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1.
Respirology ; 25(7): 690-702, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32436658

RESUMO

One-seventh of the world's adult population, or approximately one billion people, are estimated to have OSA. Over the past four decades, obesity, the main risk factor for OSA, has risen in striking proportion worldwide. In the past 5 years, the WHO estimates global obesity to affect almost two billion adults. A second major risk factor for OSA is advanced age. As the prevalence of the ageing population and obesity increases, the vulnerability towards having OSA increases. In addition to these traditional OSA risk factors, studies of the global population reveal select contributing features and phenotypes, including extreme phenotypes and symptom clusters that deserve further examination. Untreated OSA is associated with significant comorbidities and mortality. These represent a tremendous threat to the individual and global health. Beyond the personal toll, the economic costs of OSA are far-reaching, affecting the individual, family and society directly and indirectly, in terms of productivity and public safety. A better understanding of the pathophysiology, individual and ethnic similarities and differences is needed to better facilitate management of this chronic disease. In some countries, measures of the OSA disease burden are sparse. As the global burden of OSA and its associated comorbidities are projected to further increase, the infrastructure to diagnose and manage OSA will need to adapt. The use of novel approaches (electronic health records and artificial intelligence) to stratify risk, diagnose and affect treatment are necessary. Together, a unified multi-disciplinary, multi-organizational, global approach will be needed to manage this disease.


Assuntos
Obesidade/epidemiologia , Apneia Obstrutiva do Sono/epidemiologia , Fatores Etários , Inteligência Artificial , Comorbidade , Etnicidade , Carga Global da Doença , Saúde Global , Humanos , Prevalência , Fatores de Risco , Síndromes da Apneia do Sono/epidemiologia , Síndromes da Apneia do Sono/fisiopatologia , Apneia Obstrutiva do Sono/fisiopatologia
2.
Eur Respir Rev ; 27(150)2018 Dec 31.
Artigo em Inglês | MEDLINE | ID: mdl-30578331

RESUMO

Acute exacerbation of interstitial lung disease (ILD) is associated with a poor prognosis and high mortality. Numerous studies have documented acute exacerbation in idiopathic pulmonary fibrosis (IPF), but less is known about these events in other ILDs that may present a progressive-fibrosing phenotype. We propose defining acute exacerbation as an acute, clinically significant respiratory deterioration, typically less than 1 month in duration, together with computerised tomography imaging showing new bilateral glass opacity and/or consolidation superimposed on a background pattern consistent with fibrosing ILDs. Drawing on observations in IPF, it is suspected that epithelial injury or proliferation and autoimmunity are risk factors for acute exacerbation in ILDs that may present a progressive-fibrosing phenotype, but further studies are required. Current acute exacerbation management strategies are based on recommendations in IPF, but no randomised controlled trials of acute exacerbation management have been performed. Although there are no formal strategies to prevent the development of acute exacerbation, possible approaches include antifibrotic drugs (such as nintedanib and pirfenidone), and minimising exposure to infection, airborne irritants and pollutants. This review discusses the current knowledge of acute exacerbation of ILDs that may present a progressive-fibrosing phenotype and acknowledges limitations of the data available.


Assuntos
Doenças Pulmonares Intersticiais/terapia , Pulmão/efeitos dos fármacos , Fibrose Pulmonar/terapia , Progressão da Doença , Feminino , Humanos , Pulmão/diagnóstico por imagem , Pulmão/fisiopatologia , Doenças Pulmonares Intersticiais/diagnóstico por imagem , Doenças Pulmonares Intersticiais/mortalidade , Doenças Pulmonares Intersticiais/fisiopatologia , Masculino , Pessoa de Meia-Idade , Fenótipo , Prognóstico , Fibrose Pulmonar/diagnóstico por imagem , Fibrose Pulmonar/mortalidade , Fibrose Pulmonar/fisiopatologia , Medição de Risco , Fatores de Risco
3.
Biomark Med ; 10(3): 265-300, 2016.
Artigo em Inglês | MEDLINE | ID: mdl-26925513

RESUMO

Obstructive sleep apnea (OSA) is highly prevalent in patients undergoing total joint arthroplasty (TJA) and is a major risk factor for postoperative cardiovascular complications and death. Recognizing this, the American Society of Anesthesiologists urges clinicians to implement special considerations in the perioperative care of OSA patients. However, as the volume of patients presenting for TJA increases, resources to implement these recommendations are limited. This necessitates mechanisms to efficiently risk stratify patients having OSA who may be susceptible to post-TJA cardiovascular complications. We explore the role of perioperative measurement of cardiac troponins (cTns) and brain natriuretic peptides (BNPs) in helping determine which OSA patients are at increased risk for post-TJA cardiovascular-related morbidity.


