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BACKGROUND: While antifibrotic drugs significantly decrease lung function decline in idiopathic pulmonary fibrosis (IPF), there is still an unmet need to halt disease progression. Antioxidative therapy with N-acetylcysteine (NAC) is considered a potential additional therapy that can be combined with antifibrotics in some patients in clinical practice. However, data on the efficacy, tolerability, and safety of this combination are scarce. We performed a systematic review and meta-analysis to appraise the safety, tolerability, and efficacy of the combination compared to treatment with pirfenidone alone. METHODS: We systematically reviewed all the published studies with combined pirfenidone (PFD) and NAC (PFD + NAC) treatment in IPF patients. The primary outcomes referred to decline in pulmonary function tests (PFTs) and the rates of IPF patients with side effects. RESULTS: In the meta-analysis, 6 studies with 319 total IPF patients were included. The PFD + NAC group was comparable to the PFD alone group in terms of the predicted forced vital capacity (FVC%) and predicted diffusion capacity for carbon monoxide (DLco%) from treatment start to week 24. Side effects and treatment discontinuation rates were also comparable in both groups. CONCLUSION: This systematic review and meta-analysis suggests that combination with NAC does not alter the efficacy, safety, or tolerability of PFD in comparison to PFD alone in IPF patients.
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Acetilcisteína/administración & dosificación , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Piridonas/administración & dosificación , Acetilcisteína/efectos adversos , Administración por Inhalación , Antiinflamatorios no Esteroideos/administración & dosificación , Monóxido de Carbono/sangre , Quimioterapia Combinada , Depuradores de Radicales Libres/administración & dosificación , Humanos , Fibrosis Pulmonar Idiopática/fisiopatología , Piridonas/efectos adversos , Ensayos Clínicos Controlados Aleatorios como Asunto , Resultado del Tratamiento , Capacidad Vital/efectos de los fármacosRESUMEN
PPFE is a rare disease characterized by upper lobe pleural fibrosis and parenchymal fibroelastosis. Its aetiology is considered idiopathic, although possible causative factors have been described. An association of PPFE with solid tumours is unknown and has not been considered previously. We identified six patients with PPFE, four of them with a coexisting malignancy. The case series suggests that PPFE might be an implication of varying factors rather than being an exclusively idiopathic condition.
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Neoplasias de la Mama , Carcinoma Neuroendocrino , Carcinoma de Pulmón de Células no Pequeñas , Pulmón , Neoplasias Pancreáticas , Enfermedades Pleurales , Fibrosis Pulmonar , Anciano , Biopsia , Neoplasias de la Mama/complicaciones , Neoplasias de la Mama/patología , Carcinoma Neuroendocrino/complicaciones , Carcinoma Neuroendocrino/patología , Carcinoma de Pulmón de Células no Pequeñas/complicaciones , Carcinoma de Pulmón de Células no Pequeñas/patología , Diagnóstico Diferencial , Femenino , Humanos , Pulmón/diagnóstico por imagen , Pulmón/patología , Masculino , Persona de Mediana Edad , Neoplasias Pancreáticas/complicaciones , Neoplasias Pancreáticas/patología , Evaluación del Resultado de la Atención al Paciente , Enfermedades Pleurales/diagnóstico , Enfermedades Pleurales/etiología , Enfermedades Pleurales/patología , Enfermedades Pleurales/fisiopatología , Fibrosis Pulmonar/diagnóstico , Fibrosis Pulmonar/etiología , Fibrosis Pulmonar/patología , Fibrosis Pulmonar/fisiopatología , Pruebas de Función Respiratoria/métodos , Tomografía Computarizada por Rayos X/métodosRESUMEN
BACKGROUND: Ventilation/perfusion single-emission photon CT (V/P-SPECT) is widely used to detect pulmonary embolism (PE). Any pathological deficit on P-SPECT with a corresponding unremarkable V-SPECT is considered an embolism. This means that a deficit on P-SPECT with a corresponding deficit on the ventilation scan correlates with other lung pathologies such as pneumonia, bullous emphysema or tumor. In principle, it is possible to identify any of these lung pathologies on nonenhanced chest CT and so this technique has the potential to replace V-SPECT in the diagnosis of PE. Today, SPECT/CT hybrid imaging systems are increasingly applied in clinical routines. OBJECTIVES: We investigated whether embolism can be diagnosed using a combined P-SPECT/CT hybrid imaging approach without V-SPECT. METHODS: Ninety-three patients with clinically suspected embolism were investigated with standard V/P-SPECT and a nonenhanced CT scan on a combined SPECT/CT system. A diagnosis of embolism was based on V/P-SPECT (gold standard). P-SPECT/CT datasets were blinded and analyzed without any knowledge of the V-SPECT data. The accuracy of P-SPECT/CT was compared to the gold standard. RESULTS: Embolism was diagnosed in 24/93 patients using V/P-SPECT. In total, 57 lung lobes were affected. P-SPECT/CT significantly (p < 0.01) overdiagnosed embolism in nonaffected patients. In total, 36 cases with 88 affected lung lobes were shown. The sensitivity was 95.8%, the specificity 82.6%, the false-negative rate 4.2% and the false-positive rate 17.3%. CONCLUSIONS: Our results demonstrate that a nonenhanced CT scan in a novel hybrid imaging system cannot replace V-SPECT in the scintigraphy-based diagnosis of PE. V-SPECT increases specificity and reduces the number of false-positive results when compared to 'perfusion-only' SPECT/CT.
