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Zhang T.,University of British Columbia | Zhang T.,Child and Family Research Institute | Smith M.A.,Pharmaceutical Outcomes Programme | Smith M.A.,Child and Family Research Institute | And 5 more authors.
Pharmacoepidemiology and Drug Safety | Year: 2013

Background: Despite numerous clinical guidelines on asthma management, patients often receive suboptimal drug therapy. This study identified patients who received suboptimal regimens according to the National Heart, Lung and Blood Institute (NHLBI) Guidelines for the Diagnosis and Management of Asthma in a complete population (residents of British Columbia, Canada) and determined the association between patients' regimens and utilization of healthcare services. Methods: A total of 65345 asthma patients were identified using provincial health service utilization data (including all respiratory-related prescription medication dispensings, physician and hospital visits) for the 2009 fiscal year. Patient-specific regimens of inhaled short-acting bronchodilators (SABA) with or without inhaled corticosteroids (ICS) were categorized as optimal or suboptimal. Logistic regression models were used to determine the association between regimen optimality and health service utilization, adjusted for socioeconomic status, prior year hospital and emergency department (ED) visits for asthma. Results: Patients with suboptimal regimens had significantly greater risk of using health services than patients with optimal regimens of SABA and/or ICS. In particular, adolescents with suboptimal regimens were the most likely to have hospital admissions (odds ratio (OR) 3.8; 95% confidence interval (CI) 1.8-7.8), visit the ED (OR 2.2; 95% CI 1.6-3.1) and be high users of family physician services (OR 5.7; 95% CI 4.0-8.1) compared with patients in other age groups. Conclusions: Suboptimal regimens are associated with significantly high usage of health services. Identifying patients with suboptimal regimens and improving their medication management in accordance with asthma clinical guidelines are likely to result in lower health service utilization. © 2013 John Wiley & Sons, Ltd.. Source

Landis R.C.,University of the West Indies | Murkin J.M.,London Health Sciences Center | Stump D.A.,Wake forest University | Baker R.A.,Flinders University | And 16 more authors.
Heart Surgery Forum | Year: 2010

The lack of established cause and effect between putative mediators of inflammation and adverse clinical outcomes has been responsible for many failed anti-inflammatory interventions in cardiopulmonary bypass (CPB). Candidate interventions that impress in preclinical trials by suppressing a given inflammation marker might fail at the clinical trial stage because the marker of interest is not linked causally to an adverse outcome. Alternatively, there exist examples in which pharmaceutical agents or other interventions improve clinical outcomes but for which we are uncertain of any anti-inflammatory mechanism. The Outcomes consensus panel made 3 recommendations in 2009 for the conduct of clinical trials focused on the systemic inflammatory response. This panel was tasked with updating, as well as simplifying, a previous consensus statement. The present recommendations for investigators are the following: (1) Measure at least 1 inflammation marker, defined in broad terms; (2) measure at least 1 clinical end point, drawn from a list of practical yet clinically meaningful end points suggested by the consensus panel; and (3) report a core set of CPB and perfusion criteria that may be linked to outcomes. Our collective belief is that adhering to these simple consensus recommendations will help define the influence of CPB practice on the systemic inflammatory response, advance our understanding of causal inflammatory mechanisms, and standardize the reporting of research findings in the peer-reviewed literature. © 2010 Forum Multimedia Publishing, LLC. Source

Allahverdian S.,Providence Heart Lung Institute | Francis G.A.,Providence Heart Lung Institute
Trends in Cardiovascular Medicine | Year: 2010

The balance between lipid accumulation and removal from cells in the artery wall is a key factor in atherogenesis. Smooth muscle cells (SMCs) are the main cell type in human intimal thickenings and some stages of atherosclerosis; however, cholesterol homeostasis in these cells has received little attention when compared with intimal macrophages. In addition, it has been demonstrated that SMCs may change phenotype to express macrophage markers upon cholesterol loading, indicating that a large portion of what are considered monocyte-derived human macrophages in human lesions may actually have originated as SMCs. We have recently reported low expression of the key regulator of cholesterol removal to apolipoprotein A-I to form high-density lipoprotein particles, the adenosine-triphosphate-binding cassette transporter A1, in cultured intima-phenotype epithelioid rat SMCs, as well as reduced expression of adenosine-triphosphate-binding cassette transporter A1 in intimal as compared with medial SMCs in human coronary atheromas. These combined observations suggest that SMCs and SMC-derived macrophage-like cells may contribute a much larger amount of the excess cholesterol accumulated in the atherosclerotic intima than previously known. The aim of this review is to present the current state of knowledge of cholesterol homeostasis in arterial SMC and to frame questions requiring further study to understand the relative importance to SMCs in overall atheroma lipid metabolism. © 2010 Elsevier Inc. Source

