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Search Results: 1 - 10 of 219308 matches for " Peter G. Stockley "
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Inflammation in sputum relates to progression of disease in subjects with COPD: a prospective descriptive study
David G Parr, Andrew J White, Darren L Bayley, Peter J Guest, Robert A Stockley
Respiratory Research , 2006, DOI: 10.1186/1465-9921-7-136
Abstract: A cohort of 56 patients with chronic bronchitis was characterized in the stable state at baseline and after an interval of four years, using physiological measures and CT densitometry. Sputum markers of airway inflammation were quantified at baseline from spontaneously produced sputum in a sub-group (n = 38), and inflammation severity was related to subsequent disease progression.Physiological and CT measures indicated disease progression in the whole group. In the sub-group, sputum myeloperoxidase correlated with decline in FEV1 (rs = -0.344, p = 0.019, n = 37). LTB4 and albumin leakage correlated with TLCO decline (rs = -0.310, p = 0.033, rs = -0.401, p = 0.008, respectively, n = 35) and IL-8 correlated with progression of lung densitometric indices (rs = -0.464, p = 0.005, n = 38).The data support a principal causative role for neutrophilic inflammation in the pathogenesis of COPD and suggest that the measurement of sputum inflammatory markers may have a predictive role in clinical practice.Chronic obstructive pulmonary disease (COPD) is a slowly progressive condition characterised by airflow obstruction that is 'not fully reversible' [1]. The main aetiological factor is cigarette smoking and it is generally accepted that the pathogenic mechanism is the development of an abnormal inflammatory response to inhaled particles and gases in the lung. Exposure to tobacco smoke appears to be universally associated with lung inflammation, but only a proportion of smokers develop COPD. Nevertheless, an enhanced inflammatory response has been demonstrated in the lungs of susceptible individuals that is more marked with continuing exposure to tobacco smoke [2] and the level of inflammation has been shown to relate to disease severity [3-6]. In addition, sputum neutrophilia has been related to FEV1 decline over the preceding 15 years [7]. Consequently, lung inflammation is likely to play a primary pathogenic role and offers a common unifying theme to the varied clinical pheno
RNA Packing Specificity and Folding during Assembly of the Bacteriophage MS2
Ottar Rolfsson,Katerina Toropova,Victoria Morton,Simona Francese,Gabriella Basnak,Gary S. Thompson,Stephen W. Homans,Alison E. Ashcroft,Nicola J. Stonehouse,Neil A. Ranson,Peter G. Stockley
Computational and Mathematical Methods in Medicine , 2008, DOI: 10.1080/17486700802168445
Abstract: Using a combination of biochemistry, mass spectrometry, NMR spectroscopy and cryo-electron microscopy (cryo-EM), we have been able to show that quasi-equivalent conformer switching in the coat protein (CP) of an RNA bacteriophage (MS2) is controlled by a sequence-specific RNA–protein interaction. The RNA component of this complex is an RNA stem-loop encompassing just 19 nts from the phage genomic RNA, which is 3569 nts in length. This binding results in the conversion of a CP dimer from a symmetrical conformation to an asymmetric one. Only when both symmetrical and asymmetrical dimers are present in solution is assembly of the T = 3 phage capsid efficient. This implies that the conformers, we have characterized by NMR correspond to the two distinct quasi-equivalent conformers seen in the 3D structure of the virion. An icosahedrally-averaged single particle cryo-EM reconstruction of the wild-type phage (to ∼9 Å resolution) has revealed icosahedrally ordered density encompassing up to 90% of the single-stranded RNA genome. The RNA is seen with a novel arrangement of two concentric shells, with connections between them along the 5-fold symmetry axes. RNA in the outer shell interacts with each of the 90 CP dimers in the T = 3 capsid and although the density is icosahedrally averaged, there appears to be a different average contact at the different quasi-equivalent protein dimers: precisely the result that would be expected if protein conformer switching is RNA-mediated throughout the assembly pathway. This unprecedented RNA structure provides new constraints for models of viral assembly and we describe experiments aimed at probing these. Together, these results suggest that viral genomic RNA folding is an important factor in efficient assembly, and further suggest that RNAs that could sequester viral CPs but not fold appropriately could act as potent inhibitors of viral assembly.
