Stress amplifies lung tissue mechanics, inflammation and oxidative stress induced by chronic inflammation

Background: Mechanisms linking behavioral stress and inflammation are poorly understood, mainly in distal lung tissue. Objective: We have investigated whether the forced swim stress (FS) could modulate lung tissue mechanics, iNOS, cytokines, oxidative stress activation, eosinophilic recruitment, and remodeling in guinea pigs (GP) with chronic pulmonary inflammation. Methods: The GP were exposed to ovalbumin or saline aerosols (2x/wk/4wks, OVA, and SAL). Twenty-four hours after the 4th inhalation, the GP were submitted to the FS protocol (5x/wk/2wks, SAL-S, and OVA-S). Seventy-two hours after the 7th inhalation, lung strips were cut and tissue resistance (Rt) and elastance (Et) were obtained (at baseline and after OVA and Ach challenge). Strips were submitted to histopathological evaluation. Results: The adrenals' weight, the serum cortisol, and the catecholamines were measured. There was an increase in IL-2, IL-5, IL-13, IFN-gamma, iNOS, 8-iso-PGF2 alpha, and in %Rt and %Et after Ach challenge in the SAL-S group compared to the SAL one. The OVA-S group has had an increase in %Rt and %Et after the OVA challenge, in %Et after the Ach and in IL-4, 8-iso-PGF2 alpha, and actin compared to the OVA. Adrenal weight and cortisol serum were increased in stressed animals compared to nonstressed ones, and the catecholamines were unaltered. Conclusion & clinical relevance: Repeated stress has increased distal lung constriction, which was associated with an increase of actin, IL-4, and 8-iso-PGF2 alpha levels. Stress has also induced an activation of iNOS, cytokines, and oxidative stress pathways.

Temporal Trends of Asthma Mortality Rates in Brazil from 1980 to 2010

Objective. Mortality from asthma has varied among countries during the last several decades. This study aimed to identify temporal trends of asthma mortality in Brazil from 1980 to 2010. Method. We analyzed 6840 deaths of patients aged 5-34 years that occurred in Brazil with the underlying cause of asthma. We applied a log-linear model using Poisson regression to verify peaks and trends. We also calculated the point estimation and 95% confidence interval (CI 95%) of the annual percent change (APC) of the mortality rates, and the average annual percent change (AAPC) for 2001-2010. Results. A decline was observed from 1980 to 1992 [APC = -3.4 (-5.0 to -1.8)], followed by a nonsignificant rise until 1996 [APC = 6.8 (-1.4 to 15.6)], and a new downward trend from 1997 to 2010 [APC = -2.7 (-3.9 to -1.6)]. The APCs varied according to age strata: 5-14 years from 1980 to 2010 [-0.3 (-1.1 to 0.5)]; 15-24 years from 1980 to 1991 [-2.1 (-5.0 to 0.9)], from 1992 to 1996 [6.8 (-6.7 to 22.2)], and from 1997 to 2010 [-3.9 (-5.7 to -2.0)]; 24-25 years from 1980 to 1992 [-2.5 (-4.6 to -0.3)], from 1993 to 1995 [12.0 (-21.1 to 59.1)], and from 1996-2010 [-1.7 (-3.0 to -0.4)]. AAPC from 2001 to 2010 was -1.7 (-3.0 to -0.4); the decline for this period was significant for patients over 15 years old, women, and those living in the Southeast region. Conclusion. Asthma mortality rates in Brazil have been declining since the late 1990s.

