery smooth muscle cells (PASMC) from explant lungs of patients with PAH.
Measurements and Main Results: SMAD9 mutation completely abrogated miR induction, whereas canonical signaling was only reduced by one-third. miR-21 levels actually decreased, suggesting that residual canonical signaling uses up or degrades existing miR-21. BMPR2 mutations also led to loss of miR induction in two of three cases. HPAH cells proliferated faster than other PAH or controls. miR-21 and miR-27a each showed antiproliferative effects in PAEC and PASMC, and PAEC growth rate after BMP treatment correlated strongly with miR-21 fold-change. Overexpression of SMAD9 corrected miR processing and reversed the hyperproliferative phenotype.
Conclusions: HPAH-associated mutations engender a primary defect in noncanonical miR processing, whereas canonical BMP signaling is partially maintained. Smad-8 is essential for this miR pathway and its loss was not complemented by Smad-1 and -5; this may represent the first nonredundant role for Smad-8. Induction of miR-21 and miR-27a may be a critical component of BMP-induced growth suppression, loss of which likely contributes to vascular cell proliferation in HPAH.
doi:10.1164/rccm.201106-1130OC
PMCID: PMC3262031  PMID: 21920918
bone morphogenetic protein signaling; mutation; endothelium; smooth muscle
4.  The Response of Children with Asthma to Ambient Particulate Is Modified by Tobacco Smoke Exposure 
Rationale: Ambient particulate matter concentrations have been positively associated with urinary leukotriene E4 (LTE4) levels and albuterol usage in children with asthma but interactions with environmental tobacco smoke (ETS) exposure have not been demonstrated despite obvious exposure to both pollutants in an urban setting.
Objectives: To assess the health effects of concurrent ETS and ambient particulate matter exposure in children with asthma.
Methods: Albuterol usage and LTE4 levels were monitored in 82 urban schoolchildren with asthma over three consecutive fall to spring school periods. Concentrations of morning maximum ambient particulate matter <2.5 μm in aerodynamic diameter (mmPM2.5) and urine cotinine levels were also measured daily.
Measurements and Main Results: Albuterol usage and LTE4 were related to mmPM2.5 concentrations on days when urine cotinine levels were low (<10 ng/ml/mg creatinine); on these days, mean albuterol usage and LTE4 increased up to 5 or 6% per 10 μg/m3 increase in mmPM2.5. In contrast, no significant relationship was observed when cotinine was high, although mean albuterol usage and LTE4 levels were greater in this case. Model fits for LTE4 levels as a function of mmPM2.5 concentrations were improved when mmPM2.5 concentrations were logged, suggesting a nonlinear dose–response relationship between particulate matter exposure concentrations and airway mediators of asthma, for which the relationship tends to flatten at higher concentrations.
Conclusions: This study suggests that ETS modifies the acute effects of low-level ambient PM2.5 exposure on childhood asthma. This negative interaction, the smaller effect of particulate matter exposure in children exposed to higher ETS, may be related to a nonlinear dose–response relationship between asthma mediators and particulate exposures.
doi:10.1164/rccm.201010-1706OC
PMCID: PMC3262032  PMID: 21868505
air pollution; leukotriene E4; asthma; interaction; environmental tobacco smoke
5.  A Trial of Intrapleural Adenoviral-mediated Interferon-α2b Gene Transfer for Malignant Pleural Mesothelioma 
New therapeutic strategies are needed for malignant pleural mesothelioma (MPM). We conducted a single-center, open-label, nonrandomized, pilot and feasibility trial using two intrapleural doses of an adenoviral vector encoding human IFN-α (Ad.IFN-α2b). Nine subjects were enrolled at two dose levels. The first three subjects had very high pleural and systemic IFN-α concentrations resulting in severe “flu-like” symptoms necessitating dose de-escalation. The next six patients had reduced (but still significant) pleural and serum IFN-α levels, but with tolerable symptoms. Repeated vector administration appeared to prolong IFN-α expression levels. Anti-tumor humoral immune responses against mesothelioma cell lines were seen in seven of the eight subjects evaluated. No clinical responses were seen in the four subjects with advanced disease. However, evidence of disease stability or tumor regression was seen in the remaining five patients, including one dramatic example of partial tumor regression at sites not in contiguity with vector infusion. These data show that Ad.IFN-α2b has potential therapeutic benefit in MPM and that it generates anti-tumor immune responses that may induce anatomic and/or metabolic reductions in distant tumor.
