38 research outputs found
A comparison of the molecular species compositions of mammalian lung surfactant phospholipids
No full textWhile dipalmitoyl phosphatidylcholine (PC16:0/16:0) is essential for pulmonary surfactant function, roles for other individual molecular species of surfactant phospholipids have not been established. If any phospholipid species other than PC16:0/16:0 is important for surfactant function, then it may be conserved across animal species. Consequently, we have quantified, by electrospray ionisation mass spectrometry, molecular species compositions of phosphatidylcholine (PC), phosphatidylglycerol (PG) and phosphatidylinositol (PI) in surfactants from human, rabbit, rat and guinea pig lungs. While PC compositions displayed only relatively minor variations across the animal species studied, there were wide variations of PG and PI concentrations and compositions. Human surfactant PG and PI were enriched in the same three monounsaturated species (PG16:0/18:1, PG18:1/18:1 and PG18:0/18:1) with minimal amounts of PG16:0/16:0 or polyunsaturated species, while all animal surfactant PG contained increased concentrations of PG16:0/16:0 and PG16:0/18:2. Animal surfactant PIs were essentially monounsaturated except for a high content of PI18:0/20:4 (29%) in the rat. As these four surfactants all maintain appropriate lung function of the respective animal species, then all their varied compositions of acidic phospholipids must be adequate at promoting the processes of adsorption, film refinement, respreading and collapse characteristic of surfactant. We conclude that this effectively monounsaturated composition of anionic phospholipid molecular species is a common characteristic of mammalian surfactants
Bacterial cell membrane hydrolysis by secreted phospholipases A2: a major physiological role of human group IIa sPLA2 involving both bacterial cell wall penetration and interfacial catalysis
No full textThe ability of human group IIa secreted phospholipase A2 (human sPLA2) to hydrolyse the phospholipid membrane of whole cell suspensions of Gram-positive bacteria is demonstrated in real time using a continuous fluorescence displacement assay. Micrococcus luteus is used as a model system and demonstrates an almost absolute specificity for this human enzyme compared with porcine pancreatic and Naja naja venom sPLA2s. This specificity is due to selective penetration of the highly cationic human sPLA2 through the highly anionic bacterial cell wall. Disruption of the peptidoglycan cell wall by treatment with lysozyme allows all three enzymes to express similar hydrolytic activity against the anionic bacterial cell membrane. Extensive (>50%) phospholipid hydrolysis was observed and this was confirmed by electrospray mass spectrometry that allowed the identification of several molecular species of phosphatidylglycerol as the targets for hydrolysis. However, the bactericidal activity of the human enzyme under these assay conditions was low, highlighting the capacity of the organism to survive a major phospholipid insult. In addition to pure enzyme, the human sPLA2 activity in tears was demonstrated using M. luteus as substrate. In comparison to M. luteus, cell suspensions of Staphylococcus aureus were highly resistant to hydrolysis by human sPLA2 as well as to the pancreatic and venom enzymes. Treatment of this organism with the specific cell wall protease lysostaphin resulted in a dramatic enhancement in cell membrane phospholipid hydrolysis by all three sPLA2s. Overall, the results highlight the potential of the human sPLA2 as a selective antimicrobial agent against Gram-positive bacteria in vivo because this enzyme is essentially inactive against mammalian plasma membranes. However, the enzyme will be most effective in combination with other antimicrobial agents that enhance the permeability of the bacterial cell wall and where potentiation of the effectiveness of other antibiotics would be expected
Effect of obstructive sleep apnea treatment on renal function in patients with cardiovascular disease
No full textRationale: Obstructive sleep apnea (OSA) is associated with impaired renal function, but uncertainty exists over whether OSA treatment can influence renal outcomes. Objectives: To determine the effects of continuous positive airway pressure (CPAP) on renal function in subjects with coexisting OSA and cardiovascular disease. Methods: This was a substudy of the international SAVE (Sleep Apnea Cardiovascular Endpoints) trial, in which 2,717 patients with moderate to severe OSA and established coronary or cerebrovascular disease were randomized to receive either CPAP plus usual care or usual care alone. Renal function and adverse renal events were compared between the CPAP (n = 102) and usual care (n = 98) groups. Glomerular filtration rate was estimated at randomization and at the end of follow-up, and the urinary albumin-to-creatinine ratio was measured at study exit. Measurements and Main Results: In 200 substudy participants (mean age, 64 yr; median, 4% oxygen desaturation index; 20 events/h; mean estimated glomerular filtration rate at baseline, 82 ml/min/1.73 m2), the median (interquartile range) changes in estimated glomerular filtration rate (ml/min/1.73 m2/yr) were -1.64 (-3.45 to -0.740) in the CPAP group and -2.30 (-4.53 to -0.71) in the usual care group (P = 0.21) after a median of 4.4 years. There were no between-group differences in end-of-study urinary albumin-to-creatinine ratio or in the occurrence of serious renal or urinary adverse events during the trial. The level of CPAP adherence did not influence the findings. Conclusions: CPAP treatment of OSA in patients with cardiovascular disease does not alter renal function or the occurrence of renal adverse events.Kelly A. Loffler, Emma Heeley, Ruth Freed, Craig S. Anderson, Ben Brockway, Alastair Corbett, Catherina L. Chang, James A. Douglas, Katherine Ferrier, Neil Graham, Garun S. Hamilton, Michael Hlavac, Nigel McArdle, John McLachlan, Sutapa Mukherjee, Matthew T. Naughton, Francis Thien, Alan Young, Ronald R. Grunstein, Lyle J. Palmer, Richard J. Woodman, Patrick J. Hanly, and R. Doug McEvo