Occurrence of asthma symptoms and of airflow obstruction in amateur swimmers between 8 and 17 years of age

Objective: To determine the prevalence of asthma symptoms and of airflow obstruction in amateur swimmers between 8 and 17 years of age, as well as to assess the awareness of asthma and asthma management among these swimmers, their parents, and their coaches. Methods: Our sample comprised 1,116 amateur swimmers who completed a modified version of the International Study of Asthma and Allergies in Childhood written questionnaire, to which questions regarding the reasons to initiate swimming and regarding asthma management had been added. In addition, the participants underwent spirometry prior to a swimming competition. Results: The prevalence of asthma symptoms in the last 12 months was 11.5%, and 327 (29.4%) of the participants reported "wheezing or whistling" in the past. Of the 223 swimmers who reported "asthma ever" or "bronchitis ever", only 102 (45.7%) reported having ever been treated: the most common "treatment" was swimming (in 37.3%), and only 12.7% used inhaled corticosteroids. Of the 254 participants (22.7%) with airflow obstruction, only 52 (20.5%) reported having asthma symptoms. Conclusions: Asthma symptoms are present in amateur swimmers, and a considerable number of such swimmers have airflow obstruction without symptoms. It is therefore likely that the prevalence of asthma is underestimated in this population. It is worrisome that, in our study sample, the swimmers previously diagnosed with asthma were not using the recommended treatments for asthma. The clinical implications of these findings underscore the importance of implementing educational measures for amateur swimmers, as well as for their parents and coaches, to help them recognize asthma symptoms and the consequent risks in the sports environment, in order to allow prompt diagnosis and early clinical intervention.

Exercise-induced bronchoconstriction in elite long-distance runners in Brazil

Objective: To determine the prevalence of exercise-induced bronchoconstriction among elite long-distance runners in Brazil and whether there is a difference in the training loads among athletes with and without exercise-induced bronchoconstriction. Methods: This was a cross-sectional study involving elite long-distance runners with neither current asthma symptoms nor a diagnosis of exercise-induced bronchoconstriction. All of the participants underwent eucapnic voluntary hyperpnea challenge and maximal cardiopulmonary exercise tests, as well as completing questionnaires regarding asthma symptoms and physical activity, in order to monitor their weekly training load. Results: Among the 86 male athletes recruited, participation in the study was agreed to by 20, of whom 5 (25%) were subsequently diagnosed with exercise-induced bronchoconstriction. There were no differences between the athletes with and without exercise-induced bronchoconstriction regarding anthropometric characteristics, peak oxygen consumption, baseline pulmonary function values, or reported asthma symptoms. The weekly training load was significantly lower among those with exercise-induced bronchoconstriction than among those without. Conclusions: In this sample of long-distance runners in Brazil, the prevalence of exercise-induced bronchoconstriction was high.

Bronchoscopy for the diagnosis of pulmonary tuberculosis in patients with negative sputum smear microscopy results

Objective: To evaluate the diagnostic accuracy of bronchoscopy in patients with clinical or radiological suspicion of tuberculosis who were unable to produce sputum or with negative sputum smear microscopy results. Methods: A prospective cross-sectional study involving 286 patients under clinical or radiological suspicion of having pulmonary tuberculosis and submitted to bronchoscopy-BAL and transbronchial biopsy (TBB). The BAL specimens were submitted to direct testing and culture for AFB and fungi, whereas the TBB specimens were submitted to histopathological examination. Results: Of the 286 patients studied, 225 (79%) were diagnosed on the basis of bronchoscopic findings, as follows: pulmonary tuberculosis, in 127 (44%); nonspecific chronic inflammation, in 51 (18%); pneumocystis, fungal infections, or nocardiosis, in 20 (7%); bronchiolitis obliterans organizing pneumonia, alveolites, or pneumoconiosis, in 14 (5%); lung or metastatic neoplasms, in 7 (2%); and nontuberculous mycobacterium infections, in 6 (2%). For the diagnosis of tuberculosis, BAL showed a sensitivity and a specificity of 60% and 100%, respectively. Adding the TBB findings significantly increased this sensitivity (to 84%), as did adding the post-bronchoscopy sputum smear microscopy results (total sensitivity, 94%). Minor post-procedure complications occurred in 5.6% of the cases. Conclusions: Bronchoscopy is a reliable method for the diagnosis of pulmonary tuberculosis, with low complication rates. The combination of TBB and BAL increases the sensitivity of the method and facilitates the differential diagnosis with other diseases.

