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PubMed | University of Adelaide, West Australian Sleep Disorders Research Institute and University of Western Australia
Type: Journal Article | Journal: Journal of clinical sleep medicine : JCSM : official publication of the American Academy of Sleep Medicine | Year: 2015

To determine prevalence of depressive symptoms in obstructive sleep apnea (OSA) and the impact of OSA treatment on depression scores.Consecutive new patients referred for investigation of suspected OSA were approached. Consenting patients completed a patient health questionnaire (PHQ-9) for depressive symptoms when attending for laboratory polysomnography. Those with moderate/severe (apneahypopnea index [AHI] 15 events/h) and/or symptomatic mild OSA (AHI 5-14.99 events/h) were offered continuous positive airway pressure (CPAP) therapy. PHQ-9 was repeated after 3 months of CPAP with compliance recorded. Of a maximum PHQ-9 score of 27, a cut point 10 (PHQ-9 10) was used to indicate presence of clinically significant depressive symptoms.A total of 426 participants (243 males) were recruited. Mean standard deviation body mass index (BMI) was 32.1 7.1 kg/m2 and AHI 33.6 28.9 events/h. PHQ-9 was 10.5 6.1 and independently related to AHI (p < 0.001) and BMI (p < 0.001). In those without OSA, PHQ-9 10 was more common in women, but no gender difference was evident with OSA. Of 293 patients offered CPAP, 228 were compliant (mean nightly use > 5 h) over 3 months of therapy. In them, with therapy, AHI decreased from 46.7 27.4 to 6.5 1.6 events/h, PHQ-9 from 11.3 6.1 to 3.7 2.9 and PHQ-9 10 from 74.6% to 3.9% (p < 0.001 in each case). Magnitude of change in PHQ-9 was similar in men and women. Antidepressant use was constant throughout.Depressive symptoms are common in OSA and related to its severity. They improve markedly with CPAP, implying a relationship to untreated OSA.

Ferreira M.A.R.,QIMR Berghofer Medical Research Institute | Matheson M.C.,University of Melbourne | Tang C.S.,QIMR Berghofer Medical Research Institute | Tang C.S.,University of Hong Kong | And 37 more authors.
Journal of Allergy and Clinical Immunology | Year: 2014

Background To date, no genome-wide association study (GWAS) has considered the combined phenotype of asthma with hay fever. Previous analyses of family data from the Tasmanian Longitudinal Health Study provide evidence that this phenotype has a stronger genetic cause than asthma without hay fever. Objective We sought to perform a GWAS of asthma with hay fever to identify variants associated with having both diseases. Methods We performed a meta-analysis of GWASs comparing persons with both physician-diagnosed asthma and hay fever (n = 6,685) with persons with neither disease (n = 14,091). Results At genome-wide significance, we identified 11 independent variants associated with the risk of having asthma with hay fever, including 2 associations reaching this level of significance with allergic disease for the first time: ZBTB10 (rs7009110; odds ratio [OR], 1.14; P = 4 × 10-9) and CLEC16A (rs62026376; OR, 1.17; P = 1 × 10-8). The rs62026376:C allele associated with increased asthma with hay fever risk has been found to be associated also with decreased expression of the nearby DEXI gene in monocytes. The 11 variants were associated with the risk of asthma and hay fever separately, but the estimated associations with the individual phenotypes were weaker than with the combined asthma with hay fever phenotype. A variant near LRRC32 was a stronger risk factor for hay fever than for asthma, whereas the reverse was observed for variants in/near GSDMA and TSLP. Single nucleotide polymorphisms with suggestive evidence for association with asthma with hay fever risk included rs41295115 near IL2RA (OR, 1.28; P = 5 × 10-7) and rs76043829 in TNS1 (OR, 1.23; P = 2 × 10-6). Conclusion By focusing on the combined phenotype of asthma with hay fever, variants associated with the risk of allergic disease can be identified with greater efficiency. © 2014 American Academy of Allergy, Asthma & Immunology.

