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Background: Animal models using intratracheal instillation show that elastase, unopposed by α1-antitrypsin (AAT), causes alveolar damage and haemorrhage associated with emphysematous changes. The aim of the present study was to characterise any relationship between alveolar haemorrhage and human AAT deficiency (AATD) using bronchoalveolar lavage (BAL) and lung explant samples from AATD subjects. Methods: BAL samples (17 patients, 15 controls) were evaluated for free haem (iron protoporphyrin IX) and total iron concentrations. Alveolar macrophage activation patterns were assessed using RNA sequencing and validated in vitro using haem-stimulated, monocyte-derived macrophages. Lung explants (seven patients, four controls) were assessed for iron sequestration protein expression patterns using Prussian blue stain and ferritin immunohistochemistry, as well as ferritin iron imaging and elemental analysis by transmission electron microscopy. Tissue oxidative damage was assessed using 8-hydroxy-2'-deoxyguanosine immunohistochemistry. Results: BAL collected from AATD patients showed significantly elevated free haem and total iron concentrations. Alveolar and interstitial macrophages in AATD explants showed elevated iron and ferritin accumulation in large lysosomes packed by iron oxide cores with degraded ferritin protein cages. BAL macrophage RNA sequencing showed innate pro-inflammatory activation, replicated in vitro by haemin exposure, which also triggered reactive oxygen species generation. AATD explants showed massive oxidative DNA damage in both lung epithelial cells and macrophages. Conclusions: BAL and tissue markers of alveolar haemorrhage, together with molecular and cellular evidence of macrophage innate pro-inflammatory activation and oxidative damage, are consistent with free haem stimulation. Overall, this initial study provides evidence for a pathogenetic role of elastase-induced alveolar haemorrhage in AATD emphysema.
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Sarcoidosis and chronic beryllium disease (CBD) are phenocopies, however the latter one has a clear trigger factor that is beryllium exposure. This study analyses single nucleotide polymorphisms (SNPs) in a large cohort for beryllium-exposed persons. SNPs were chosen for their relevance in sarcoidosis. Even though one of largest cohorts of beryllium-exposed persons was analysed, no statistically relevant association between any SNP and CBD could be verified. Notably, some SNPs exhibit inverse OR for beryllium sensitization and CBD with nominally statistical significance, which allows hypothesizing about pathophysiological role of genes for the disease triggering and development.
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Beriliose/genética , Berílio/efeitos adversos , Butirofilinas/genética , DNA/genética , Exposição Ocupacional/efeitos adversos , Polimorfismo de Nucleotídeo Único , Beriliose/metabolismo , Butirofilinas/metabolismo , Doença Crônica , Feminino , Humanos , MasculinoRESUMO
Protein-protein interaction (PPI) network models interconnections between protein-encoding genes. A group of proteins that perform similar functions are often connected to each other in the PPI network. The corresponding genes form pathways or functional modules. Mutation in protein-encoding genes affect behavior of pathways. This results in initiation, progression, and severity of diseases that propagates through pathways. In this work, we integrate mutation, survival information of patients, and PPI network to identify connected subnetworks associated with survival. We define the computational problem using a fitness function called log-rank statistic to score subnetworks. Log-rank statistic compares the survival between two populations. We propose a novel method, Survival Associated Mutated Subnetwork (SAMS) that adopts genetic algorithm strategy to find the connected subnetwork within the PPI network whose mutation yields highest log-rank statistic. We test on real cancer and synthetic datasets. SAMS generate solutions in negligible time while the state-of-art method in literature takes exponential time. Log-rank statistic of SAMS selected mutated subnetworks are comparable to the method. Our result genesets show significant overlap with well-known cancer driver genes derived from curated datasets and studies in literature, display high text-mining score in terms of number of citations combined with disease-specific keywords in PubMed, and identify pathways having high biological relevance.