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Errores Diagnósticos/prevención & control , Embolia Pulmonar/diagnóstico , Anciano , Anciano de 80 o más Años , Investigación sobre la Eficacia Comparativa , Femenino , Humanos , Masculino , Persona de Mediana Edad , Imagen de Perfusión/métodos , Sensibilidad y Especificidad , Tomografía Computarizada de Emisión de Fotón Único/métodos , Relación Ventilacion-PerfusiónRESUMEN
BACKGROUND: Pirfenidone is a novel antifibrotic drug for the treatment of mild-to-moderate idiopathic pulmonary fibrosis (IPF). However, adverse events may offset treatment benefits and compliance. OBJECTIVES: To assess recent course of disease, adverse events and compliance in patients who started pirfenidone. METHODS: In an observational cohort study, 63 patients with mild-to-moderate IPF who started pirfenidone between May 2011 and June 2013 were reviewed. Pulmonary function, adverse events and treatment compliance were recorded at each clinic visit. Disease progression was defined as a reduction of vital capacity ≥10% and/or diffusion capacity (DLCO) ≥15%. RESULTS: Follow-up time on pirfenidone treatment was 11 (±7) months. Sixty-six percent of the patients continued with pirfenidone monotherapy and 34% of the patients received pirfenidone combined with corticosteroids (CCS) and/or N-acetylcysteine (NAC). There was a nonsignificant reduction in mean decline of percent predicted forced vital capacity after treatment start (0.7 ± 10.9%) compared to the pretreatment period (6.6 ± 6.7%, p = 0.098). Sixty-two percent of the patients had stable disease on pirfenidone treatment. Adverse events affected 85% of the patients, leading to discontinuation of pirfenidone in 20%. Adverse events and treatment discontinuation were seen more frequently in patients with concomitant CCS and/or NAC treatment. CONCLUSIONS: Adverse events affect the majority of patients treated with pirfenidone, but are mostly manageable with supportive measures. In this heterogeneous patient group, a nonsignificant effect of pirfenidone treatment on pulmonary function was seen, underlining the need for more data on patient selection criteria and efficacy of pirfenidone, particularly in patients with coexistent emphysema and concomitant NAC/CCS treatment.
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Antiinflamatorios no Esteroideos/uso terapéutico , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Piridonas/uso terapéutico , Acetilcisteína/uso terapéutico , Corticoesteroides/uso terapéutico , Anciano , Estudios de Cohortes , Progresión de la Enfermedad , Erupciones por Medicamentos/etiología , Quimioterapia Combinada , Expectorantes/uso terapéutico , Fatiga/inducido químicamente , Femenino , Enfermedades Gastrointestinales/inducido químicamente , Alemania , Humanos , Masculino , Cumplimiento de la Medicación , Persona de Mediana Edad , Estudios Retrospectivos , Centros de Atención Terciaria , Resultado del Tratamiento , Capacidad Vital , Pérdida de PesoRESUMEN
Pulmonary fibrosis greatly impacts patients and their partners. Unmet needs of patients are increasingly acknowledged; the needs of partners often remain unnoticed. Little is known about the best way to educate patients and partners. We investigated pulmonary fibrosis patients' and partners' perspectives and preferences in care, and the differences in these between the Netherlands and Germany. Additionally, we evaluated whether interactive interviewing could be a novel education method in this population. Patients and partners were interviewed during pulmonary fibrosis patient information meetings. In the Netherlands, voting boxes were used and results were projected directly. In Germany, questionnaires were used. In the Netherlands, 278 patients and partners participated; in Germany, 51. Many participants experienced anxiety. Almost all experienced misunderstanding, because people do not know what pulmonary fibrosis is. All expressed a need for information, psychological support and care for partners. Use of the interactive voting system was found to be pleasant (70%) and informative (94%). This study improves the knowledge of care needs of patients with pulmonary fibrosis and their partners. There were no major differences between the Netherlands and Germany. Interactive interviewing could be an attractive method to acquire insights into the needs and preferences of patients and partners, while providing them with information at the same time.