Clinical trial registered with www.clinicaltrials.gov (NCT 01212367).
doi:10.1164/rccm.201103-0554CR
PMCID: PMC3262033  PMID: 21642245
clinical trials; immunotherapy; gene therapy
6.  Anthrax Infection 
Bacillus anthracis infection is rare in developed countries. However, recent outbreaks in the United States and Europe and the potential use of the bacteria for bioterrorism have focused interest on it. Furthermore, although anthrax was known to typically occur as one of three syndromes related to entry site of (i.e., cutaneous, gastrointestinal, or inhalational), a fourth syndrome including severe soft tissue infection in injectional drug users is emerging. Although shock has been described with cutaneous anthrax, it appears much more common with gastrointestinal, inhalational (5 of 11 patients in the 2001 outbreak in the United States), and injectional anthrax. Based in part on case series, the estimated mortalities of cutaneous, gastrointestinal, inhalational, and injectional anthrax are 1%, 25 to 60%, 46%, and 33%, respectively. Nonspecific early symptomatology makes initial identification of anthrax cases difficult. Clues to anthrax infection include history of exposure to herbivore animal products, heroin use, or clustering of patients with similar respiratory symptoms concerning for a bioterrorist event. Once anthrax is suspected, the diagnosis can usually be made with Gram stain and culture from blood or surgical specimens followed by confirmatory testing (e.g., PCR or immunohistochemistry). Although antibiotic therapy (largely quinolone-based) is the mainstay of anthrax treatment, the use of adjunctive therapies such as anthrax toxin antagonists is a consideration.
doi:10.1164/rccm.201102-0209CI
PMCID: PMC3361358  PMID: 21852539
Bacillus anthracis; diagnosis; pathogenesis; treatment
7.  The Hispanic Paradox Unraveled? 
doi:10.1164/rccm.201109-1684ED
PMCID: PMC3262040  PMID: 22162880
8.  New Mexican Hispanic Smokers Have Lower Odds of Chronic Obstructive Pulmonary Disease and Less Decline in Lung Function Than Non-Hispanic Whites 
Rationale: The epidemiology of cigarette smoking–related chronic obstructive pulmonary disease (COPD) is not well characterized in Hispanics in the United States. Understanding how ethnicity influences COPD is important for a number of reasons, from informing public health policies to dissecting the genetic and environmental effects that contribute to disease.
Objectives: The present study assessed differences in risk between Hispanics and non-Hispanic whites for longitudinal and cross-sectional COPD phenotypes. Genetic ancestry was used to verify findings based on self-reported ethnicity. Hispanics in New Mexico are primarily differentiated from non-Hispanic whites by their proportion of Native American ancestry.
Methods: The study was performed in a New Mexican cohort of current and former smokers. Self-reported Hispanic and non-Hispanic white ethnicity was validated by defining genetic ancestry proportions at the individual level using 48 single-nucleotide polymorphism markers. Self-reported ethnicity and genetic ancestry were independently used to assess associations with cross-sectional and longitudinal measures of lung function. Multivariable models were adjusted for indicators of smoking behavior.
Measurements and Main Results: Self-reported Hispanic ethnicity was significantly associated with lower odds of COPD (odds ratio, 0.49; 95% confidence interval, 0.35–0.71; P = 0.007), and this protection was validated by the observation that Hispanic smokers have reduced risk of rapid decline in lung function (odds ratio, 0.48; 95% confidence interval, 0.30–0.78; P = 0.003). Similar findings were noted when Native American genetic ancestry proportions were used as predictors instead of self-report of Hispanic ethnicity.
Conclusions: Hispanic ethnicity is inversely associated with cross-sectional and longitudinal spirometric COPD phenotypes even after adjustment for smoking. Native American genetic ancestry may account for this “Hispanic protection.”
doi:10.1164/rccm.201103-0568OC
PMCID: PMC3262041  PMID: 21908412
9.  The Societal Impact of Single Versus Bilateral Lung Transplantation for Chronic Obstructive Pulmonary Disease 
Rationale: Bilateral lung transplantation (BLT) improves survival compared with single lung transplantation (SLT) for some individuals with chronic obstructive pulmonary disease (COPD). However, it is unclear which strategy optimally uses this scarce societal resource.
Objectives: To compare the effect of SLT versus BLT strategies for COPD on waitlist outcomes among the broader population of patients listed for lung transplantation.
