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1.
Rheumatology (Oxford) ; 62(5): 1877-1886, 2023 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-36173318

RESUMEN

OBJECTIVES: To establish a framework by which experts define disease subsets in systemic sclerosis associated interstitial lung disease (SSc-ILD). METHODS: A conceptual framework for subclinical, clinical and progressive ILD was provided to 83 experts, asking them to use the framework and classify actual SSc-ILD patients. Each patient profile was designed to be classified by at least four experts in terms of severity and risk of progression at baseline; progression was based on 1-year follow-up data. A consensus was reached if ≥75% of experts agreed. Experts provided information on which items were important in determining classification. RESULTS: Forty-four experts (53%) completed the survey. Consensus was achieved on the dimensions of severity (75%, 60 of 80 profiles), risk of progression (71%, 57 of 80 profiles) and progressive ILD (60%, 24 of 40 profiles). For profiles achieving consensus, most were classified as clinical ILD (92%), low risk (54%) and stable (71%). Severity and disease progression overlapped in terms of framework items that were most influential in classifying patients (forced vital capacity, extent of lung involvement on high resolution chest CT [HRCT]); risk of progression was influenced primarily by disease duration. CONCLUSIONS: Using our proposed conceptual framework, international experts were able to achieve a consensus on classifying SSc-ILD patients along the dimensions of disease severity, risk of progression and progression over time. Experts rely on similar items when classifying disease severity and progression: a combination of spirometry and gas exchange and quantitative HRCT.


Asunto(s)
Enfermedades Pulmonares Intersticiales , Esclerodermia Sistémica , Humanos , Enfermedades Pulmonares Intersticiales/complicaciones , Esclerodermia Sistémica/complicaciones , Capacidad Vital , Tomografía Computarizada por Rayos X/métodos , Índice de Severidad de la Enfermedad , Pulmón
2.
Respir Res ; 24(1): 6, 2023 Jan 09.
Artículo en Inglés | MEDLINE | ID: mdl-36624431

RESUMEN

BACKGROUND: Systemic sclerosis (SSc) is a rare, complex, connective tissue disorder. Interstitial lung disease (ILD) is common in SSc, occurring in 35-52% of patients and accounting for 20-40% of mortality. Evolution of therapeutic options has resulted in a lack of consensus on how to manage this condition. This Delphi study was initiated to develop consensus recommendations based on expert physician insights regarding screening, progression, treatment criteria, monitoring of response, and the role of recent therapeutic advances with antifibrotics and immunosuppressants in patients with SSc-ILD. METHODS: A modified Delphi process was completed by pulmonologists (n = 13) and rheumatologists (n = 12) with expertise in the management of patients with SSc-ILD. Panelists rated their agreement with each statement on a Likert scale from - 5 (complete disagreement) to + 5 (complete agreement). Consensus was predefined as a mean Likert scale score of ≤ - 2.5 or ≥ + 2.5 with a standard deviation not crossing zero. RESULTS: Panelists recommended that all patients with SSc be screened for ILD by chest auscultation, spirometry with diffusing capacity of the lungs for carbon monoxide, high-resolution computed tomography (HRCT), and/or autoantibody testing. Treatment decisions were influenced by baseline and changes in pulmonary function tests, extent of ILD on HRCT, duration and degree of dyspnea, presence of pulmonary hypertension, and potential contribution of reflux. Treatment success was defined as stabilization or improvement of signs or symptoms of ILD and functional status. Mycophenolate mofetil was identified as the initial treatment of choice. Experts considered nintedanib a therapeutic option in patients with progressive fibrotic ILD despite immunosuppressive therapy or patients contraindicated/unable to tolerate immunotherapy. Concomitant use of nintedanib with MMF/cyclophosphamide can be considered in patients with advanced disease at initial presentation, aggressive ILD, or significant disease progression. Although limited consensus was achieved on the use of tocilizumab, the experts considered it a therapeutic option for patients with early SSc and ILD with elevated acute-phase reactants. CONCLUSIONS: This modified Delphi study generated consensus recommendations for management of patients with SSc-ILD in a real-world setting. Findings from this study provide a management algorithm that will be helpful for treating patients with SSc-ILD and addresses a significant unmet need.