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Algoritmos , Mutação/genética , Neoplasias/genética , Neoplasias/mortalidade , Mapas de Interação de Proteínas/genética , Biologia Computacional/métodos , Variações do Número de Cópias de DNA/genética , HumanosRESUMO
Idiopathic pulmonary fibrosis (IPF) is a chronic lung disease of unknown cause characterized by alveolar epithelial damage, patchy interstitial fibrosis and diffuse microvascular abnormalities. In IPF, alveolar clustering of iron-laden alveolar macrophages-a common sign of microhemorrhage, has been associated with vascular abnormalities and worsening of pulmonary hypertension. As iron-dependent ROS generation has been shown to induce unrestrained macrophage activation in disease models of vascular damage, we explored alveolar macrophage activation phenotype in IPF patients (n = 16) and healthy controls (CTR, n = 7) by RNA sequencing of bronchoalveolar lavage (BAL) cells. The frequencies of macrophages in BAL cells were 86+4% and 83.4+8% in IPF and CTR groups, respectively (p-value = 0.41). In IPF patients, BAL cells showed increased iron-dependent ROS generation (p-value<0.05 vs CTR). Gene expression analysis showed overrepresentation of Gene Ontology processes/functions and KEGG pathways enriched in upregulated M1-type inflammatory (p-value<0.01), M2-type anti-inflammatory/tissue remodeling (p-value<0.0001), and MTPP-type chronic inflammatory/angiogenic (p-value<0.0001) chemokine and cytokine genes. The ex vivo finding was confirmed by the induction of iron-dependent ROS generation and chemokine/cytokine overexpression of Ccl4, Cxcl10 (M1), Il1rn (M2), Cxcl2, and Cxcl7 (MTPP) in MH-S murine immortalized alveolar macrophages exposed to ferric ammonium citrate in culture (p-value<0.05 vs CTR). The data show alveolar macrophage expression of a pro-inflammatory, tissue remodeling and angiogenic complex activation pattern, suggesting that iron accumulation may play a role in macrophage activation.
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Líquido da Lavagem Broncoalveolar/citologia , Fibrose Pulmonar Idiopática/metabolismo , Inflamação/metabolismo , Ferro/metabolismo , Macrófagos/metabolismo , Neovascularização Patológica , Adulto , Idoso , Quimiocinas/metabolismo , Feminino , Perfilação da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Espécies Reativas de Oxigênio/metabolismo , Análise de Sequência de RNAAssuntos
Antígenos de Bactérias/imunologia , Mycobacterium tuberculosis/imunologia , Testes Sorológicos/métodos , Tuberculose/diagnóstico , Adulto , Austrália , Proteínas de Bactérias/imunologia , Bulgária , Coinfecção/imunologia , Feminino , Infecções por HIV/imunologia , Humanos , Índia , Testes de Liberação de Interferon-gama/métodos , Itália , Masculino , Pessoa de Meia-Idade , Sensibilidade e Especificidade , África do Sul , Tuberculose/imunologia , Adulto JovemRESUMO
Recent ATS/ERS/JRS/ALAT guidelines for the diagnosis and management of Idiopathic Pulmonary Fibrosis (IPF) have defined key features and specific high-resolution computerized tomography (HRCT) patterns for the diagnosis of UIP. The aim is the sorting of patients with suspected IPF into three subgroups, confident, possible or inconsistent with UIP patterns, after a multidisciplinary discussion (MDD). Specialists in respiratory diseases, radiologists and pathologists should reach IPF diagnosis based on either patients' clinical, radiological and laboratory data, either submitting patients to surgical biopsy. After ATS/ERS/JRS/ALAT recommendations have been applied, it has been identified a subgroup of patients showing uniform apical-basal distribution of honeycombing and reticular abnormalities that could not be categorized as confident, or possible nor inconsistent with UIP. These patients were subsequently diagnosed with IPF after MDD and lung biopsy. Inclusion of this pattern in the recommendation for IPF diagnosis would be worth considering.