Methods: We developed a Markov model to simulate the transplant waitlist using transplant registry data to define waitlist size, donor frequency, the risk of death awaiting transplant, and disease- and procedure-specific post-transplant survival. We then applied this model to 1,000 simulated patients and compared the number of patients under each strategy who received a transplant, the number who died before transplantation, and total post-transplant survival.
Measurements and Main Results: Under baseline assumptions, the SLT strategy resulted in more patients transplanted (809 vs. 758) and fewer waitlist deaths (157 vs. 199). The strategies produced similar total post-transplant survival (SLT = 4,586 yr vs. BLT = 4,577 yr). In sensitivity analyses, SLT always maximized the number of patients transplanted. The strategy that maximized post-transplant survival depended on the relative survival benefit of BLT versus SLT among patients with COPD, donor interval, and waitlist size.
Conclusions: In most circumstances, a policy of SLT for COPD improves access to organs for other potential recipients without significant reductions in total post-transplant survival. However, there may be substantial geographic variations in the effect of such a policy on the balance between these outcomes.
doi:10.1164/rccm.201104-0695OC
PMCID: PMC3262042  PMID: 21868502
lung transplantation; resource allocation; chronic obstructive pulmonary disease; bioethics
10.  Autophagy 
Autophagy is a highly conserved homeostatic pathway by which cells transport damaged proteins and organelles to lysosomes for degradation. Dysregulation of autophagy contributes to the pathogenesis of clinically important disorders in a variety of organ systems but, until recently, little was known about its relationship to diseases of the lung. However, there is now growing evidence at the basic research level that autophagy is linked to the pathogenesis of important pulmonary disorders such as chronic obstructive pulmonary disease, cystic fibrosis, and tuberculosis. In this review, we provide an introduction to the field of autophagy research geared to clinical and research pulmonologists. We focus on the best-studied autophagic mechanism, macroautophagy, and summarize studies that link the regulation of this pathway to pulmonary disease. Last, we offer our perspective on how a better understanding of macroautophagy might be used for designing novel therapies for pulmonary disorders.
doi:10.1164/rccm.201106-0966CI
PMCID: PMC3262043  PMID: 21836133
autophagy; macroautophagy; lung; disease; chronic obstructive pulmonary disease
11.  Con: The Case for Expanded Lung Cancer Research Support 
doi:10.1164/rccm.201104-0697ED
PMCID: PMC3262044  PMID: 22162887
12.  Sleep Fragmentation Induces Cognitive Deficits Via Nicotinamide Adenine Dinucleotide Phosphate Oxidase–dependent Pathways in Mouse 
Rationale: Sleep fragmentation (SF) is one of the major characteristics of sleep apnea, and has been implicated in its morbid consequences, which encompass excessive daytime sleepiness and neurocognitive impairments. We hypothesized that absence of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activity is neuroprotective in SF-induced cognitive impairments.
Objectives: To examine whether increased NADPH oxidase activity may play a role in SF-induced central nervous system dysfunction.
Methods: The effect of chronic SF during the sleep-predominant period on sleep architecture, sleep latency, spatial memory, and oxidative stress parameters was assessed in mice lacking NADPH oxidase activity (gp91phox-/Y) and wild-type littermates.
Measurements and Main Results: SF for 15 days was not associated with differences in sleep duration, sleep state distribution, or sleep latency in both gp91phox-/Y and control mice. However, on a standard place training task, gp91phox-/Y mice displayed normal learning and were protected from the spatial learning deficits observed in wild-type littermates exposed to SF. Moreover, anxiety levels were increased in wild-type mice exposed to SF, whereas no changes emerged in gp91phox-/Y mice. Additionally, wild-type mice, but not gp91phox-/Y mice, had significantly elevated NADPH oxidase gene expression and activity, and in malondialdehyde and 8-oxo-2′-deoxyguanosine levels in cortical and hippocampal lysates after SF exposures.
Conclusions: This work substantiates an important role for NADPH oxidase in hippocampal memory impairments induced by SF, modeling sleep apnea. Targeting NADPH oxidase, therefore, is expected to minimize hippocampal impairments from both intermittent hypoxia and SF associated with the disease.
doi:10.1164/rccm.201107-1173OC
PMCID: PMC3262045  PMID: 21868506
NADPH oxidase; sleep fragmentation; neurocognitive impairments
13.  Impact of Race on Asthma Treatment Failures in the Asthma Clinical Research Network 
Rationale: Recent studies suggest that people with asthma of different racial backgrounds may respond differently to various therapies.
Objectives: To use data from well-characterized participants in prior Asthma Clinical Research Network (ACRN) trials to determine whether racial differences affected asthma treatment failures.
