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We aimed to investigate whether changes in prefrontal cortex (PFC) oxyhemoglobin (O 2 Hb) and deoxyhemoglobin (HHb) associates with inspiratory muscle effort during inspiratory threshold loading (ITL) in healthy participants. Participants performed an incremental ITL. Breathing pattern, partial pressure of end-tidal CO 2 (P ET CO 2 ), mouth pressure and O 2 Hb and HHb over the right dorsolateral PFC, sternocleidomastoid (SCM), and diaphragm/intercostals (Dia/IC) were monitored. Fourteen healthy participants (8 men; 29 ± 5 years) completed testing. Dyspnea was higher post- than pre-ITL (5 ± 1 vs. 0 ± 1, respectively; P<0.05). PFC O 2 Hb increased (P < 0.001) and HHb decreased (P = 0.001) at low loads but remained stable with increasing ITL intensities. PFC total hemoglobin increased at task failure compared to rest. SCM HHb increased throughout increasing intensities. SCM and Dia/IC total hemoglobin increased in the at task failure compared to rest. P ET CO 2 did not change (P = 0.528). PFC is activated early during the ITL but does not show central fatigue at task failure despite greater dyspnea and an imbalance of SCM oxygen demand and delivery., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Objective: Pulmonary embolism is a severe source of mortality and morbidity in patients with severe and critical coronavirus disease 2019. It is not yet clear whether the tendency to thrombosis is increased in the mild-to-moderate course of COVID-19. Our research aims to show the clinical benefit of Q-SPECT/CT in diagnosing PD in outpatients treated with mild-to-moderate course of COVID-19 and to determine the frequency of perfusion defects in these patients having relatively lower risk., Methods: All patients who underwent Q-SPECT/CT with suspicion of embolism were examined retrospectively. Only patients with low clinical probability and mild-to-moderate course of COVID-19 for PE were included in the study. The patients were evaluated comparatively as those with and without perfusion defects. Patients were divided into laboratory suspicion, clinical suspicion, or clinical and laboratory suspicion., Results: In outpatients with mild-to-moderate COVID-19 with low clinical probability for PE, PD without CT abnormality was detected with a rate of 36.6% with Q-SPECT/CT performed for complaints of high D-dimer and/or dyspnea. None of the patients had PD at more proximal level than the segment level. PD with no concomitant CT abnormality was observed with a rate of 56.5% in patients with both clinical and laboratory suspicion. For D-dimer = 0.5 mg/dL cut-off sensitivity is 85%, for D-dimer = 1.5 mg/dL cut-off specificity 81%., Conclusion: Thrombosis tendency is also present in outpatients with mild-to-moderate COVID-19, and these patients should also be offered anticoagulant prophylaxis during the COVID-19 period., (© 2021. The Japanese Society of Nuclear Medicine.)

Objective: This study was performed to explore the association of the high-resolution computed tomography (HRCT) score with ventilator weaning and 28-day mortality of patients with acute respiratory distress syndrome (ARDS)., Method: In total, 197 patients treated for ARDS from October 2004 to December 2015 were retrospectively analyzed. Univariate analysis and multifactor regression analysis were used to determine the relationship of the HRCT score with ventilator weaning and 28-day mortality. Curve-fitting analysis and threshold analysis were further used to explore the association of the HRCT score with ventilator weaning and 28-day mortality., Results: The multifactor regression analysis showed that the HRCT score was significantly associated with a lower rate of ventilator weaning and a higher risk of 28-day mortality in patients with ARDS. HRCT scores of 257.0 and 243.2 were the thresholds for ventilator weaning and 28-day mortality, respectively. When the HRCT score was below the threshold, every 1-point increase in the HRCT score was associated with a 4.6% decrease in the ventilator weaning rate and a 4.6% increase in the 28-day mortality rate., Conclusion: The HRCT score was associated with ventilator weaning and 28-day mortality with a threshold of 257.0 and 243.2 points, respectively.

Background: Air travel is physically demanding and, because obesity is rising, physicians increasingly need to assess whether such patients can fly safely. Our aim was to compare the diagnostic accuracy of two routinely used exercise tests, 50-m walk test and 6-min walk test, and hypoxic challenge testing (HCT) in obese individuals. We further explored the diagnostic potential of perceived dyspnea as measured with the Borg scale because this is often recorded subsequent to walking tests., Methods: In this prospective study, we examined 21 obese participants (10 women, age 51 ± 15 [mean  ±  SD], BMI 36 ± 5  kg/m 2 ). The most prevalent comorbidity was COPD (n = 11). The reference standard for in-flight hypoxia, defined as oxygen saturation below 90%, was established in an altitude chamber. Diagnostic accuracy of each index test was estimated by area under the receiver operating characteristic curve (AUC)., Results: Of the 21 participants, 13 (9 with COPD) were identified with in-flight hypoxia. HCT was the only test separating the reference groups significantly with AUC 0.87 (95% CI,  0.62-0.96). Neither of the walking tests predicted noticeably above chance level: 50 m walk test had an AUC of 0.63 (0.36-0.84) and 6MWT had an AUC of 0.64 (0.35-0.86). We further observed good prognostic ability of subjective dyspnea assessment when recorded after 6MWT with an AUC of 0.80 (0.55-0.93)., Conclusions: In-flight hypoxia in obese individuals can be predicted by HCT but not by simple walking tests., (Copyright © 2019 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Background: During acute bronchial obstruction, despite a higher work of breathing, blood supply and oxygen availability may be reduced in intercostal muscles because of mechanical constraints. This hypothesis was assessed in healthy subjects breathing with and without expiratory load (ETL)., Methods: Eleven men (24 ± 2 years) breathed at rest for 5 min in unloaded condition and for 20 min through a 20-cmH 2 O ETL. Tissue saturation index (TSI) and changes (Δ) in concentration of total and oxy-haemoglobin ([tHb] and [O 2 Hb]) were measured in the seventh intercostal space by near-infrared spectroscopy., Results: [tHb] and [O 2 Hb] decreased with ETL (-5.16 μM and -3.54 μM; p < 0.05). TSI did not vary. Negative correlations were observed between Δ[O 2 Hb] and changes in expiratory flow rate (ΔVt/Te) and between ΔTSI and Δ V˙E (r = -0.78 and -0.74; p ≤ 0.01)., Conclusion: Despite decreases in Hb concentrations, saturation in oxygen was not reduced with ETL in intercostal muscles, suggesting a satisfactory ventilatory and/or hemodynamic arrangement., (Copyright © 2018 Elsevier B.V. All rights reserved.)

BACKGROUND In the present study we evaluated clinical and echocardiography findings of pregnant women with dyspnea. MATERIAL AND METHODS Pregnant women with and without dyspnea and admitted to the Gynecology and Obstetrics Clinic of a tertiary hospital between December 2017 and June 2018 were enrolled in this case-control study. All patients underwent echocardiography in the third trimester (≥27 weeks). Pregnant women who were older than 18 years, who had dyspnea, and who were in the third trimester of their pregnancy (≥27 weeks) were included in the study. RESULTS Left ventricle end-diastolic diameter (LVEDd) was 47.38±3.68 mm in the study group and 43,70±8,84 mm in the control group (P=0.041). On the other hand, left ventricle end-systolic diameter (LVESd) was determined to be 30.86±3.90 mm in the study group and 34,45±6,56 mm in the control group (P=0.013). Systolic pulmonary artery pressure (sPAP), calculated through tricuspid insufficiency and analyzed, was found to be 24.69±9.10 mmHg in the study group and 20.39±6.80 mmHg in the control group (p=0.038). CONCLUSIONS When echocardiography findings of pregnant women with dyspnea were analyzed, it was determined that their left ventricle end-diastolic diameter (LVEDd), left ventricle end-systolic diameter (LVESd), and systolic pulmonary artery pressure (sPAP), calculated through tricuspid insufficiency, were higher than those of women in the control group, although they were within normal limit range. Therefore, we recommend that women with dyspnea should see a cardiologist and undergo an echocardiogram test so that the cardiac causes of dyspnea can be clinically revealed.

