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      Effect of the asthma–chronic obstructive pulmonary disease syndrome on the stroke, Parkinson's disease, and dementia: a national cohort study

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          Abstract

          Background

          To evaluate the association of asthma–chronic obstructive pulmonary disease syndrome (ACOS) with neurodegenerative diseases (stroke, Parkinson's disease and dementia) and the role of the steroids in the neurodegenerative diseases among the ACOS cohort.

          Materials and Methods

          Comparison of the ACOS cohort ( N = 10,260) with the non-ACOS cohort ( n = 20,513) based on the patients aged ≧40 years in the National Health Insurance Research Database from January 1, 2000 to December 31, 2010. These patients follow up to diagnosis of neurodegenerative diseases or the December 31, 2011; using multivariable Cox proportional hazards models.

          Results

          After adjustment for potential confounders, the [adjusted hazard ratio (aHR), 95% confidence interval (CI)] in the ACOS cohort were [1.39, 1.28–1.50] [1.56, 1.34–1.81] and [1.43, 1.29–1.59] for stroke, Parkinson's disease, dementia; respectively. The [aHR, 95% CI] for ACOS cohort with (inhaler corticosteroids ≧0.13 gram/ oral steroids ≧0.08gram) were with less risk (all aHR<1, p values <0.05) for these 3 neurodegenerative diseases except Parkinson's disease with inhaler corticosteroids >0.43 gram. The risk of stroke and dementia were the lower in patients with < 250 μg/d of a fluticasone equivalent inhaler corticosteroids (aHR = 0.53, 95% CI = 0.35–0.79; aHR = 0.53, 95% CI = 0.31–0.90, respectively).

          Conclusions

          The ACOS cohort had a higher risk of the neurodegenerative diseases. The lower dose of the inhaler corticosteroids with cumulative dose ≧0.13 gram have the less risk of stroke and dementia.

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          Most cited references76

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          Corticosteroid resistance in patients with asthma and chronic obstructive pulmonary disease.

          Reduced responsiveness to the anti-inflammatory effects of corticosteroids is a major barrier to effective management of asthma in smokers and patients with severe asthma and in the majority of patients with chronic obstructive pulmonary disease (COPD). The molecular mechanisms leading to steroid resistance are now better understood, and this has identified new targets for therapy. In patients with severe asthma, several molecular mechanisms have been identified that might account for reduced steroid responsiveness, including reduced nuclear translocation of glucocorticoid receptor (GR) α after binding corticosteroids. This might be due to modification of the GR by means of phosphorylation as a result of activation of several kinases (p38 mitogen-activated protein kinase α, p38 mitogen-activated protein kinase γ, and c-Jun N-terminal kinase 1), which in turn might be due to reduced activity and expression of phosphatases, such as mitogen-activated protein kinase phosphatase 1 and protein phosphatase A2. Other mechanisms proposed include increased expression of GRβ, which competes with and thus inhibits activated GRα; increased secretion of macrophage migration inhibitory factor; competition with the transcription factor activator protein 1; and reduced expression of histone deacetylase (HDAC) 2. HDAC2 appears to mediate the action of steroids to switch off activated inflammatory genes, but in patients with COPD, patients with severe asthma, and smokers with asthma, HDAC2 activity and expression are reduced by oxidative stress through activation of phosphoinositide 3-kinase δ. Strategies for managing steroid resistance include alternative anti-inflammatory drugs, but a novel approach is to reverse steroid resistance by increasing HDAC2 expression, which can be achieved with theophylline and phosphoinositide 3-kinase δ inhibitors. Long-acting β2-agonists can also increase steroid responsiveness by reversing GRα phosphorylation. Identifying the molecular mechanisms of steroid resistance in asthmatic patients and patients with COPD can thus lead to more effective anti-inflammatory treatments. Copyright © 2013 American Academy of Allergy, Asthma & Immunology. Published by Mosby, Inc. All rights reserved.
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            Hypoxemia in patients with COPD: cause, effects, and disease progression