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Fibrose Pulmonar Idiopática/diagnóstico por imagem , Comunicação Interdisciplinar , Guias de Prática Clínica como Assunto , Tomografia Computadorizada por Raios X/métodos , Idoso , Líquido da Lavagem Broncoalveolar/citologia , Broncoscopia/métodos , Estudos de Coortes , Feminino , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Masculino , Pessoa de Meia-Idade , Testes de Função Respiratória , Sensibilidade e EspecificidadeRESUMO
In idiopathic pulmonary fibrosis (IPF), lung accumulation of excessive extracellular iron and macrophage haemosiderin may suggest disordered iron homeostasis leading to recurring microscopic injury and fibrosing damage. The current study population comprised 89 consistent IPF patients and 107 controls. 54 patients and 11 controls underwent bronchoalveolar lavage (BAL). Haemosiderin was assessed by Perls' stain, BAL fluid malondialdehyde (MDA) by high-performance liquid chromatography, BAL cell iron-dependent oxygen radical generation by fluorimetry and the frequency of hereditary haemochromatosis HFE gene variants by reverse dot blot hybridisation. Macrophage haemosiderin, BAL fluid MDA and BAL cell unstimulated iron-dependent oxygen radical generation were all significantly increased above controls (p<0.05). The frequency of C282Y, S65C and H63D HFE allelic variants was markedly higher in IPF compared with controls (40.4% versus 22.4%, OR 2.35, p=0.008) and was associated with higher iron-dependent oxygen radical generation (HFE variant 107.4±56.0, HFE wild type (wt) 59.4±36.4 and controls 16.7±11.8â fluorescence units per 10(5) BAL cells; p=0.028 HFE variant versus HFE wt, p=0.006 HFE wt versus controls). The data suggest iron dysregulation associated with HFE allelic variants may play an important role in increasing susceptibility to environmental exposures, leading to recurring injury and fibrosis in IPF.
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Variação Genética , Hemocromatose/genética , Antígenos de Histocompatibilidade Classe I/genética , Fibrose Pulmonar Idiopática/genética , Ferro/química , Proteínas de Membrana/genética , Adulto , Alelos , Lavagem Broncoalveolar , Líquido da Lavagem Broncoalveolar/química , Estudos de Casos e Controles , Cromatografia Líquida de Alta Pressão , Feminino , Fluorometria , Proteína da Hemocromatose , Hemossiderina/metabolismo , Humanos , Inflamação/metabolismo , Macrófagos/metabolismo , Masculino , Malondialdeído/química , Pessoa de Meia-Idade , Oxigênio/química , Espécies Reativas de Oxigênio/químicaRESUMO
RATIONALE: Beryllium continues to have a wide range of industrial applications. Exposure to beryllium can lead to sensitization (BeS) and chronic beryllium disease (CBD). OBJECTIVES: The purpose of this statement is to increase awareness and knowledge about beryllium exposure, BeS, and CBD. METHODS: Evidence was identified by a search of MEDLINE. The committee then summarized the evidence, drew conclusions, and described their approach to diagnosis and management. MAIN RESULTS: The beryllium lymphocyte proliferation test is the cornerstone of both medical surveillance and the diagnosis of BeS and CBD. A confirmed abnormal beryllium lymphocyte proliferation test without evidence of lung disease is diagnostic of BeS. BeS with evidence of a granulomatous inflammatory response in the lung is diagnostic of CBD. The determinants of progression from BeS to CBD are uncertain, but higher exposures and the presence of a genetic variant in the HLA-DP ß chain appear to increase the risk. Periodic evaluation of affected individuals can detect disease progression (from BeS to CBD, or from mild CBD to more severe CBD). Corticosteroid therapy is typically administered when a patient with CBD exhibits evidence of significant lung function abnormality or decline. CONCLUSIONS: Medical surveillance in workplaces that use beryllium-containing materials can identify individuals with BeS and at-risk groups of workers, which can help prioritize efforts to reduce inhalational and dermal exposures.
