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Showing papers in "American Journal of Respiratory and Critical Care Medicine in 2009"


Journal ArticleDOI
TL;DR: New definitions for asthma control, severity, and exacerbations are developed, based on current treatment principles and clinical and research relevance, to provide a basis for a multicomponent assessment of asthma by clinicians, researchers, and other relevant groups in the design, conduct, and evaluation of clinical trials, and in clinical practice.
Abstract: Background: The assessment of asthma control is pivotal to the evaluation of treatment response in individuals and in clinical trials. Previously, asthma control, severity, and exacerbations were defined and assessed in many different ways.Purpose: The Task Force was established to provide recommendations about standardization of outcomes relating to asthma control, severity, and exacerbations in clinical trials and clinical practice, for adults and children aged 6 years or older.Methods: A narrative literature review was conducted to evaluate the measurement properties and strengths/weaknesses of outcome measures relevant to asthma control and exacerbations. The review focused on diary variables, physiologic measurements, composite scores, biomarkers, quality of life questionnaires, and indirect measures.Results: The Task Force developed new definitions for asthma control, severity, and exacerbations, based on current treatment principles and clinical and research relevance. In view of current knowledge ...

1,642 citations


Journal ArticleDOI
TL;DR: Asthma can be divided into at least two distinct molecular phenotypes defined by degree of Th2 inflammation, and Th2 cytokines are likely to be a relevant therapeutic target in only a subset of patients with asthma.
Abstract: Rationale: T-helper type 2 (Th2) inflammation, mediated by IL-4, IL-5, and IL-13, is considered the central molecular mechanism underlying asthma, and Th2 cytokines are emerging therapeutic targets. However, clinical studies increasingly suggest that asthma is heterogeneous.Objectives: To determine whether this clinical heterogeneity reflects heterogeneity in underlying molecular mechanisms related to Th2 inflammation.Methods: Using microarray and polymerase chain reaction analyses of airway epithelial brushings from 42 patients with mild-to-moderate asthma and 28 healthy control subjects, we classified subjects with asthma based on high or low expression of IL-13–inducible genes. We then validated this classification and investigated its clinical implications through analyses of cytokine expression in bronchial biopsies, markers of inflammation and remodeling, responsiveness to inhaled corticosteroids, and reproducibility on repeat examination.Measurements and Main Results: Gene expression analyses ident...

1,566 citations


Journal ArticleDOI
TL;DR: Doppler echocardiography may frequently be inaccurate in estimating pulmonary artery pressure and cardiac output in patients being evaluated for PH, according to a prospective study on patients with various forms of PH.
Abstract: Rationale: Transthoracic Doppler echocardiography is recommended for screening for the presence of pulmonary hypertension (PH). However, some recent studies have suggested that Doppler echocardiographic pulmonary artery pressure estimates may frequently be inaccurate.Objectives: Evaluate the accuracy of Doppler echocardiography for estimating pulmonary artery pressure and cardiac output.Methods: We conducted a prospective study on patients with various forms of PH who underwent comprehensive Doppler echocardiography within 1 hour of a clinically indicated right-heart catheterization to compare noninvasive hemodynamic estimates with invasively measured values.Measurements and Main Results: A total of 65 patients completed the study protocol. Using Bland-Altman analytic methods, the bias for the echocardiographic estimates of the pulmonary artery systolic pressure was −0.6 mm Hg with 95% limits of agreement ranging from +38.8 to −40.0 mm Hg. Doppler echocardiography was inaccurate (defined as being greater ...

902 citations


Journal ArticleDOI
TL;DR: Mortality did not decrease between 1994 (when a consensus definition of ALI/ARDS was published) and 2006, and is lower in RCTs than observational studies.
Abstract: Rationale: It is commonly stated that mortality from acute respiratory distress syndrome (ARDS) and acute lung injury (ALI) is decreasing.Objectives: To systematically review the literature assessing ARDS mortality over time and to determine patient- and study-level factors independently associated with mortality.Methods: We searched multiple databases (MEDLINE, EMBASE, CINAHL, Cochrane CENTRAL) for prospective observational studies or randomized controlled trials (RCTs) published during the period 1984 to 2006 that enrolled 50 or more patients with ALI/ARDS and reported mortality. We pooled mortality estimates using random-effects meta-analysis and examined mortality trends before and after 1994 (when a consensus definition of ALI/ARDS was published) and factors associated with mortality using meta-regression models.Measurements and Main Results: Of 4,966 studies, 89 met inclusion criteria (53 observational, 36 RCTs). There was a total of 18,900 patients (mean age 51.6 years; 39% female). Overall pooled ...