Purpose: Patients with hematological malignancies often present with reduced muscle and physical functions, which are caused by the disease or related treatment. Moreover, patients with hematological malignancies rapidly develop low hemoglobin levels, and this may affect muscle and physical functions. This study aimed to identify the influence of hemoglobin levels on muscle and physical functions in patients with hematological malignancies., Methods: Using a cross-sectional study design, this study included 60 patients with hematological malignancies (mean age = 68.0 ± 10.2 years, women 56.7%) who were hospitalized for chemotherapy- and radiotherapy-related side effects and underwent examination for skeletal muscle mass (SMM), muscle strength, physical function, activities of daily living (ADLs), psychological status, and quality-of-life (QOL), including physical symptoms. Participants were divided into 3 groups according to tertiles of hemoglobin levels: low (n = 19), middle (n = 20), and high (n = 21). Evaluation items were compared among the 3 groups., Results: There was no significant difference among the 3 groups in terms of SMM. The low hemoglobin group showed significantly higher values of fatigue and dyspnea and lower values of muscle strength, ADLs, and QOL than the high hemoglobin group., Conclusions: Hemoglobin levels did not affect SMM; however, muscle weakness, decrease in physical function, physical symptoms such as fatigue and dyspnea, and decline in ADLs and QOL were observed in patients with low hemoglobin levels.

Background: Procalcitonin (PCT) concentrations increase during bacterial infections and could improve diagnosis of pneumonia and risk stratification in patients with acute dyspnea., Methods: PCT concentrations were measured <24 h of admission in 310 patients with acute dyspnea and compared to C-reactive protein (CRP) and white blood cells (WBC) in the total cohort and the subset of patients with concomitant acute heart failure (HF)., Results: We diagnosed pneumonia in 16 out of 140 patients with acute HF (11%) and in 45 out of 170 patients with non-HF-related dyspnea (27%). PCT concentrations were higher in patients with pneumonia vs. patients without pneumonia, both among acute HF patients (median 2.79 [Q1-3 0.18-5.80] vs. 0.10 [0.07-0.14] ng/mL, p < .001) and non-HF patients (0.22 [Q1-3 0.13-0.77] vs. 0.07 [0.05-0.10] ng/mL, p < .001). CRP and WBC were also higher in patients with pneumonia in both groups, but among acute HF patients, only PCT concentrations were associated with pneumonia in multivariate analysis. In patients with acute HF, receiver-operating statistics area under the curve (ROC-AUC) to diagnose pneumonia was 0.90 (95% CI 0.81-0.98) for PCT, 0.84 (0.73-0.94) for CRP, and 0.72 (0.57-0.87) for WBC. The corresponding ROC-AUCs among patients with non-HF-related dyspnea were 0.88 (0.82-0.93), 0.94 (0.90-0.98), and 0.79 (0.72-0.87), respectively. During a median follow-up of 823 days (Q1-3 471-998) 114 patients died, and PCT and CRP, but not WBC concentrations were associated with all-cause mortality., Conclusion: In acute HF patients, PCT concentrations were superior to CRP and WBC to diagnose concurrent pneumonia., (Copyright © 2018 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Background: Circulating fibroblast growth factor 23 (FGF23) concentrations have been linked to left ventricular remodeling and unfavorable cardiovascular outcomes, but whether FGF23 is associated with heart failure (HF) diagnosis and outcome in unselected patients with dyspnea is unknown. Accordingly, we assessed the diagnostic and prognostic properties of FGF23 in patients presenting to the emergency department with acute dyspnea., Methods and Results: FGF23 was measured in 314 patients admitted with acute dyspnea and the diagnostic and prognostic merit was compared to that of N-terminal pro-B-type natriuretic peptide (NT-proBNP). The diagnosis of acute HF was adjudicated by two independent physicians. Circulating FGF23 concentrations on hospital admission were higher in patients with acute HF vs. patients with non-HF related dyspnea: median 3.60 (IQR 1.24-8.77) vs. 1.00 (0.43-2.20) pmol/L; P<0.001. The receiver-operating statistics area under the curve for acute HF diagnosis was 0.750 (0.699-0.797) for FGF23 and 0.853 (0.809-0.890) for NT-proBNP. Adjusting for clinical risk indices and cardiac biomarkers in multivariate Cox regression analysis, admission FGF23 concentrations were associated with mortality in the total study population (hazard ratio [HR] per 1 SD in ln FGF23 1.74 [1.40-2.16]). FGF23 also reclassified patients into their correct risk strata on top of clinical variables significantly associated with outcomes in the total cohort (net reclassification index 0.386 [0.161-0.612]). In patients with acute HF, both admission FGF23 and NT-proBNP concentrations were associated with mortality., Conclusion: Circulating FGF23 concentrations provide incremental prognostic information to established risk indices in patients with acute dyspnea, but do not improve diagnostic accuracy over NT-proBNP measurements., (Copyright © 2017 The Canadian Society of Clinical Chemists. Published by Elsevier Inc. All rights reserved.)

Introduction: Acute dyspnea is a common chief complaint among patients who visit an emergency room and presents diagnostic challenges for clinicians in both identifying the etiology and determining the clinical severity. The study of biomarkers in the prognostication and risk stratification of these patients has been increasing, including the investigation of the prognostic value for mid-regional pro-adrenomedullin (MR-proADM). Areas covered: In this review, the authors cover what is known about MR-proADM testing in patients presenting with acute dyspnea and the supporting evidence of its prognostic value in common conditions in medical patients with acute dyspnea, including acute heart failure, community acquired pneumonia, acute exacerbation of chronic obstructive pulmonary disease, and acute pulmonary embolism. Expert commentary: Numerous studies have proposed MR-proADM as a more accurate, prognostic tool in the evaluation of acute dyspnea than other biomarkers and consensus risk scores such as Sequential Organ Failure Assessment (SOFA) and quick SOFA (qSOFA). The authors review recent prospective studies, systematic reviews, and meta-analyses that demonstrate its prognostic value and role in risk stratification, including its use in biomarker-based triage algorithms as part of the diagnostic evaluation of the acutely dyspneic patient.

Purpose: The use of nebulized opioids for the palliation of dyspnea in terminally ill patients is reviewed., Summary: More than 50% of patients with advanced diseases experience dyspnea during their final stages of life. Systemically administered opioids are recommended for the management of dyspnea in these patients, but adverse effects may limit their use. Nebulization offers an alternative route for administering opioids, providing relief of dyspnea while minimizing adverse events. An extensive literature search was conducted to identify publications evaluating nebulized opioids for the palliation of dyspnea in patients at end-of-life. Ten studies that evaluated nebulized morphine, fentanyl, hydromorphone, and morphine-6-glucuronide were reviewed; 1 of these studies evaluated 4 different opioids. Of these 10 studies, 2 had double-blind, placebo-controlled, randomized crossover designs; 1 was retrospective, and the remaining 7 were prospective studies. A total of 181 patients, all adults, were evaluated. Subjective improvement in dyspnea from baseline was observed in 9 of the 10 studies. Nebulized morphine 20 mg every 4 hours was the most common opioid studied. Other doses of nebulized opioids included fentanyl 25 and 100 μg and hydromorphone 5 mg. Nine studies reported subjective improvement of dyspnea from baseline after administering nebulized opioids. Six studies evaluated objective outcomes and showed decreased respiratory rate (morphine, fentanyl, and hydromorphone) and heart rate (hydromorphone) and increased oxygen saturation (fentanyl). Mild-to-moderate adverse effects such as claustrophobia due to nebulizer mask, drowsiness, cough, and bitter taste were described., Conclusion: Nebulized opioids may provide subjective relief of dyspnea in terminally ill patients with mild-to-moderate adverse effects., Competing Interests: DisclosuresThe authors have declared no potential conflicts of interest., (Copyright © 2017 by the American Society of Health-System Pharmacists, Inc. All rights reserved.)