            Chronic obstructive pulmonary disease (COPD) is a leading cause of death and disability internationally. Alveolar hypoxia and consequent hypoxemia increase in prevalence as disease severity increases. Ventilation/perfusion mismatch resulting from progressive airflow limitation and emphysema is the key driver of this hypoxia, which may be exacerbated by sleep and exercise. Uncorrected chronic hypoxemia is associated with the development of adverse sequelae of COPD, including pulmonary hypertension, secondary polycythemia, systemic inflammation, and skeletal muscle dysfunction. A combination of these factors leads to diminished quality of life, reduced exercise tolerance, increased risk of cardiovascular morbidity, and greater risk of death. Concomitant sleep-disordered breathing may place a small but significant subset of COPD patients at increased risk of these complications. Long-term oxygen therapy has been shown to improve pulmonary hemodynamics, reduce erythrocytosis, and improve survival in selected patients with severe hypoxemic respiratory failure. However, the optimal treatment for patients with exertional oxyhemoglobin desaturation, isolated nocturnal hypoxemia, or mild-to-moderate resting daytime hypoxemia remains uncertain.
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              Inflammation in chronic obstructive pulmonary disease and its role in cardiovascular disease and lung cancer

              Paul King (2015)
              Chronic obstructive pulmonary disease (COPD) is characterized by lung inflammation that persists after smoking cessation. This inflammation is heterogeneous but the key inflammatory cell types involved are macrophages, neutrophils and T cells. Other lung cells may also produce inflammatory mediators, particularly the epithelial cells. The main inflammatory mediators include tumor necrosis factor alpha, interleukin-1, interleukin-6, reactive oxygen species and proteases. COPD is also associated with systemic inflammation and there is a markedly increased risk of cardiovascular disease (particularly coronary artery disease) and lung cancer in patients with COPD. There is strong associative evidence that the inflammatory cells/mediators in COPD are also relevant to the development of cardiovascular disease and lung cancer. There are a large number of potential inhibitors of inflammation in COPD that may well have beneficial effects for these comorbidities. This is a not well-understood area and there is a requirement for more definitive clinical and mechanistic studies to define the relationship between the inflammatory process of COPD and cardiovascular disease and lung cancer.
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                Author and article information

                Journal
                Oncotarget
                Oncotarget
                Oncotarget
                ImpactJ
                Oncotarget
                Impact Journals LLC
                1949-2553
                23 February 2018
                26 December 2017
                : 9
                : 15
                : 12418-12431
                Affiliations
                1 Ditmanson Medical Foundation Chia-Yi Christian Hospital, Chiayi, Taiwan
                2 Chia Nan University of Pharmacy and Science, Tainan, Taiwan
                3 Meiho University, Pingtung, Taiwan
                4 Pingtung Christian Hospital, Pingtung, Taiwan
                5 Department of Internal Medicine, E-Da Hospital, I-Shou University, Kaohsiung, Taiwan
                6 Management Office for Health Data, China Medical University Hospital, Taichung, Taiwan
                7 College of Medicine, China Medical University, Taichung, Taiwan
                8 Graduate Institute of Clinical Medical Science and School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
                9 Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, China Medical University Hospital, Taichung, Taiwan
                Author notes
                Correspondence to: Wu-Huei Hsu, pccm.hsu@ 123456gmail.com
                [*]

                These authors contributed equally to this work

                Article
                23811
                10.18632/oncotarget.23811
                5844758
                29552322
                57fcae68-2f74-4edb-bd54-a4f36c1fdda3
                Copyright: © 2018 Yeh et al.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License 3.0 (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 25 April 2017
                : 10 November 2017
                Categories
                Clinical Research Paper

                Oncology & Radiotherapy
                asthma–chronic obstructive pulmonary disease syndrome (acos),stroke,parkinson's disease (pd),dementia,inhaler steroids

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