716 citations


Journal ArticleDOI
TL;DR: Investigations should be undertaken to reduce the number of days of ICU delirium and to study the impact of this reduction on important health outcomes, including mortality and functional and cognitive status.
Abstract: Rationale: Delirium is a frequent occurrence in older intensive care unit (ICU) patients, but the importance of the duration of delirium in contributing to adverse long-term outcomes is unclear. Objectives: To examine the association of the number of days of ICU delirium with mortality in an older patient population. Methods: We performed a prospective cohort study in a 14-bed ICU in an urban acute care hospital. The patient population comprised 304 consecutive admissions 60 years of age and older. Measurements and Main Results: The main outcome was 1-year mortality after ICU admission. Patients were assessed daily for delirium with the Confusion Assessment Method for the ICU and a validated chart review method. The median duration of ICU delirium was 3 days (range, 1–46 d). During the follow-up period, 153 (50%) patients died. After adjusting for relevant covariates, including age, severity of illness, comorbid conditions, psychoactive medication use, and baseline cognitive and functional status, the number of days of ICU delirium was significantly associated with time to death within 1 year post-ICU admission (hazard ratio, 1.10; 95% confidence interval, 1.02–1.18). Conclusions: Number of days of ICU delirium was associated with higher 1-year mortality after adjustment for relevant covariates in an older ICU population. Investigations should be undertaken to reduce the number of days of ICU delirium and to study the impact of this reduction on important health outcomes, including mortality and functional and cognitive status.

643 citations


Journal ArticleDOI
TL;DR: Repetitive element DNA methylation varied in association with time-related variables, such as day of the week and season, and found decreased repeated-element methylation after exposure to traffic particles.
Abstract: Rationale: Exposure to particulate air pollution has been related to increased hospitalization and death, particularly from cardiovascular disease. Lower blood DNA methylation content is found in processes related to cardiovascular outcomes, such as oxidative stress, aging, and atherosclerosis.Objectives: We evaluated whether particulate pollution modifies DNA methylation in heavily methylated sequences with high representation throughout the human genome.Methods: We measured DNA methylation of long interspersed nucleotide element (LINE)-1 and Alu repetitive elements by quantitative polymerase chain reaction–pyrosequencing of 1,097 blood samples from 718 elderly participants in the Boston area Normative Aging Study. We used covariate-adjusted mixed models to account for within-subject correlation in repeated measures. We estimated the effects on DNA methylation of ambient particulate pollutants (black carbon, particulate matter with aerodynamic diameter ≤ 2.5 μm [PM2.5], or sulfate) in multiple time windo...

625 citations


Journal ArticleDOI
TL;DR: A committee is established to define the key questions related to pulmonary exacerbations, review the clinical evidence using an evidence-based methodology, and provide recommendations to clinicians that will be helpful to clinicians in the treatment of individuals with cystic fibrosis.
Abstract: The natural history of cystic fibrosis lung disease is one of chronic progression with intermittent episodes of acute worsening of symptoms frequently called acute pulmonary exacerbations These exacerbations typically warrant medical intervention. It is important that appropriate therapies are recommended on the basis of available evidence of efficacy and safety. The Cystic Fibrosis Foundation therefore established a committee to define the key questions related to pulmonary exacerbations, review the clinical evidence using an evidence-based methodology, and provide recommendations to clinicians. It is hoped that these guidelines will be helpful to clinicians in the treatment of individuals with cystic fibrosis.

617 citations


Journal ArticleDOI
TL;DR: Survival of patients with SSc-PAH in the modern treatment era is better than in historical series, and a significant proportion of patientswith mild functional impairment or exercise-induced pulmonary arterial hypertension have evidence of disease progression.
Abstract: Rationale: Pulmonary arterial hypertension in association with connective tissue disease (CTD-PAH) has historically had a poor prognosis, with a 1-year survival rate among patients with systemic sclerosis–associated pulmonary arterial hypertension (SSc-PAH) of 45%. However, more therapies have become available.Objectives: To investigate the survival and characteristics of all patients diagnosed with CTD-PAH in the U.K. pulmonary hypertension service.Methods: National registry of all incident cases of CTD-PAH diagnosed consecutively between January 2001 and June 2006.Measurements and Main Results: Patients with CTD-PAH (429; 73% SSc-PAH) were diagnosed by a catheter-based approach. One- and 3-year survival rates were 78 and 47% for patients with isolated SSc-PAH. Survival was worse for those with respiratory disease–associated SSc-PAH (3-yr survival, 28%; P = 0.005) whereas survival among patients with exercise-induced SSc-PAH was superior (3-yr survival, 86%; P = < 0.001). Age, sex, mixed venous oxygen sa...