Assuntos
Artroplastia , Biomarcadores/metabolismo , Miocárdio/metabolismo , Medição de Risco , Apneia Obstrutiva do Sono/metabolismo , Estudos de Viabilidade , Humanos , Complicações Pós-Operatórias/etiologia
4.
Chest ; 143(2): 461-470, 2013 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-22878868

RESUMO

BACKGROUND: New evidence links nicotine to the regulation of T cell-mediated inflammation via a 7 nicotinic cholinergic receptor activation, and chronic nicotine exposure (smoking) reduces the incidence of granulomatous diseases. We sought to determine whether nicotine treatment was well tolerated while effectively normalizing immune responses in patients with active pulmonary sarcoidosis. METHODS: Consenting adults with symptomatic sarcoidosis (n 5 13) were randomly assigned to receive 12 weeks of nicotine treatment plus conventional therapy or conventional therapy alone. Obtained blood cells were evaluated for their responsiveness to selected Toll-like receptor (TLR) and nucleotide oligomerization domain-like receptor ligands and T cell surface marker expression before and after nicotine treatment. Asymptomatic patients (n 5 6) and disease-free subjects (n 5 6) served as comparative control subjects. Adverse events were monitored for the duration of the study. RESULTS: Compared with the asymptomatic group, symptomatic patients had impaired peripheral responses to TLR2, TLR4, and TLR9 ligands (anergy) and reduced peripheral populations of CD4 1 FoxP3 1 regulatory T cells (Tregs). Nicotine treatment was associated with restoration of TLR2 and TLR9 responsiveness, and expansion of Tregs, including the CD4 1 CD25 2 FoxP3 1 phenotype. There were no serious adverse events or signs of nicotine dependency. CONCLUSIONS: Nicotine treatment in active pulmonary sarcoidosis was well tolerated and restored peripheral immune responsiveness to TLR2 and TLR9 agonists and expansion of FoxP3 1 Tregs, including a specific "preactivated" (CD25 2 ) phenotype. The immune phenotype of patients with symptomatic sarcoidosis treated with nicotine closely resembled that of asymptomatic patients, supporting the notion that nicotine treatment may be beneficial in this patient population.


Assuntos
Nicotina/uso terapêutico , Agonistas Nicotínicos/uso terapêutico , Sarcoidose Pulmonar/tratamento farmacológico , Receptor 2 Toll-Like/metabolismo , Receptor Toll-Like 9/metabolismo , Antígenos de Superfície/metabolismo , Feminino , Fatores de Transcrição Forkhead/metabolismo , Humanos , Imunidade Celular/efeitos dos fármacos , Masculino , Pessoa de Meia-Idade , Nicotina/farmacologia , Agonistas Nicotínicos/farmacologia , Fenótipo , Sarcoidose Pulmonar/metabolismo , Sarcoidose Pulmonar/patologia , Linfócitos T Reguladores/metabolismo , Linfócitos T Reguladores/patologia , Receptor 2 Toll-Like/imunologia , Receptor Toll-Like 9/imunologia , Resultado do Tratamento
5.
Semin Respir Crit Care Med ; 33(5): 555-71, 2012 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-23001808

RESUMO

The eosinophilic lung diseases are a group of pulmonary disorders characterized by an increase in blood and/or lung eosinophils. These disorders can be primary pulmonary disorders or the secondary manifestation of other systemic or pulmonary conditions, infection, drug reaction, or malignancy. The approach to a patient with eosinophilic lung disease involves a thorough history and physical examination, review of exposures and appropriate testing, often including bronchoscopy or lung biopsy, to establish a specific etiology and determine therapy. Eosinophilic lung disease can be suspected based on either the finding of pulmonary disease with blood eosinophilia, pulmonary disease with bronchoalveolar lavage eosinophilia, or pulmonary disease with lung tissue eosinophilia on lung biopsy.