Methods: We analyzed baseline phenotypes and treatment failure rates (worsening asthma resulting in systemic corticosteroid use, hospitalization, emergency department visit, prolonged decrease in peak expiratory flow, increase in albuterol use, or safety concerns) in subjects participating in 10 ACRN trials (1993–2003). Self-declared race was reported in each trial and treatment failure rates were stratified by race.
Measurements and Main Results: A total of 1,200 unique subjects (whites = 795 [66%]; African Americans = 233 [19%]; others = 172 [14%]; mean age = 32) were included in the analyses. At baseline, African Americans had fewer asthma symptoms (P < 0.001) and less average daily rescue inhaler use (P = 0.007) than whites. There were no differences in baseline FEV1 (% predicted); asthma quality of life; bronchial hyperreactivity; or exhaled nitric oxide concentrations. A total of 147 treatment failures were observed; a significantly higher proportion of African Americans (19.7%; n = 46) experienced a treatment failure compared with whites (12.7%; n = 101) (odds ratio = 1.7; 95% confidence interval, 1.2–2.5; P = 0.007). When stratified by treatment, African Americans receiving long-acting β-agonists were twice as likely as whites to experience a treatment failure (odds ratio = 2.1; 95% confidence interval, 1.3–3.6; P = 0.004), even when used with other controller therapies.
Conclusions: Despite having fewer asthma symptoms and less rescue β-agonist use, African-Americans with asthma have more treatment failures compared with whites, especially when taking long-acting β-agonists.
doi:10.1164/rccm.201103-0514OC
PMCID: PMC3361331  PMID: 21885625
asthma; long-acting β-agonist; African Americans; race; treatment failure
15.  Termination of Respiratory Events with and without Cortical Arousal in Obstructive Sleep Apnea 
Rationale: A total of 20–30% of respiratory events in obstructive sleep apnea are terminated without clear arousal. Arousals are thought to predispose to further events by promoting hyperventilation, hypocapnia, and upper-airway dilator muscle hypotonia. Therefore, events terminated without arousal may promote stable breathing.
Objectives: To compare physiologic changes at respiratory event termination with American Sleep Disorders Association (ASDA) Arousal to No Arousal, and determine whether secondary respiratory events are less common and have higher dilator muscle activity after No Arousal compared with ASDA Arousal.
Methods: Patients with obstructive sleep apnea wore sleep staging, genioglossus (EMGGG), and tensor palatini (EMGTP) electrodes plus a nasal mask and pneumotachograph. During stable sleep, continuous positive airway pressure (CPAP) was lowered for 3-minute periods to induce respiratory events. Physiologic variables were compared between events terminated with (1) ASDA Arousal, (2) No Arousal, or (3) sudden CPAP increase (CPAPinc, control).
Measurements and Main Results: Sixteen subjects had adequate data. EMGGG, EMGTP, and heart rate increased after ASDA Arousal (340 ± 57%, 215 ± 28%, and 110.7 ± 2.3%) and No Arousal (185 ± 32%, 167 ± 15%, and 108.5 ± 1.6%) but not CPAPinc (90 ± 10%, 94 ± 11%, and 102.1 ± 1%). Ventilation increased more after ASDA Arousal than No Arousal and CPAPinc, but not after accounting for the severity of respiratory event. Fewer No Arousals were followed by secondary events than ASDA Arousals. However, low dilator muscle activity did not occur after ASDA Arousal or No Arousal (EMGGG rose from 75 ± 5 to 125 ± 7%) and secondary events were less severe than initial events (ventilation rose 4 ± 0.4 to 5.5 ± 0.51 L/min).
Conclusions: Respiratory events that were terminated with ASDA Arousal were more severely flow-limited, had enhanced hyperventilation after event termination, and were more often followed by secondary events than No arousal. However, secondary events were not associated with low dilator muscle activity and airflow was improved after both No Arousal and ASDA Arousal.
doi:10.1164/rccm.201106-0975OC
PMCID: PMC3262022  PMID: 21836132
pharyngeal muscle activity; upper airway obstruction; genioglossus; tensor palatini; obstructive respiratory event
16.  Risk Factors for Chronic Kidney Disease in Adults with Cystic Fibrosis 
Rationale: Adults with cystic fibrosis (CF) possess multiple potential risk factors for chronic kidney disease, including CF-related diabetes (CFRD) and lifetime nephrotoxic drug exposure.