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BACKGROUND: Chronic inflammation and remodeling of the airways remain a hallmark of cystic fibrosis (CF). However, knowledge of the associated mucosal micro-anatomical changes is limited. We evaluated the potential of optical coherence tomography (OCT) for in vivo imaging of the upper airway mucosa in CF patients. METHODS: A flexible OCT probe was used for cross-sectional imaging of the nasal mucosa in 25 CF patients and 25 healthy controls. RESULTS: OCT images showed mucosal details including epithelium, basement membrane, lamina propria with seromucinous glands, and underlying cartilaginous structures. Mean nasal mucosa and epithelial layer thickness were increased in CF compared to controls. In CF patients, antibiotic therapy was associated with reduced nasal mucosa thickening. CONCLUSIONS: OCT detected mucosal changes associated with upper airway inflammation and response to antibiotic therapy in CF patients. OCT may be a useful tool for quantitative in vivo assessment of structural changes of the airway mucosa.
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Fibrosis Quística/complicaciones , Mucosa Nasal/patología , Rinitis/diagnóstico , Tomografía de Coherencia Óptica/métodos , Adulto , Enfermedad Crónica , Fibrosis Quística/diagnóstico , Femenino , Estudios de Seguimiento , Humanos , Masculino , Reproducibilidad de los Resultados , Rinitis/etiología , Factores de TiempoRESUMEN
INTRODUCTION: Comorbidities significantly influence the clinical course of idiopathic pulmonary fibrosis (IPF). However, their prognostic impact is not fully understood. We therefore aimed to determine the impact of comorbidities, as individual and as whole, on survival in IPF. METHODS: The database of a tertiary referral centre for interstitial lung diseases was reviewed for comorbidities, their treatments, their frequency and survival in IPF patients. RESULTS: 272 patients were identified of which 12% had no, 58% 1-3 and 30% 4-7 comorbidities, mainly cardiovascular, pulmonary and oncologic comorbidities. Median survival according to the frequency of comorbidities differed significantly with 66 months for patients without comorbidities, 48 months when 1-3 comorbidities were reported and 35 months when 4-7 comorbidities were prevalent (p = 0.004). A multivariate Cox proportional hazard analyses identified other cardiac diseases and lung cancer as significant predictors of death, gastro-oesophageal reflux disease (GERD) and diastolic dysfunction had a significant positive impact on survival. A significant impact of comorbidities associated therapies on survival was not discovered. This included the use of proton pump inhibitors at baseline, which was not associated with a survival benefit (p = 0.718). We also established a predictive tool for highly prevalent comorbidities, termed IPF comorbidome which demonstrates a new relationship of IPF and comorbidities. CONCLUSION: Comorbidities are frequent in IPF patients. Some comorbidities, especially lung cancer, mainly influence survival in IPF, while others such as GERD may inherit a more favourable effect. Moreover, their cumulative incidence impacts survival.
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Comorbilidad , Fibrosis Pulmonar Idiopática/mortalidad , Anciano , Demografía , Femenino , Humanos , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Fibrosis Pulmonar Idiopática/fisiopatología , Estimación de Kaplan-Meier , Masculino , Modelos de Riesgos Proporcionales , Inhibidores de la Bomba de Protones/uso terapéutico , Análisis de SupervivenciaRESUMEN
1. In systemic vessels, haem-oxygenase (HO) is induced during oxidative stress and known to modulate vasodilatation and vascular remodelling. At birth, with the transition from placental to air breathing, the pulmonary vessels are exposed to oxidative stress and undergo well-documented remodelling processes. Thus, we investigated the role of HO in the lung during adaptation to extra-uterine life using a pig and mouse model. In addition to the novel data presented with regard to one isoform, HO-1, this study is among the first to describe the pulmonary vascular remodelling in the mouse after birth. 2. We show, for the first time, that another isoform, HO-2, is present constitutively at birth and HO-1 protein is induced in the porcine and murine lung after birth in vascular and airway structures, peaking at 14 days in the pig and at about 4 days in the mouse. Furthermore, we show that HO-1 mRNA declines after birth in the mouse lung. 3. Inhibitors of HO did not modify vasodilator responses in vessels from 14-day-old pigs. 4. Moreover, lungs from HO-1-deficient mice developed normally after birth. 5. HO-1 is induced at birth but plays no role in the development of vasodilator responses or remodelling that occurs at this time. These data suggest that HO-1 expression at birth is a redundant response to oxidative stress in the lungs of healthy mammals. However, it remains possible that this pathway protects if complications occur during or after birth.