Assuntos
Eosinofilia/fisiopatologia , Pneumopatias/fisiopatologia , Eosinofilia Pulmonar/fisiopatologia , Biópsia/métodos , Broncoscopia/métodos , Eosinofilia/diagnóstico , Eosinofilia/terapia , Humanos , Pneumopatias/diagnóstico , Pneumopatias/terapia , Eosinofilia Pulmonar/diagnóstico , Eosinofilia Pulmonar/terapia
7.
Drugs Aging ; 25(9): 717-28, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-18729545

RESUMO

Chronic obstructive pulmonary disease (COPD) is a very common lung disease most often related to a history of smoking. It becomes more prevalent with increasing age but remains under-diagnosed and under-treated in the elderly population. The Global Initiative for Obstructive Lung Disease (GOLD) programme has been instrumental in providing standard diagnostic criteria as well as recommendations for prevention and management of COPD. GOLD recommendations define COPD as a post-bronchodilator forced expiratory volume in 1 second (FEV(1))/forced vital capacity (FVC) of <70%, with the severity based on the value of FEV(1). This recommendation is different from that of many previous reports that have recommended diagnosing obstruction using the statistically derived lower limit of normal (LLN), which varies for each person according to age, height, ethnicity and gender. While the use of a 70% ratio may be simpler, it may result in under-diagnosis of airflow obstruction in younger people and over-diagnosis in the elderly. This is particularly important as the elderly may be most sensitive to many of the adverse effects of medications used in the treatment of COPD, including corticosteroids and anticholinergic bronchodilators.Most of the studies comparing the LLN and a fixed ratio of 70% have not been performed with post-bronchodilator testing as recommended by GOLD. Generation of post-bronchodilator reference sets and studies comparing the LLN with the post-bronchodilator FEV(1)/FVC ratio of <70% will help resolve this issue. One recent study examined patients admitted to hospitals who had an FEV(1)/FVC ratio of <70% but above the LLN, and found they were at increased risk of death and COPD complications. This would support the use of GOLD criteria. Further studies examining this population are needed.In addition to the uncertainties about what diagnostic criteria should be utilized for diagnosis of airflow obstruction, different organizations make different recommendations on screening spirometry. A conservative recommendation is to perform spirometry in symptomatic individuals. It is important to remember that while COPD is under-diagnosed in the elderly, this group is also at a higher risk of being falsely classified as having airflow obstruction using the 70% ratio recommended by GOLD. This can result in unnecessary use of medications and increased risk of adverse effects to which the elderly are more prone.


Assuntos
Broncodilatadores/farmacologia , Doença Pulmonar Obstrutiva Crônica/fisiopatologia , Idoso , Envelhecimento , Ensaios Clínicos como Assunto , Volume Expiratório Forçado , Humanos , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Doença Pulmonar Obstrutiva Crônica/tratamento farmacológico , Valores de Referência , Testes de Função Respiratória , Índice de Gravidade de Doença , Espirometria/métodos , Capacidade Vital
8.
Am J Respir Crit Care Med ; 177(9): 983-8, 2008 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-18263805

RESUMO

RATIONALE: Monocytes are central to the initiation of the inflammatory response in sepsis, with caspase-1 activation playing a key role. Monocyte deactivation during sepsis has been linked to poor outcomes. OBJECTIVES: Given the importance of caspase-1 in the immune response, we investigated whether monocytes from patients early in septic shock demonstrate alterations in mRNAs for caspase-1-related molecules. METHODS: Patients with septic shock (n = 26; age >18 years), critically ill intensive care unit patients (n = 20), and healthy volunteers (n = 22) were enrolled in a prospective cohort study in a university intensive care unit. Demographic, biological, physiologic, and plasma cytokine measurements were obtained. Monocytes were assayed for ex vivo tumor necrosis factor-alpha production, and fresh monocyte mRNA was analyzed by quantitative reverse-transcription polymerase chain reaction for Toll-like receptors, NOD-LRR proteins, cytokines, and nuclear factor-kappaB-related genes. MEASUREMENTS AND MAIN RESULTS: Relative copy numbers for the inflammasome mRNAs for ASC, caspase-1, NALP1, and Pypaf-7 were significantly lower in patients with septic shock compared with critically ill control subjects. NALP1 mRNA levels were linked to survival in patients with sepsis (P = 0.0068) and correlated with SAPS II scores (r = -0.63). CONCLUSIONS: These data suggest that monocyte deactivation occurs during the earliest stages of the systemic inflammatory response and that changes in inflammasome mRNA expression are part of this process.