Ferreira M.A.R.,Royal Brisbane Hospital | Matheson M.C.,University of Melbourne | Duffy D.L.,Royal Brisbane Hospital | Marks G.B.,University of Sydney | And 44 more authors.
The Lancet | Year: 2011

We aimed to identify novel genetic variants affecting asthma risk, since these might provide novel insights into molecular mechanisms underlying the disease. We did a genome-wide association study (GWAS) in 2669 physician-diagnosed asthmatics and 4528 controls from Australia. Seven loci were prioritised for replication after combining our results with those from the GABRIEL consortium (n=26 475), and these were tested in an additional 25 358 independent samples from four in-silico cohorts. Quantitative multi-marker scores of genetic load were constructed on the basis of results from the GABRIEL study and tested for association with asthma in our Australian GWAS dataset. Two loci were confirmed to associate with asthma risk in the replication cohorts and reached genome-wide significance in the combined analysis of all available studies (n=57 800): rs4129267 (OR 1·09, combined p= 2·4×10-8) in the interleukin-6 receptor (IL6R) gene and rs7130588 (OR 1·09, p=1·8×10-8) on chromosome 11q13.5 near the leucine-rich repeat containing 32 gene (LRRC32, also known as GARP). The 11q13.5 locus was significantly associated with atopic status among asthmatics (OR 1·33, p=7×10-4), suggesting that it is a risk factor for allergic but not non-allergic asthma. Multi-marker association results are consistent with a highly polygenic contribution to asthma risk, including loci with weak effects that might be shared with other immune-related diseases, such as NDFIP1, HLA-B, LPP, and BACH2. The IL6R association further supports the hypothesis that cytokine signalling dysregulation affects asthma risk, and raises the possibility that an IL6R antagonist (tocilizumab) may be effective to treat the disease, perhaps in a genotype-dependent manner. Results for the 11q13.5 locus suggest that it directly increases the risk of allergic sensitisation which, in turn, increases the risk of subsequent development of asthma. Larger or more functionally focused studies are needed to characterise the many loci with modest effects that remain to be identified for asthma. National Health and Medical Research Council of Australia. A full list of funding sources is provided in the webappendix. © 2011 Elsevier Ltd.

Green F.H.Y.,University of Calgary | Williams D.J.,University of Calgary | James A.,West Australian Sleep Disorders Research Institute | James A.,University of Western Australia | And 3 more authors.
Thorax | Year: 2010

Background: Fatal asthma is characterised by enlargement of bronchial mucous glands and tenacious plugs of mucus in the airway lumen. Myoepithelial cells, located within the mucous glands, contain contractile proteins which provide structural support to mucous cells and actively facilitate glandular secretion. Objectives: To determine if myoepithelial cells are increased in the bronchial submucosal glands of patients with fatal asthma. Methods: Autopsied lungs from 12 patients with fatal asthma (FA), 12 patients with asthma dying of non-respiratory causes (NFA) and 12 non-asthma control cases (NAC) were obtained through the Prairie Provinces Asthma Study. Transverse sections of segmental bronchi from three lobes were stained for mucus and smooth muscle actin and the area fractions of mucous plugs, mucous glands and myoepithelial cells determined by point counting. The fine structure of the myoepithelial cells was examined by electron microscopy. Results: FA was characterised by significant increases in mucous gland (p = 0.003), mucous plug (p = 0.004) and myoepithelial cell areas (p = 0.017) compared with NAC. When the ratio of myoepithelial cell area to total gland area was examined, there was a disproportionate and significant increase in FA compared with NAC (p = 0.014). Electron microscopy of FA cases revealed hypertrophy of the myoepithelial cells with increased intracellular myofilaments. The NFA group showed changes in these features that were intermediate between the FA and NAC groups but the differences were not significant. Conclusions: Bronchial mucous glands and mucous gland myoepithelial cell smooth muscle actin are increased in fatal asthma and may contribute to asphyxia due to mucous plugging.

Wan Y.I.,University of Nottingham | Shrine N.R.G.,University of Leicester | Soler Artigas M.,University of Leicester | Wain L.V.,University of Leicester | And 29 more authors.
Thorax | Year: 2012

Background: The genetic basis for developing asthma has been extensively studied. However, association studies to date have mostly focused on mild to moderate disease and genetic risk factors for severe asthma remain unclear. Objective: To identify common genetic variants affecting susceptibility to severe asthma. Methods: A genome-wide association study was undertaken in 933 European ancestry individuals with severe asthma based on Global Initiative for Asthma (GINA) criteria 3 or above and 3346 clean controls. After standard quality control measures, the association of 480 889 genotyped single nucleotide polymorphisms (SNPs) was tested. To improve the resolution of the association signals identified, non-genotyped SNPs were imputed in these regions using a dense reference panel of SNP genotypes from the 1000 Genomes Project. Then replication of SNPs of interest was undertaken in a further 231 cases and 1345 controls and a meta-analysis was performed to combine the results across studies. Results: An association was confirmed in subjects with severe asthma of loci previously identified for association with mild to moderate asthma. The strongest evidence was seen for the ORMDL3/GSDMB locus on chromosome 17q12-21 (rs4794820, p=1.03×10 (-8)following meta-analysis) meeting genome-wide significance. Strong evidence was also found for the IL1RL1/IL18R1 locus on 2q12 (rs9807989, p=5.59×10 (-8) following meta-analysis) just below this threshold. No novel loci for susceptibility to severe asthma met strict criteria for genome-wide significance. Conclusions: The largest genome-wide association study of severe asthma to date was carried out and strong evidence found for the association of two previously identified asthma susceptibility loci in patients with severe disease. A number of novel regions with suggestive evidence were also identified warranting further study.