Background: The aim of this study was to evaluate the efficiency of a simple prototype device for training respiratory muscles in lung function, respiratory muscle strength, walking capacity, quality of life (QOL), dyspnea, and oxidative stress in patients with COPD., Methods: Thirty COPD patients with moderate severity of the disease were randomized into three groups: control (n=10, 6 males and 4 females), standard training (n=10, 4 males and 6 females), and prototype device (n=10, 5 males and 5 females). Respiratory muscle strength (maximal inspiratory pressure [PImax] and maximal expiratory pressure [PEmax]), lung function (forced vital capacity [FVC], percentage of FVC, forced expiratory volume in 1 second [FEV 1 ], percentage of FEV 1 [FEV 1 %], and FEV 1 /FVC), 6-minute walking distance (6MWD), QOL, and oxidative stress markers (total antioxidant capacity [TAC]), glutathione (GSH), malondialdehyde (MDA), and nitric oxide (NO) were evaluated before and after 6 weeks of training. Moreover, dyspnea scores were assessed before; during week 2, 4, and 6 of training; and at rest after training., Results: All parameters between the groups had no statistical difference before training, and no statistical change in the control group after week 6. FVC, FEV 1 /FVC, PImax, PEmax, QOL, MDA, and NO showed significant changes after 6 weeks of training with either the standard or prototype device, compared to pre-training. FEV 1 , FEV 1 %, 6MWD, TAC, and GSH data did not change statistically. Furthermore, the results of significant changes in all parameters were not statistically different between training groups using the standard and prototype device. The peak dyspnea scores increased significantly in week 4 and 6 when applying the standard or prototype device, and then lowered significantly at rest after 6 weeks of training, compared to pre-training., Conclusion: This study proposes that a simple prototype device can be used clinically in COPD patients as a standard device to train respiratory muscles, improving lung function and QOL, as well as involving MDA and NO levels., Competing Interests: Disclosure The authors report no conflicts of interest in this work.

Activities of superoxide dismutase and catalase characterizing antioxidant status of the nervous tissue and its resistance to free radical oxidation were measured in the brainstem of rats with hydroxybutyrate-induced pathological periodic breathing. Hydroxybutyrate modified the pro- and antioxidant status in the brainstem respiratory center. It markedly inhibited catalase activity; in rats without the signs of periodic breathing, hydroxybutyrate up-regulated superoxide dismutase activity and to a lesser extent increased the resistance of the membrane structures in the medulla oblongata to induction of free radical oxidation. In rats with periodic breathing pattern, hydroxybutyrate induced more pronounced increase in the sensitivity of membrane structures in the medulla oblongata to induction of free radical oxidation.

Background: Compared with methacholine challenge, exhaled nitric oxide is less expensive, is performed as a simpler point-of-care maneuver, and may provide treatment guiding information., Objective: To determine whether exhaled nitric oxide levels can predict the outcome of methacholine challenge in patients without obvious baseline obstruction., Methods: This retrospective database and medical record review included adults presenting to a tertiary care center from November 1, 2009, through August 31, 2013, who underwent methacholine challenge and exhaled nitric oxide measurement within 2 weeks of each other. Database extraction identified age, sex, body mass index, baseline corticosteroid use, testing indication, forced expiratory volume in 1 second (FEV 1 ), and testing results. Individuals taking corticosteroid-containing medication or who had an FEV 1 less than the lower limit of normal at baseline were excluded., Results: A total of 1,322 individuals were identified, with 774 meeting the eligibility criteria. A total of 123 methacholine challenges (16%) had positive results. Fractional exhaled nitric oxide was statistically higher in those with positive methacholine challenge results (mean [SD], 41.9 [54.5] ppb vs 25.2 [19.7] ppb; P < .01). Receiver operating characteristic curve revealed an area under the curve of 0.572 (P < .01), suggesting a poor correlation between exhaled nitric oxide level and methacholine challenge outcome. Fractional exhaled nitric oxide of greater than 50 ppb has a sensitivity, specificity, positive predictive value, and negative predictive value of 12%, 89%, 17%, and 84%, respectively, for a positive methacholine challenge result., Conclusion: In this large, retrospective cohort of corticosteroid-naive pulmonary patients with normal FEV 1 on baseline spirometry, exhaled nitric oxide poorly predicts the outcome of a methacholine challenge., (Copyright © 2016 American College of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: Few studies have investigated the short-term respiratory effects of ambient air pollution in chronic obstructive pulmonary disease (COPD) patients in the context of high pollution levels in Asian cities., Methods: A panel of 23 stable COPD patients was repeatedly measured for biomarkers of airway inflammation including exhaled nitric oxide (FeNO) and exhaled hydrogen sulfide (FeH2S) (215 measurements) and recorded for daily respiratory symptoms (794person-days) in two study periods in Beijing, China in January-September 2014. Daily ambient air pollution data were obtained from nearby central air-monitoring stations. Mixed-effects models were used to estimate the associations between exposures and health measurements with adjustment for potential confounders including temperature and relative humidity., Results: Increasing levels of air pollutants were associated with significant increases in both FeNO and FeH2S. Interquartile range (IQR) increases in PM2.5 (76.5μg/m(3), 5-day), PM10 (75.0μg/m(3), 5-day) and SO2 (45.7μg/m(3), 6-day) were associated with maximum increases in FeNO of 13.6% (95% CI: 4.8%, 23.2%), 9.2% (95% CI: 2.1%, 16.8%) and 34.2% (95% CI: 17.3%, 53.4%), respectively; and the same IQR increases in PM2.5 (6-day), PM10 (6-day) and SO2 (7-day) were associated with maximum increases in FeH2S of 11.4% (95% CI: 4.6%, 18.6%), 7.8% (95% CI: 2.3%, 13.7%) and 18.1% (95% CI: 5.5%, 32.2%), respectively. Increasing levels of air pollutants were also associated with increased odds ratios of sore throat, cough, sputum, wheeze and dyspnea., Conclusions: FeH2S may serve as a novel biomarker to detect adverse respiratory effects of air pollution. Our results provide potential important public health implications that ambient air pollution may pose risk to respiratory health in the context of high pollution levels in densely-populated cities in the developing world., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Dyspnea and reduced exercise capacity, caused, in part, by respiratory muscle dysfunction, are common symptoms in patients with heart failure (HF). However, the etiology of diaphragmatic dysfunction has not been identified. To investigate the effects of HF on diaphragmatic function, models of HF were surgically induced in CD-1 mice by transverse aortic constriction (TAC) and acute myocardial infarction (AMI), respectively. Assessment of myocardial function, isolated diaphragmatic strip function, myofilament force-pCa relationship, and phosphorylation status of myofilament proteins was performed at either 2 or 18 wk postsurgery. Echocardiography and invasive hemodynamics revealed development of HF by 18 wk postsurgery in both models. In vitro diaphragmatic force production was preserved in all groups while morphometric analysis revealed diaphragmatic atrophy and fibrosis in 18 wk TAC and AMI groups. Isometric force-pCa measurements of myofilament preparations revealed reduced Ca(2+) sensitivity of force generation and force generation at half-maximum and maximum Ca(2+) activation in 18 wk TAC. The rate of force redevelopment (ktr) was reduced in all HF groups at high levels of Ca(2+) activation. Finally, there were significant changes in the myofilament phosphorylation status of the 18 wk TAC group. This includes a decrease in the phosphorylation of troponin T, desmin, myosin light chain (MLC) 1, and MLC 2 as well as a shift in myosin isoforms. These results indicate that there are multiple changes in diaphragmatic myofilament function, which are specific to the type and stage of HF and occur before overt impairment of in vitro force production., (Copyright © 2016 the American Physiological Society.)

Background: There are a variable number of obese subjects with self-reported diagnosis of asthma but without current or previous evidence of airflow limitation, bronchial reversibility, or airway hyperresponsiveness (misdiagnosed asthma). However, the mechanisms of asthma-like symptoms in obesity remain unclear., Objectives: We sought to evaluate the perception of dyspnea during bronchial challenge and exercise testing in obese patients with asthma and misdiagnosed asthma compared with obese control subjects to identify the mechanisms of asthma-like symptoms in obesity., Methods: In a cross-sectional study we included obese subjects with asthma (n = 25), misdiagnosed asthma (n = 23), and no asthma or respiratory symptoms (n = 27). Spirometry, lung volumes, exhaled nitric oxide levels, and systemic biomarker levels were measured. Dyspnea scores during adenosine bronchial challenge and incremental exercise testing were obtained., Results: During bronchial challenge, patients with asthma or misdiagnosed asthma reached a higher Borg-FEV1 slope than control subjects. Moreover, maximum dyspnea and the Borg-oxygen uptake (V'O2) slope were significantly greater during exercise in subjects with asthma or misdiagnosed asthma than in control subjects. The maximum dyspnea achieved during bronchial challenge correlated with IL-1β levels, whereas peak respiratory frequency, ventilatory equivalent for CO2, and IL-6 and IL-1β levels were independent predictors of the Borg-V'O2 slope during exercise (r(2) = 0.853, P < .001)., Conclusions: A false diagnosis of asthma (misdiagnosed asthma) in obese subjects is attributable to an increased perception of dyspnea, which, during exercise, is mainly associated with systemic inflammation and excessive ventilation for metabolic demands., (Copyright © 2015 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