Objectives: To determine whether cumulative intravenous (IV) aminoglycoside exposure and CFRD increase the risk of chronic kidney disease in adults with CF.
Methods: This was a cohort study using adults (≥ 18 yr) in the CF Foundation registry from 2001–2008. Chronic kidney disease (stage 3 or greater) was defined by an estimated glomerular filtration rate of less than 60 ml/min/1.73 m2. Time-dependent multivariable Cox proportional hazards models were used to determine whether cumulative number of acute pulmonary exacerbations (surrogate for IV aminoglycoside exposure) and CFRD requiring insulin increase the risk of chronic kidney disease, adjusting for confounders.
Measurements and Main Results: The study cohort included 11,912 adults with a median follow-up of 4 years. During the study period, 204 subjects had chronic kidney disease, with an annual disease prevalence of 2.3%. Disease prevalence doubled with every 10-year increase in age. CFRD requiring insulin therapy substantially increased the risk of chronic kidney disease (1–4 yr of CFRD requiring insulin vs. no CFRD, hazard ratio [HR] = 2.40, 95% confidence interval [CI] 1.74–3.32; ≥ 5 yr, HR = 4.56, 95% CI 2.84–7.31). Pulmonary exacerbations did not significantly increase the risk of chronic kidney disease (one to five exacerbations vs. none, HR = 0.79, 95% CI 0.56–1.11; six to nine exacerbations, HR = 0.92, 95% CI 0.58–1.46; ≥ 10 exacerbations, HR = 1.16, 95% CI 0.75–1.81).
Conclusions: CF-related diabetes is a significant risk factor for chronic kidney disease in adults with CF, but additional studies examining IV aminoglycoside exposure directly are required.
doi:10.1164/rccm.201105-0932OC
PMCID: PMC3262023  PMID: 21799076
kidney; renal insufficiency; aminoglycosides; diabetes
17.  Sarcoidosis Blood Transcriptome Reflects Lung Inflammation and Overlaps with Tuberculosis 
Rationale: Sarcoidosis is a granulomatous disease of unknown etiology, although M. tuberculosis may play a role in the pathogenesis. The traditional view holds that inflammation in sarcoidosis is compartmentalized to involved organs.
Objectives: To determine whether whole blood gene expression signatures reflect inflammatory pathways in the lung in sarcoidosis and whether these signatures overlap with tuberculosis.
Methods: We analyzed transcriptomic data from blood and lung biopsies in sarcoidosis and compared these profiles with blood transcriptomic data from tuberculosis and other diseases.
Measurements and Main Results: Applying machine learning algorithms to blood gene expression data, we built a classifier that distinguished sarcoidosis from health in derivation and validation cohorts (92% sensitivity, 92% specificity). The most discriminative genes were confirmed by quantitative PCR and correlated with disease severity. Transcript profiles significantly induced in blood overlapped with those in lung biopsies and identified shared dominant inflammatory pathways (e.g., Type-I/II interferons). Sarcoidosis and tuberculosis shared more overlap in blood gene expression compared with other diseases using the 86-gene signature reported to be specific for tuberculosis and the sarcoidosis signature presented herein, although reapplication of machine learning algorithms could identify genes specific for sarcoidosis.
Conclusions: These data indicate that blood transcriptome analysis provides a noninvasive method for identifying inflammatory pathways in sarcoidosis, that these pathways may be leveraged to complement more invasive procedures for diagnosis or assessment of disease severity, and that sarcoidosis and tuberculosis share overlap in gene regulation of specific inflammatory pathways.
doi:10.1164/rccm.201106-1143OC
PMCID: PMC3262024  PMID: 21852540
gene expression profiling; interferons; algorithms; computational biology
18.  Tuberculosis Drug Development 
An unprecedented number of new tuberculosis (TB) medications are currently in development, and there will be great pressure to deploy these new drugs among all populations after their efficacy is demonstrated. People living with HIV experience a large burden of TB and have a particularly pressing need for TB treatments that are shorter and less toxic. In addition, all people living with HIV now require antiretroviral therapy during TB treatment. A roadmap of the research, programmatic, and regulatory considerations includes the following: (1) inclusion of people living with HIV early in clinical trials for treatment and prevention using new TB medications, (2) prioritization of key studies of HIV–TB drug interactions and interactions between new TB agents, and (3) optimization of clinical trial infrastructure, laboratory capacity, and drug susceptibility testing.