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Adaptación Fisiológica/fisiología , Hemo Oxigenasa (Desciclizante)/biosíntesis , Pulmón/fisiología , Contracción Muscular/fisiología , Arteria Pulmonar/fisiología , Fenómenos Fisiológicos Respiratorios , Animales , Animales Recién Nacidos , Western Blotting , Hemo Oxigenasa (Desciclizante)/genética , Hemo-Oxigenasa 1 , Pulmón/irrigación sanguínea , Pulmón/enzimología , Pulmón/crecimiento & desarrollo , Proteínas de la Membrana , Ratones , Ratones Noqueados , Músculo Liso Vascular/crecimiento & desarrollo , Músculo Liso Vascular/fisiología , Arteria Pulmonar/crecimiento & desarrollo , Reacción en Cadena de la Polimerasa de Transcriptasa Inversa , PorcinosRESUMEN
BACKGROUND: Cigarette smoke is the leading risk factor for the development of chronic obstructive pulmonary disease (COPD) an inflammatory condition characterised by neutrophilic inflammation and release of proinflammatory mediators such as interleukin-8 (IL-8). Human airway smooth muscle cells (HASMC) are a source of proinflammatory cytokines and chemokines. We investigated whether cigarette smoke could directly induce the release of chemokines from HASMC. METHODS: HASMC in primary culture were exposed to cigarette smoke extract (CSE) with or without TNFalpha. Chemokines were measured by enzyme-linked immunosorbent assay (ELISA) and gene expression by real time polymerase chain reaction (PCR). Data were analysed using one-way analysis of variance (ANOVA) followed by Bonferroni's t test RESULTS: CSE (5, 10 and 15%) induced IL-8 release and expression without effect on eotaxin or RANTES release. At 20%, there was less IL-8 release. TNFalpha enhanced CSE-induced IL-8 release and expression. However, CSE (5-30%) inhibited TNFalpha-induced eotaxin and RANTES production. The effects of CSE on IL-8 release were inhibited by glutathione (GSH) and associated with the induction of the oxidant sensing protein, heme oxygenase-1. CONCLUSION: Cigarette smoke may directly cause the release of IL-8 from HASMC, an effect enhanced by TNF-alpha which is overexpressed in COPD. Inhibition of eotaxin and RANTES by cigarette smoke is consistent with the predominant neutrophilic but not eosinophilic inflammation found in COPD.
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Quimiocina CCL5/metabolismo , Quimiocinas CC/metabolismo , Interleucina-8/metabolismo , Pulmón/metabolismo , Músculo Liso/metabolismo , Miocitos del Músculo Liso/metabolismo , Breas/farmacología , Células Cultivadas , Quimiocina CCL11 , Relación Dosis-Respuesta a Droga , Humanos , Pulmón/citología , Pulmón/efectos de los fármacos , Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacosRESUMEN
BACKGROUND: The elastolytic enzyme matrix metalloproteinase (MMP)-12 has been implicated in the development of airway inflammation and remodeling. We investigated whether human airway smooth muscle cells could express and secrete MMP-12, thereby participating in the pathogenesis of airway inflammatory diseases. METHODS: Laser capture microdissection was used to collect smooth muscle cells from human bronchial biopsy sections. MMP-12 mRNA expression was analysed by quantitative real-time RT-PCR. MMP-12 protein expression and secretion from cultured primary airway smooth muscle cells was further analysed by Western blot. MMP-12 protein localization in bronchial tissue sections was detected by immunohistochemistry. MMP-12 activity was determined by zymography. The TransAM AP-1 family kit was used to measure c-Jun activation and nuclear binding. Analysis of variance was used to determine statistical significance. RESULTS: We provide evidence that MMP-12 mRNA and protein are expressed by in-situ human airway smooth muscle cells obtained from bronchial biopsies of normal volunteers, and of patients with asthma, COPD and chronic cough. The pro-inflammatory cytokine, interleukin (IL)-1beta, induced a >100-fold increase in MMP-12 gene expression and a >10-fold enhancement in MMP-12 activity of primary airway smooth muscle cell cultures. Selective inhibitors of extracellular signal-regulated kinase, c-Jun N-terminal kinase and phosphatidylinositol 3-kinase reduced the activity of IL-1beta on MMP-12, indicating a role for these kinases in IL-1beta-induced induction and release of MMP-12. IL-1beta-induced MMP-12 activity and gene expression was down-regulated by the corticosteroid dexamethasone but up-regulated by the inflammatory cytokine tumour necrosis factor (TNF)-alpha through enhancing activator protein-1 activation by IL-1beta. Transforming growth factor-beta had no significant effect on MMP-12 induction. CONCLUSION: Our findings indicate that human airway smooth muscle cells express and secrete MMP-12 that is up-regulated by IL-1beta and TNF-alpha. Bronchial smooth muscle cells may be an important source of elastolytic activity, thereby participating in remodeling in airway diseases such as COPD and chronic asthma.