Audiometric evaluation of patients treated for pulmonary tuberculosis

Objective: To evaluate the hearing status of patients being treated for pulmonary tuberculosis at referral hospitals in Brazil. Methods: This was a descriptive study involving 97 male and female inpatients/outpatients between 18 and 60 years of age who were undergoing treatment for active pulmonary tuberculosis at one of two referral hospitals in the state of Rio de Janeiro. After being interviewed, all of the patients underwent pure tone audiometry. Results: OF the 97 patients studied, 65 (67%) were male, 52 (54%) were receiving first-line treatment, and 45 (46%) were receiving second-line treatment, which included aminoglycosides. Smoking, alcohol consumption, exposure to noise, and ototoxic medication use were identified in 65 (67%), 51 (53%), 53 (55%), and 45 (46.4%) of the patients, respectively. The most common auditory and vestibular complaints were dizziness, in 28 patients (28.8%); tinnitus, in 27 (27.8%); and hypoacusis, in 23 (23.7%). Conclusions: Due to the great number of patients with hearing loss in the present study, we recommend that all patients under tuberculosis treatment be submitted to auditory monitoring.

Streptococcus pneumoniae: susceptibility to penicillin and moxifloxacin

Objective: To determine the minimum inhibitory concentrations (MICs) of parenteral penicillin and moxifloxacin against Streptococcus pneumoniae strains isolated at a hospital center. Methods: In-vitro, prospective study involving 100 S. pneumoniae isolates collected from patients who had been treated, between October of 2008 and July of 2010, at the Hospital das Clinicas complex of the University of Sao Paulo School of Medicine, located in the city of Sao Paulo, Brazil. The isolates were obtained from respiratory tract cultures or blood samples unrelated to meningeal infections, and they were tested for penicillin and moxifloxacin susceptibility by E-test. The MIC category interpretations were based on updated standards. Results: All isolates were fully susceptible to parenteral penicillin (MIC <= 2 mu g/mL), and, consequently, they were also susceptible to amoxicillin, ampicillin, third/fourth generation cephalosporins, and ertapenem. Of the S. pneumoniae strains, 99% were also susceptible to moxifloxacin, and only one strain showed an MIC = 1.5 mu g/mL (intermediate). Conclusions: Our results showed high susceptibility rates to parenteral penicillin and moxifloxacin among S. pneumoniae isolates unrelated to meningitis, which differs from international reports. Reports on penicillin resistance should be based on updated breakpoints for non-meningitis isolates in order to guide the selection of an antimicrobial therapy and to improve the prediction of the clinical outcomes.

Influence of cardiopulmonary bypass on cefuroxime plasma concentration and pharmacokinetics in patients undergoing coronary surgery

The aims of this study were to evaluate the influence of cardiopulmonary bypass (CPB) on the plasma concentrations and pharmacokinetics of cefuroxime and to assess whether the cefuroxime dose regimen (a 1.5 g dose, followed by 750 mg every 6 h for 24 h) is adequate for cardiac surgery antibiotic prophylaxis. A prospective, controlled, observational study compared patients undergoing coronary surgery with CPB (CPB group, n = 10) or off-pump surgery (off-pump group, n = 9). After each cefuroxime dose, blood samples were sequentially collected and analysed using high-efficiency chromatography. For demographic data and pharmacokinetic parameters, the authors used Fisher's exact test for nominal variables and Student's t-test and the Mann-Whitney U-test for parametric and non-parametric variables, respectively. Plasma concentrations were compared using ANOVA, and the percentage of patients with a remaining plasma concentration of > 16 mg/l within 6 h after each bolus was quantified in tabular form. After each cefuroxime bolus was administered, both groups presented a significant decrease in plasma concentration over time (P < 0.001), without differences between the groups. The mean CPB time of 59.7 +/- 21.1 min did not change cefuroxime plasma concentrations or pharmacokinetics. The mean clearance +/- SD (ml/kg/min) and median elimination half-life (h) of the CPB group versus the off-pump group were 1.7 +/- 0.7 versus 1.6 +/- 0.6 (P = 0.67), respectively, and 2.2 versus 2.3 (P = 0.49), respectively. Up to 3 h following the first bolus of 1.5 g, but not after 6 h, all patients had plasma concentrations > 16 mg/l (CPB group = 20% and off-pump group = 44%). However, after all 750 mg boluses were administered, concentrations < 16 mg/dl were reached within 3 h. CPB does not influence cefuroxime plasma concentrations. The dosing regimen is adequate for the intraoperative period, but in the immediate postoperative period, it requires further review.