Asunto(s)
Enfermedades Pulmonares Intersticiales , Esclerodermia Sistémica , Humanos , Consenso , Inmunosupresores/uso terapéutico , Enfermedades Pulmonares Intersticiales/diagnóstico , Enfermedades Pulmonares Intersticiales/tratamiento farmacológico , Enfermedades Pulmonares Intersticiales/etiología , Pulmón , Ácido Micofenólico/uso terapéutico , Esclerodermia Sistémica/complicaciones , Esclerodermia Sistémica/diagnóstico , Esclerodermia Sistémica/terapia
3.
Respirology ; 25(7): 690-702, 2020 07.
Artículo en Inglés | MEDLINE | ID: mdl-32436658

RESUMEN

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.


Asunto(s)
Obesidad/epidemiología , Apnea Obstructiva del Sueño/epidemiología , Factores de Edad , Inteligencia Artificial , Comorbilidad , Etnicidad , Carga Global de Enfermedades , Salud Global , Humanos , Prevalencia , Factores de Riesgo , Síndromes de la Apnea del Sueño/epidemiología , Síndromes de la Apnea del Sueño/fisiopatología , Apnea Obstructiva del Sueño/fisiopatología
4.
J Med Assoc Thai ; 96 Suppl 5: S42-8, 2013 Dec.
Artículo en Inglés | MEDLINE | ID: mdl-24851572

RESUMEN

OBJECTIVE: To identify the perception level, and knowledge level of health risks due to waterpipe tobacco smoking, and knowledge about prohibition of waterpipe tobacco smoking, of foreign tourists in Thailand. MATERIAL AND METHOD: This is a descriptive cross-sectional study, carried out among foreign tourists in nightspots on Khao San Road area of Bangkok. Structured interview questionnaire was the data collection instrument for 176 convenience-sampling. RESULTS: More than half (52.3%) of the foreign tourists had a poor level of perception about waterpipe smoking. Majority of foreign tourists (75.5%) had low level of knowledge on the health risks. More than 50% didn't know about the illegal status of waterpipe smoking in Thailand. Chi-square analysis showed that the region where tourists reside was statistically associated with the perception level regarding waterpipe smoking. Age of waterpipe smoking initiation was associated with the region and gender Age of tourists was associated with the knowledge on prohibition of waterpipe smoking. CONCLUSION: Raising awareness among foreign tourists through media advocacy about the rules and regulations regarding waterpipe smoking is necessary to support tobacco control policy. Strict enforcement of the existing law on prohibiting waterpipe smoking should be implemented, Authorities should inform owners/managers of waterpipe, tobacco-smoking prohibition, and require them to put up prohibition signs in their establishments, in both Thai and English languages.


Asunto(s)
Conocimientos, Actitudes y Práctica en Salud , Fumar/efectos adversos , Viaje , Agua , Adolescente , Adulto , Factores de Edad , Estudios Transversales , Femenino , Humanos , Actividades Recreativas , Masculino , Fumar/legislación & jurisprudencia , Encuestas y Cuestionarios , Tailandia
5.
Chest ; 164(4): 963-974, 2023 10.
Artículo en Inglés | MEDLINE | ID: mdl-37054776

RESUMEN

Climate change adversely impacts global health. Increasingly, temperature variability, inclement weather, declining air quality, and growing food and clean water supply insecurities threaten human health. Earth's temperature is projected to increase up to 6.4 °C by the end of the 21st century, exacerbating the threat. Public and health care professionals, including pulmonologists, perceive the detrimental effects of climate change and air pollution and support efforts to mitigate its effects. In fact, evidence is strong that premature cardiopulmonary death is associated with air pollution exposure via inhalation through the respiratory system, which functions as a portal of entry. However, little guidance is available for pulmonologists in recognizing the effects of climate change and air pollution on the diverse range of pulmonary disorders. To educate and mitigate risk for patients competently, pulmonologists must be armed with evidence-based findings of the impact of climate change and air pollution on specific pulmonary diseases. Our goal is to provide pulmonologists with the background and tools to improve patients' health and to prevent adverse outcomes despite climate change-imposed threats. In this review, we detail current evidence of climate change and air pollution impact on a diverse range of pulmonary disorders. Knowledge enables a proactive and individualized approach toward prevention strategies for patients, rather than merely treating ailments reactively.