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Bronquios/citología , Bronquios/metabolismo , Interleucina-1/administración & dosificación , Metaloendopeptidasas/metabolismo , Músculo Liso/metabolismo , Miocitos del Músculo Liso/metabolismo , Factor de Necrosis Tumoral alfa/administración & dosificación , Bronquios/efectos de los fármacos , Células Cultivadas , Relación Dosis-Respuesta a Droga , Regulación Enzimológica de la Expresión Génica/efectos de los fármacos , Regulación Enzimológica de la Expresión Génica/fisiología , Humanos , Metaloproteinasa 12 de la Matriz , Músculo Liso/efectos de los fármacos , Miocitos del Músculo Liso/efectos de los fármacosRESUMEN
Chronic obstructive pulmonary disease is characterized by progressive airflow limitation and pulmonary inflammation. Inhaled corticosteroids (ICS) have been shown to be effective in the reduction of the number of exacerbations and the rate of deterioration in health status in patients with more advanced chronic obstructive pulmonary disease (COPD). Therefore current international guidelines recommend ICS for patients with severe COPD (FEV1 < 50%) with at least one exacerbation within the last year. We determined the short-term effect of the inhaled corticosteroid beclomethasone in HFA 134 formulation (Ventolair) on Health related Quality of Life (HRQOL), pulmonary function and the release of the cytokines Interleukin-10 (IL-10), Granulocyte-Macrophage Colony-stimulating Factor (GM-CSF), Interferon-gamma (IFN-gamma) and Macrophage Inflammatory Protein-1alpha (MIP-1alpha) from peripheral blood monocytes of patients with COPD (n = 11) in a 12 week double blind cross over placebo-controlled study. Baseline lung function and the St. George Respiratory Questionnaire (SGRQ) were performed at the start and the end of each treatment phase. Monocytes were separated from blood at the end of each treatment phase. The treatment with Ventolair) resulted in an increase of PEF from 4.92 to 5.53 l/s and a decrease of RV% TLC (% predicted) values from 144.52 to 131.36. Inhaled HFA beclomethasone did not affect the cytokine release of IL-10, IFN-gamma, GM-CSF and MIP-1alpha. All cytokines were measured using commercially available Enzyme Linked Immun Sorbent Assay (ELISA) kits. The symptom score of the St. George Respiratory Questionnaire significantly decreased from 55.12 to 47.77 units in the active period compared to the placebo period after the treatment with HFA beclomethasone. The present study shows that a short-term treatment with inhaled steroid beclomethasone in fine particle HFA formulation decreases the hyperinflation and improves the PEF and the COPD symptoms.
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Antiinflamatorios/uso terapéutico , Beclometasona/uso terapéutico , Glucocorticoides/uso terapéutico , Enfermedad Pulmonar Obstructiva Crónica/tratamiento farmacológico , Administración por Inhalación , Estudios Cruzados , Citocinas/sangre , Método Doble Ciego , Ensayo de Inmunoadsorción Enzimática , Femenino , Volumen Espiratorio Forzado/efectos de los fármacos , Humanos , Hidrocortisona/sangre , Pulmón/efectos de los fármacos , Masculino , Persona de Mediana Edad , Monocitos/efectos de los fármacos , Monocitos/metabolismo , Enfermedad Pulmonar Obstructiva Crónica/sangre , Calidad de VidaRESUMEN
OBJECTIVES: To describe changes over time in extent of idiopathic pulmonary fibrosis (IPF) at multidetector computed tomography (MDCT) assessed by semi-quantitative visual scores (VSs) and fully automatic histogram-based quantitative evaluation and to test the relationship between these two methods of quantification. METHODS: Forty IPF patients (median age: 70 y, interquartile: 62-75 years; M:F, 33:7) that underwent 2 MDCT at different time points with a median interval of 13 months (interquartile: 10-17 months) were retrospectively evaluated. In-house software YACTA quantified automatically lung density histogram (10th-90th percentile in 5th percentile steps). Longitudinal changes in VSs and in the percentiles of attenuation histogram were obtained in 20 untreated patients and 20 patients treated with pirfenidone. Pearson correlation analysis was used to test the relationship between VSs and selected percentiles. RESULTS: In follow-up MDCT, visual overall extent of parenchymal abnormalities (OE) increased in median by 5%/year (interquartile: 0%/y; +11%/y). Substantial difference was found between treated and untreated patients in HU changes of the 40th and of the 80th percentiles of density histogram. Correlation analysis between VSs and selected percentiles showed higher correlation between the changes (Δ) in OE and Δ 40th percentile (r=0.69; p<0.001) as compared to Δ 80th percentile (r=0.58; p<0.001); closer correlation was found between Δ ground-glass extent and Δ 40th percentile (r=0.66, p<0.001) as compared to Δ 80th percentile (r=0.47, p=0.002), while the Δ reticulations correlated better with the Δ 80th percentile (r=0.56, p<0.001) in comparison to Δ 40th percentile (r=0.43, p=0.003). CONCLUSIONS: There is a relevant and fully automatically measurable difference at MDCT in VSs and in histogram analysis at one year follow-up of IPF patients, whether treated or untreated: Δ 40th percentile might reflect the change in overall extent of lung abnormalities, notably of ground-glass pattern; furthermore Δ 80th percentile might reveal the course of reticular opacities.
