Current Issue : April - June Volume : 2012 Issue Number : 2 Articles : 8 Articles
Background: The Global initiative for chronic Obstructive Lung Disease (GOLD) defines COPD as a fixed postbronchodilator\r\nratio of forced expiratory volume in 1 second and forced vital capacity (FEV1/FVC) below 0.7. Agedependent\r\ncut-off values below the lower fifth percentile (LLN) of this ratio derived from the general population\r\nhave been proposed as an alternative. We wanted to assess the diagnostic accuracy and prognostic capability of\r\nthe GOLD and LLN definition when compared to an expert-based diagnosis.\r\nMethods: In a prospective cohort study, 405 patients aged = 65 years with a general practitionerââ?¬â?¢s diagnosis of\r\nCOPD were recruited and followed up for 4.5 (median; quartiles 3.9; 5.1) years. Prevalence rates of COPD according\r\nto GOLD and three LLN definitions and diagnostic performance measurements were calculated. The reference\r\nstandard was the diagnosis of COPD of an expert panel that used all available diagnostic information, including\r\nspirometry and bodyplethysmography.\r\nResults: Compared to the expert panel diagnosis, ââ?¬Ë?GOLD-COPDââ?¬â?¢ misclassified 69 (28%) patients, and the three LLNs\r\nmisclassified 114 (46%), 96 (39%), and 98 (40%) patients, respectively. The GOLD classification led to more false\r\npositives, the LLNs to more false negative diagnoses. The main predictors beyond the FEV1/FVC ratio for an expert\r\ndiagnosis of COPD were the FEV1 % predicted, and the residual volume/total lung capacity ratio (RV/TLC). Adding\r\nFEV1 and RV/TLC to GOLD or LLN improved the diagnostic accuracy, resulting in a significant reduction of up to\r\n50% of the number of misdiagnoses. The expert diagnosis of COPD better predicts exacerbations, hospitalizations\r\nand mortality than GOLD or LLN.\r\nConclusions: GOLD criteria over-diagnose COPD, while LLN definitions under-diagnose COPD in elderly patients as\r\ncompared to an expert panel diagnosis. Incorporating FEV1 and RV/TLC into the GOLD-COPD or LLN-based\r\ndefinition brings both definitions closer to expert panel diagnosis of COPD, and to daily clinical practice....
Background: The development of COPD in subjects with alpha-1 antitrypsin (AAT) deficiency is likely to be\r\ninfluenced by modifier genes. Genome-wide association studies and integrative genomics approaches in COPD\r\nhave demonstrated significant associations with SNPs in the chromosome 15q region that includes CHRNA3\r\n(cholinergic nicotine receptor alpha3) and IREB2 (iron regulatory binding protein 2).\r\nWe investigated whether SNPs in the chromosome 15q region would be modifiers for lung function and COPD in\r\nAAT deficiency.\r\nMethods: The current analysis included 378 PIZZ subjects in the AAT Genetic Modifiers Study and a replication\r\ncohort of 458 subjects from the UK AAT Deficiency National Registry. Nine SNPs in LOC123688, CHRNA3 and IREB2\r\nwere selected for genotyping. FEV1 percent of predicted and FEV1/FVC ratio were analyzed as quantitative\r\nphenotypes. Family-based association analysis was performed in the AAT Genetic Modifiers Study. In the replication\r\nset, general linear models were used for quantitative phenotypes and logistic regression models were used for the\r\npresence/absence of emphysema or COPD.\r\nResults: Three SNPs (rs2568494 in IREB2, rs8034191 in LOC123688, and rs1051730 in CHRNA3) were associated with\r\npre-bronchodilator FEV1 percent of predicted in the AAT Genetic Modifiers Study. Two SNPs (rs2568494 and\r\nrs1051730) were associated with the post-bronchodilator FEV1 percent of predicted and pre-bronchodilator FEV1/FVC\r\nratio; SNP-by-gender interactions were observed. In the UK National Registry dataset, rs2568494 was significantly\r\nassociated with emphysema in the male subgroup; significant SNP-by-smoking interactions were observed.\r\nConclusions: IREB2 and CHRNA3 are potential genetic modifiers of COPD phenotypes in individuals with severe\r\nAAT deficiency and may be sex-specific in their impact....