Safety and efficacy of sitaxsentan 50 and 100 mg in patients with pulmonary arterial hypertension

Objective: To assess safety and efficacy of sitaxsentan 50 and 100 mg in patients with pulmonary arterial hypertension (PAH). Background: Sitaxsentan is a highly selective endothelin-A receptor antagonist that was recently withdrawn by the manufacturer because of a pattern of idiosyncratic liver injury. Methods: Before sitaxsentan withdrawal, this 18-week double-blind, placebo-controlled study randomized patients with PAH to receive placebo or sitaxsentan 50 or 100 mg once daily. The primary efficacy endpoint was change from baseline in 6-min walk distance (6MWD) at week 18. Changes in World Health Organization (WHO) functional class and time to clinical worsening (TTCW) were secondary endpoints. The primary efficacy analysis was powered for sitaxsentan 100 mg versus placebo. Results: Of 98 randomized patients, 61% were WHO functional class II at baseline. Improvement from baseline to week 18 in 6MWD occurred with sitaxsentan 100 but not 50 mg; a strong placebo effect was observed. At week 18, WHO functional class was improved or maintained in more patients receiving sitaxsentan 100 mg than placebo (P = 0.038); 0% versus 12% of patients deteriorated, respectively. TTCW was not significantly different for 100-mg sitaxsentan patients than placebo (P = 0.090). Adverse events (AEs) occurring more frequently with sitaxsentan (50 or 100 mg) included headache, peripheral edema, dizziness, nausea, extremity pain, and fatigue; most AEs were of mild or moderate severity. Conclusion: Sitaxsentan 100 mg improved functional class but not 6MWD in PAH patients who were mostly WHO functional class II at baseline. No patient receiving sitaxsentan 100 mg experienced clinical worsening; sitaxsentan was well tolerated. (C) 2011 Elsevier Ltd. All rights reserved.

Extracellular matrix composition in COPD

Extracellular matrix (ECM) composition has an important role in determining airway structure. We postulated that ECM lung composition of chronic obstructive pulmonary disease (COPD) patients differs from that observed in smoking and nonsmoking subjects without airflow obstruction. We determined the fractional areas of elastic fibres, type-I, -III and -IV collagen, versican, decorin, biglycan, lumican, fibronectin and tenascin in different compartments of the large and small airways and lung parenchyma in 26 COPD patients, 26 smokers without COPD and 16 nonsmoking control subjects. The fractional area of elastic fibres was higher in non-obstructed smokers than in COPD and nonsmoking controls, in all lung compartments. Type-I collagen fractional area was lower in the large and small airways of COPD patients and in the small airways of non-obstructed smokers than in nonsmokers. Compared with nonsmokers, COPD patients had lower versican fractional area in the parenchyma, higher fibronectin fractional area in small airways and higher tenascin fractional area in large and small airways compartments. In COPD patients, significant correlations were found between elastic fibres and fibronectin and lung function parameters. Alterations of the major ECM components are widespread in all lung compartments of patients with COPD and may contribute to persistent airflow obstruction.