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Fibrosis Pulmonar Idiopática/diagnóstico por imagen , Pulmón/diagnóstico por imagen , Tomografía Computarizada Multidetector/métodos , Anciano , Progresión de la Enfermedad , Femenino , Humanos , Fibrosis Pulmonar Idiopática/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Piridonas/uso terapéutico , Estudios Retrospectivos , Resultado del TratamientoRESUMEN
BACKGROUND: Idiopathic interstitial pneumonias (IIP) are associated with an increased lung cancer (LC) risk. However, data on the prognostic and therapeutic impact are limited. We therefore aimed to analyze the outcome of IIP patients with LC under different treatment modalities. METHODS: Patients with IIPs diagnosed in a tertiary interstitial lung diseases (ILD) center were reviewed for LC diagnosis. RESULTS: Of 265 patients with idiopathic pulmonary fibrosis (IPF), 142 with non-specific interstitial pneumonia (NSIP), and 71 with cryptogenic organizing pneumonia (COP), 16%, 4%, and 6% were affected byLC, respectively. Patient characteristics were: IPF: 93% male, median age 67 years, forced vital capacity (FVC) 82%, diffusion capacity for Carbon monoxide (DLCO) 41%, mean survival 20 months. NSIP: 67% male, median age 70 years, FVC 72%, DLCO 43%, mean survival 35 months. COP: 50% male, median age 66 years, FVC 93%, DLCO 77%, mean survival 88 months. Significant treatment-related toxicities occurred in 55% IPF, 20% NSIP und 0% COP patients. 30-days postoperative mortality was 25% in IPF, and 0% in NSIP/COP while rate of radiation pneumonitis was 24% in IPF. CONCLUSIONS: LC is a frequent comorbidity in IIP, with a higher incidence and reduced survival in IPF compared to other IIPs. LC treatment is associated with significant toxicity, specifically in IPF. Interdisciplinary evaluation of therapeutic options in IIP patients diagnosed with LC is therefore mandatory.
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Neumonías Intersticiales Idiopáticas/epidemiología , Neoplasias Pulmonares/terapia , Pulmón , Adulto , Anciano , Anciano de 80 o más Años , Biopsia , Comorbilidad , Femenino , Alemania/epidemiología , Humanos , Neumonías Intersticiales Idiopáticas/diagnóstico , Neumonías Intersticiales Idiopáticas/mortalidad , Neumonías Intersticiales Idiopáticas/fisiopatología , Estimación de Kaplan-Meier , Pulmón/patología , Pulmón/fisiopatología , Pulmón/cirugía , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidad , Neoplasias Pulmonares/fisiopatología , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Estudios Retrospectivos , Factores de Riesgo , Centros de Atención Terciaria , Factores de Tiempo , Tomografía Computarizada por Rayos X , Resultado del TratamientoRESUMEN
Asthma is associated with abnormal airway smooth muscle (ASM) growth that may contribute to airway narrowing and hyperresponsiveness. We investigated the role of mitogen-activated protein kinase (MAPK) pathway in IL-1beta induced ASM proliferation in the rat. Rat tracheal ASM cells were dissociated and maintained in culture. We examined the effect of selective MAPK inhibitors, SB239063 (a p38 MAPK inhibitor), U0126 (a mitogen-activated and extracellular regulated kinase kinase, MEK-1, inhibitor which inhibits downstream extracellular regulated kinase, ERK, activity), and SP600125 (a c-jun N-terminal kinase, JNK, inhibitor) on IL-1beta-induced proliferation. Proliferation of ASM cells was significantly increased following exposure to IL-1beta in a dose-dependent manner. p38, JNK and ERK MAPKs were activated by IL-1beta in a time-dependent manner, with peak activation time at 30, 60 min and at 6 h, respectively. This activation was inhibited by their respective inhibitors. SP600125 (20 microM) had no effect on IL-1beta-induced ERK and p38 phosphorylation. SB239063, U0126 and SP600125 dose-dependently inhibited IL-1beta-dependent proliferation at doses that inhibit the activities of p38, ERK and JNK MAPKs, respectively. No additive or synergistic effects were observed on proliferative responses with any combination of these compounds. In conclusion, the three major MAPK pathways, ERK as well as the p38 MAPK and JNK pathways, are independent regulators of IL-1beta-dependent proliferation of rat ASM.
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Proliferación Celular/efectos de los fármacos , Interleucina-1/fisiología , Sistema de Señalización de MAP Quinasas/fisiología , Proteínas Quinasas Activadas por Mitógenos/metabolismo , Músculo Liso/enzimología , Tráquea/enzimología , Animales , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Músculo Liso/efectos de los fármacos , Músculo Liso/fisiología , Ratas , Ratas Endogámicas BN , Tráquea/efectos de los fármacos , Tráquea/fisiologíaRESUMEN
1. Human airway smooth muscle cells (HASMC) contribute to airway inflammation in asthma by virtue of their capacity to produce several inflammatory mediators including IL-8, GM-CSF and RANTES. The intracellular signal pathway underlying the production of these cytokines in HASMC is not entirely elucidated. 2. We examined the role of the mitogen-activated protein kinase (MAPK) c-jun N-terminal kinase (JNK) in TNFalpha- and IL-1beta-induced GM-CSF, RANTES and IL-8 production in HASMC by using a novel specific inhibitor for JNK (SP600125). 3. Confluent HASMC were treated with TNFalpha or IL-1beta (10 ng ml(-1)) for 24 h in the presence or absence of SP600125 (1-100 micro M). JNK activity was determined by a kinase assay. Phosphorylation of JNK, p38 MAPK and ERK was examined by Western blotting. Culture supernatants were assayed for GM-CSF, RANTES and IL-8 content by ELISA. 4. Maximum TNFalpha- or IL-1beta-induced phosphorylation of JNK in HASMC occurred after 15 min and returned to baseline levels after 4 h. SP600125 inhibited TNFalpha- and IL-1beta-induced JNK activity in HASMC as shown by the reduced phosphorylation of its substrate c-jun. Furthermore, GM-CSF, RANTES and to a lesser extent IL-8 release from HASMC treated with TNFalpha and IL-1beta was inhibited dosedependently by SP600125. 5. JNK activation is involved in TNFalpha- and IL-1beta-induced GM-CSF, RANTES and IL-8 production from HASMC. JNK may therefore represent a critical pathway for cytokine production in HASMC.