In many diseases across a range of pathologies (e.g., cardiopulmonary, neuromuscular, and cancer), chronic dyspnea, particularly on exertion, is a major debilitating symptom often associated with clinical anxiety/depression. This study aims to explore the interaction between mood state and exertional dyspnea in a healthy population. Following familiarization, 20 healthy subjects (27-54 years old) performed six 5-min treadmill tests on three separate days. On each day subjects viewed randomly assigned images designed to induce positive, negative, or neutral mood states (International Affective Picture System). For each condition, at minute intervals, subjects rated dyspnea (sensory and affective domains) in the first test and mood (valence and arousal domains) in the second test. Oxygen uptake (V̇O2 , liters/min), carbon dioxide production (V̇CO2, liters/min), ventilation (V̇E, liters/min), respiratory frequency (f(R), beats/min), and heart rate (HR, bpm), were measured throughout the exercise. V̇O2, V̇CO2, V̇E, HR, and f(R) were not statistically significantly different among the three mood states (P > 0.05). Mood valence was significantly higher with parallel viewing of positive (last 2-min mean ± SE = 6.9 ± 0.2) compared with negative pictures (2.4 ± 0.2; P < 0.001). Both sensory and affective domains of dyspnea were significantly higher during negative (sensory: 5.6 ± 0.3; affective: 3.3 ± 0.5) compared with positive mood (sensory: 4.4 ± 0.4, P < 0.001; affective: 2.1 ± 0.4, P = 0.002). These findings suggest that positive mood alleviates both the sensory and affective domains of exertional dyspnea in healthy subjects. Thus the treatment of anxiety/depression in dyspenic populations could be a worthwhile therapeutic strategy in increasing symptom-limited exercise tolerance, thereby contributing to improved quality of life., (Copyright © 2016 the American Physiological Society.)

Background: Donor lymphocyte infusion (DLI) is used for treatment of hematologic malignancy relapse or mixed chimerism after allogeneic hematopoietic stem cell transplantation. Although graft-versus-host disease is well recognized as one of the adverse effects of DLI, there are limited reports on noninfectious pulmonary complications (NIPCs) after DLI., Case Report: A 55-year-old woman with acute myeloid leukemia received DLI for conversion from recipient predominant to complete donor chimerism on Day +193 after allogeneic HSCT. Eight weeks later, she complained of dyspnea with fever; chest computed tomography revealed diffuse, bilateral, ground glass opacity and reticular appearance. She was diagnosed as having NIPC based on serum and bronchoalveolar lavage fluid (BALF) findings. She was successfully treated with prednisolone (PSL) and completely recovered., Discussion: We analyzed the cell profile from the BALF and 27 cytokines and chemokines in the serum using the Bio-Plex platform. The cells consisted of recipient predominant macrophages and T cells. The serum cytokine and chemokine profile showed significant elevation of interleukin (IL)-1β, IL-6, IL-8, tumor necrosis factor-α, macrophage inflammatory protein (MIP)-1α, and MIP-1β, which declined with the improvement of symptoms after initiation of PSL treatment., Conclusion: Inflammatory effectors by recipient cells, rather than allogeneic responses by donor cells, played an important role in the pathogenesis of NIPCs after DLI in the present case., (© 2015 AABB.)

Dyspnea is a common symptom physiologically associated with strenuous exercise and pathologically reflecting well-known diseases and conditions that are predominantly pulmonary, cardiovascular, and weight-related in origin. Dyspnea improves with appropriate measures that enhance physical performance and treatment of the underlying diseases. Dyspnea is less commonly triggered by other causes such as the environment (e.g., ozone), drugs, and others, some of which do not seem to affect bronchopulmonary function as evidenced by normal results of comprehensive pulmonary function testing. In cardiovascular medicine, dyspnea has recently attracted attention because it has been reported that this symptom occurs more frequently with the administration of the new oral reversibly-binding platelet P2Y12 receptor inhibitors ticagrelor [1-6], cangrelor [7-10], and elinogrel [11]. This paper succinctly addresses the current understanding of the pathophysiology, clinical presentation, and diagnostics of dyspnea, associated either with bronchopulmonary function impairment, as triggered mainly by pulmonary and cardiovascular diseases, or without bronchopulmonary function impairment, as induced by endogenous or external compounds such as drugs in order to provide a context for understanding, recognizing and managing P2Y12 inhibitor-induced dyspnea., (Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.)

This study was designed to investigate the association of perceived dyspnoea intensity with cortical oxygenation and cortical activation during exercise in patients with chronic obstructive pulmonary disease (COPD) and exertional hypoxaemia.Low-intensity exercise was performed at a constant work rate by patients with COPD and exertional hypoxaemia (n=11) or no hypoxaemia (n=16), and in control participants (n=11). Cortical oxyhaemoglobin (oxy-Hb) and deoxyhaemoglobin (deoxy-Hb) concentrations were measured by multichannel near-infrared spectroscopy. Increased deoxy-Hb is assumed to reflect impaired oxygenation, whereas decreased deoxy-Hb signifies cortical activation.Exercise decreased cortical deoxy-Hb in control and nonhypoxaemic patients. Deoxy-Hb was increased in hypoxaemic patients and oxygen supplementation improved cortical oxygenation. Decreased deoxy-Hb in the pre-motor cortex (PMA) was significantly correlated with exertional dyspnoea in control participants and patients with COPD without hypoxaemia. In contrast, increased cortical deoxy-Hb concentration was correlated with dyspnoea in patients with COPD and hypoxaemia. With the administration of oxygen supplementation, exertional dyspnoea was correlated with decreased deoxy-Hb in the PMA of COPD patients with hypoxaemia.During exercise, cortical oxygenation was impaired in patients with COPD and hypoxaemia compared with control and nonhypoxaemic patients; this difference was ameliorated with oxygen supplementation. Exertional dyspnoea was related to activation of the pre-motor cortex in COPD patients., (Copyright ©ERS 2015.)

Background: Telomere syndromes have their most common manifestation in idiopathic pulmonary fibrosis and emphysema. The short telomere defect in these patients may manifest systemically as bone marrow failure and liver disease. We sought to understand the causes of dyspnea in telomerase and telomere gene mutation carriers who have no parenchymal lung disease., Methods: Clinical and pathologic data were reviewed as part of a Johns Hopkins-based natural history study of short telomere syndromes including dyskeratosis congenita., Results: Hepatopulmonary syndrome (HPS) was diagnosed in nine of 42 cases (21%). Their age at presentation was significantly younger than that of cases initially presenting with pulmonary fibrosis and emphysema (median, 25 years vs 55 years; P < .001). Cases had evidence of intra- and extrapulmonary arteriovascular malformations that caused shunt physiology. Nodular regenerative hyperplasia was the most frequent histopathologic abnormality, and it was seen in the absence of cirrhosis. Dyspnea and portal hypertension were progressive, and the median time to death or liver transplantation was 6 years (range, 4-10 years; n = 6). In cases that underwent liver transplantation, dyspnea and hypoxia improved, but pulmonary fibrosis subsequently developed., Conclusions: This report identifies HPS as a frequent cause of dyspnea in telomerase and telomere gene mutation carriers. While it usually precedes the development of parenchymal lung disease, HPS may also co-occur with pulmonary fibrosis and emphysema. Recognizing this genetic diagnosis is critical for management, especially in the lung and liver transplantation setting.

Few therapies exist for the relief of dyspnea in restrictive lung disorders. Accumulating evidence suggests that nebulized opioids selective for the mu-receptor subtype may relieve dyspnea by modulating intrapulmonary opioid receptor activity. Our respective primary and secondary objectives were to test the hypothesis that nebulized fentanyl (a mu-opioid receptor agonist) relieves dyspnea during exercise in the presence of abnormal restrictive ventilatory constraints and to identify the physiological mechanisms of this improvement. In a randomized, double-blind, placebo-controlled crossover study, we examined the effect of 250 μg nebulized fentanyl, chest wall strapping (CWS), and their interaction on detailed physiological and perceptual responses to constant work rate cycle exercise (85% of maximum incremental work rate) in 14 healthy, fit young men. By design, CWS decreased vital capacity by ∼20% and mimicked the negative consequences of a mild restrictive lung disorder on exercise endurance time and on dyspnea, breathing pattern, dynamic operating lung volumes, and diaphragmatic electromyographic and respiratory muscle function during exercise. Compared with placebo under both unrestricted control and CWS conditions, nebulized fentanyl had no effect on exercise endurance time, integrated physiological response to exercise, sensory intensity, unpleasantness ratings of exertional dyspnea. Our results do not support a role for intrapulmonary opioids in the neuromodulation of exertional dyspnea in health nor do they provide a physiological rationale for the use of nebulized fentanyl in the management of dyspnea due to mild restrictive lung disorders, specifically those arising from abnormalities of the chest wall and not affiliated with airway inflammation., (Copyright © 2015 the American Physiological Society.)