Background: Asthma is a chronic inflammatory disease of the airways but recent studies have shown that alveoli\r\nare also subject to pathophysiological changes. This study was undertaken to compare hydrogen peroxide (H2O2)\r\nconcentrations in different parts of the lung using a new technique of fractioned breath condensate sampling.\r\nMethods: In 52 children (9-17 years, 32 asthmatic patients, 20 controls) measurements of exhaled nitric oxide\r\n(FENO), lung function, H2O2 in exhaled breath condensate (EBC) and the asthma control test (ACT) were performed.\r\nExhaled breath condensate was collected in two different fractions, representing mainly either the airways or the\r\nalveoli. H2O2 was analysed in the airway and alveolar fractions and compared to clinical parameters.\r\nResults: The exhaled H2O2 concentration was significantly higher in the airway fraction than in the alveolar fraction\r\ncomparing each single pair (p = 0.003, 0.032 and 0.040 for the whole study group, the asthmatic group and the\r\ncontrol group, respectively). Asthma control, measured by the asthma control test (ACT), correlated significantly\r\nwith the H2O2 concentrations in the alveolar fraction (r = 0.606, p = 0.004) but not with those in the airway\r\nfraction in the group of children above 12 years. FENO values and lung function parameters did not correlate to the\r\nH2O2 concentrations of each fraction.\r\nConclusion: The new technique of fractionated H2O2 measurement may differentiate H2O2 concentrations in\r\ndifferent parts of the lung in asthmatic and control children. H2O2 concentrations of the alveolar fraction may be\r\nrelated to the asthma control test in children....
Background: Normal bronchial tissue expression of GRPR, which encodes the gastrin-releasing peptide receptor,\r\nhas been previously reported by us to be associated with lung cancer risk in 78 subjects, especially in females. We\r\nsought to define the contribution of GRPR expression in bronchial epithelia to lung cancer risk in a larger casecontrol\r\nstudy where adjustments could be made for tobacco exposure and sex.\r\nMethods: We evaluated GRPR mRNA levels in histologically normal bronchial epithelial cells from 224 lung cancer\r\npatients and 107 surgical cancer-free controls. Associations with lung cancer were tested using logistic regression\r\nmodels.\r\nResults: Bronchial GRPR expression was significantly associated with lung cancer (OR = 4.76; 95% CI = 2.32-9.77) in\r\na multivariable logistic regression (MLR) model adjusted for age, sex, smoking status and pulmonary function. MLR\r\nanalysis stratified by smoking status indicated that ORs were higher in never and former smokers (OR = 7.74; 95%\r\nCI = 2.96-20.25) compared to active smokers (OR = 1.69; 95% CI = 0.46-6.33). GRPR expression did not differ by\r\nsubject sex, and lung cancer risk associated with GRPR expression was not modified by sex.\r\nConclusions: GRPR expression in non-cancerous bronchial epithelium was significantly associated with the\r\npresence of lung cancer in never and former smokers. The association in never and former smokers was found in\r\nmales and females. Association with lung cancer did not differ by sex in any smoking group....
Background: Previous studies showed that heparinâ��s anti-allergic activity is molecular weight dependent and\r\nresides in oligosaccharide fractions of <2500 daltons.\r\nObjective: To investigate the structural sequence of heparinâ��s anti-allergic domain, we used nitrous acid\r\ndepolymerization of porcine heparin to prepare an oligosaccharide, and then fractionated it into disaccharide,\r\ntetrasaccharide, hexasaccharide, and octasaccharide fractions. The anti-allergic activity of each oligosaccharide\r\nfraction was tested in allergic sheep.\r\nMethods: Allergic sheep without (acute responder) and with late airway responses (LAR; dual responder) were\r\nchallenged with Ascaris suum antigen with and without inhaled oligosaccharide pretreatment and the effects on\r\nspecific lung resistance and airway hyperresponsiveness (AHR) to carbachol determined. Additional inflammatory\r\ncell recruitment studies were performed in immunized ovalbumin-challenged BALB/C mice with and without\r\ntreatment.\r\nResults: The inhaled tetrasaccharide fraction was the minimal effective chain length to show anti-allergic activity.\r\nThis fraction showed activity in both groups of sheep; it was also effective in inhibiting LAR and AHR, when\r\nadministered after the antigen challenge. Tetrasaccharide failed to modify the bronchoconstrictor responses to\r\nairway smooth muscle agonists (histamine, carbachol and LTD4), and had no effect on antigen-induced histamine\r\nrelease in bronchoalveolar lavage fluid in sheep. In mice, inhaled tetrasaccharide also attenuated the ovalbumininduced\r\nperibronchial inflammatory response and eosinophil influx in the bronchoalveolar lavage fluid. Chemical\r\nanalysis identified the active structure to be a pentasulfated tetrasaccharide ([IdoU2S (1�®4)GlcNS6S (1�®4) IdoU2S\r\n(1�®4) AMan-6S]) which lacked anti-coagulant activity.\r\nConclusions: These results demonstrate that heparin tetrasaccharide possesses potent anti-allergic and antiinflammatory\r\nproperties, and that the domains responsible for anti-allergic and anti-coagulant activity are distinctly\r\ndifferent....