592 citations


Journal ArticleDOI
TL;DR: The results suggest that vitamin D insufficiency is relatively frequent in an equatorial population of children with asthma and in these children, lower vitamin D levels are associated with increased markers of allergy and asthma severity.
Abstract: Rationale: Maternal vitamin D intake during pregnancy has been inversely associated with asthma symptoms in early childhood. However, no study has examined the relationship between measured vitamin D levels and markers of asthma severity in childhood.Objectives: To determine the relationship between measured vitamin D levels and both markers of asthma severity and allergy in childhood.Methods: We examined the relation between 25-hydroxyvitamin D levels (the major circulating form of vitamin D) and markers of allergy and asthma severity in a cross-sectional study of 616 Costa Rican children between the ages of 6 and 14 years. Linear, logistic, and negative binomial regressions were used for the univariate and multivariate analyses.Measurements and Main Results: Of the 616 children with asthma, 175 (28%) had insufficient levels of vitamin D (<30 ng/ml). In multivariate linear regression models, vitamin D levels were significantly and inversely associated with total IgE and eosinophil count. In multivariate ...

581 citations


Journal ArticleDOI
TL;DR: Differences in DNA methylation patterns occur in children exposed to tobacco smoke and that variation in detoxification genes may alter these associations are demonstrated to demonstrate life-long effects of in utero exposures may be mediated through alterations inDNA methylation.
Abstract: Rationale: Prenatal exposure to tobacco smoke increases the risk for diseases later in the child's life that may be mediated through alterations in DNA methylation.Objectives: To demonstrate that differences in DNA methylation patterns occur in children exposed to tobacco smoke and that variation in detoxification genes may alter these associations.Methods: Methylation of DNA repetitive elements, LINE1 and AluYb8, was measured using bisulfite conversion and pyrosequencing in buccal cells of 348 children participating in the Children's Health Study. Gene-specific CpG methylation differences associated with smoke exposure were screened in 272 participants in the Children's Health Study children using an Illumina GoldenGate panel. CpG loci that demonstrated a statistically significant difference in methylation were validated by pyrosequencing. Estimates were standardized across loci using a Z score to enable cross-comparison of results.Measurements and Main Results: DNA methylation patterns were associated w...

575 citations


Journal ArticleDOI
TL;DR: It is found that healthy never-smoker females achieve full lung growth earlier than males, and their rate of decline with age was slightly, but not significantly, lower, and there is a range of susceptibility to the effects of smoking.
Abstract: Rationale: Understanding normal lung development and aging in health and disease, both in men and in women, is essential to interpreting any therapeutic intervention.Objectives: We aimed to describe lung function changes in healthy never-smoking males and females, from adolescence to old age, and to determine the effects of smoking and those derived from quitting.Methods: Prospective cohort study within all participants of the Framingham Offspring cohort who had two or more valid spirometry measurements during follow-up (n = 4,391; age range at baseline 13 to 71 yr), with a median follow-up time of 23 years.Measurements and Main Results: To best fit the curves describing FEV1 changes with age to raw data, we used a generalized additive model with smooth terms and incorporating the subject-specific (longitudinal) random effects. We found that: (1) healthy never-smoker females achieve full lung growth earlier than males, and their rate of decline with age was slightly, but not significantly, lower; (2) smok...

Journal ArticleDOI
TL;DR: Biomarker-guided GM-CSF therapy in sepsis is safe and effective for restoring monocytic immunocompetence and may shorten the time of mechanical ventilation and hospital/intensive care unit stay.
Abstract: Rationale: Sustained sepsis-associated immunosuppression is associated with uncontrolled infection, multiple organ dysfunction, and death.Objectives: In the first controlled biomarker-guided immuno...

Journal ArticleDOI
TL;DR: Fibrocytes are an indicator for disease activity of IPF and might be useful as a clinical marker for disease progression and suggest prediction of early mortality in patients with IPF.
Abstract: Rationale: The clinical management of idiopathic pulmonary fibrosis (IPF) remains a major challenge due to lack of effective drug therapy or accurate indicators for disease progression. Fibrocytes are circulating mesenchymal cell progenitors that are involved in tissue repair and fibrosis.Objectives: To test the hypothesis that assay of these cells may provide a biomarker for activity and progression of IPF.Methods: Fibrocytes were defined as cells positive for CD45 and collagen-1 by flow cytometry and quantified in patients with stable IPF and during acute exacerbation of the disease. We investigated the clinical and prognostic value of fibrocyte counts by comparison with standard clinical parameters and survival. We used healthy age-matched volunteers and patients with acute respiratory distress syndrome as control subjects.Measurements and Main Results: Fibrocytes were significantly elevated in patients with stable IPF (n = 51), with a further increase during acute disease exacerbation (n = 7; P < 0.00...