Background: Differentiating between cardiac and obstructive causes for dyspnoea is essential for proper management, but is difficult in the prehospital setting., Objective: To assess if prehospital levels of end-tidal carbon dioxide (ETCO2) differed in obstructive compared to cardiac causes of dyspnoea, and could suggest one diagnosis over the other., Methods: We conducted a retrospective cohort study among patients transported by emergency medical services during a 29-month period who were diagnosed with either obstructive pulmonary disease or congestive heart failure (CHF) by ICD-9 codes. Initial prehospital vital signs, including ETCO2, were recorded. Records were linked by manual archiving of emergency medical services and hospital data., Results: There were 106 patients with a diagnosis of obstructive or cardiac causes of dyspnoea that had prehospital ETCO2 levels measured during the study period. ETCO2 was significantly lower in patients diagnosed with CHF (31 mm Hg 95% CI 27 to 35) versus obstructive pulmonary disease (39 mm Hg 95% CI 35 to 42; p<0.001). Lower ETCO2 levels predicted CHF, with an area under the Receiver Operating Characteristics Curve of 0.70 (95% CI 0.60 to 0.81). Using ETCO2 <40 mm Hg as a cut-off, the sensitivity for predicting heart failure was 93% (95% CI 88% to 98%), the specificity was 43% (95% CI 33% to 52%), the positive predictive value was 38% (95% CI 29% to 48%), and the negative predictive value was 94% (95% CI 89% to 99%)., Conclusions: Lower levels of ETCO2 were associated with CHF, and may serve as an objective diagnostic adjunct to predict this cause of dyspnoea in the prehospital setting., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.)

Background: Little is known about the relationship between hemoglobin concentrations, functional status and health related quality of life (HRQL) in chronic obstructive pulmonary disease (COPD). Our aim was to investigate the prevalence of anemia and the association of hemoglobin with shortness of breath, exercise capacity, muscle strength and HRQL, in COPD patients., Methods: A total of 105 COPD patients (77 males, 71.6 ± 9.2 years) were studied. Patients were classified as anemic and non anemic using the WHO criteria. We used the Medical Research Council Dyspnoea scale (MRCs) to measure shortness of breath. Exercise capacity was assessed using the six minute walking distance (6MWD) and the peak of VO2 during the maximal cycle ergometer test (VO2max). We used the Quadriceps and Handgrip strength assessment to determine muscle strength. The Saint George Respiratory Questionnaire was used to investigate HRQL. The physiological/functional characteristics of the two groups were compared. Regression models adjusting for confounders examined the independent association of anemia and of hemoglobin levels with clinical and functional outcomes., Results: Anemic patients (12.3%) showed a significantly higher MRCs, a lower 6MWD, VO2max, and a worse quality of life. On the contrary, there was no difference in muscle strength between the two groups. In the regression models, hemoglobin was independently associated with reduced exercise capacity and HRQL., Conclusions: Anemia in COPD was a risk factor for poorer exercise capacity and quality of life, and these outcomes were linearly associated with hemoglobin. Our results should stimulate further research into exploring whether increasing hemoglobin has a beneficial effect on the outcomes in COPD.

Background: We have identified candidate protein and microRNA (miRNA) biomarkers for dyspnea by studying serum, lavage fluid, and urine from military personnel who reported serious respiratory symptoms after they were deployed to Iraq or Afghanistan., Methods: Forty-seven soldiers with the complaint of dyspnea who enrolled in the STudy of Active Duty Military Personnel for Environmental Dust Exposure (STAMPEDE) underwent comprehensive pulmonary evaluations at the San Antonio Military Medical Center. The evaluation included fiber-optic bronchoscopy with bronchoalveolar lavage. The clinical findings from the STAMPEDE subjects pointed to seven general underlying diagnoses or findings including airway hyperreactivity, asthma, low diffusivity of carbon monoxide, and abnormal cell counts. The largest category was undiagnosed. As an exploratory study, not a classification study, we profiled proteins or miRNAs in lavage fluid, serum, or urine in this group to look for any underlying molecular patterns that might lead to biomarkers. Proteins in lavage fluid and urine were identified by accurate mass tag (database-driven) proteomics methods while miRNAs were profiled by a hybridization assay applied to serum, urine, and lavage fluid., Results: Over seventy differentially expressed proteins were reliably identified both from lavage and from urine in forty-eight dyspnea subjects compared to fifteen controls with no known lung disorder. Six of these proteins were detected both in urine and lavage. One group of subjects was distinguished from controls by expressing a characteristic group of proteins. A related group of dyspnea subjects expressed a unique group of miRNAs that included one miRNA that was differentially overexpressed in all three fluids studied. The levels of several miRNAs also showed modest but direct associations with several standard clinical measures of lung health such as forced vital capacity or gas exchange efficiency., Conclusions: Candidate proteins and miRNAs associated with the general diagnosis of dyspnea have been identified in subjects with differing medical diagnoses. Since these markers can be measured in readily obtained clinical samples, further studies are possible that test the value of these findings in more formal classification or case-control studies in much larger cohorts of subjects with specific lung diseases such as asthma, emphysema, or some other well-defined lung disease.

Unlabelled: Near-infrared spectroscopy (NIRS) enables continuous non-invasive measurements of regional oxygen saturation (rSO2). The aim was to evaluate the dynamics of rSO2 of the brain, preductal and postductal tissues during postnatal transition in preterm infants with and without respiratory support (RS). This single-centre study was designed as an exploratory prospective observational study. Fifty one preterm infants (≥ 30 + 0 and < 37 + 0 weeks) delivered by caesarean section were included. RS using a T-Piece-Resuscitator and supplemental oxygen were given according to guidelines. NIRS measurements were carried out by using Invos Monitor (Covidien; USA) for the first 15 min of life. Three NIRS transducers were attached on the forehead (rSO2brain), the right forearm (rSO2arm) and the left lower leg (rSO2leg). Two groups were compared based on need for RS: normal transition (NT) and RS group., Results: In NT group rSO2brain increased over time and was significantly higher than rSO2arm, whereas in RS group rSO2brain and rSO2arm increased without significant differences. Courses of rSO2arm and rSO2leg increased over time and showed a converging pattern with initially lower values of rSO2leg in NT group and a diverging pattern with lower levels of rSO2leg in RS group. Overall, rSO2 levels were higher in NT compared to RS group., Conclusion: Our findings indicate that the decreased rSO2 levels in RS group compared to NT group are not only caused by lower arterial oxygen saturation levels, but also by a compromised perfusion even in infants with only mild respiratory distress.

Background: Congestive physical findings such as pulmonary rales and third heart sound (S3) are hallmarks of acute heart failure (AHF). However, their role in outcome prediction remains unclear. We sought to investigate the association between congestive physical findings upon admission, steady-state biomarkers at the time of discharge, and long-term outcomes in AHF patients., Methods: We analyzed the data of 133 consecutive AHF patients with an established diagnosis of ischemic or non-ischemic (dilated or hypertrophic) cardiomyopathy, admitted to a single-center university hospital between 2006 and 2010. The treating physician prospectively recorded major symptoms and congestive physical findings of AHF: paroxysmal nocturnal dyspnea, orthopnea, pulmonary rales, jugular venous distension (JVD), S3, and edema. The primary endpoint was defined as rehospitalization for HF., Results: Majority (63.9%) of the patients had non-ischemic etiology and, at the time of admission, S3 was seen in 69.9% of the patients, JVD in 54.1%, and pulmonary rales in 43.6%. The mean follow-up period was 726 ± 31 days. Patients with pulmonary rales (p < 0.001) and S3 (p  =  0.011) had worse readmission rates than those without these findings; the presence of these findings was also associated with elevated troponin T (TnT) levels at the time of discharge (odds ratio [OR] 2.8; p  =  0.02 and OR 2.6; p  =  0.05, respectively)., Conclusion: Pulmonary rales and S3 were associated with inferior readmission rates and elevated TnT levels on discharge. The worsening of the readmission rate owing to congestive physical findings may be a consequence of on-going myocardial injury.