doi:10.1164/rccm.201106-0995PP
PMCID: PMC3361323  PMID: 21868507
tuberculosis; HIV/AIDS; drug development
19.  Intracranial Hemorrhage 
Intracranial hemorrhage is a life-threatening condition, the outcome of which can be improved by intensive care. Intracranial hemorrhage may be spontaneous, precipitated by an underlying vascular malformation, induced by trauma, or related to therapeutic anticoagulation. The goals of critical care are to assess the proximate cause, minimize the risks of hemorrhage expansion through blood pressure control and correction of coagulopathy, and obliterate vascular lesions with a high risk of acute rebleeding. Simple bedside scales and interpretation of computed tomography scans assess the severity of neurological injury. Myocardial stunning and pulmonary edema related to neurological injury should be anticipated, and can usually be managed. Fever (often not from infection) is common and can be effectively treated, although therapeutic cooling has not been shown to improve outcomes after intracranial hemorrhage. Most functional and cognitive recovery takes place weeks to months after discharge; expected levels of functional independence (no disability, disability but independence with a device, dependence) may guide conversations with patient representatives. Goals of care impact mortality, with do-not-resuscitate status increasing the predicted mortality for any level of severity of intraparenchymal hemorrhage. Future directions include refining the use of bedside neuromonitoring (electroencephalogram, invasive monitors), novel approaches to reduce intracranial hemorrhage expansion, minimizing vasospasm, and refining the assessment of quality of life to guide rehabilitation and therapy.
doi:10.1164/rccm.201103-0475CI
PMCID: PMC3361326  PMID: 22167847
intracranial hemorrhage; cerebral hemorrhage; subarachnoid hemorrhage; outcomes
20.  Role of Growth Arrest and DNA Damage–inducible α in Akt Phosphorylation and Ubiquitination after Mechanical Stress-induced Vascular Injury 
Rationale: The stress-induced growth arrest and DNA damage–inducible α (GADD45a) gene is up-regulated by mechanical stress with GADD45a knockout (GADD45a−/−) mice demonstrating both increased susceptibility to ventilator-induced lung injury (VILI) and reduced levels of the cell survival and vascular permeability signaling effector (Akt). However, the functional role of GADD45a in the pathogenesis of VILI is unknown.
Objectives: We sought to define the role of GADD45a in the regulation of Akt activation induced by mechanical stress.
Methods: VILI-challenged GADD45a−/− mice were administered a constitutively active Akt1 vector and injury was assessed by bronchoalveolar lavage cell counts and protein levels. Human pulmonary artery endothelial cells (EC) were exposed to 18% cyclic stretch (CS) under conditions of GADD45a silencing and used for immunoprecipitation, Western blotting or immunofluoresence. EC were also transfected with mutant ubiquitin vectors to characterize site-specific Akt ubiquitination. DNA methylation was measured using methyl-specific polymerase chain reaction assay.
Measurements and Main Results: Studies exploring the linkage of GADD45a with mechanical stress and Akt regulation revealed VILI-challenged GADD45a−/− mice to have significantly reduced lung injury on overexpression of Akt1 transgene. Increased mechanical stress with 18% CS in EC induced Akt phosphorylation via E3 ligase tumor necrosis factor receptor–associated factor 6 (TRAF6)–mediated Akt K63 ubiquitination resulting in Akt trafficking and activation at the membrane. GADD45a is essential to this process because GADD45a-silenced endothelial cells and GADD45a−/− mice exhibited increased Akt K48 ubiquitination leading to proteasomal degradation. These events involve loss of ubiquitin carboxyl terminal hydrolase 1 (UCHL1), a deubiquitinating enzyme that normally removes K48 polyubiquitin chains bound to Akt thus promoting Akt K63 ubiquitination. Loss of GADD45a significantly reduces UCHL1 expression via UCHL1 promoter methylation resulting in increased Akt K48 ubiquitination and reduced Akt levels.
Conclusions: These studies highlight a novel role for GADD45a in the regulation of site-specific Akt ubiquitination and activation and implicate a significant functional role for GADD45a in the clinical predisposition to VILI.
doi:10.1164/rccm.201103-0447OC
PMCID: PMC3763933  PMID: 21816939
GADD45a; AKT; UCHL1; ubiquitin; mechanical stress
21.  Relationship between Serum Vitamin D, Disease Severity, and Airway Remodeling in Children with Asthma 
Rationale
Little is known about vitamin D status and its effect on asthma pathophysiology in children with severe, therapy-resistant asthma (STRA).
Objectives
Relationships between serum vitamin D, lung function, and pathology were investigated in pediatric STRA.