Asunto(s)
Contaminantes Atmosféricos , Contaminación del Aire , Cambio Climático , Enfermedades Pulmonares , Humanos , Contaminantes Atmosféricos/efectos adversos , Contaminación del Aire/efectos adversos , Alérgenos/efectos adversos , Neumólogos/educación , Enfermedades Pulmonares/diagnóstico , Enfermedades Pulmonares/etiología , Enfermedades Pulmonares/prevención & control , Enfermedades Pulmonares/terapia
6.
Semin Respir Crit Care Med ; 33(5): 555-71, 2012 Oct.
Artículo en Inglés | MEDLINE | ID: mdl-23001808

RESUMEN

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.


Asunto(s)
Eosinofilia/fisiopatología , Enfermedades Pulmonares/fisiopatología , Eosinofilia Pulmonar/fisiopatología , Biopsia/métodos , Broncoscopía/métodos , Eosinofilia/diagnóstico , Eosinofilia/terapia , Humanos , Enfermedades Pulmonares/diagnóstico , Enfermedades Pulmonares/terapia , Eosinofilia Pulmonar/diagnóstico , Eosinofilia Pulmonar/terapia
7.
Curr Drug Deliv ; 18(5): 596-606, 2021.
Artículo en Inglés | MEDLINE | ID: mdl-32881671

RESUMEN

AIM: To develop a co-crytsal of Telmisartan for enhancing its solubility in water. BACKGROUND: Intermolecular interaction happens in crystal packing; it utilizes and helps to understand the design of new solid with their respective chemical and physical properties called crystal engineering. It is a blueprint of molecular solids with specific chemical and physical properties through an understanding and handling of intermolecular interaction for increasing the solubility, in case of poor water-soluble drugs. OBJECTIVES: The study was taken under consideration with an aim to generate and synthesize a cocrystal form of Telmisartan (TEL) with L-lysine to improve its water solubility, dissolution, and micrometric properties. METHODS: Using dry grinding technique, solvent evaporation and cooling crystallization, the results revealed a generation of co-crystals with enhanced solubility by liquid drop grinding method. Hence, this process was further explored to investigate various formulations and process parameters that could significantly affect the crystal solubility, dissolution, and micrometric properties. RESULTS: The solubility of TEL co-crystals was enhanced by L-lysine. Further, the optimized batch was subjected to its micrometric evaluation and physiochemical characterization like FT-IR, NMR, PXRD. The result of the micrometric evaluation showed better results as compared to standards. The dissolution studies also showed a better dissolution rate for TEL co-crystal tablets than TEL tablets formulation. CONCLUSION: Co-crystals of TEL with L-lysine showed better solubility and dissolution rate.


Asunto(s)
Cristalografía , Lisina , Telmisartán/química , Aminoácidos/química , Preparaciones Farmacéuticas , Solubilidad , Espectroscopía Infrarroja por Transformada de Fourier
8.
Am J Respir Crit Care Med ; 177(9): 983-8, 2008 May 01.
Artículo en Inglés | MEDLINE | ID: mdl-18263805

RESUMEN

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.