Aims: Chronic heart failure (CHF) causes inspiratory (diaphragm) muscle weakness and fatigue that contributes to dyspnoea and limited physical capacity in patients. However, the mechanisms that lead to diaphragm dysfunction in CHF remain poorly understood. Cytokines and angiotensin II are elevated in CHF and stimulate the activity of the enzyme sphingomyelinase (SMase) and accumulation of its reaction product ceramide. In the diaphragm, SMase or ceramide exposure in vitro causes weakness and fatigue. Thus, elevated SMase activity and ceramide content have been proposed as mediators of diaphragm dysfunction in CHF. In the present study, we tested the hypotheses that diaphragm dysfunction was accompanied by increases in diaphragm SMase activity and ceramide content., Methods and Results: Myocardial infarction was used to induce CHF in rats. We measured diaphragm isometric force, SMase activity by high-performance liquid chromatography, and ceramide subspecies and total ceramide using mass spectrometry. Diaphragm force was depressed and fatigue accelerated by CHF. Diaphragm neutral SMase activity was increased by 20% in CHF, while acid SMase activity was unchanged. We also found that CHF increased the content of C18 -, C20 -, and C24 -ceramide subspecies and total ceramide. Downstream of ceramide degradation, diaphragm sphingosine was unchanged, and sphingosine-1-phosphate level was increased in CHF., Conclusion: Our major novel finding was that diaphragm dysfunction in CHF rats was accompanied by higher diaphragm neutral SMase activity, which is expected to cause the observed increase in diaphragm ceramide content., (© 2014 The Authors. European Journal of Heart Failure © 2014 European Society of Cardiology.)

A 50-year-old man presented with dyspnoea while sitting, standing and walking but resolved completely in supine position. On cardiorespiratory examinations, fine crackles were noted over bibasal area. Chest X-ray showed bilateral reticulonodular shadows, restrictive pattern on spirometry, elevated alveolar arterial O2 gradient on arterial blood gas. High-resolution CT of the thorax revealed pattern as 'confident' or 'certain' radiographic diagnosis of idiopathic pulmonary fibrosis (IPF). Bubble-contrast echocardiography in recumbent, sitting and upright positions revealed no intracardiac (right to left shunt) or intrapulmonary shunts. This case highlights the necessity of awareness of this syndrome in cases of interstitial lung diseases (ILDs) also. Although 188 cases have been described thus far of platypnoea-orthodeoxia syndrome (P-OS) of various aetiologies, to the best of our knowledge, it is the first ever case of P-OS in ILD/IPF. Both lung bases were predominantly affected in this patient, platypnoea and orthodeoxia were attributed to areas of low/zero ventilation/perfusion (V/Q) ratio (zone 1 phenomena) as no other obvious explanation was found.

Cardiovascular diseases (CVD) are the major cause of death worldwide. The identification of markers able to detect the early stages of such diseases and/or their progression is fundamental in order to adopt the best actions in order to reduce the worsening of clinical condition. Brain natriuretic peptide (BNP) and NT-proBNP are the best known markers of heart failure (HF), while troponins ameliorated the diagnosis of acute and chronic coronary artery diseases. Nevertheless, many limitations reduce their accuracy. Physicians have tried to develop further detectable molecules in order to improve the detection of the early moments of CVD and prevent their development. Soluble ST2 (suppression of tumorigenicity 2) is a blood protein confirmed to act as a decoy receptor for interleukin-33. It seems to be markedly induced in mechanically overloaded cardiac myocytes. Thus, HF onset or worsening of a previous chronic HF status, myocardial infarct able to induce scars that make the myocardium unable to stretch well, etc, are all conditions that could be detected by measuring blood levels of soluble ST2. The aim of this review is to explore the possible role of ST2 derived-protein as an early marker of cardiovascular diseases, above all in heart failure and ischemic heart diseases.

Experimentally induced pain can be attenuated by concomitant heterotopic nociceptive stimuli (counterirritation). Animal data indicate that this stems from supraspinal "diffuse noxious inhibitory controls" (DNICs) triggered by C and Aδ fibers. In humans, only noxious stimuli induce counterirritation. This points at C fibers, but the effects of pharmacologically stimulating C fibers have not been studied. Intravenous adenosine activates pulmonary C fibers and induces dyspnea. This study tests the hypothesis that putative activation of pulmonary C fibers by adenosine would trigger DNICs in humans and induce counterirritation. Twelve healthy volunteers were included (with valid results available in 9) and studied according to a double-blind, randomized, cross-over design (intravenous adenosine, 140 μg·kg(-1)·min(-1), during 5 min vs. placebo). We measured ventilatory variables and end-tidal CO2 tension, dyspnea intensity by visual analog scale, and the intensity of putative chest pain. The primary outcome was the amplitude of the RIII component of the nociceptive flexor reflex recorded by biceps femoris electromyogram in response to painful electrical sural nerve stimulation (RIII), taken as a substitute for pain perception. Placebo did not induce any significant effect. Adenosine induced dyspnea, hyperpnea, tachycardia, and significant RIII inhibition (24 ± 8% at the 4th min, P < 0.0001). The temporal dynamics of adenosine-induced dyspnea and RIII inhibition differed (immediate onset followed by a slow decrease for dyspnea, slower onset for RIII inhibition). Intravenous adenosine in normal humans induces counterirritation, fueling the notion that C-fiber stimulation trigger DNICs in humans. The temporal dissociation between adenosine-induced dyspnea and RIII inhibition suggests that C fibers other than pulmonary ones might be involved.

Ticagrelor, a recently approved platelet antagonist indicated for the reduction of thrombotic cardiovascular events in patients with acute coronary syndrome (ACS), has been reported to cause dyspnea in more than 13% of patients. Dyspnea is not a clinically relevant adverse event with other medications indicated for ACS. One suggested mechanism of ticagrelor-induced dyspnea involves an increase in systemic adenosine concentrations through adenosine deaminase inhibition. Dyspnea, a subjective finding resulting from physiologic and sensory mechanisms, may be a consequence of increased systemic adenosine concentrations, leading to amplified and prolonged receptor activity. Current literature suggests, however, that pulmonary status is not compromised, with no reduction of efficacy seen in patients with ticagrelor-induced dyspnea, thus allowing clinicians to continue therapy without reservation. Still, patients with a history of asthma and chronic obstructive pulmonary disease may be more susceptible to ticagrelor-induced dyspnea, potentially leading to nonadherence and exacerbations of morbidity. Therefore, it is paramount that health care providers continually monitor these patients with the aims of maintaining medication therapy adherence and providing relevant options if dyspnea becomes intolerable., (© 2013 Pharmacotherapy Publications, Inc.)

Background: Although studies in adults have shown a non-TH2 obese asthma phenotype, whether a similar phenotype exists in children is unclear., Objective: We hypothesized that asthmatic children with obesity, defined as a body mass index above the 95th percentile for age and sex, would have poorer asthma control as well as decreased quality of life, increased health care utilization, and decreased pulmonary function measures as a function of increased TH1 versus TH2 polarization., Methods: This study involved a post hoc analysis of cross sectional data from 269 children 6 to 17 years of age enrolled in the National Heart, Lung, and Blood Institute Severe Asthma Research Program. Children answered questionnaires and underwent spirometry, plethysmography, exhaled nitric oxide determination, and venipuncture for TH1/TH2 cytokine determination. Asthma control was defined according to national asthma treatment guidelines that are based on prespecified thresholds for lung function and symptom frequency., Results: Fifty-eight children (22%) were overweight and 67(25%) were obese. Obese children did not have poorer asthma control but were more likely to report nonspecific symptoms such as dyspnea and nocturnal awakenings. Obese children did have decreased asthma-related quality of life and increased health care utilization, but this was not associated with airflow limitation. Instead, obese children had decreased functional residual capacity. A unique pattern of TH1 or TH2 polarization was not observed., Conclusions: Poor asthma control in obese children with asthma may be overestimated because of enhanced perception of nonspecific symptoms such as dyspnea that results from altered mechanical properties of the chest wall. Careful assessment of physiologic as well as symptom-based measures is needed in the evaluation of obese children with respiratory symptoms.