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Beriliose/diagnóstico , Beriliose/terapia , Berílio/toxicidade , Hipersensibilidade/diagnóstico , Hipersensibilidade/terapia , Exposição Ocupacional/efeitos adversos , Beriliose/etiologia , Doença Crônica , Humanos , Hipersensibilidade/etiologiaRESUMO
BACKGROUND: Studies of Idiopathic Pulmonary Fibrosis (IPF) epidemiology show regional variations of incidence and prevalence; no epidemiological studies have been carried out in Italy. OBJECTIVE: To determine incidence and prevalence rates of IPF in the population of a large Italian region. METHODS: in this cross-sectional study study data were collected on all patients of 18 years of age and older admitted as primary or secondary idiopathic fibrosing alveolitis (ICD9-CM 516.3) to Lazio hospitals, from 1/1/2005 to 31/12/2009, using regional hospital discharge, population and cause of death databases. Reporting accuracy was assessed on a random sample of hospital charts carrying the ICD9-CM 516.3, 516.8, 516.9 and 515 codes, by reviewing radiology and pathology findings to define cases as IPF "confident", "possible" or "inconsistent". RESULTS: Annual prevalence and incidence of IPF were estimated at 25.6 per 100,000 and 7.5 per 100,000 using the ICD9-CM code 516.3 without chart audit while they were estimated at 31.6 per 100,000 and at 9,3 per 100,000 for the IPF "confident" definition after hospital chart audit. CONCLUSION: The data provide a first estimate of IPF incidence in Italy and indicate that incidence and prevalence in southern European regions may be similar to those observed in northern Europe and North America.
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Fibrose Pulmonar Idiopática/epidemiologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Estudos Transversais , Bases de Dados Factuais , Feminino , Inquéritos Epidemiológicos , Humanos , Fibrose Pulmonar Idiopática/diagnóstico , Fibrose Pulmonar Idiopática/mortalidade , Incidência , Itália/epidemiologia , Masculino , Pessoa de Meia-Idade , Admissão do Paciente , Prevalência , Estudos Retrospectivos , Fatores de Tempo , Adulto JovemRESUMO
RATIONALE: A number of observations suggest that iron accumulates in the lungs of patients with idiopathic pulmonary fibrosis (IPF) with vascular abnormalities, including pulmonary hypertension. OBJECTIVES: The aim of this study was to determine the prevalence and intensity of accumulation of alveolar epithelial lining fluid (ELF) iron and of alveolar macrophage hemosiderin in IPF and its relationship with disease severity. METHODS: Forty seven IPF patients and 14 healthy controls were retrospectively evaluated for iron accumulation in the lower respiratory tract using total iron spectrophotometric measures and for hemosiderin accumulation using the Perls' stain with the Golde score. MEASUREMENTS AND MAIN RESULTS: Total iron levels in ELF were significantly increased in IPF patients compared to non-smoking controls (p < 0.05); there were no differences with healthy smokers (p = 0.2). Hemosiderin accumulation in alveolar macrophages was similar in never smoking and ever smoking IPF patients (p = 0.5), was significantly higher in IPF patients than in both smoking and non-smoking healthy controls (p < 0.05, all comparisons) and was positively correlated with echocardiographic estimates of pulmonary artery systolic pressure (p < 0.05) and with increasing disease severity scores (p < 0.05). CONCLUSIONS: The data show exaggerated accumulation of iron in IPF broncho-alveolar ELF and alveolar cells with no association with tobacco smoke, thus suggesting, occult pulmonary hemorrhage as a likely cause.
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Hemorragia/diagnóstico , Fibrose Pulmonar Idiopática/fisiopatologia , Ferro/metabolismo , Macrófagos Alveolares/metabolismo , Adulto , Idoso , Estudos de Casos e Controles , Feminino , Hemossiderina/metabolismo , Humanos , Masculino , Pessoa de Meia-Idade , Alvéolos Pulmonares/metabolismo , Estudos Retrospectivos , Índice de Gravidade de Doença , Fumar/metabolismo , EspectrofotometriaRESUMO
INTRODUCTION: Ambulatory oxygen (O2) is prescribed to interstitial lung disease (ILD) patients with mild hypoxemia, breathlessness and dyspnea on exertion. Oxygen titration is generally done with the 6 minute walk test (6MWT) to determine the O2 flow preventing oxygen saturation by pulse oximetry (SpO2) from falling below 88%. His study was designed to generate a 6MWT index predicting the O2 flow allowing completion of the 6MWT without oxygen desaturation. METHODS: Oxygen titration data from a group of 66 ILD patients and 30 controls, were used to generate the algorithm determining an index (O2-GAP) predicting oxygen flow required to complete a 6MWT without desaturation below 88%. This index was validated in a group of 93 ILD patients. RESULTS: The O2-GAP index, as obtained from the derivation population, (r(2) = 0.97, p < 0.001) was shown to correctly predict the oxygen flow required to complete the 6MWT without SpO2 falling below 88% validated in the validation population (r(2) = 0.842; p < 0.001). CONCLUSIONS: The O2-GAP index appears to be a useful tool to titrate ambulatory O2 with a single 6MWT on room air in ILD patients with breathlessness and dyspnea on exertion.