Journal ArticleDOI
TL;DR: The data support the need for full evaluation in infancy and argue for new treatment strategies, especially those targeting neutrophilic inflammation, if the promise of NBS for CF is to be realized.
Abstract: Rationale: The promise of newborn screening (NBS) for cystic fibrosis (CF) has not been fully realized, and the extent of improvement in respiratory outcomes is unclear. We hypothesized that significant lung disease was present at diagnosis.Objectives: To determine the extent of lung disease in a geographically defined population of infants with CF diagnosed after detection by NBS.Methods: Fifty-seven infants (median age, 3.6 mo) with CF underwent bronchoalveolar lavage and chest computed tomography (CT) using a three-slice inspiratory and expiratory protocol.Measurements and Main Results: Despite the absence of respiratory symptoms in 48 (84.2%) of infants, a substantial proportion had lung disease with bacterial infection detected in 12 (21.1%), including Staphylococcus aureus (n = 4) and Pseudomonas aeruginosa (n = 3); neutrophilic inflammation (41. 4 × 103 cells/ml representing 18.7% of total cell count); proinflammatory cytokines, with 44 (77.2%) having detectable IL-8; and 17 (29.8%) having detectab...

Journal ArticleDOI
TL;DR: High temperatures have a specific impact on respiratory admissions, particularly in the elderly population, but the underlying mechanisms are poorly understood, as well as global warming and progressive population aging.
Abstract: RATIONALE: Episode analyses of heat waves have documented a comparatively higher impact on mortality than on morbidity (hospital admissions) in European cities. The evidence from daily time series studies is scarce and inconsistent. OBJECTIVES: To evaluate the impact of high environmental temperatures on hospital admissions during April to September in 12 European cities participating in the Assessment and Prevention of Acute Health Effects of Weather Conditions in Europe (PHEWE) project. METHODS: For each city, time series analysis was used to model the relationship between maximum apparent temperature (lag 0-3 days) and daily hospital admissions for cardiovascular, cerebrovascular, and respiratory causes by age (all ages, 65-74 age group, and 75+ age group), and the city-specific estimates were pooled for two geographical groupings of cities. MEASUREMENTS AND MAIN RESULTS: For respiratory admissions, there was a positive association that was heterogeneous between cities. For a 1 degrees C increase in maximum apparent temperature above a threshold, respiratory admissions increased by +4.5% (95% confidence interval, 1.9-7.3) and +3.1% (95% confidence interval, 0.8-5.5) in the 75+ age group in Mediterranean and North-Continental cities, respectively. In contrast, the association between temperature and cardiovascular and cerebrovascular admissions tended to be negative and did not reach statistical significance. CONCLUSIONS: High temperatures have a specific impact on respiratory admissions, particularly in the elderly population, but the underlying mechanisms are poorly understood. Why high temperature increases cardiovascular mortality but not cardiovascular admissions is also unclear. The impact of extreme heat events on respiratory admissions is expected to increase in European cities as a result of global warming and progressive population aging.

Journal ArticleDOI
TL;DR: A positive and statistically significant association was found between county-specific estimates of the short-term effects of PM(2.5) on cardiovascular and respiratory hospitalizations and county- specific levels of vanadium, elemental carbon, or nickel PM( 2.5), and communities with higher PM(1.7) content of nickel, vanadium and elemental carbon and/or their related sources were found to have higher risk of hospitalizations.
Abstract: Rationale: There are unexplained geographical and seasonal differences in the short-term effects of fine particulate matter (PM2.5) on human health. The hypothesis has been advanced to include the possibility that such differences might be due to variations in the PM2.5 chemical composition, but evidence supporting this hypothesis is lacking. Objectives: To examine whether variation in the relative risks (RR) of hospitalization associated with ambient exposure to PM2.5 total mass reflects differences in PM2.5 chemical composition. Methods: We linked two national datasets by county and by season: (1) long-term average concentrations of PM2.5 chemical components for 2000–2005 and (2) RRs of cardiovascular and respiratory hospitalizations for persons 65 years or older associated with a 10-μg/m3 increase in PM2.5 total mass on the same day for 106 U.S. counties for 1999 through 2005. Measurements and Main Results: We found a positive and statistically significant association between county-specific estimates of the short-term effects of PM2.5 on cardiovascular and respiratory hospitalizations and county-specific levels of vanadium, elemental carbon, or nickel PM2.5 content. Conclusions: Communities with higher PM2.5 content of nickel, vanadium, and elemental carbon and/or their related sources were found to have higher risk of hospitalizations associated with short-term exposure to PM2.5.