Chronic Obstructive Pulmonary Disease (COPD) can be briefly described as air flow limitation and chronic dyspnea associated to an inflammatory response of the respiratory tract to noxious particles and gases. Its main feature is the obstruction of airflow and consequent chronic dyspnea. Despite recent advances, and the development of new therapeutic, medical and clinical approaches, a curative therapy is yet to be achieved. Therapies involving the use of tissue-specific or donor derived cells present a promising alternative in the treatment of degenerative diseases and injuries. Recent studies demonstrate that mesenchymal stem cells have the capacity to modulate immune responses in acute lung injury and pulmonary fibrosis in animal models, as well as in human patients. Due to these aspects, different groups raised the possibility that the stem cells from different sources, such as those found in bone marrow or adipose tissue, could act preventing the emphysematous lesion progression. In this paper, it is proposed a review of the current state of the art and future perspectives on the use of cell therapy in obstructive lung diseases.

The risk stratification in patients presenting with acute dyspnoea remains a challenge. We therefore conducted a prospective, observational cohort study enrolling 292 patients presenting to the emergency department with acute dyspnoea. A proteomic approach for antibody-free targeted protein quantification based on high-end MS was used to measure LTBP2 [latent TGF (transforming growth factor)-binding protein 2] levels. Final diagnosis and death during follow-up were adjudicated blinded to LTBP2 levels. AHF (acute heart failure) was the final diagnosis in 54% of patients. In both AHF (P<0.001) and non-AHF (P=0.015) patients, LTBP2 levels at presentation were significantly higher in non-survivors compared with survivors with differences on median levels being 2.2- and 1.5-fold respectively. When assessing the cause of death, LTBP2 levels were significantly higher in patients dying from pulmonary causes (P=0.0005). Overall, LTBP2 powerfully predicted early pulmonary death {AUC (area under the curve), 0.95 [95% CI (confidence interval), 0.91-0.98]}. In ROC (receiver operating characteristic) curve analyses for the prediction of 1-year mortality LTBP2 achieved an AUC of 0.77 (95% CI, 0.71-0.84); comparable with the predictive potential of NT-proBNP [N-terminal pro-B-type natriuruetic peptide; 0.77 (95% CI, 0.72-0.82)]. Importantly, the predictive potential of LTBP2 persisted in patients with AHF as the cause of dypnea (AUC 0.78) and was independent of renal dysfunction (AUC 0.77). In a multivariate Cox regression analysis, LTBP2 was the strongest independent predictor of death [HR (hazard ratio), 3.76 (95% CI, 2.13-6.64); P<0.0001]. In conclusion, plasma levels of LTBP2 present a novel and powerful predictor of all-cause mortality, and particularly pulmonary death. Cause-specific prediction of death would enable targeted prevention, e.g. with pre-emptive antibiotic therapy.

Abnormal heat shock protein (HSP) levels have been observed in a number of human tumours, where they are involved in all hallmarks of cancer. Since bovine urothelial tumours share striking morphological and biochemical features with their human counterparts, the aim of this study was to evaluate the immunohistochemical levels of Hsp27, Hsp60, Hsp72, Hsp73 and Hsp90 in 28 normal bovine urinary bladders and 30 bovine papillomavirus-positive urothelial tumours (9 in situ carcinomas, 9 low-grade and 12 high-grade carcinomas) and adjacent premalignant lesions obtained from cows suffering from chronic enzootic haematuria, in order to investigate the role of these proteins in the process of urothelial carcinogenesis. A semi-quantitative method was used for the analysis of the results. Western blot analysis was also used to confirm HSP expression in normal controls. All investigated HSPs were expressed in normal bovine urothelium, showing characteristic patterns of immunolabelling throughout urothelial cell layers, which usually appeared to be conserved in urothelial hyperplasia and dysplasia. On the other hand, gradual loss of Hsp27 immunostaining resulted to be significantly associated with increasing histological grade of malignancy (P < 0.01). As well, a significantly reduced immunosignal of Hsp73 and Hsp90 was observed in high-grade and low-/high-grade carcinomas, respectively (P < 0.01). In contrast, Hsp60 (P < 0.01) and Hsp72 (P < 0.05) immunoreactivity appeared to be significantly increased both in premalignant and malignant lesions when compared to that observed in normal urothelium, thus suggesting an early involvement of these proteins in neoplastic transformation of urinary bladder mucosa.

Aclidinium, an inhaled, long-acting antimuscarinic agent, has been developed as a twice-daily maintenance treatment for chronic obstructive pulmonary disease (COPD). Treatment with the approved dosage of aclidinium (400 μg twice daily) statistically significantly improved bronchodilation, disease-specific health status, dyspnoea, night-time COPD symptoms and use of rescue medication compared with placebo in pivotal studies of 12 (ACCORD COPD I) or 24 (ATTAIN) weeks duration in patients with moderate to severe COPD. The improvements in bronchodilation, health status and dyspnoea were clinically meaningful compared with placebo after 24 weeks of treatment in ATTAIN; generally similar results were seen after 12 weeks of treatment in both trials. Aclidinium also statistically significantly reduced the incidence of COPD exacerbations compared with placebo in these studies (albeit neither trial was designed to assess exacerbation frequency). Inhaled aclidinium has a low systemic bioavailability; the approved dosage was generally well tolerated in clinical trials of up to 52 weeks duration. Aclidinium had an adverse event profile that was similar to that of placebo and characterized by low incidences of major adverse cardiovascular events and potential anticholinergic adverse events.

Background and Objective: Patients with chronic obstructive pulmonary disease (COPD) present with reduced exercise capacity due to impaired oxygen consumption (VO(2)), caused primarily by pulmonary dysfunction and deleterious peripheral adaptations. Assuming that COPD patients present with slower VO(2) and heart rate (HR) on-kinetics, we hypothesized that this finding is related to disease severity as measured by the BODE Index. In this context, the present study intends to evaluate the relationship between VO(2) uptake on-kinetics during high-intensity exercise and the BODE Index in patients with COPD., Methods: Twenty males with moderate-to-severe stable COPD and 13 healthy control subjects matched by age and sex were evaluated. COPD patients were screened by the BODE Index and then underwent an incremental cardiopulmonary exercise test and a constant speed treadmill session at 70% of maximal intensity for 6 minutes. The onset of the exercise (first 360 seconds) response for O(2) uptake and HR was modeled according to a monoexponential fit., Results: Oxygen consumption and HR on-kinetics were slower in the COPD group compared with controls. Additionally, VO(2) on-kinetic parameters revealed a strong positive correlation (r = 0.77, P < 0.05) with BODE scores and a moderate negative correlation with walking distance (r = -0.45, P < 0.05)., Conclusion: Our data show that moderate-to-severe COPD is related to impaired oxygen delivery and utilization during the onset of intense exercise.

Background: There is considerable evidence that oxidative stress is increased in patients with COPD, although little information is available about its relationship with the structural and functional alterations produced by COPD. In this study, we evaluated the relationship between 8-isoprostane in exhaled breath condensate (EBC) of stable patients with COPD and the main parameters of the disease (such as dyspnea), stages of severity, lung parenchyma densities, lung function impairment, and exercise tolerance in order to identify the predictors of airway oxidative stress., Methods: In a cross-sectional study, we included 76 men with moderate to very severe COPD. 8-Isoprostane levels in EBC were measured by enzyme immunoassay. Regional lung densities were measured by lung densitometry with high-resolution CT scanning. Arterial blood gas levels, lung volumes, and diffusing capacity were determined. Patients performed a 6-min walk test and an incremental exercise test with measurement of breathing pattern and operating lung volumes., Results: Significant severity-related differences in 8-isoprostane were identified according to the BMI, obstruction, dyspnea, and exercise (BODE) index. 8-Isoprostane levels were related to smoking intensity, lung densities in expiration, static lung volumes, PaO(2), diffusion capacity, distance walked in 6 min, peak oxygen uptake, and anaerobic threshold. Concentration of 8-isoprostane was higher in the 60 patients (79%) who developed dynamic hyperinflation than in the remaining 16 (21%) who did not. In a multivariate linear regression analysis using 8-isoprostane as a dependent variable, end-expiratory lung volume change and PaO(2) were retained in the prediction model (r(2) = 0.734, P < .001)., Conclusions: In stable patients with COPD, oxygen level and dynamic hyperinflation are related to airway oxidative stress.