Williamson J.P.,Sir Charles Gairdner Hospital | Williamson J.P.,University of Western Australia | McLaughlin R.A.,University of Western Australia | Noffsinger W.J.,Sir Charles Gairdner Hospital | And 16 more authors.
American Journal of Respiratory and Critical Care Medicine | Year: 2011

Rationale: Our understanding of how airway remodeling affects regional airway elastic properties is limited due to technical difficulties in quantitatively measuring dynamic, in vivo airway dimensions. Such knowledge could help elucidate mechanisms of excessive airway narrowing. Objectives: To use anatomical optical coherence tomography (aOCT) to compare central airway elastic properties in control subjects and those with obstructive lung diseases. Methods: After bronchodilation, airway lumen area (Ai) was measured using aOCT during bronchoscopy in control subjects (n = 10) and those with asthma (n = 16), chronic obstructive pulmonary disease (COPD) (n = 9), and bronchiectasis (n = 8). Ai was measured in each of generations 0 to 5 while airway pressure was increased from -10 to 20 cm H2O. Airway compliance (Caw) and specific compliance (sCaw) were derived from the transpulmonary pressure (PL) versus Ai curves. Measurements and Main Results: Caw decreased progressively as airway generation increased, but sCaw did not differ appreciably across the generations. In subjects with asthma and bronchiectasis, Caw and sCaw were similar to control subjects and the PL-Ai curves were left-shifted. No significant differences were observed between control and COPD groups. Conclusions: Proximal airway elastic properties are altered in obstructive lung diseases. Although central airway compliance does not differ from control subjects in asthma, bronchiectasis, or COPD, Ai is lower in asthma and the PL-Ai relationship is left-shifted in both asthma and bronchiectasis, suggesting that airways are maximally distended at lower inflating pressures. Such changes reflect alteration in the balance between airway wall distensibility and radial traction exerted on airways by surrounding lung parenchyma favoring airway narrowing.

Williamson J.P.,Sir Charles Gairdner Hospital | Williamson J.P.,University of Western Australia | Armstrong J.J.,University of Western Australia | McLaughlin R.A.,University of Western Australia | And 13 more authors.
European Respiratory Journal | Year: 2010

Airway dimensions are difficult to quantify bronchoscopically because of optical distortion and a limited ability to gauge depth. Anatomical optical coherence tomography (aOCT), a novel imaging technique, may overcome these limitations. This study evaluated the accuracy of aOCT against existing techniques in phantom, excised pig and in vivo human airways. Three comparative studies were performed: 1) micrometer-derived area measurements in 10 plastic tubes were compared with aOCT-derived area; 2) aOCT-derived airway compliance curves from excised pig airways were compared with curves derived using an endoscopic technique; and 3) airway dimensions from the trachea to subsegmental bronchi were measured using aOCT in four anaesthetised patients during bronchoscopy and compared with computed tomography (CT) measurements. Measurements in plastic tubes revealed aOCT to be accurate and reliable. In pig airways, aOCT-derived compliance measurements compared closely with endoscopic data. In human airways, dimensions measured with aOCT and CT correlated closely. Bland - Altman plots showed that aOCT diameter and area measurements were higher than CT measurements by 7.6% and 15.1%, respectively. Airway measurements using aOCT are accurate, reliable and compare favourably with existing imaging techniques. Using aOCT with conventional bronchoscopy allows real-time measurement of airway dimensions and could be useful clinically in settings where knowledge of airway calibre is required. Copyright©ERS Journals Ltd 2010.

Williamson J.P.,Sir Charles Gairdner Hospital | Phillips M.J.,University of Western Australia | Hillman D.R.,Sir Charles Gairdner Hospital | Hillman D.R.,West Australian Sleep Disorders Research Institute | And 2 more authors.
Internal Medicine Journal | Year: 2010

Lung cancer is the most common cause of cancer death in Australia, Europe and the USA. Up to 20-30% of these cancers eventually affect the central airways and result in reduced quality of life, dyspnoea, haemoptysis, post-obstructive pneumonia and ultimately death. Non-malignant processes may also lead to central airway obstruction and can have similar symptoms. With the development of newer technologies, the last 20 years have seen the emergence of the field of interventional pulmonology to deal specifically with the diagnosis and management of thoracic malignancy, including obstruction of the central airways. This review discusses the pathology, pre-procedure work-up and management options for obstructing central airway lesions. Several treatment modalities exist for dealing with endobronchial pathology with local availability and expertise guiding choice of treatment. While the literature lacks large, multicentre, randomized studies defining the optimal management strategy for a given problem, there is growing evidence from numerous case studies of improved physiology, of quality of life and possibly of survival with modern interventional techniques. © 2010 Royal Australasian College of Physicians.