Asunto(s)
Caspasa 1/genética , Expresión Génica , ARN Mensajero/genética , Choque Séptico/genética , Proteínas Adaptadoras Transductoras de Señales/biosíntesis , Proteínas Adaptadoras Transductoras de Señales/genética , Adulto , Anciano , Apoptosis , Proteínas Reguladoras de la Apoptosis/biosíntesis , Proteínas Reguladoras de la Apoptosis/genética , Proteínas Adaptadoras de Señalización CARD , Caspasa 1/biosíntesis , Enfermedad Crítica , Proteínas del Citoesqueleto/biosíntesis , Proteínas del Citoesqueleto/genética , Femenino , Estudios de Seguimiento , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Masculino , Persona de Mediana Edad , Monocitos/enzimología , Proteínas NLR , Estudios Prospectivos , ARN Mensajero/metabolismo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , Índice de Severidad de la Enfermedad , Choque Séptico/metabolismo , Choque Séptico/patología , Factores de Tiempo
9.
Lancet Respir Med ; 7(3): 227-238, 2019 03.
Artículo en Inglés | MEDLINE | ID: mdl-30527956

RESUMEN

BACKGROUND: Rare genetic variants cause pulmonary arterial hypertension, but the contribution of common genetic variation to disease risk and natural history is poorly characterised. We tested for genome-wide association for pulmonary arterial hypertension in large international cohorts and assessed the contribution of associated regions to outcomes. METHODS: We did two separate genome-wide association studies (GWAS) and a meta-analysis of pulmonary arterial hypertension. These GWAS used data from four international case-control studies across 11 744 individuals with European ancestry (including 2085 patients). One GWAS used genotypes from 5895 whole-genome sequences and the other GWAS used genotyping array data from an additional 5849 individuals. Cross-validation of loci reaching genome-wide significance was sought by meta-analysis. Conditional analysis corrected for the most significant variants at each locus was used to resolve signals for multiple associations. We functionally annotated associated variants and tested associations with duration of survival. All-cause mortality was the primary endpoint in survival analyses. FINDINGS: A locus near SOX17 (rs10103692, odds ratio 1·80 [95% CI 1·55-2·08], p=5·13 × 10-15) and a second locus in HLA-DPA1 and HLA-DPB1 (collectively referred to as HLA-DPA1/DPB1 here; rs2856830, 1·56 [1·42-1·71], p=7·65 × 10-20) within the class II MHC region were associated with pulmonary arterial hypertension. The SOX17 locus had two independent signals associated with pulmonary arterial hypertension (rs13266183, 1·36 [1·25-1·48], p=1·69 × 10-12; and rs10103692). Functional and epigenomic data indicate that the risk variants near SOX17 alter gene regulation via an enhancer active in endothelial cells. Pulmonary arterial hypertension risk variants determined haplotype-specific enhancer activity, and CRISPR-mediated inhibition of the enhancer reduced SOX17 expression. The HLA-DPA1/DPB1 rs2856830 genotype was strongly associated with survival. Median survival from diagnosis in patients with pulmonary arterial hypertension with the C/C homozygous genotype was double (13·50 years [95% CI 12·07 to >13·50]) that of those with the T/T genotype (6·97 years [6·02-8·05]), despite similar baseline disease severity. INTERPRETATION: This is the first study to report that common genetic variation at loci in an enhancer near SOX17 and in HLA-DPA1/DPB1 is associated with pulmonary arterial hypertension. Impairment of SOX17 function might be more common in pulmonary arterial hypertension than suggested by rare mutations in SOX17. Further studies are needed to confirm the association between HLA typing or rs2856830 genotyping and survival, and to determine whether HLA typing or rs2856830 genotyping improves risk stratification in clinical practice or trials. FUNDING: UK NIHR, BHF, UK MRC, Dinosaur Trust, NIH/NHLBI, ERS, EMBO, Wellcome Trust, EU, AHA, ACClinPharm, Netherlands CVRI, Dutch Heart Foundation, Dutch Federation of UMC, Netherlands OHRD and RNAS, German DFG, German BMBF, APH Paris, INSERM, Université Paris-Sud, and French ANR.