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Teste de Esforço/métodos , Exercício Físico/fisiologia , Oxigênio/sangue , Idoso , Algoritmos , Análise de Variância , Estudos de Casos e Controles , Dispneia/sangue , Dispneia/etiologia , Dispneia/fisiopatologia , Feminino , Humanos , Masculino , Oximetria , Estudos Prospectivos , Testes de Função Respiratória , Caminhada/fisiologiaRESUMO
Current diagnostic standards for Mycobacterium tuberculosis (MTB) infection do not distinguish between active and latent tuberculosis (TB). To identify specific biomarkers characterizing the different forms of TB infection, we investigated in parallel with the QuantiFERON -TB Gold In-Tube (QFT-IT) the use of flow cytometry measuring CD4 and CD8 MTB-specific immune response in 17 active-TB patients, 21 health care workers (HCW), 14 recent contacts of TB patients (RC-TB), and 10 bacille Calmette Guerin (BCG)-vaccinated healthy controls (BCG-HC). A correlation (r = 0.4526, P = 0.0002) was found only between the amount of IFN-γ measured by QFT-IT and the frequency of CD4+/CD69+/IFN-γ+ T cells. The frequency of CD4+/CD69+/IFNγ+ responding T cells was higher in active-TB patients (0.254 ± 0.336%, P < 0.01) compared to the other groups. The response of QFT-IT antigen-specific CD8+/CD69+/IFNγ+ T cells was significantly higher in RC-TB (0.245 ± 0.305%, P < 0.05) compared to the other study groups.
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Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Tuberculose/diagnóstico , Adulto , Idoso , Idoso de 80 Anos ou mais , Antígenos CD/metabolismo , Antígenos de Diferenciação de Linfócitos T/metabolismo , Vacina BCG/administração & dosagem , Biomarcadores/análise , Contagem de Linfócito CD4 , Linfócitos T CD4-Positivos/microbiologia , Linfócitos T CD8-Positivos/microbiologia , Estudos de Casos e Controles , Estudos Transversais , Feminino , Citometria de Fluxo , Pessoal de Saúde , Humanos , Interferon gama/imunologia , Lectinas Tipo C/metabolismo , Masculino , Pessoa de Meia-Idade , Mycobacterium tuberculosis , Tuberculose/imunologia , Adulto JovemRESUMO
BACKGROUND: Surgical biopsy of interstitial lung disease (ILD) performed through general anesthesia and video-assisted thoracic surgery (VATS) is still associated with not negligible mortality and morbidity rates. We hypothesized feasibility and minimized side-effects of VATS lung biopsy performed by regional anesthesia methods in awake patients. METHODS: Thirty patients with clinical and radiologic diagnosis of undetermined ILD underwent awake VATS lung biopsy under thoracic epidural anesthesia (20 patients) or intercostal blocks (10 patients). Primary outcome was technical feasibility scored from 0 (not performed) to 4 (excellent). Cardiorespiratory variables, including the ratio of arterial oxygen to fraction of inspired oxygen (PaO(2)/FiO(2)) and arterial carbon dioxide (PaCO(2)) were also assessed at fixed time points. RESULTS: Mean age was 62 ± 10 years. No patient needed conversion to general anesthesia. The feasibility score was 3.4 ± 0.7. Feasibility score correlated with percent predicted diffusing capacity of lung for carbon monoxide (R = 0.67, p = 0.0001). Operative time and global in-operating room time (anesthesia time + operative time) was 22 ± 5 minutes and 47 ± 11 minutes, respectively. The average number of biopsies was 1.8 ± 0.4 per patient. There was no operative mortality and 1 minor complication (3.3%). Mean hospital stay was 1.4 ± 0.7 days and procedure-related cost was 2700 ± 472 euros. Both anesthesia methods resulted in optimal feasibility although by intercostal blocks procedure-related cost was lower (2,410 ± 337 vs 2,800 ± 486 euros, p < 0.002) than by epidural anesthesia. Precise histopathologic diagnosis was achieved in 29 (97%) patients. CONCLUSIONS: Our study has shown that in patients with ILD, awake VATS lung biopsy was easily feasible by regional anesthesia and resulted in low morbidity, excellent diagnostic yield, short hospital stay, and low cost.