Biventricular structural and functional responses to aortic constriction in a rabbit model of chronic right ventricular pressure overload

Objectives: Chronic right ventricular (RV) pressure overload results in pathologic RV hypertrophy and diminished RV function. Although aortic constriction has been shown to improve systolic function in acute RV failure, its effect on RV responses to chronic pressure overload is unknown. Methods: Adjustable vascular banding devices were placed on the main pulmonary artery and descending aorta. In 5 animals (sham group), neither band was inflated. In 9 animals (PAB group), only the pulmonary arterial band was inflated, with adjustments on a weekly basis to generate systemic or suprasystemic RV pressure at 28 days. In 9 animals, both pulmonary arterial and aortic devices were inflated (PAB+AO group), the pulmonary arterial band as for the PAB group and the aortic band adjusted to increase proximal systolic blood pressure by approximately 20 mm Hg. Effects on the functional performance were assessed 5 weeks after surgery by conductance catheters, followed by histologic and molecular assessment. Results: Contractile performance was significantly improved in the PAB+AO group versus the PAB group for both ventricles. Relative to sham-operated animals, both banding groups showed significant differences in myocardial histologic and molecular responses. Relative to the PAB group, the PAB+AO group showed significantly decreased RV cardiomyocyte diameter, decreased RV collagen content, and reduced RV expression of endothelin receptor type B, matrix metalloproteinase 9, and transforming growth factor beta genes. Conclusions: Aortic constriction in an experimental model of chronic RV pressure overload not only resulted in improved biventricular systolic function but also improved myocardial remodeling. These data suggest that chronically increased left ventricular afterload leads to a more physiologically hypertrophic response in the pressure-overloaded RV. (J Thorac Cardiovasc Surg 2012;144:1494-501)

Six minute walk test Z score: Correlations with cystic fibrosis severity markers

Background: The six-minute-walk-test (6MWT) has been increasingly used in cystic fibrosis (CF) patients. However, few studies in children have correlated 6MWT with current parameters used to evaluate CF severity. Moreover, no study transformed the values of distance walked from meters into Z scores to avoid bias like age and gender, which are sources of 6MWT variability. Methods: A cross-sectional descriptive study was performed to analyze the correlations (Spearman) among forced expiratory volume in one second (FEV1), body mass index (BMI), chest radiography (CXR), chest tomography (CT), and 6MWT Z score (Z-6MWT). Clinically stable CF patients, aged 6-21 years, were included. Results: 34 patients, 14F/20M, mean age 12.1 +/- 4.0 years were studied. The mean Z-6MWT was -1.1 +/- 1.106. The following correlations versus Z-6MWT were found: FEV1 (r=0.59, r(2)=0.32, p=0.0002), BMI Z score (r=0.42, r(2)=0.17, p=0.013), CXR (r=0.34, r(2)=0.15, p=0.0472) and CT (r=-0.45, r(2)=0.23, p=0.0073). Conclusions: In conclusion there was a significant, but poor, correlation between the six minute walk test Z score and the cystic fibrosis severity markers currently in use. (C) 2011 European Cystic Fibrosis Society. Published by Elsevier B.V. All rights reserved.

Punção aspirativa guiada por ultrassom endobrônquico no diagnóstico e estadiamento de linfadenopatia mediastinal: experiência inicial no Brasil

OBJETIVO: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA, punção aspirativa por agulha guiada por ultrassom endobrônquico) é um método novo em diagnóstico e estadiamento linfonodal mediastinal. O objetivo do estudo foi avaliar os resultados preliminares obtidos com EBUS-TBNA no diagnóstico de lesões e no estadiamento linfonodal mediastinal. MÉTODOS: Foram avaliados pacientes com tumores ou adenopatias mediastinais e com diagnóstico ou suspeita de câncer de pulmão. Os procedimentos foram realizados com os pacientes sob sedação ou anestesia geral. O material coletado foi preparado em lâminas fixadas em álcool absoluto para citologia e em formol para bloco de células. RESULTADOS: Foram incluídos 50 pacientes (30 do sexo masculino), com média de idade de 58,3 ± 13,5 anos. Foram realizadas 201 punções em 81 linfonodos ou massas mediastinais (média de 2,5 punções). O material obtido foi considerado adequado para análise citológica em 37 pacientes (74%), dos quais 21 (57%) foram diagnosticados com malignidade. Nos 16 pacientes remanescentes, 1 teve diagnóstico de tuberculose, 6 tiveram seguimento clínico, e 9 foram submetidos a investigação adicional (2 diagnosticados com neoplasia - resultados falso-negativos). O rendimento do exame foi maior nos procedimentos com objetivo diagnóstico, em pacientes com lesões em múltiplas estações, e nas punções da estação linfonodal subcarinal. Um paciente apresentou sangramento endobrônquico resolvido com medidas locais. Não houve mortalidade na série. CONCLUSÕES: Esta experiência preliminar confirmou que o EBUS-TBNA é procedimento seguro, e que o nosso rendimento diagnóstico, inferior ao da literatura, foi compatível com a curva de aprendizado do método.