Background: While most of the clinical benefits of inhaled corticosteroid (ICS) therapy may occur at low doses,\r\nresults of dose-ranging studies are inconsistent. Although symptom/lung function response to low and high dose\r\nICS medication is comparable, it is uncertain whether low dose ICSs are as effective as high dose in the treatment\r\nof inflammation and remodeling.\r\nMethods: 22 mild or moderate asthmatic adult subjects (corticosteroid free for > 2 months) participated in a\r\nrandomized, parallel group study to compare effects of fluticasone propionate (FP) 200 mcg/day and 1000 mcg/\r\nday. Alveolar macrophage (AM)-derived cytokines and basement membrane thickness (BMT) were measured at\r\nbaseline and after 7 weeks treatment while symptoms, spirometry, exhaled nitric oxide (eNO) and airway\r\nhyperresponsiveness (AHR) to mannitol at baseline and 6 weeks.\r\nResults: FP improved spirometry, eNO, symptoms and AHR with no difference between low and high dose FP.\r\nBoth high and low dose FP reduced GM-CSF, TNF-alpha and IL-1ra, with no change in BMT and with no\r\ndifferences between low and high dose FP.\r\nConclusions: 200 �µg/day of FP was as effective as 1000 �µg/day in improving asthma control, airway inflammation,\r\nlung function and AHR in adults in the short term. Future studies should examine potential differential effects\r\nbetween low and high dose combination therapy (ICS/long acting beta agonist) on inflammation and airway\r\nremodeling over longer treatment periods....
Background: This retrospective cohort study compared the risks of exacerbations and COPD-related healthcare\r\ncosts between patients with chronic obstructive pulmonary disease (COPD) initiating tiotropium (TIO) alone and\r\npatients initiating triple therapy with fluticasone-salmeterol combination (FSC) added to TIO.\r\nMethods: Managed-care enrollees who had an index event of = 1 pharmacy claim for TIO during the study period\r\n(January 1, 2003-April 30, 2008) and met other eligibility criteria were categorized into one of two cohorts\r\ndepending on their medication use. Patients in the TIO+FSC cohort had combination therapy with TIO and FSC,\r\ndefined as having an FSC claim on the same date as the TIO claim. Patients in the TIO cohort had no such FSC\r\nuse. The risks of COPD exacerbations and healthcare costs were compared between cohorts during 1 year of\r\nfollow-up.\r\nResults: The sample comprised 3333 patients (n = 852 TIO+FSC cohort, n = 2481 TIO cohort). Triple therapy with\r\nFSC added to TIO compared with TIO monotherapy was associated with significant reductions in the adjusted risks\r\nof moderate exacerbation (hazard ratio 0.772; 95% confidence interval [CI] 0.641, 0.930) and any exacerbation\r\n(hazard ratio 0.763; 95% CI 0.646, 0.949) and a nonsignificant reduction in COPD-related adjusted monthly medical\r\ncosts.\r\nConclusions: Triple therapy with FSC added to TIO compared with TIO monotherapy was associated with\r\nsignificant reductions in the adjusted risks of moderate exacerbation and any exacerbation over a follow-up period\r\nof up to 1 year. These improvements were gained with triple therapy at roughly equal cost of that of TIO alone....
New paradigms have been recently proposed in the pathogenesis of both chronic obstructive pulmonary disease\r\n(COPD) and idiopathic pulmonary fibrosis (IPF), evidencing surprising similarities between these deadly diseases,\r\ndespite their obvious clinical, radiological and pathologic differences. There is growing evidence supporting a\r\nââ?¬Å?double hitââ?¬Â pathogenic model where in both COPD and IPF the cumulative action of an accelerated senescence\r\nof pulmonary parenchyma (determined by either telomere dysfunction and/or a variety of genetic predisposing\r\nfactors), and the noxious activity of cigarette smoke-induced oxidative damage are able to severely compromise\r\nthe regenerative potential of two pulmonary precursor cell compartments (alveolar epithelial precursors in IPF,\r\nmesenchymal precursor cells in COPD/emphysema). The consequent divergent derangement of signalling\r\npathways involved in lung tissue renewal (mainly Wnt and Notch), can eventually lead to the distinct abnormal\r\ntissue remodelling and functional impairment that characterise the alveolar parenchyma in these diseases\r\n(irreversible fibrosis and bronchiolar honeycombing in IPF, emphysema and airway chronic inflammation in COPD)....
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