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Anestesia por Condução , Doenças Pulmonares Intersticiais/patologia , Cirurgia Torácica Vídeoassistida , Vigília , Biópsia/métodos , Estudos de Viabilidade , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND: The clinical utility of bronchoalveolar lavage fluid (BAL) cell analysis for the diagnosis and management of patients with interstitial lung disease (ILD) has been a subject of debate and controversy. The American Thoracic Society (ATS) sponsored a committee of international experts to examine all relevant literature on BAL in ILD and provide recommendations concerning the use of BAL in the diagnosis and management of patients with suspected ILD. PURPOSE: To provide recommendations for (1) the performance and processing of BAL and (2) the interpretation of BAL nucleated immune cell patterns and other BAL characteristics in patients with suspected ILD. METHODS: A pragmatic systematic review was performed to identify unique citations related to BAL in patients with ILD that were published between 1970 and 2006. The search was updated during the guideline development process to include published literature through March 2011. This is the evidence upon which the committee's conclusions and recommendations are based. RESULTS: Recommendations for the performance and processing of BAL, as well as the interpretation of BAL findings, were formulated by the committee. CONCLUSIONS: When used in conjunction with comprehensive clinical information and adequate thoracic imaging such as high-resolution computed tomography of the thorax, BAL cell patterns and other characteristics frequently provide useful information for the diagnostic evaluation of patients with suspected ILD.
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Líquido da Lavagem Broncoalveolar/citologia , Lavagem Broncoalveolar/normas , Doenças Pulmonares Intersticiais/diagnóstico , Adulto , Lavagem Broncoalveolar/métodos , Contagem de Células/métodos , Contagem de Células/normas , Diagnóstico Diferencial , Citometria de Fluxo/métodos , Citometria de Fluxo/normas , Humanos , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Manejo de Espécimes/métodos , Manejo de Espécimes/normas , Tomografia Computadorizada por Raios XRESUMO
The natural history of idiopathic pulmonary fibrosis (IPF) is not well defined and its clinical course is variable. We sought to investigate the survival and incidence of acute exacerbations (AEs) and their significant predictors in newly diagnosed patients. 70 patients newly diagnosed with IPF were prospectively followed for at least 3 yrs. Baseline evaluation included Medical Research Council dyspnoea score (MRCDS), 6-min walk test, pulmonary function tests, all of which were repeated at 6 months, and high-resolution computed tomography. A retrospective cohort of 68 patients was used for confirmation. Mean survival from the time of diagnosis was 30 months, with a 3-yr mortality of 46%. A Risk stratificatiOn ScorE (ROSE) based on MRCDS > 3, 6-min walking distance ≤ 72% predicted and composite physiologic index > 41 predicted 3-yr mortality with high specificity. 6-month progression of ROSE predicted rapid progression. 3-yr incidence of AE was 18.6%, mostly occurring in the first 18 months; risk factors for AE were concomitant emphysema and low diffusing coefficient of the lung for carbon monoxide. Results were confirmed in an independent cohort of patients. In newly diagnosed IPF, advanced disease at presentation, rapid progression and AEs are the determinants of 3-yr survival. The purpose of the multifactorial ROSE is to risk-stratify patients in order to predict survival and detect rapid disease progression.