Methods
Serum 25-hydroxyvitamin D [25(OH)D3] was measured in 86 children (mean age, 11.7 yr): 36 with STRA, 26 with moderate asthma (MA), and 24 without asthma (control subjects). Relationships between 25(OH)D3, the asthma control test (ACT), spirometry, corticosteroid use, and exacerbations were assessed. Twenty-two of 36 children with STRA underwent fiberoptic bronchoscopy, bronchoalveolar lavage, and endobronchial biopsy with assessment of airway inflammation and remodeling.
Measurements and Main Results
25(OH)D3 levels (median [IQR]) were significantly lower in STRA (28 [22–38] nmol/L) than in MA (42.5 [29–63] nmol/L) and control subjects (56.5 [45–67] nmol/L) (P < 0.001). There was a positive relationship between 25(OH)D3 levels and percent predicted FEV1 (r = 0.4, P < 0.001) and FVC (r = 0.3, P = 0.002) in all subjects. 25(OH)D3 levels were positively associated with ACT (r = 0.6, P < 0.001), and inversely associated with exacerbations (r=−0.6, P < 0.001) and inhaled steroid dose (r=−0.39, P = 0.001) in MA and and STRA. Airway smooth muscle (ASM) mass, but not epithelial shedding or reticular basement membrane thickness, was inversely related to 25(OH)D3 levels (r=−0.6, P = 0.008). There was a positive correlation between ASM mass and bronchodilator reversibility (r = 0.6, P = 0.009) and an inverse correlation between ASM mass and ACT (r = −0.7, P < 0.001).
Conclusions
Lower vitamin D levels in children with STRA were associated with increased ASM mass and worse asthma control and lung function. The link between vitamin D, airway structure, and function suggests vitamin D supplementation may be useful in pediatric STRA.
doi:10.1164/rccm.201107-1239OC
PMCID: PMC3471128  PMID: 21908411
vitamin D; asthma; remodeling; airway smooth muscle; pediatrics
22.  Parental Stress Increases the Detrimental Effect of Traffic Exposure on Children's Lung Function 
Rationale: Emerging evidence indicates that psychosocial stress enhances the effect of traffic exposure on the development of asthma.
Objectives: We hypothesized that psychosocial stress would also modify the effect of traffic exposure on lung function deficits.
Methods: We studied 1,399 participants in the Southern California Children's Health Study undergoing lung function testing (mean age, 11.2 yr). We used hierarchical mixed models to assess the joint effect of traffic-related air pollution and stress on lung function.
Measurements and Main Results: Psychosocial stress in each child's household was assessed based on parental response to the perceived stress scale (range, 0–16) at study entry. Exposures to nitric oxide, nitrogen dioxide, and total oxides of nitrogen (NOx), surrogates of the traffic-related pollution mixture, were estimated at schools and residences based on a land-use regression model. Among children from high-stress households (parental perceived stress scale >4) deficits in FEV1 of 4.5 (95% confidence interval, −6.5 to −2.4) and of 2.8% (−5.7 to 0.3) were associated with each 21.8 ppb increase in NOx at homes and schools, respectively. These pollutant effects were significantly larger in the high-stress compared with lower-stress households (interaction P value 0.007 and 0.05 for residential and school NOx, respectively). No significant NOx effects were observed in children from low-stress households. A similar pattern of association was observed for FVC. The observed associations for FEV1 and FVC remained after adjusting for sociodemographic factors and after restricting the analysis to children who do not have asthma.
Conclusions: A high-stress home environment is associated with increased susceptibility to lung function effects of air pollution both at home and at school.
doi:10.1164/rccm.201104-0720OC
PMCID: PMC3208647  PMID: 21700914
parental stress; traffic exposure; lung function; children
23.  Delayed Access and Survival in Idiopathic Pulmonary Fibrosis 
Rationale: Idiopathic pulmonary fibrosis is often initially misdiagnosed. Delays in accessing subspecialty care could lead to worse outcomes among those with idiopathic pulmonary fibrosis.
Objectives: To examine the association between delayed access to subspecialty care and survival time in idiopathic pulmonary fibrosis.
Methods: We performed a prospective cohort study of 129 adults who met American Thoracic Society criteria for idiopathic pulmonary fibrosis evaluated at a tertiary care center. Delay was defined as the time from the onset of dyspnea to the date of initial evaluation at a tertiary care center. We used competing risk survival methods to examine survival time and time to transplantation.