Journal ArticleDOI
TL;DR: BMSCs act in a paracrine manner via the release of immunomodulatory factors to ameliorate the parenchymal and vascular injury of BPD in vivo.
Abstract: Rationale: Neonatal chronic lung disease, known as bronchopulmonary dysplasia (BPD), remains a serious complication of prematurity despite advances in the treatment of extremely low birth weight infants. Objectives: Given the reported protective actions of bone marrow stromal cells (BMSCs; mesenchymal stem cells) in models of lung and cardiovascular injury, we tested their therapeutic potential in a murine model of BPD. Methods: Neonatal mice exposed to hyperoxia (75% O2) were injected intravenously on Day 4 with either BMSCs or BMSC-conditioned media (CM) and assessed on Day 14 for lung morphometry, vascular changes associated with pulmonary hypertension, and lung cytokine profile. Measurements and Main Results: Injection of BMSCs but not pulmonary artery smooth muscle cells (PASMCs) reduced alveolar loss and lung inflammation, and prevented pulmonary hypertension. Although more donor BMSCs engrafted in hyperoxic lungs compared with normoxic controls, the overall low numbers suggest protective mechanisms other than direct tissue repair. Injection of BMSC-CM had a more pronounced effect than BMSCs, preventing both vessel remodeling and alveolar injury. Treated animals had normal alveolar numbers at Day 14 of hyperoxia and a drastically reduced lung neutrophil and macrophage accumulation compared with PASMC–CM-treated controls. Macrophage stimulating factor 1 and osteopontin, both present at high levels in BMSC-CM, may be involved in this immunomodulation. Conclusions: BMSCs act in a paracrine manner via the release of immunomodulatory factors to ameliorate the parenchymal and vascular injury of BPD in vivo. Our study suggests that BMSCs and factor(s) they secrete offer new therapeutic approaches for lung diseases currently lacking effective treatment.

Journal ArticleDOI
TL;DR: Perceived conflicts in intensive care units were often considered severe and were significantly associated with job strain, and workload, inadequate communication, and end-of-life care emerged as important potential targets for improvement.
Abstract: RATIONALE: Many sources of conflict exist in intensive care units (ICUs). Few studies recorded the prevalence, characteristics, and risk factors for conflicts in ICUs. OBJECTIVES: To record the prevalence, characteristics, and risk factors for conflicts in ICUs. METHODS: One-day cross-sectional survey of ICU clinicians. Data on perceived conflicts in the week before the survey day were obtained from 7,498 ICU staff members (323 ICUs in 24 countries). MEASUREMENTS AND MAIN RESULTS: Conflicts were perceived by 5,268 (71.6%) respondents. Nurse-physician conflicts were the most common (32.6%), followed by conflicts among nurses (27.3%) and staff-relative conflicts (26.6%). The most common conflict-causing behaviors were personal animosity, mistrust, and communication gaps. During end-of-life care, the main sources of perceived conflict were lack of psychological support, absence of staff meetings, and problems with the decision-making process. Conflicts perceived as severe were reported by 3,974 (53%) respondents. Job strain was significantly associated with perceiving conflicts and with greater severity of perceived conflicts. Multivariate analysis identified 15 factors associated with perceived conflicts, of which 6 were potential targets for future intervention: staff working more than 40 h/wk, more than 15 ICU beds, caring for dying patients or providing pre- and postmortem care within the last week, symptom control not ensured jointly by physicians and nurses, and no routine unit-level meetings. CONCLUSIONS: Over 70% of ICU workers reported perceived conflicts, which were often considered severe and were significantly associated with job strain. Workload, inadequate communication, and end-of-life care emerged as important potential targets for improvement.

Journal ArticleDOI
TL;DR: Treatment with golimumab did not demonstrate a favorable risk-benefit profile in this study population of patients with severe persistent asthma, and an unfavorable risk- benefit profile led to early discontinuation of study-agent administration after the Week-24 database lock.
Abstract: Rationale The treatment effect of golimumab, a human monoclonal antibody against tumor necrosis factor (TNF)-alpha, in severe persistent asthma is unknown. Objectives To assess the safety and efficacy of golimumab in a large population of patients with uncontrolled, severe persistent asthma. Methods From 2004 to 2006, 309 patients with severe and uncontrolled asthma, despite high-dose inhaled corticosteroids and long-acting beta(2) agonists, were randomized 1:1:1:1 to monthly subcutaneous injections of placebo or golimumab (50, 100, or 200 mg) through Week 52. Coprimary endpoints were the change from baseline through Week 24 in prebronchodilator percent-predicted FEV(1) and the number of severe asthma exacerbations through Week 24. Measurements and main results No significant differences were observed for the change in percent-predicted FEV1 (least squares mean: placebo, 2.44 [95% confidence interval (CI) -0.574 to 5.461]; combined 100-mg and 200-mg, 2.91 [0.696-5.116]) or severe exacerbations (mean +/- SD: placebo, 0.5 +/- 1.07 vs. combined 100-mg and 200-mg 0.5 +/- 0.97) through week 24. Through Week 24, 2.6% of patients treated with placebo vs. 19.5% of those treated with golimumab discontinued the study agent, and 1.3% and 7.8% discontinued study participation, respectively. An unfavorable risk-benefit profile led to early discontinuation of study-agent administration after the Week-24 database lock. Through Week 76, 20.5% of patients treated with placebo and 30.3% of patients treated with golimumab experienced serious adverse events, with serious infections occurring more frequently in golimumab-treated patients. One death and all eight malignancies occurred in the active groups. Conclusions Overall, treatment with golimumab did not demonstrate a favorable risk-benefit profile in this study population of patients with severe persistent asthma. Clinical trial registered with www.clinicaltrials.gov (NCT00207740).