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Quimiocina CCL5/metabolismo , Factor Estimulante de Colonias de Granulocitos y Macrófagos/metabolismo , Interleucina-8/metabolismo , Pulmón/citología , Pulmón/metabolismo , Proteínas Quinasas Activadas por Mitógenos/fisiología , Miocitos del Músculo Liso/metabolismo , Células Cultivadas , Relación Dosis-Respuesta a Droga , Inhibidores Enzimáticos/farmacología , Humanos , Interleucina-1/farmacología , Proteínas Quinasas JNK Activadas por Mitógenos , Pulmón/efectos de los fármacos , Proteínas Quinasas Activadas por Mitógenos/antagonistas & inhibidores , Miocitos del Músculo Liso/efectos de los fármacos , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Natural substances extracted from lichens and boldo tree were tested in vivo and in vitro as possible UV-light filters. The protection factors were compared with that found for the references: Nivea sun Spray LSF 5, octylmethoxycinnamate (OMC) and 4-tert.-butyl-4'-methoxy dibenzoylmethane (BM-DBM). The stability of the single compounds was studied through UV-Vis spectroscopy. Usnic acid resulted to be the best UVB filter, with an in vivo protection factor similar to Nivea sun Spray LSF 5. Most of the single compounds studied in vitro resulted to have higher or similar filtering power than octylmethoxycinnamate. The protection factors as well as the good UV-light absorption of their photo-products suggest that these natural substances may be useful as new filters in sun-screen preparations.
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Supervivencia Celular/efectos de la radiación , Líquenes/química , Extractos Vegetales/farmacología , Protectores contra Radiación/farmacología , Rayos Ultravioleta , Aporfinas/farmacología , Membrana Celular/efectos de los fármacos , Membrana Celular/ultraestructura , Supervivencia Celular/efectos de los fármacos , Humanos , Células Jurkat , Extractos Vegetales/aislamiento & purificación , Protectores contra Radiación/aislamiento & purificación , Protectores Solares/química , Protectores Solares/aislamiento & purificación , Protectores Solares/farmacologíaRESUMEN
Airway stenting can be a life-preserving intervention in patients with critical airway obstruction. It may be safely performed using flexible bronchoscopy under conscious sedation as a day-case procedure in selected patients, but a high incidence of complications limits its use to palliation of malignancy or bridging treatment in benign disease.
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Obstrucción de las Vías Aéreas/terapia , Broncoscopía/métodos , Cuidados Paliativos/métodos , Stents/normas , Obstrucción de las Vías Aéreas/etiología , Broncoscopía/efectos adversos , Diseño de Equipo/tendencias , Humanos , Trasplante de Pulmón/efectos adversos , Neoplasias/complicaciones , Neoplasias/terapia , Cuidados Paliativos/normas , Selección de Paciente , Stents/efectos adversos , Estenosis Traqueal/complicaciones , Estenosis Traqueal/terapiaRESUMEN
INTRODUCTION: Mediastinal lymphadenopathy in patients with an extrathoracic malignancy is a common clinical scenario. Invasive sampling of intrathoracic lymph nodes may be performed by mediastinoscopy or endoscopic ultrasound-guided fine needle aspiration. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) is an alternative to mediastinoscopy and endoscopic ultrasound in patients with lung cancer and sarcoidosis. The utility of EBUS-TBNA in patients with extrathoracic malignancy was evaluated. METHODS: Consecutive patients who were suspected to have intrathoracic lymph node metastases from an extrathoracic malignancy underwent EBUS-TBNA. When EBUS-TBNA did not provide a specific diagnosis, patients underwent mediastinoscopy or clinical follow-up of at least 6 months duration. RESULTS: One hundred sixty-one patients meeting the inclusion criteria underwent EBUS-TBNA in five UK centers over a 3-year period. EBUS-TBNA diagnosed mediastinal or hilar metastases in 71 (44%) patients, new lung cancer in 20 (12%) patients, and sarcoidosis in 14 (9%) patients. The sensitivity, negative predictive value for malignancy, and overall accuracy for EBUS-TBNA were 87%, 73% and 88%, respectively. One hundred ten (68%) patients in the study had a final diagnosis of malignant intrathoracic lymphadenopathy. CONCLUSION: Because of the high prevalence of alternative diagnoses, pathological evaluation is important in patients with extrathoracic malignancy and suspected mediastinal or hilar lymph node metastases. EBUS-TBNA is a safe and sensitive technique and may be considered a first-line investigation in these patients.