Conformational flexibility and molecular interactions of an archaeal homologue of the Shwachman-Bodian-Diamond syndrome protein
C Leong Ng, David G Waterman, Eugene V Koonin, Alison D Walters, James PJ Chong, Michail N Isupov, Andrey A Lebedev, David HJ Bunka, Peter G Stockley, Miguel Ortiz-Lombardía, Alfred A Antson
BMC Structural Biology , 2009, DOI: 10.1186/1472-6807-9-32
Abstract: We determined the crystal structure of the SBDS orthologue from Methanothermobacter thermautotrophicus (mthSBDS). This structure shows that SBDS proteins are highly flexible, with the N-terminal FYSH domain and the C-terminal ferredoxin-like domain capable of undergoing substantial rotational adjustments with respect to the central domain. Affinity chromatography identified several proteins from the large ribosomal subunit as possible interacting partners of mthSBDS. Moreover, SELEX (Systematic Evolution of Ligands by EXponential enrichment) experiments, combined with electrophoretic mobility shift assays (EMSA) suggest that mthSBDS does not interact with RNA molecules in a sequence specific manner.It is suggested that functional interactions of SBDS proteins with their partners could be facilitated by rotational adjustments of the N-terminal and the C-terminal domains with respect to the central domain. Examination of the SBDS protein structure and domain movements together with its possible interaction with large ribosomal subunit proteins suggest that these proteins could participate in ribosome function.The Methanothermobacter thermautotrophicus mth685 gene, which encodes the homologue of the Shwachman-Bodian-Diamond syndrome (SBDS) protein, is located in the predicted exosome superoperon [1]. The SBDS proteins are highly conserved [Pfam:PF01172] in archaea and eukaryota [2]. Mutations of the human SBDS gene are associated with the condition known as Shwachman-Diamond syndrome (SDS), an autosomal recessive disorder with clinical features including hematological and skeletal abnormalities and also exocrine pancreatic insufficiency [OMIM:260400]. The most common mutations associated with SDS include the polypeptide chain truncation K62X caused by the introduction of an in-frame stop codon (183–184TA → CT mutation) and a donor splicing site mutation, 258+2T → C, which causes premature truncation of the encoded protein by frameshift (84Cfs3). In addition, several po
Moderation in Australia-Policy and Achievements
STOCKLEY,CREINA;
Biological Research , 2004, DOI: 10.4067/S0716-97602004000200005
Abstract: alcohol has been consumed in australia since european settlement in 1788. in 1998, approximately 60 % of australians consumed an alcoholic beverage at least once per week. the effects of alcohol on the human body are dose dependent, where the harmful effects of alcohol are generally observed only when alcohol consumption exceeds moderate consumption levels of 30 to 40 g of alcohol per day. the discovery that a j-shaped curve described the relationship between level of alcohol consumption and risk of cardiovascular disease was, however, only made in 1990_cardiovascular disease is the leading cause of death in the western world. thus prior to 1990, australian public health policy focused primarily on the harmful effects of alcohol consumption and the health benefits of a moderate level of alcohol consumption have only recently been recognized in public policy. this paper chronicles changes in australian federal government policy on alcohol since the initial draft national health policy on alcohol in australia was presented to the ministerial council on drug strategy in 1987 to the national drug strategic plan for action 2001 to 2003-2004 which was launched in july last year
Moderation in Australia-Policy and Achievements
CREINA STOCKLEY
Biological Research , 2004,
Abstract: Alcohol has been consumed in Australia since European settlement in 1788. In 1998, approximately 60 % of Australians consumed an alcoholic beverage at least once per week. The effects of alcohol on the human body are dose dependent, where the harmful effects of alcohol are generally observed only when alcohol consumption exceeds moderate consumption levels of 30 to 40 g of alcohol per day. The discovery that a J-shaped curve described the relationship between level of alcohol consumption and risk of cardiovascular disease was, however, only made in 1990_cardiovascular disease is the leading cause of death in the western world. Thus prior to 1990, Australian public health policy focused primarily on the harmful effects of alcohol consumption and the health benefits of a moderate level of alcohol consumption have only recently been recognized in public policy. This paper chronicles changes in Australian Federal government policy on alcohol since the initial draft National health policy on alcohol in Australia was presented to the Ministerial Council on Drug Strategy in 1987 to the National Drug Strategic plan for action 2001 to 2003-2004 which was launched in July last year
Therapeutic efficacy of alpha-1 antitrypsin augmentation therapy on the loss of lung tissue: an integrated analysis of 2 randomised clinical trials using computed tomography densitometry
Robert A Stockley, David G Parr, Eeva Piitulainen, Jan Stolk, Berend C Stoel, Asger Dirksen
Respiratory Research , 2010, DOI: 10.1186/1465-9921-11-136