Finucane K.E.,Sir Charles Gairdner Hospital | Finucane K.E.,West Australian Sleep Disorders Research Institute | Singh B.,Sir Charles Gairdner Hospital | Singh B.,West Australian Sleep Disorders Research Institute
Journal of Applied Physiology | Year: 2012

Diaphragm efficiency estimated as power output relative to activation in chronic obstructive pulmonary disease. J Appl Physiol 113: 1567-1575, 2012. First published September 20, 2012; doi:10.1152/japplphysiol.01453.2011.-Muscle efficiency increases with fiber length and decreases with load. Diaphragm efficiency (Effdi) in healthy humans, measured as power output (Wdi) relative to the root mean square of diaphragm electromyogram (RMSdi), increases with hyperpnea due to phasic activity of abdominal muscles acting to increase diaphragm length at end expiration (Ldi ee) and decrease inspiratory load. In chronic obstructive pulmonary disease (COPD), hyperpnea may decrease Effdi if Ldi ee decreases and load increases due to airflow obstruction and dynamic hyperinflation. To examine this hypothesis, we measured Effdi in six COPD subjects (mean forced expiratory volume in 1 s: 54% predicted) when breathing air and at intervals during progressive hypercapnic hyperpnea. W di was measured as the product of mean inspiratory transdiaphragmatic pressure (ΔPdimean), diaphragm tidal volume measured fluoroscopically, and 1/inspiratory duration. Results were compared with those of six healthy subjects reported previously. In COPD, Ldi ee was normal when breathing air. ΔPdimean and W di increased normally, and RMSdi increased disproportionately (P = 0.01) with hyperpnea, and, unlike health, inspiratory capacity (IC), Ldi ee, and Effdi did not increase. IC and Ldi ee were constant with hyperpnea because mean expiratory flow increased as expiratory duration decreased (r2 = 0.65), and because expiratory flow was terminated actively by the balance between expiratory and inspiratory muscle forces near end expiration, and these forces increased proportionately with hyperpnea (r2 = 0.49). At maximum ventilation, diaphragm radius of curvature at end inspiration increased in COPD (P = 0.04) but not controls; diaphragm radius of curvature at end inspiration and ln(Effdi) were negatively correlated (P = 0.01). Thus in COPD with modest airflow obstruction, Effdi did not increase normally with hyperpnea due to a constant Ldi ee and inspiratory flattening of the diaphragm. Copyright © 2012 the American Physiological Society.

Tsartsali L.,Imperial College London | Hislop A.A.,University College London | McKay K.,University of Sydney | James A.L.,West Australian Sleep Disorders Research Institute | And 7 more authors.
Thorax | Year: 2011

Background: The bronchial epithelium and underlying reticular basement membrane (RBM) have a close spatial and functional inter-relationship and are considered an epithelial - mesenchymal trophic unit (EMTU). An understanding of RBM development is critical to understanding the extent and time of appearance of its abnormal thickening that is characteristic of asthma. Methods: RBM thickness and epithelial height were determined in histological sections of cartilaginous bronchi obtained postmortem from 47 preterm babies and infants (median age 40 weeks gestation (22 weeks gestation-8 months)), 40 children (2 years (1 month-17 years)) and 23 adults (44 (17-90) years) who had died from non-respiratory causes, and had no history of asthma. Results: The RBM was visible by light microscopy at 30 weeks gestation. RBM thickness increased in successive age groups in childhood; in infants (r=0.63, p<0.001) and in children between 1 month and 17 years (r=0.82, p<0.001). After 18 years, RBM thickness decreased with increasing age (r=-0.42, p<0.05). Epithelial height showed a similar relationship with age, a positive relationship from preterm to 17 years (r=0.50, p<0.001) and a negative relationship in adulthood (r=-0.84, p<0.0001). There was a direct relationship between epithelial height and RBM thickness (r=0.6, p<0.001). Conclusions: The RBM in these subjects was microscopically identifiable by 30 weeks gestation. It thickened during childhood and adolescence. In adults, there was either no relationship with age, or a slow reduction in thickness in older age. Developmental changes of RBM thickness were accompanied by similar changes in epithelial height, supporting the close relationship between RBM and epithelium within the EMTU.

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