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Biopsia con Aguja Fina , Broncoscopía , Endosonografía , Enfermedades Linfáticas/diagnóstico , Neoplasias/complicaciones , Enfermedades Torácicas/diagnóstico , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Estudios de Seguimiento , Humanos , Enfermedades Linfáticas/etiología , Metástasis Linfática , Masculino , Mediastinoscopía , Persona de Mediana Edad , Estadificación de Neoplasias , Neoplasias/patología , Pronóstico , Sensibilidad y Especificidad , Tasa de Supervivencia , Enfermedades Torácicas/etiología , Adulto JovenRESUMEN
Cigarette smoke is the leading risk factor for the development of chronic obstructive pulmonary disease. We have recently shown that cigarette smoke extract synergises with tumour necrosis factor alpha (TNFalpha) in the induction of interleukin-8 (IL-8) from human airway smooth muscle cells. We have investigated the effect of fluticasone propionate, a corticosteroid, and salmeterol, a beta 2-adrenergic receptor agonist, on cigarette smoke extract-induced IL-8 production by human airway smooth muscle cells. Human airway smooth muscle cells in primary culture were exposed to cigarette smoke extract and/or TNFalpha (1 ng ml(-1)) with and without pretreatment with fluticasone (10(-13)-10(-8)M) and/or salmeterol (10(-11)-10(-6)M). IL-8 was analysed by ELISA. Fluticasone dose-dependently inhibited IL-8 release induced by cigarette smoke extract, TNFalpha or combined cigarette smoke extract and TNFalpha. However, while IL-8 release in the presence of cigarette smoke extract alone was completely inhibited by fluticasone, IL-8 production induced by cigarette smoke extract and TNFalpha was only partially reduced. Salmeterol alone had no effect on cigarette smoke extract and/or TNFalpha-induced IL-8 production from human airway smooth muscle cells. Combined fluticasone and salmeterol did not cause further inhibitory effects compared to fluticasone alone. Fluticasone but not salmeterol is effective in reducing cigarette smoke extract-induced IL-8 production in human airway smooth muscle cells. The reduced inhibition of cigarette smoke extract- and TNFalpha-induced IL-8 release by fluticasone may explain why corticosteroids are less effective in chronic obstructive pulmonary disease where increased amounts of TNFalpha are present.
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Agonistas Adrenérgicos beta/farmacología , Albuterol/análogos & derivados , Androstadienos/farmacología , Bronquios/efectos de los fármacos , Glucocorticoides/farmacología , Interleucina-8/biosíntesis , Músculo Liso/efectos de los fármacos , Humo , Albuterol/farmacología , Bronquios/citología , Bronquios/metabolismo , Células Cultivadas , Relación Dosis-Respuesta a Droga , Fluticasona , Humanos , Músculo Liso/citología , Músculo Liso/metabolismo , Xinafoato de Salmeterol , Nicotiana , Factor de Necrosis Tumoral alfa/farmacologíaRESUMEN
Neutrophils are an important component of airway inflammation and may interact with human airway smooth muscle cells (HASMC). We investigated the effect of neutrophils and of neutrophil-derived proteases on HASMC survival. When co-incubated with neutrophils (0.1-1 x 10(6) cells/ml), attachment of human ASMC was reduced to 12.3 +/- 4.3% compared with untreated controls after 72 h. HASMC showed nuclear condensation and fragmentation (41.6 +/- 8.1% compared with baseline of 3.1 +/- 0.4%), and the biochemical markers of apoptosis, annexin V binding (9.7 +/- 0.7%; baseline 1.1 +/- 0.3%) and cleaved caspase-3 expression, were observed. The proteolytic activity released by neutrophils was essential for the proapoptotic effect because inhibition of elastase activity by alpha(1)-antitrypsin and MeOSuc-Ala-Ala-Pro-Ala-CMK (MSACK) reduced HASMC apoptosis. Human neutrophil elastase (0.1-3 microg/ml) induced apoptosis of HASMC, as well as other neutrophil serine proteases, cathepsin G, and proteinase 3. Fibronectin degradation products were present in HASMC supernatants exposed to neutrophil-conditioned media and to neutrophil elastase. The local release of proteases from neutrophils present in airway smooth muscle cells may lead to HASMC apoptosis as a result of matrix degradation and loss of cell attachment. This may limit pathologic changes such as ASMC hyperplasia and extracellular matrix deposition seen in airway remodeling.