Asunto(s)
Cadenas alfa de HLA-DP/genética , Cadenas beta de HLA-DP/genética , Hipertensión Arterial Pulmonar , Factores de Transcripción SOXF/genética , Femenino , Predisposición Genética a la Enfermedad , Variación Genética , Estudio de Asociación del Genoma Completo , Técnicas de Genotipaje/métodos , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Hipertensión Arterial Pulmonar/diagnóstico , Hipertensión Arterial Pulmonar/genética , Hipertensión Arterial Pulmonar/metabolismo , Hipertensión Arterial Pulmonar/mortalidad , Medición de Riesgo , Transducción de Señal/genética , Análisis de Supervivencia
10.
Drugs Aging ; 25(9): 717-28, 2008.
Artículo en Inglés | MEDLINE | ID: mdl-18729545

RESUMEN

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.


Asunto(s)
Broncodilatadores/farmacología , Enfermedad Pulmonar Obstructiva Crónica/fisiopatología , Anciano , Envejecimiento , Ensayos Clínicos como Asunto , Volumen Espiratorio Forzado , Humanos , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Valores de Referencia , Pruebas de Función Respiratoria , Índice de Severidad de la Enfermedad , Espirometría/métodos , Capacidad Vital
12.
Eur Respir Rev ; 27(150)2018 Dec 31.
Artículo en Inglés | MEDLINE | ID: mdl-30578331

RESUMEN

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.


Asunto(s)
Enfermedades Pulmonares Intersticiales/terapia , Pulmón/efectos de los fármacos , Fibrosis Pulmonar/terapia , Progresión de la Enfermedad , Femenino , Humanos , Pulmón/diagnóstico por imagen , Pulmón/fisiopatología , Enfermedades Pulmonares Intersticiales/diagnóstico por imagen , Enfermedades Pulmonares Intersticiales/mortalidad , Enfermedades Pulmonares Intersticiales/fisiopatología , Masculino , Persona de Mediana Edad , Fenotipo , Pronóstico , Fibrosis Pulmonar/diagnóstico por imagen , Fibrosis Pulmonar/mortalidad , Fibrosis Pulmonar/fisiopatología , Medición de Riesgo , Factores de Riesgo
13.
Curr Opin Pharmacol ; 6(3): 284-92, 2006 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-16650800

RESUMEN

Idiopathic pulmonary fibrosis is the most common form of the interstitial lung diseases and is characterized by chronic progressive pulmonary parenchymal fibrosis. Although the diagnosis and pathophysiology of this disease have been better characterized over the past few years, there remains no effective therapy for this disease. Therapies initially aimed at inflammation have proven ineffective, and newer strategies targeting aspects of aberrant wound repair involving alveolar epithelial cells or septal endothelial cells are now being investigated. Therapeutic strategies include the anti-fibrotic agents pirfenidone and interferon-gamma. Agents targeting specific cytokines, including connective tissue growth factor, transforming growth factor-beta and chemokines, are being evaluated. The restoration of oxidant balance and inhibition of leukotrienes represent other strategies. Additionally, the role of the coagulation/fibrinolytic systems and angiogenesis has also been examined.


Asunto(s)
Inhibidores de la Angiogénesis/uso terapéutico , Antiinflamatorios no Esteroideos/uso terapéutico , Antioxidantes/uso terapéutico , Pulmón/irrigación sanguínea , Neovascularización Patológica/prevención & control , Fibrosis Pulmonar/tratamiento farmacológico , Inhibidores de la Angiogénesis/farmacología , Animales , Antiinflamatorios no Esteroideos/farmacología , Anticuerpos Monoclonales/uso terapéutico , Antioxidantes/farmacología , Factor de Crecimiento del Tejido Conjuntivo , Humanos , Proteínas Inmediatas-Precoces/inmunología , Proteínas Inmediatas-Precoces/metabolismo , Péptidos y Proteínas de Señalización Intercelular/inmunología , Péptidos y Proteínas de Señalización Intercelular/metabolismo , Pulmón/efectos de los fármacos , Molibdeno/farmacología , Molibdeno/uso terapéutico , Fibrosis Pulmonar/metabolismo , Fibrosis Pulmonar/patología , Piridonas/farmacología , Piridonas/uso terapéutico , Ensayos Clínicos Controlados Aleatorios como Asunto
14.
Chest ; 130(1): 200-6, 2006 Jul.
Artículo en Inglés | MEDLINE | ID: mdl-16840402

RESUMEN

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.