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Pulmão/fisiopatologia , Fibrose Pulmonar/mortalidade , Idoso , Progressão da Doença , Feminino , Humanos , Incidência , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Prospectivos , Fibrose Pulmonar/fisiopatologia , Curva ROC , Testes de Função Respiratória , Fatores de Risco , Análise de SobrevidaRESUMO
OBJECTIVE: The study objective was to assess in a randomized controlled study (NCT00566839) the comparative results of awake nonresectional or nonawake resectional lung volume reduction surgery. METHOD: Sixty-three patients were randomly assigned by computer to receive unilateral video-assisted thoracic surgery lung volume reduction surgery by a nonresectional technique performed through epidural anesthesia in 32 awake patients (awake group) or the standard resectional technique performed through general anesthesia in 31 patients (control group). Primary outcomes were hospital stay and changes in forced expiratory volume in 1 second. During follow-up, the need of contralateral treatment because of loss of postoperative benefit was considered a failure event as death. RESULTS: Intergroup comparisons (awake vs control) showed no difference in gender, age, and body mass index. Hospital stay was shorter in the awake group (6 vs 7.5 days, P = .04) with 21 versus 10 patients discharged within 6 days (P = .01). At 6 months, forced expiratory volume in 1 second improved significantly in both study groups (0.28 vs 0.29 L) with no intergroup difference (P = .79). In both groups, forced expiratory volume in 1 second improvements lasted more than 24 months. At 36 months, freedom from contralateral treatment was 55% versus 50% (P = .5) and survival was 81% versus 87% (P = .5). CONCLUSIONS: In this randomized study, awake nonresectional lung volume reduction surgery resulted in significantly shorter hospital stay than the nonawake procedure. There were no differences between study groups in physiologic improvements, freedom from contralateral treatment, and survival. We speculate that compared with the nonawake procedure, awake lung volume reduction surgery can offer similar clinical benefit but a faster postoperative recovery.
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Anestesia Epidural , Anestesia Geral , Pneumonectomia/métodos , Idoso , Conscientização , Humanos , Pessoa de Meia-Idade , Estudos Prospectivos , Cirurgia Torácica VídeoassistidaRESUMO
Tobacco smoke exposure is the cause of exaggerated inflammatory responses and tissue destruction leading to chronic bronchitis and emphysema. A number of studies have used biochemical and immunological technologies to identify biomarkers of severity, risk and pharmacological target of disease. Recently, genomic and proteomic studies have been carried out to explore tobacco smoke-induced lung damage mechanisms. Eight of these studies, including 81 healthy non-smokers, 138 healthy smokers and 24 smokers with COPD, had open platform generated data available online and were reviewed in order to identify markers of smoke-induced damage by analyzing differential gene and protein expression in healthy individuals exposed to tobacco smoke in comparison with chronic obstructive pulmonary disease (COPD) smokers and healthy non-smokers. To this end the Ingenuity Pathways Analysis, a web-based application enables identifying the main biological functions and pathways, was used. The pathway most significantly associated with healthy smokers was the Nrf2-mediated Oxidative Stress Response (p-value < 0.01): out of the 22 genes/proteins identified in healthy smokers, 19 were up-regulated and three down-regulated, compared to non-smokers. Interestingly, four genes/proteins of the same pathway were differentially regulated in COPD, one up-regulated and three down-regulated, compared to healthy smokers. Moreover, in the comparison between COPD and healthy smokers, our analysis showed that the most relevant pathway was the Mitochondrial Dysfunction (p-value < 0.01) with 12 differentially regulated genes/proteins. This data-mining review supports the notion that Nrf2-regulated anti-oxidant genes play a central role in protection against tobacco smoke toxic effects and may be amenable to use as COPD risk biomarkers. Furthermore, this review suggests that mitochondrial dysfunction may be involved in the development of COPD.