Abstract: Data from these similar trials, a 2-center Danish-Dutch study (n = 54) and the 3-center EXAcerbations and CT scan as Lung Endpoints (EXACTLE) study (n = 65), were pooled to increase the statistical power. The change in 15th percentile of lung density (PD15) measured by CT scan was obtained from both trials. All subjects had 1 CT scan at baseline and at least 1 CT scan after treatment. Densitometric data from 119 patients (AAT [Alfalastin? or Prolastin?], n = 60; placebo, n = 59) were analysed by a statistical/endpoint analysis method. To adjust for lung volume, volume correction was made by including the change in log-transformed total lung volume as a covariate in the statistical model.Mean follow-up was approximately 2.5 years. The mean change in lung density from baseline to last CT scan was -4.082 g/L for AAT and -6.379 g/L for placebo with a treatment difference of 2.297 (95% CI, 0.669 to 3.926; p = 0.006). The corresponding annual declines were -1.73 and -2.74 g/L/yr, respectively.The overall results of the combined analysis of 2 separate trials of comparable design, and the only 2 controlled clinical trials completed to date, has confirmed that IV AAT augmentation therapy significantly reduces the decline in lung density and may therefore reduce the future risk of mortality in patients with AAT deficiency-related emphysema.The EXACTLE study was registered in ClinicalTrials.gov as 'Antitrypsin (AAT) to Treat Emphysema in AAT-Deficient Patients'; ClinicalTrials.gov Identifier: NCT00263887.In subjects with a hereditary deficiency of alpha-1 antitrypsin (AAT), the pathophysiology of emphysema is believed to be a direct consequence of tissue damage caused by a reduced ability of AAT to inactivate neutrophil elastase, which is released by migrating neutrophils in response to inflammatory stimuli [1]. It is logical that augmentation of the circulating levels (and hence lung levels) of AAT would confer normal protection by restoring the inhibitory capacity of AAT in
Exploring the optimum approach to the use of CT densitometry in a randomised placebo-controlled study of augmentation therapy in alpha 1-antitrypsin deficiency
David G Parr, Asger Dirksen, Eeva Piitulainen, Chunqin Deng, Marion Wencker, Robert A Stockley
Respiratory Research , 2009, DOI: 10.1186/1465-9921-10-75
Abstract: Patients with AATD (n = 77) were randomised to weekly infusions of 60 mg/kg human AAT (Prolastin?) or placebo over 2 to 2.5 years. Lung volume was included as a covariate in an endpoint analysis and a comparison was made of different CT densitometric indices (15th percentile lung density [PD15], mean lung density [MLD] and voxel index at a threshold of -910 [VI-910] and -950 [VI-950] Hounsfield Units) obtained from whole lung scans at baseline and at 24 to 30 months. Targeted regional sampling was compared with whole lung assessment.Whole lung analysis of the total change (baseline to last CT scan) compared with placebo indicated a concordant trend that was suggestive of a treatment effect for all densitometric indices (MLD [1.402 g/L, p = 0.204]; VI-910 [-0.611, p = 0.389]; VI-950 [-0.432, p = 0.452]) and that was significant using PD15 (1.472 g/L, p = 0.049). Assessment of the progression of emphysema in the apical, middle and basal regions of the lung by measurement with PD15 showed that this treatment effect was more evident when the basal third was sampled (1.722 g/L, p = 0.040). A comparison between different densitometric indices indicated that the influence of inspiratory variability between scans was greatest for PD15, but when adjustment for lung volume was made this index was the most sensitive measure of emphysema progression.PD15 is the most sensitive index of emphysema progression and of treatment modification. Targeted sampling may be more sensitive than whole lung analysis.Registered in ClinicalTrials.gov as 'Antitrypsin (AAT) to Treat Emphysema in AAT-Deficient Patients'; ClinicalTrials.gov Identifier: NCT00263887.Computed tomographic (CT) imaging is the most sensitive and specific method for diagnosis of emphysema in vivo [1,2]. In addition, it provides quantitative data that correlate with pathological morphometry [3-6] and has been shown to be a valid tool for monitoring emphysema in clinical studies of alpha 1-antitrypsin deficiency (AATD) [7,8]
Detection of emphysema progression in alpha 1-antitrypsin deficiency using CT densitometry; Methodological advances
David G Parr, Martin Sevenoaks, ChunQin Deng, Berend C Stoel, Robert A Stockley
Respiratory Research , 2008, DOI: 10.1186/1465-9921-9-21
Abstract: Emphysema progression over a 2-year interval was assessed in 71 patients (alpha 1-antitrypsin deficiency with PiZ phenotype) with CT densitometry, using the 15th percentile point (Perc15) and voxel index (VI) -950 Hounsfield Units (HU) and -910 HU (VI -950 and -910) on whole lung, limited single slices, and apical, central and basal thirds. The relationship between whole lung densitometric progression (ΔCT) and change in CT-derived lung volume (ΔCTVol) was characterised, and adjustment for lung volume using statistical modelling was evaluated.CT densitometric progression was statistically significant for all methods. ΔCT correlated with ΔCTVol and linear regression indicated that nearly one half of lung density loss was secondary to apparent hyperinflation. The most accurate measure was obtained using a random coefficient model to adjust for lung volume and the greatest progression was detected by targeted sampling of the middle third of the lung.Progressive hyperinflation may contribute significantly to loss of lung density, but volume effects and absolute tissue loss can be identified by statistical modelling. Targeted sampling of the middle lung region using Perc15 appears to be the most robust measure of emphysema progression.Emphysema is defined as 'abnormal, permanent enlargement of airspaces distal to the terminal bronchioles, accompanied by destruction of their walls, and without obvious fibrosis' [1]. The proteolytic tissue destruction that is pathognomonic of emphysema should directly cause a reduction in lung density, but additional loss arises from lung hyperinflation that is secondary to increased lung compliance. Lung density changes can be measured using computed tomography (CT) scanning, and CT lung densitometry is now widely accepted to be the most sensitive and specific measure of emphysema in vivo [2-7]. However, several technical issues remain unresolved. The level of inspiration during scan acquisition influences lung density and, in sequential
Is there a role for wine in cancer and the degenerative diseases of aging?