Journal ArticleDOI
TL;DR: Intratracheal delivery of BMSCs on Postnatal Day 4 improved survival and exercise tolerance while attenuating alveolar and lung vascular injury and pulmonary hypertension, and stem cell-based therapies may offer new therapeutic avenues for lung diseases that currently lack efficient treatments.
Abstract: Rationale: Bronchopulmonary dysplasia (BPD) and emphysema are characterized by arrested alveolar development or loss of alveoli; both are significant global health problems and currently lack effective therapy Bone marrow–derived mesenchymal stem cells (BMSCs) prevent adult lung injury, but their therapeutic potential in neonatal lung disease is unknownObjectives: We hypothesized that intratracheal delivery of BMSCs would prevent alveolar destruction in experimental BPDMethods: In vitro, BMSC differentiation and migration were assessed using co-culture assays and a modified Boyden chamber In vivo, the therapeutic potential of BMSCs was assessed in a chronic hyperoxia-induced model of BPD in newborn ratsMeasurements and Main Results: In vitro, BMSCs developed immunophenotypic and ultrastructural characteristics of type II alveolar epithelial cells (AEC2) (surfactant protein C expression and lamellar bodies) when co-cultured with lung tissue, but not with culture medium alone or liver Migration assays

Journal ArticleDOI
TL;DR: Objective surrogate and direct measures of adherence should be performed as part of a difficult asthma assessment and are important before prescibing expensive novel biological therapies.
Abstract: Rationale: With the advent of new and expensive therapies for severe refractory asthma, targeting the appropriate patients is important. An important issue is identifying nonadherence with current therapies. The extent of nonadherence in a population with difficult asthma has not been previously reported.Objectives: To examine the prevalence of nonadherence to corticosteroid medication in a population with difficult asthma referred to a Specialist Clinic and to examine the relationship of poor adherence to asthma outcome.Methods: General practitioner prescription refill records for the previous 6 months for inhaled combination therapy and short-acting β-agonists were compared with initial prescriptions and expressed as a percentage. Blood plasma prednisolone and cortisol assay levels were used to examine the utility of these measures in assessing adherence to oral prednisolone. Patient demographics, hospital admissions, lung function, oral prednisolone courses, and quality of life data were analyzed to in...

Journal ArticleDOI
TL;DR: VLCD combined with active lifestyle counseling resulting in marked weight reduction is a feasible and effective treatment for the majority of patients with mild OSA, and the achieved beneficial outcomes are maintained at 1-year follow-up.
Abstract: Rationale: Obesity is the most important risk factor for obstructive sleep apnea (OSA). However, although included in clinical guidelines, no randomized controlled studies have been performed on the effects of weight reduction on mild OSA.Objectives: The aim of this prospective, randomized controlled parallel-group 1-year follow-up study was to determine whether a very low calorie diet (VLCD) with supervised lifestyle counseling could be an effective treatment for adults with mild OSA.Methods: Seventy-two consecutive overweight patients (body mass index, 28–40) with mild OSA were recruited. The intervention group (n = 35) completed the VLCD program with supervised lifestyle modification, and the control group (n = 37) received routine lifestyle counseling. The apnea–hypopnea index (AHI) was the main objectively measured outcome variable. Change in symptoms and the 15D-Quality of Life tool were used as subjective measurements.Measurements and Main Results: The lifestyle intervention was found to effectivel...