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Antioxidantes/metabolismo , Nicotiana , Doença Pulmonar Obstrutiva Crônica/metabolismo , Fumaça/efeitos adversos , Fumar/metabolismo , Biomarcadores/metabolismo , Biologia Computacional , Mineração de Dados , Regulação da Expressão Gênica , Humanos , Pulmão/metabolismo , Fator 2 Relacionado a NF-E2/fisiologia , Estresse Oxidativo/genética , Doença Pulmonar Obstrutiva Crônica/etiologia , Fumar/efeitos adversosRESUMO
Metabolic syndrome (MS) is a complex disorder recognized clinically by the findings of abdominal obesity, elevated triglycerides, atherogenic dyslipidaemia, elevated blood pressure, high blood glucose and/or insulin resistance. It is associated with a pro-thrombotic and a pro-inflammatory state. A growing body of evidence suggests that individuals in the community with moderate airflow limitation may have co-existing systemic inflammation with this background. Therefore, we examined a population of 237 patients with metabolic disorder for the concomitant presence of functional pulmonary involvement, as assessed by FEV(1) and FVC impairment. Criteria for the identification of the MS included 3 or more of the following: waist circumference: (>102 cm in men, >88 cm in women), triglycerides levels (> or =150 mg/dl), high-density lipoprotein cholesterol levels (<40 mg/dl in men, <50 mg/dl in women), blood pressure (> or =135/> or =85 mmHg), and fasting glucose levels (>100 mg/dl). 119 subjects were diagnosed MS. Non-smokers patients suffering from MS presented lower spirometric values, with a trend to ventilatory restrictive more than obstructive pattern. Also in smokers patients with MS there was a trend to harmonic decrease in FEV(1) and FVC but not in FEV(1)/FVC ratio, although the changes did not reach statistical significance. Mainly abdominal circumference, and also insulin resistance were retained as independent predictors of both FEV(1) and FVC changes. However, HDL-C was the strongest predictor of FEV(1) and FVC changes, with an inverse association.
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HDL-Colesterol/sangue , Diabetes Mellitus Tipo 2/sangue , Síndrome Metabólica/sangue , Diabetes Mellitus Tipo 2/fisiopatologia , Feminino , Volume Expiratório Forçado/fisiologia , Humanos , Masculino , Síndrome Metabólica/fisiopatologia , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , EspirometriaRESUMO
BACKGROUND AND AIM OF THE WORK: Carbohydrate antigen CA 15-3 is a glycoprotein whose expression, aberrant intracellular localization and changes in glycosylation have been associated with a wide range of cancers. Pulmonary fibrosis represents the final evolution of a chronic inflammation and is defined by the overgrowth of fibroblasts and exaggerated extracellular matrix deposition. The aim of the present study was to evaluate the possible diagnostic role of CA 15-3 in fibrosis in different idiopathic interstitial pneumonias. METHODS: CA 15-3 was measured in serum samples from healthy subjects (n=25) and patients affected with idiopathic pulmonary fibrosis (IPF/UIP) (n=20), sarcoidosis (n=22) at different stages (I, II, and III) and systemic sclerosis (n=25). CA 15-3 protein expression was also evaluated by immunohistochemistry in 21 lung biopsies and in 6 primary lung fibroblasts cell lines. RESULTS: The CA 15-3 serum levels were significantly higher in patients with IPF/UIP and with clinically advanced sarcoidosis (stage III). Serum CA 15-3 levels were slightly increased in patients with systemic sclerosis. No difference was observed between serum CA 15-3 levels in patients with sarcoidosis at stages I and II compared with control subjects. In IPF/UIP and in sarcoidosis at stage III elevated CA 15-3 serum levels significantly correlated with decreased total lung capacity, decreased diffusing capacity of carbon monoxide and high resolution computed tomography findings. Immunohistochemical analysis showed an intense specific CA 15-3 staining in fibroblasts within fibroblastic foci, surrounding sarcoid granulomas and in all cell cultures of lung fibroblasts from IPF/UIP lungs. CONCLUSIONS: Our results indicate that increased CA 15-3 levels are associated with pulmonary interstitial damage, fibroblast activity and progression to fibrosis of the lung. Therefore, CA-15-3 may be considered a sensitive marker useful in the identification of patients with advanced fibrosis and more severe prognosis.