Tanaka G.,Providence Heart Lung Institute | Aminuddin F.,Providence Heart Lung Institute | Akhabir L.,Providence Heart Lung Institute | He J.-Q.,Providence Heart Lung Institute | And 6 more authors.
BMC Medical Genetics | Year: 2011

Background: Oxidative stress induced by smoking is considered to be important in the pathogenesis of Chronic Obstructive Pulmonary Disease (COPD). Heme oxygenase-1 (HMOX1) is an essential enzyme in heme catabolism that is induced by oxidative stress and may play a protective role as an antioxidant in the lung. We determined whether HMOX1 polymorphisms were associated with lung function in COPD patients and whether the variants had functional effects.Methods: We genotyped five single nucleotide polymorphisms (SNPs) in the HMOX1 gene in Caucasians who had the fastest (n = 278) and the slowest (n = 304) decline of FEV1% predicted, selected from smokers in the NHLBI Lung Health Study. These SNPs were also studied in Caucasians with the lowest (n = 535) or the highest (n = 533) baseline lung function. Reporter genes were constructed containing three HMOX1 promoter polymorphisms and the effect of these polymorphisms on H2O2and hemin-stimulated gene expression was determined. The effect of the HMOX1 rs2071749 SNP on gene expression in alveolar macrophages was investigated.Results: We found a nominal association (p = 0.015) between one intronic HMOX1 SNP (rs2071749) and lung function decline but this did not survive correction for multiple comparisons. This SNP was in perfect linkage disequilibrium with rs3761439, located in the promoter of HMOX1. We tested rs3761439 and two other putatively functional polymorphisms (rs2071746 and the (GT)npolymorphism) in reporter gene assays but no significant effects on gene expression were found. There was also no effect of rs2071749 on HMOX1 gene expression in alveolar macrophages.Conclusions: We found no association of the five HMOX1 tag SNPs with lung function decline and no evidence that the three promoter polymorphisms affected the regulation of the HMOX1 gene. © 2011 Tanaka et al; licensee BioMed Central Ltd. Source

Sze M.A.,Providence Heart Lung Institute | Sze M.A.,University of British Columbia | Dimitriu P.A.,University of British Columbia | Suzuki M.,Providence Heart Lung Institute | And 19 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2015

Rationale: The relatively sparse but diverse microbiome in human lungs may become less diverse in chronic obstructive pulmonary disease (COPD). This article examines the relationship of this microbiome to emphysematous tissue destruction, number of terminal bronchioles, infiltrating inflammatory cells, and host gene expression. Methods: Culture-independent pyrosequencing microbiome analysis was used to examine the V3-V5 regions of bacterial 16S ribosomal DNA in 40 samples of lung from 5 patients with COPD (Global Initiative for Chronic Obstructive Lung Disease [GOLD] stage 4) and 28 samples from 4 donors (controls). A second protocol based on the V1-V3 regions was used to verify the bacterial microbiome results. Within lung tissue samples the microbiome was compared with results of micro-computed tomography, infiltrating inflammatory cells measured by quantitative histology, and host gene expression. Measurements and Main Results: Ten operational taxonomic units (OTUs) was found sufficient to discriminate between control and GOLD stage 4 lung tissue, which included known pathogens such as Haemophilus influenzae. We also observed a decline in microbial diversity that was associated with emphysematous destruction, remodeling of the bronchiolar and alveolar tissue, and the infiltration of the tissue by CD4+ T cells. Specific OTUs were also associated with neutrophils, eosinophils, and B-cell infiltration (P < 0.05). The expression profiles of 859 genes and 235 genes were associated with either enrichment or reductions of Firmicutes and Proteobacteria, respectively, at a false discovery rate cutoff of less than 0.1. Conclusions: These results support the hypothesis that there is a host immune response to microorganisms within the lung microbiome that appears to contribute to the pathogenesis of COPD. Copyright © 2015 by the American Thoracic Society. Source

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