The oral, selective phosphodiesterase type-4 inhibitor roflumilast reduces exacerbations and improves lung function in patients with severe-to-very severe chronic obstructive pulmonary disease (COPD). We investigated the efficacy and safety of roflumilast used concomitantly with long-acting β(2)-agonists (LABAs) to reduce exacerbations, and the influence of exacerbation history. Pooled data were analysed from two 12-month, placebo-controlled roflumilast (500 μg once daily) studies involving 3,091 patients with severe-to-very severe COPD. Approximately half of patients used concomitant LABAs; 39% used concomitant short-acting muscarinic antagonists (SAMAs); 27% were frequent exacerbators (two or more exacerbations per year). Roflumilast reduced the rate of moderate or severe exacerbations, with LABA (rate ratio (RR) 0.79, 95% CI 0.69-0.91; p=0.001) or without LABA (RR 0.85, 95% CI 0.74-0.99; p=0.039) and prolonged time both to first (p=0.035 with LABA, p=0.300 without LABA) and second (p=0.018 with LABA, p=0.049 without LABA) exacerbations. Frequent exacerbators experienced a reduction in moderate or severe exacerbations (RR 0.78, 95% CI 0.66-0.91; p=0.002). Similarly, roflumilast remained effective with concomitant SAMA. No differences arose in adverse events between these subgroups. Roflumilast may be used to reduce exacerbations and improve dyspnoea and lung function, without increasing adverse events in COPD patients receiving concomitant LABAs.

The transient receptor potential melastatin 8 (TRPM8) ion channel is gated by cool and noxious cold temperatures. The activation threshold is in the range of ≈25-28°C, which aligns well with the discharge of airway afferents. TRPM8 is widely expressed across species and evolutionary changes in the TRPM8 amino acid sequence may tune the temperatures at which it is gated. The discovery of TRPM8 and its molecular/biophysical characterization provides a robust candidate for airway afferents responding to cool/cold temperatures. TRPM8 may provide a mechanistic link for the manipulation of respiratory sensations such as dyspnea or mechanisms leading to cold-induced asthma and cough., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Indacaterol is a novel, inhaled, ultra-long-acting β(2)-agonist bronchodilator for maintenance use in patients with COPD. The aim of this paper is to assess the effect of indacaterol on dyspnoea and health status, using pooled study data to evaluate the relative efficacy of indacaterol and existing bronchodilators., Methods: Individual patient data were pooled from three randomized, placebo-controlled studies (NCT00393458; NCT00567996; NCT00463567), conducted in patients with moderate-to-severe COPD. Treatments were double-blind indacaterol 150 μg (n = 746) or 300 μg (n = 853) once-daily, formoterol 12 μg twice-daily (n = 556), salmeterol 50 μg twice-daily (n = 333) and placebo (n = 1185); and open-label tiotropium 18 μg once-daily (n = 415). Evaluation after 6 months' treatment was by transition dyspnoea index (TDI; minimum clinically important difference [MCID] ≥1 point), and St George's Respiratory Questionnaire (SGRQ; MCID ≥4 units)., Results: Differences from placebo in TDI total score were 1.01 (indacaterol 150 μg) 1.28 (indacaterol 300 μg), 0.74 (formoterol), 0.92 (salmeterol) and 0.88 (tiotropium) (all p < 0.05), with corresponding odds ratios versus placebo for exceeding the MCID from baseline of 1.91, 2.69, 2.02, 1.79 and 1.49 (all p < 0.05). Differences versus placebo in SGRQ total score were -4.4 (indacaterol 150 μg), -3.4 (indacaterol 300 μg), -2.8 (formoterol), -4.0 (salmeterol) and -1.7 (tiotropium) (all p < 0.05), with corresponding odds ratios versus placebo for exceeding the MCID of 1.95, 1.63, 1.54, 1.82 and 1.29 (all p < 0.05 apart from tiotropium)., Conclusions: Indacaterol provided clinically important improvements in dyspnoea and health status that were at least as good as and often better than those observed with existing bronchodilator treatments for COPD., (Copyright © 2011 Elsevier Ltd. All rights reserved.)

Background: Patients with sarcoidosis frequently exhibit exertional dyspnea. Although the functional limitation might be related to ventilatory problems, some patients exhibited exertional dyspnea without significant abnormalities of pulmonary function tests (PFT). Therefore, the mechanisms responsible for exercise intolerance remain unclear., Objectives: The aim of this retrospective study was to determine the mechanisms responsible for exercise intolerance., Methods: Cardiopulmonary exercise testing (CPET) was performed in 157 dyspneic sarcoid patients (stage I: 29; stage II-III: 95; stage IV: 33) and VO2 peak was correlated with radiological stage and resting PFT., Results: VO2 peak was decreased in 73% patients, did not differ according to radiological stage and was correlated with VC, FVC, FEV1, TLC and DLCO. FVC was the major significant predictor of VO2 peak explaining 17% of VO2 variation. Among CPET variables, peak heart rate and VE/VO2 at ventilatory threshold explained 22% of VO2 alteration in stage I and stage II-III, and 9% in stage IV. In stage IV, V(D)/V(T) peak explained 41% of VO2 alteration., Conclusion: In conclusion, in the lower stages circulatory impairment and impaired heart rate response to exercise are involved in the exercise capacity limitation, whereas in stage IV the ventilatory and gas exchange impairment may be more important. CPET must be performed to accurately characterize the mechanisms responsible for exercise limitation and help the clinician in the management of the disease., (Copyright © 2011 S. Karger AG, Basel.)

Background: Exertional dyspnea is the primary symptom that limits exercise in patients with chronic obstructive pulmonary disease (COPD). It is unknown which activated brain area is associated with this symptom in COPD patients., Objectives: To investigate the activation of cortical areas associated with dyspnea during exercise in COPD patients., Methods: COPD patients (n = 10) and age-matched controls (n = 10) performed mild-intensity constant work rate cycle exercise (40% of their symptom-limited peak work rates) for 10 min, while cerebral hemodynamics and oxygenation were measured by near-infrared spectroscopy (NIRS). Ventilatory responses (breathing pattern and pulmonary gas exchange) and Borg scale ratings of dyspnea and leg fatigue were measured during exercise. Three NIRS probes were placed over the prefrontal and temporoparietal cortical regions of the subjects' heads. Changes in cortical oxyhemoglobin (oxy-Hb), deoxyhemoglobin (deoxy-Hb), and total hemoglobin (total Hb) concentrations from baseline recordings were measured. Increased oxy-Hb (oxygenation) was assumed to reflect cortical activation., Results: Oxy-Hb concentration was significantly increased in the prefrontal region during exercise in both groups but not in the temporoparietal regions. The change in prefrontal oxy-Hb concentration of COPD patients was not different from that of controls. Dyspnea scores were positively correlated with changes in oxy-Hb concentrations of the prefrontal regions in both groups. Multivariate analysis showed that oxy-Hb concentration in the prefrontal region was the best predictor of dyspnea in both groups., Conclusions: Exertional dyspnea was related to activation (oxygenation) of the prefrontal cortex in COPD patients and control subjects., (Copyright © 2011 S. Karger AG, Basel.)

Background: Patients with Chronic Heart Failure (CHF) develop similar symptoms of exertional breathlessness and fatigue as patients with COPD. Although pulmonary (exercise based) rehabilitation (PR) is an integral part of the management of COPD, the potential for exercise rehabilitation (ER) to assist patients with CHF may not be as readily appreciated. We investigated whether combined ER for patients with CHF and COPD was feasible and effective using the model of PR., Methods: 57 patients with CHF were randomized 2:1 to 7 weeks ER (CHF-ER) or 7 weeks of usual care (CHF-UC). As a comparator 55 patients with COPD were simultaneously recruited to the same ER program (COPD-ER). The primary outcome measure was the Incremental Shuttle Walk Test (ISWT) and the secondary outcome measures were the Endurance Shuttle Walk Test (ESWT), isometric quadriceps strength and health status., Results: 27 CHF and 44 COPD patients completed ER and 17 patients with CHF completed UC. The CHF-ER group made significant improvements, compared to CHF-UC, in the mean (95%CI) ISWT distance; 62(35-89)m vs -6(-11 to 33)m p < 0.001. The CHF-ER group also made statistically significant improvements in health status. The improvements in exercise performance and health status were similar between patients with CHF and COPD, treated with ER., Conclusion: Patients with CHF who undergo ER improve similarly in their exercise performance and health status to COPD. Combined training programs for COPD and CHF are effective and feasible, such that service provision could be targeted around common disability rather than the primary organ disease.