Creina S Stockley
International Journal of Wine Research , 2009, DOI: http://dx.doi.org/10.2147/IJWR.S4591
Abstract: there a role for wine in cancer and the degenerative diseases of aging? Review (5829) Total Article Views Authors: Creina S Stockley Published Date June 2009 Volume 2009:1 Pages 195 - 207 DOI: http://dx.doi.org/10.2147/IJWR.S4591 Creina S Stockley The Australian Wine Research Institute, Adelaide, South Australia, Australia Abstract: Population aging is associated with the increased incidence cancer and of degenerative diseases. Population aging is occurring on a global scale, with faster aging projected for the coming decades than has occurred in the past. Globally, the population aged 60 years and over is projected to nearly triple by 2050, while the population aged 80 years and over is projected to experience a more than fivefold increase. Increased numbers of older individuals may have implications for associated expenditure on income support, housing and health services, although a healthy, independent older population can also form a valued social resource, for example in providing care for others, sharing skills and knowledge, and engaging in volunteer activities. Simple dietary measures such as moderate wine consumption to supplement a healthy exercise and nutrition routine, or as an adjunct to prescription medicines when appropriate, are thus needed to maintain an aging population. The role of wine in cancer and the degenerative diseases of aging is thus discussed.
Relationship between frequency, length, and treatment outcome of exacerbations to baseline lung function and lung density in alpha-1 antitrypsin-deficient COPD
Vijayasaratha K, Stockley RA
International Journal of Chronic Obstructive Pulmonary Disease , 2012, DOI: http://dx.doi.org/10.2147/COPD.S31797
Abstract: tionship between frequency, length, and treatment outcome of exacerbations to baseline lung function and lung density in alpha-1 antitrypsin-deficient COPD Original Research (870) Total Article Views Authors: Vijayasaratha K, Stockley RA Published Date November 2012 Volume 2012:7 Pages 789 - 796 DOI: http://dx.doi.org/10.2147/COPD.S31797 Received: 14 March 2012 Accepted: 17 October 2012 Published: 27 November 2012 Kesavaperumal Vijayasaratha,1 Robert A Stockley2 1Lung Investigation Unit, 2Research and Development, University Hospital Birmingham NHS Trust, Birmingham, UK Background: Diary cards are useful for analyzing exacerbations in chronic obstructive pulmonary disease (COPD), although factors influencing the length and frequency of each episode are poorly understood. This study investigated factors that influence the features of exacerbations in patients with alpha-1 antitrypsin (AAT) deficiency (PiZ phenotype) and COPD. Methods: Daily diary cards were collected over 2 years. Patients had emphysema visualized and quantified by computed tomography scan, and had at least one documented exacerbation in the previous year. Results: The patients (n = 23) had a mean age of 52.5 years, forced expiratory volume in one second (FEV1) of 1.2 L (38.4% predicted), corrected gas transfer (KCO) of 0.90 mmol/min/kPa/L (59.7% predicted), and 15th percentile lung density of 44.55 g/L. Two hundred and sixty-three exacerbations (164 treated) were identified. The frequency of treated exacerbations correlated negatively with KCO% predicted (r = 0.432; P = 0.022). Exacerbation length (determined for 17 of the patients for whom diary card data through the episode were available) correlated negatively with baseline 15th percentile lung density (r = 0.361; P = 0.003), and increased the longer treatment was delayed (r = 0.503; P < 0.001). Treatment delay was shorter with higher day 1 symptom score, lower baseline FEV1, FEV1/forced vital capacity, and lower 15th percentile lung density (r = 0.368, 0.272, 0.461, and 0.786; P = 0.004, 0.036, <0.001, and <0.001, respectively). Time to resolution of exacerbation after treatment initiation was not affected by treatment delay, but correlated negatively with KCO% predicted (r = 0.647; P = 0.007). Conclusion: In alpha-1 antitrypsin deficiency, the frequency and length of resolution of exacerbation were related to baseline gas transfer. Treatment delay adversely affected exacerbation length, and lung density was the best independent predictor of delay in starting treatment.
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