Journal ArticleDOI
TL;DR: Allergic sensitization through the airway primes modest Th2 responses but strong Th17 responses that promote airway neutrophilia and acute AHR, which support a causal role for neutrophils in severe asthma.
Abstract: Rationale: In humans, immune responses to inhaled aeroallergens develop in the lung and draining lymph nodes. Many animal models of asthma bypass this route and instead use intraperitoneal injections of allergen using aluminum hydroxide as an adjuvant.Objectives: We investigated whether allergic sensitization through the airway elicits immune responses qualitatively different than those arising in the peritoneum.Methods: Mice were sensitized to allergen through the airway using low-dose LPS as an adjuvant, or through the peritoneum using aluminum hydroxide as an adjuvant. After a single allergen challenge, ELISA and flow cytometry were used to measure cytokines and leukocyte subsets. Invasive measurements of airway resistance were used to measure allergen-induced airway hyperreactivity (AHR).Measurements and Main Results: Sensitization through the peritoneum primed strong Th2 responses and eosinophilia, but not AHR, after a single allergen challenge. By contrast, allergic sensitization through the airway ...

Journal ArticleDOI
TL;DR: Vitamin D does not improve clinical outcome among patients with tuberculosis and the trial showed no overall effect on mortality in patients with TB; it is possible that the dose used was insufficient.
Abstract: Rationale: Vitamin D has been shown to be involved in the host immune response toward Mycobacterium tuberculosis. Objectives: To test whether vitamin D supplementation of patients with tuberculosis (TB) improved clinical outcome and reduced mortality. Methods: We conducted a randomized, double-blind, placebocontrolled trial in TB clinics at a demographic surveillance site in Guinea-Bissau. We included 365 adult patients with TB starting antituberculosis treatment; 281 completed the 12-month followup. The intervention was 100,000 IU of cholecalciferol or placebo at inclusion and again 5 and 8 months after the start of treatment. Measurements and Main Results: The primary outcome was reduction in a clinical severity score (TBscore) for all patients with pulmonary TB. The secondary outcome was 12-month mortality. No serious adverse effects were reported; mild hypercalcemia was rare and present in both arms. Reduction in TBscore and sputum smear conversion rates did not differ among patients treated with vitamin D or placebo. Overall mortality was 15% (54 of 365) at 1 year of follow-up and similar in both arms (30 of 187 for vitamin D treated and 24 of 178 for placebo; relative risk, 1.19 [0.58–1.95]). HIV infection was seen in 36% (131 of 359): 21% (76 of 359) HIV-1, 10% (36 of 359) HIV-2, and 5% (19 of 357) HIV-112. Conclusions: Vitamin D does not improve clinical outcome among patients with TB and the trial showed no overall effect on mortality in patients with TB; it is possible that the dose used was insufficient. Clinical trial registered with www.controlled-trials.com/isrctn

Journal ArticleDOI
TL;DR: In severe sepsis, early administration of broad-spectrum antibiotics in all patients and administration of drotrecogin alfa (activated) in the most severe patients reduce mortality.
Abstract: Rationale: Several Surviving Sepsis Campaign Guidelines recommendations are reevaluated.Objectives: To analyze the effectiveness of treatments recommended in the sepsis guidelines.Methods: In a prospective observational study, we studied all adult patients with severe sepsis from 77 intensive care units. We recorded compliance with four therapeutic goals (central venous pressure 8 mm Hg or greater for persistent hypotension despite fluid resuscitation and/or lactate greater than 36 mg/dl, central venous oxygen saturation 70% or greater for persistent hypotension despite fluid resuscitation and/or lactate greater than 36 mg/dl, blood glucose greater than or equal to the lower limit of normal but less than 150 mg/dl, and inspiratory plateau pressure less than 30 cm H2O for mechanically ventilated patients) and four treatments (early broad-spectrum antibiotics, fluid challenge in the event of hypotension and/or lactate greater than 36 mg/dl, low-dose steroids for septic shock, drotrecogin alfa [activated] fo...

Journal ArticleDOI
TL;DR: In patients with chronic obstructive pulmonary disease, budesonide/formoterol added to tiotropium versus tiotopium alone provides rapid and sustained improvements in lung function, health status, morning symptoms and activities, and reduces severe exacerbations.
Abstract: Rationale: Budesonide/formoterol and tiotropium are commonly used maintenance treatments for patients with chronic obstructive pulmonary disease. Combining these medications may provide additional benefits.Objectives: To assess the efficacy and tolerability of budesonide/formoterol added to tiotropium in patients eligible for inhaled corticosteroid/long-acting β2-agonist combination therapy.Methods: In this 12-week, randomized, double-blind, parallel-group, multicenter study, after a 2-week run-in, 660 subjects (75% male; mean age, 62 yr; FEV1, 1.1 L; 38% predicted normal), 40 years of age or older, received tiotropium (18 μg once daily) plus either budesonide/formoterol (320/9 μg) (n = 329) or placebo (n = 331) twice daily.Measurements and Main Results: Clinic predose (primary outcome) and postdose FEV1, predose and postdose forced vital capacity and inspiratory capacity, and health status were measured. Other outcomes included daily measurements taken at home (pre- and postdose morning FEV1 and peak exp...