Asunto(s)
Envejecimiento/fisiología , Enfermedad Pulmonar Obstructiva Crónica/diagnóstico , Índice de Severidad de la Enfermedad , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Antropometría , Femenino , Volumen Espiratorio Forzado , Humanos , Masculino , Persona de Mediana Edad , Enfermedad Pulmonar Obstructiva Crónica/clasificación , Espirometría
15.
Biomark Med ; 10(3): 265-300, 2016.
Artículo en Inglés | MEDLINE | ID: mdl-26925513

RESUMEN

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.


Asunto(s)
Artroplastia , Biomarcadores/metabolismo , Miocardio/metabolismo , Medición de Riesgo , Apnea Obstructiva del Sueño/metabolismo , Estudios de Factibilidad , Humanos , Complicaciones Posoperatorias/etiología
18.
Chest ; 143(2): 461-470, 2013 Feb 01.
Artículo en Inglés | MEDLINE | ID: mdl-22878868

RESUMEN

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.


Asunto(s)
Nicotina/uso terapéutico , Agonistas Nicotínicos/uso terapéutico , Sarcoidosis Pulmonar/tratamiento farmacológico , Receptor Toll-Like 2/metabolismo , Receptor Toll-Like 9/metabolismo , Antígenos de Superficie/metabolismo , Femenino , Factores de Transcripción Forkhead/metabolismo , Humanos , Inmunidad Celular/efectos de los fármacos , Masculino , Persona de Mediana Edad , Nicotina/farmacología , Agonistas Nicotínicos/farmacología , Fenotipo , Sarcoidosis Pulmonar/metabolismo , Sarcoidosis Pulmonar/patología , Linfocitos T Reguladores/metabolismo , Linfocitos T Reguladores/patología , Receptor Toll-Like 2/inmunología , Receptor Toll-Like 9/inmunología , Resultado del Tratamiento
19.
Am J Respir Cell Mol Biol ; 26(2): 224-30, 2002 Feb.
Artículo en Inglés | MEDLINE | ID: mdl-11804874

RESUMEN

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.


Asunto(s)
Caspasas/metabolismo , Factor Estimulante de Colonias de Macrófagos/farmacología , Monocitos/fisiología , Fosfatidilinositol 3-Quinasas/metabolismo , Proteínas Serina-Treonina Quinasas , Proteínas Proto-Oncogénicas/metabolismo , Androstadienos/farmacología , Caspasa 3 , Caspasa 9 , Supervivencia Celular , Células Cultivadas , Cromonas/farmacología , Fragmentación del ADN , Activación Enzimática , Inhibidores Enzimáticos/farmacología , Factor Estimulante de Colonias de Granulocitos y Macrófagos/farmacología , Humanos , Interleucina-1/farmacología , Interleucina-18/farmacología , L-Lactato Deshidrogenasa/metabolismo , Lipopolisacáridos/farmacología , Monocitos/efectos de los fármacos , Monocitos/enzimología , Morfolinas/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Fosforilación , Proteínas Proto-Oncogénicas c-akt , Factor de Necrosis Tumoral alfa/farmacología , Wortmanina
20.
J Immunol ; 169(11): 6427-34, 2002 Dec 01.
Artículo en Inglés | MEDLINE | ID: mdl-12444151

RESUMEN

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.


Asunto(s)
Factor Estimulante de Colonias de Macrófagos/farmacología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Fosfatidilinositol 3-Quinasas/metabolismo , Androstadienos/farmacología , Supervivencia Celular/efectos de los fármacos , Cromonas/farmacología , Fragmentación del ADN/efectos de los fármacos , Activación Enzimática/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Flavonoides/farmacología , Humanos , Peróxido de Hidrógeno/farmacología , Técnicas In Vitro , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Monocitos/citología , Morfolinas/farmacología , Inhibidores de las Quinasa Fosfoinosítidos-3 , Especies Reactivas de Oxígeno/metabolismo , Wortmanina
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