Assuntos
Caspase 1/genética , Expressão Gênica , RNA Mensageiro/genética , Choque Séptico/genética , Proteínas Adaptadoras de Transdução de Sinal/biossíntese , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Idoso , Apoptose , Proteínas Reguladoras de Apoptose/biossíntese , Proteínas Reguladoras de Apoptose/genética , Proteínas Adaptadoras de Sinalização CARD , Caspase 1/biossíntese , Estado Terminal , Proteínas do Citoesqueleto/biossíntese , Proteínas do Citoesqueleto/genética , Feminino , Seguimentos , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/genética , Peptídeos e Proteínas de Sinalização Intracelular/metabolismo , Masculino , Pessoa de Meia-Idade , Monócitos/enzimologia , Proteínas NLR , Estudos Prospectivos , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Índice de Gravidade de Doença , Choque Séptico/metabolismo , Choque Séptico/patologia , Fatores de Tempo
9.
Chest ; 130(1): 200-6, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16840402

RESUMO

BACKGROUND: The American Thoracic Society recommends using the lower limit of normal (LLN) method to diagnose obstructive lung disease. However, few studies have investigated the clinical relevance of these recommendations. We compared the LLN derived from available data sets to a fixed ratio (FEV1/FVC, < 75% or 70%) and also to the FEV1/FVC percent predicted ratio to determine the impact of changing the FEV1/FVC "cutoff" on the spirometric diagnosis of obstructive lung disease. METHODS: FEV1, FVC, FEV1/FVC ratio, age, race, sex, height, and weight were recorded from 1,503 pulmonary function tests. Predicted values were calculated using the Third National Health and Nutrition Examination Study data set (Hankinson), and reference values from studies by Crapo, Knudson, and Morris. In addition, the LLN of the FEV1/FVC ratio was calculated for the Hankinson and Crapo reference values. RESULTS: The number of studies interpreted as obstructed varied from 37% using the Hankinson data set to 55% using the 75% fixed ratio method. Comparing the LLN method vs the 70% fixed ratio method resulted in 7.5% (Hankinson LLN vs 70% fixed) and 6.9% (Crapo LLN vs 70% fixed), which were discordant results. Age was the strongest predictor of discordance, and 16% of subjects > 74 years of age had discordant results comparing Hankinson values to the 70% fixed method. CONCLUSION: At the extremes of age and height, a large number of spirometry test results will be interpreted as showing an obstructive defect if a 70% fixed ratio method is used for interpretation compared with the LLN derived from the Hankinson data set.


Assuntos
Envelhecimento/fisiologia , Doença Pulmonar Obstrutiva Crônica/diagnóstico , Índice de Gravidade de Doença , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Antropometria , Feminino , Volume Expiratório Forçado , Humanos , Masculino , Pessoa de Meia-Idade , Doença Pulmonar Obstrutiva Crônica/classificação , Espirometria
10.
J Immunol ; 169(11): 6427-34, 2002 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-12444151

RESUMO

We previously reported that activation of the phosphatidylinositol (PI) 3-kinase pathway was important in M-CSF-induced monocyte survival. Because M-CSF also induces activation of the mitogen-activated protein (MAP) kinase extracellular-regulated kinase (Erk), we focused on dissecting the mechanism used by M-CSF to induce Erk activation in human monocytes. We found that, in addition to the MAP/Erk kinase inhibitor PD098059, the PI 3-kinase inhibitors LY294002 and wortmannin both suppressed Erk activation in M-CSF-treated monocytes, suggesting that 3-phosphorylated products of PI 3-kinase played a role in Erk activation. Investigating the biochemical pathways regulated by PI 3-kinase to activate Erk, we found that, in response to M-CSF, normal human monocytes induced reactive oxygen species (ROS), which were suppressed by the PI 3-kinase inhibitor wortmannin but not by the solvent control DMSO or the MAP/Erk kinase inhibitor PD098059. We next found that, in the absence of M-CSF, ROS could induce Erk activation in human monocytes. Exogenous H(2)O(2) induced Erk activation in human monocytes, which was suppressed by exogenous catalase. To determine whether ROS induced by M-CSF played a role in Erk activation, we found that N-acetylcysteine and diphenyleneiodonium both suppressed Erk activation in M-CSF-treated monocytes. Erk activation by M-CSF also seemed to play a role in cellular survival in monocytes. These data suggest that, in M-CSF-stimulated human monocytes, PI 3-kinase products and ROS production play a role in Erk activation and monocyte survival.