Journal ArticleDOI
TL;DR: Severe asthma exacerbations are associated with a more rapid decline in lung function and treatment with low doses of inhaled corticosteroid is associated with an attenuation of the decline.
Abstract: Rationale: To evaluate the association between asthma exacerbations and the decline in lung function, as well as the potential effects of an inhaled corticosteroid, budesonide, on exacerbation-related decline in patients with asthma.Objectives: To determine whether severe asthma exacerbations are associated with a persistent decline in lung function.Methods: The START (inhaled steroid treatment as regular therapy in early asthma) study was a 3-year, randomized, double-blind study of 7,165 patients (5–66 yr) with persistent asthma for less than 2 years, to determine whether early intervention with low-dose inhaled budesonide prevents severe asthma-related events (exacerbations requiring hospitalization or emergency treatment) and decline in lung function.Measurements and Main Results: There were 315 patients who experienced at least one severe asthma exacerbation, of which 305 were analyzable, 190 in the placebo group and 115 in the budesonide group. In the placebo group, the change in post-bronchodilator ...

Journal ArticleDOI
TL;DR: Both EMT and bone marrow progenitors contribute to S100A4-positive fibroblasts in bleomycin-induced lung fibrosis, however, neither origin is a principal contributor to lung myofibroblast.
Abstract: Rationale: Lung fibroblasts are key mediators of fibrosis resulting in accumulation of excessive interstitial collagen and extracellular matrix, but their origins are not well defined.Objectives: We aimed to elucidate the contribution of lung epithelium–derived fibroblasts via epithelial–mesenchymal transition (EMT) in the intratracheal bleomycin model.Methods: Primary type II alveolar epithelial cells were cultured from Immortomice and exposed to transforming growth factor-β1 and epidermal growth factor. Cell fate reporter mice that permanently mark cells of lung epithelial lineage with β-galactosidase were developed to study EMT, and bone marrow chimeras expressing green fluorescent protein under the control of the fibroblast-associated S100A4 promoter were generated to examine bone marrow–derived fibroblasts. Mice were given intratracheal bleomycin (0.08 unit). Immunostaining was performed for S100A4, β-galactosidase, green fluorescent protein, and α-smooth muscle actin.Measurements and Main Results: I...

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TL;DR: A role for nonantigen-specific CD4(+)CD25(+)Foxp3(+) regulatory T cells in attenuating the allergic airway response following oral treatment with L. reuteri is found and may have therapeutic potential in controlling the Th2 bias observed in atopic individuals.
Abstract: Rationale: We have previously demonstrated that oral treatment with live Lactobacillus reuteri can attenuate major characteristics of the asthmatic response in a mouse model of allergic airway inflammation. However, the mechanisms underlying these effects remain to be determined.Objectives: We tested the hypothesis that regulatory T cells play a major role in mediating L. reuteri–induced attenuation of the allergic airway response.Methods: BALB/c mice were treated daily with L. reuteri by gavage. Flourescent-activated cell sorter analysis was used to determine CD4+CD25+Foxp3+T cell populations in spleens following treatment with L. reuteri or vehicle control. Cell proliferation assays were performed on immunomagnetic bead separated CD4+CD25+ and CD4+CD25− T cells. CD4+CD25+ T cells isolated from, ovalbumin naive, L. reuteri treated mice were transferred into ovalbumin-sensitized mice. Following antigen challenge the airway responsiveness, inflammatory cell influx and cytokine levels in bronchoalveolar lav...

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TL;DR: It is suggested that long-term CPAP treatment in moderate to severe OSA and ischemic stroke is associated with a reduction in excess risk of mortality.
Abstract: Rationale: Obstructive sleep apnea (OSA) is an independent risk factor for stroke, but little is known about the role of continuous positive airway pressure (CPAP) on mortality in patients with stroke.Objectives: To analyze the independent impact of long-term CPAP treatment on mortality in patients with ischemic stroke.Methods: Prospective observational study in 166 patients with ischemic stroke. Sleep study was performed in all of them and CPAP treatment was offered in the case of moderate to severe cases. Patients were followed-up for 5 years to analyze the risk of mortality.Measurements and Main Results: Of 223 patients consecutively admitted for stroke, a sleep study was performed on 166 of them (2 mo after the acute event). Thirty-one had an apnea–hypopnea index (AHI) of less than 10; 39 had an AHI between 10 and 19, and 96 had an AHI of 20 or greater. CPAP treatment was offered when AHI was 20 or greater. Patients were followed up in our outpatient clinic at 1, 3, and 6 months, and for every 6 month...