Measurements and Main Results: The mean age was 63 years and 76% were men. The median delay was 2.2 years (interquartile range 1.0–3.8 yr), and the median follow-up time was 1.1 years. Age and lung function at the time of evaluation did not vary by delay. A longer delay was associated with an increased risk of death independent of age, sex, forced vital capacity, third-party payer, and educational attainment (adjusted hazard ratio per doubling of delay was 1.3, 95% confidence interval 1.03 to 1.6). Longer delay was not associated with a lower likelihood of undergoing lung transplantation.
Conclusions: Delayed access to a tertiary care center is associated with a higher mortality rate in idiopathic pulmonary fibrosis independent of disease severity. Early referral to a specialty center should be considered for those with known or suspected interstitial lung disease.
doi:10.1164/rccm.201104-0668OC
PMCID: PMC3208648  PMID: 21719755
access to healthcare; healthcare disparities; idiopathic pulmonary fibrosis; interstitial lung disease; survival
24.  The Effect of Insurance Status on Mortality and Procedural Use in Critically Ill Patients 
Rationale: Lack of health insurance may be an independent risk factor for mortality and differential treatment in critical illness.
Objectives: To determine whether uninsured critically ill patients had differences in 30-day mortality and critical care service use compared with those with private insurance and to determine if outcome variability could be attributed to patient-level or hospital-level effects.
Methods: Retrospective cohort study using Pennsylvania hospital discharge data with detailed clinical risk adjustment, from fiscal years 2005 and 2006, consisting of 167 general acute care hospitals, with 138,720 critically ill adult patients 64 years of age or younger.
Measurements and Main Results: Measurements were 30-day mortality and receipt of five critical care procedures. Uninsured patients had an absolute 30-day mortality of 5.7%, compared with 4.6% for those with private insurance and 6.4% for those with Medicaid. Increased 30-day mortality among uninsured patients persisted after adjustment for patient characteristics (odds ratio [OR], 1.25 for uninsured vs. insured; 95% confidence interval [CI], 1.04–1.50) and hospital-level effects (OR, 1.26; 95% CI, 1.05–1.51). Compared with insured patients, uninsured patients had decreased risk-adjusted odds of receiving a central venous catheter (OR, 0.84; 95% CI, 0.72–0.97), acute hemodialysis (OR, 0.59; 95% CI, 0.39–0.91), and tracheostomy (OR, 0.43; 95% CI, 0.29–0.64).
Conclusions: Lack of health insurance is associated with increased 30-day mortality and decreased use of common procedures for the critically ill in Pennsylvania. Differences were not attributable to hospital-level effects, suggesting that the uninsured have a higher mortality and receive fewer procedures when compared with privately insured patients treated at the same hospitals.
doi:10.1164/rccm.201101-0089OC
PMCID: PMC3208649  PMID: 21700910
insurance; intensive care unit; critical care; mortality
25.  Chest Computed Tomography Scores of Severity Are Associated with Future Lung Disease Progression in Children with Cystic Fibrosis 
Rationale: Most children with cystic fibrosis (CF) experience a slow decline in spirometry, although some children continue to be at risk for more significant lung disease progression. Chest computed tomography (CT) scans have been shown to be more sensitive to changes in lung disease than spirometry and may provide a means for predicting future lung disease progression.
Objectives: We hypothesized that Brody chest CT scan scores obtained in 2000 in a prospectively monitored cohort of children with CF would be associated with the most recent measures of lung disease severity.
Methods: Brody chest CT scan scores were calculated for 81 children enrolled in the Wisconsin CF Neonatal Screening Project. Multivariable linear regression was used to determine associations between Brody scores and the most recent (age 21 yr or June 30, 2010, whichever was later) measures of CF lung disease.
Measurements and Main Results: The mean observation time after the chest CT scan was 7.5 years. Brody chest CT scan scores were significantly associated with the most recent measures of spirometry (P < 0.001) and Wisconsin and Brasfield chest radiograph scores (P < 0.001). The strength of this association was much stronger than spirometry obtained near the time of the chest CT scan (P < 0.01) but not chest radiograph scores.
Conclusions: Chest CT scan scores are associated with future lung disease severity, and quantitative chest imaging (chest CT scan and chest radiograph scores) is more strongly associated with future lung disease severity than measures of spirometry. These findings may help clinicians identify patients at risk of future lung disease progression.
doi:10.1164/rccm.201105-0816OC
PMCID: PMC3208650  PMID: 21737586
chest x-ray; pulmonary function tests; FEV1; quantitative chest radiography

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