Assuntos
Fator Estimulador de Colônias de Macrófagos/farmacologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Monócitos/efeitos dos fármacos , Monócitos/metabolismo , Fosfatidilinositol 3-Quinases/metabolismo , Androstadienos/farmacologia , Sobrevivência Celular/efeitos dos fármacos , Cromonas/farmacologia , Fragmentação do DNA/efeitos dos fármacos , Ativação Enzimática/efeitos dos fármacos , Inibidores Enzimáticos/farmacologia , Flavonoides/farmacologia , Humanos , Peróxido de Hidrogênio/farmacologia , Técnicas In Vitro , Proteínas Quinases Ativadas por Mitógeno/antagonistas & inibidores , Monócitos/citologia , Morfolinas/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Espécies Reativas de Oxigênio/metabolismo , Wortmanina
11.
Am J Respir Cell Mol Biol ; 26(2): 224-30, 2002 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-11804874

RESUMO

A number of inflammatory cytokines and growth factors promote monocyte survival; however, the biochemical events stimulated by these factors are poorly defined. We previously showed that the monocyte survival factor macrophage colony-stimulating factor (M-CSF) activated monocyte survival through a PI 3-kinase-dependent pathway resulting in the phosphorylation of Akt and the suppression of the activation of caspase-3. Because other cytokines and bacterial cell wall products also induce monocyte survival, we hypothesized that these factors may also suppress caspase-3 and caspase-9 activation and activate Akt in human monocytes. To test this hypothesis, we found that interleukin (IL)-1beta, tumor necrosis factor (TNF)-alpha, lipopolysaccharide (LPS), granulocyte macrophage-colony-stimulating factor (GM-CSF), and IL-18 appeared to suppress DNA fragmentation, caspase-9, and caspase-3 activation in human monocytes. Moreover, these stimuli appeared to induce the serine and threonine phosphorylation of Akt, which was reduced by the PI 3-kinase inhibitor LY294002. Using in vitro kinase assays, M-CSF appeared to induce more Akt activity than did the other survival factors. Treatment of monocytes with either LY294002 or wortmannin resulted in caspase-3 activation in the presence of these survival factors. These results suggest that monocyte survival factors may suppress DNA fragmentation, caspase-9, and caspase-3 activation in a PI 3-kinase-dependent manner, perhaps through the activation of Akt.


Assuntos
Caspases/metabolismo , Fator Estimulador de Colônias de Macrófagos/farmacologia , Monócitos/fisiologia , Fosfatidilinositol 3-Quinases/metabolismo , Proteínas Serina-Treonina Quinases , Proteínas Proto-Oncogênicas/metabolismo , Androstadienos/farmacologia , Caspase 3 , Caspase 9 , Sobrevivência Celular , Células Cultivadas , Cromonas/farmacologia , Fragmentação do DNA , Ativação Enzimática , Inibidores Enzimáticos/farmacologia , Fator Estimulador de Colônias de Granulócitos e Macrófagos/farmacologia , Humanos , Interleucina-1/farmacologia , Interleucina-18/farmacologia , L-Lactato Desidrogenase/metabolismo , Lipopolissacarídeos/farmacologia , Monócitos/efeitos dos fármacos , Monócitos/enzimologia , Morfolinas/farmacologia , Inibidores de Fosfoinositídeo-3 Quinase , Fosforilação , Proteínas Proto-Oncogênicas c-akt , Fator de Necrose Tumoral alfa/farmacologia , Wortmanina
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