Late remote ischemic preconditioning in children undergoing cardiopulmonary bypass: A randomized controlled trial

Objective: Cardiopulmonary bypass is associated with ischemia-reperfusion injury to multiple organs. We aimed to evaluate whether remote ischemic preconditioning performed the day before surgery for congenital heart disease with cardiopulmonary bypass attenuates the postoperative inflammatory response and myocardial dysfunction. Methods: This was a prospective, randomized, single-blind, controlled trial. Children allocated to remote ischemic preconditioning underwent 4 periods of 5 minutes of lower limb ischemia by a blood pressure cuff intercalated with 5 minutes of reperfusion. Blood samples were collected 4, 12, 24, and 48 hours after cardiopulmonary bypass to evaluate nuclear factor kappa B activation in leukocytes by quantification of mRNA of I kappa B alpha by real-time quantitative polymerase chain reaction and for interleukin-8 and 10 plasma concentration measurements by enzyme-linked immunosorbent assay. Myocardial dysfunction was assessed by N-terminal pro-B-type natriuretic peptide and cardiac troponin I plasma concentrations, measured by chemiluminescence, and clinical parameters of low cardiac output syndrome. Results: Twelve children were allocated to remote ischemic preconditioning, and 10 children were allocated to the control group. Demographic data and Risk Adjustment for Congenital Heart Surgery 1 classification were comparable in both groups. Remote ischemic preconditioning group had lower postoperative values of N-terminal pro-B-type natriuretic peptide, but cardiac troponin I levels were not significantly different between groups. Interleukin-8 and 10 concentrations and I kappa B alpha gene expression were similar in both groups. Postoperative morbidity was similar in both groups; there were no postoperative deaths in either group. Conclusions: Late remote ischemic preconditioning did not provide clinically relevant cardioprotection to children undergoing cardiopulmonary bypass. (J Thorac Cardiovasc Surg 2012;144:178-83)

Sleep in patients with large pleural effusion: impact of thoracentesis

This study aimed to evaluate the sleep quality and impact of thoracentesis on sleep in patients with a large pleural effusion. Patients with large unilateral pleural effusion were evaluated by the Pittsburgh Sleep Quality Index (PSQI) questionnaire and dyspnea Borg scale. Full polysomnography (PSG) was performed on the night before and 36 h after thoracentesis. We studied 19 patients, 11 males and 8 females, age 55 +/- 18 years and body mass index of 26 +/- 5 kg/m(2). The baseline sleep quality was poor (PSQI = 9.1 +/- 3.5). Thoracentesis removed 1.624 +/- 796 mL of pleural fluid and resulted in a significant decrease in dyspnea Borg scale (2.3 +/- 2.1 vs. 0.8 +/- 0.9, p < 0.001). The PSG before and after thoracentesis showed no significant change in apnea-hypopnea index and sleep time with oxygen saturation < 90%. There was a significant improvement in sleep efficiency (76% vs. 81%, p = 0.006), decrease percent sleep stage 1 (16% vs. 14%, p = 0.002), and a trend improvement in total sleep time (344 +/- 92 vs. 380 +/- 69 min, p = 0.056) and percentage of rapid eye movement sleep (15% vs. 20%, p = 0.053). No significant changes occurred in six patients that performed two consecutive PSG before thoracentesis. The improvement in sleep quality was not associated with the volume of pleural fluid withdrawn or changes in dyspnea. Patients with large pleural effusion have poor subjective and objective sleep quality that improves after thoracentesis.