Predictors of long-term adherence to continuous positive airway pressure in patients with obstructive sleep apnea and cardiovascular disease
No full textStudy Objectives: Poor adherence to continuous positive airway pressure (CPAP) commonly affects therapeutic response in obstructive sleep apnea (OSA). We aimed to determine predictors of adherence to CPAP among participants of the Sleep Apnea and cardioVascular Endpoints (SAVE) trial. Methods: SAVE was an international, randomized, open trial of CPAP plus usual care versus usual care (UC) alone in participants (45-75 years) with co-occurring moderate-to-severe OSA (≥12 episodes/h of ≥4% oxygen desaturation) and established cardiovascular (CV) disease. Baseline sociodemographic, health and lifestyle factors, OSA symptoms, and 1-month change in daytime sleepiness, as well as CPAP side effects and adherence (during sham screening, titration week, and in the first month), were entered in univariate linear regression analyses to identify predictors of CPAP adherence at 24 months. Variables with p <0.2 were assessed for inclusion in a multivariate linear mixed model with country, age, and sex included a priori and site as a random effect. Results: Significant univariate predictors of adherence at 24 months in 1,121 participants included: early adherence measures, improvement in daytime sleepiness at 1 month, fixed CPAP pressure, some measures of OSA severity, cardiovascular disease history, breathing pauses, and very loud snoring. While observed adherence varied between countries, adherence during sham screening, initial titration, and the first month of treatment retained independent predictive value in the multivariate model along with fixed CPAP pressure and very loud snoring. Conclusions: Early CPAP adherence had the greatest predictive value for identifying those at highest risk of non-adherence to long-term CPAP therapy.Emer Van Ryswyk, Craig S. Anderson, Nicholas A. Antic, Ferran Barbe, Lia Bittencourt, Ruth Freed, Emma Heeley, Zhihong Liu, Kelly A. Loffler, Geraldo Lorenzi-Filho, Yuanming Luo, Maria J. Masdeu Margalef, R. Doug McEvoy, Olga Mediano, Sutapa Mukherjee, Qiong Ou, Richard Woodman, Xilong Zhang, and Ching Li Chai-Coetzer, on behalf of the SAVE Investigators and Coordinator
Signal generation in prescription event monitoring: investigation of a possible signal of colitis during rofecoxib treatment
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Sex Differences in Long-Term Mortality After Stroke in the INSTRUCT (INternational STRoke oUtComes sTudy)
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Background—
Women are reported to have greater mortality after stroke than men, but the reasons are uncertain. We examined sex differences in mortality at 1 and 5 years after stroke and identified factors contributing to these differences.
Methods and Results—
Individual participant data for incident strokes were obtained from 13 population-based incidence studies conducted in Europe, Australasia, South America, and the Caribbean between 1987 and 2013. Data on sociodemographics, stroke-related factors, prestroke health, and 1- and 5-year survival were obtained. Poisson modeling was used to estimate the mortality rate ratio (MRR) for women compared with men at 1 year (13 studies) and 5 years (8 studies) after stroke. Study-specific adjusted MRRs were pooled to create a summary estimate using random-effects meta-analysis. Overall, 16 957 participants with first-ever stroke followed up at 1 year and 13 216 followed up to 5 years were included. Crude pooled mortality was greater for women than men at 1 year (MRR 1.35; 95% confidence interval, 1.24–1.47) and 5 years (MRR 1.24; 95% confidence interval, 1.12–1.38). However, these pooled sex differences were reversed after adjustment for confounding factors (1 year MRR, 0.81; 95% confidence interval, 0.72–0.92 and 5-year MRR, 0.76; 95% confidence interval, 0.65–0.89). Confounding factors included age, prestroke functional limitations, stroke severity, and history of atrial fibrillation.
Conclusions—
Greater mortality in women is mostly because of age but also stroke severity, atrial fibrillation, and prestroke functional limitations. Lower survival after stroke among the elderly is inevitable, but there may be opportunities for intervention, including better access to evidence-based care for cardiovascular and general health.
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Controllable forms for stabilising pole assignment design of generalised bilinear systems
No full textBilinear structures are able to represent nonlinear phenomena more accurately than linear models, and thereby help to extend the range of satisfactory control performance. However, closed loop characteristics are typically designed by simulation and stability is not guaranteed. In this reported work, it is shown how bilinear systems are a special case of the more general state dependent parameter (SDP) model, which can subsequently be utilised to design stabilising feedback controllers using a special form of nonlinear pole assignment. To establish the link, however, an important generalisation of the SDP pole assignment method is developed
Measuring the Progressivity of the Pharmaceutical Benefits Scheme
No full textAbstract
Through the Pharmaceutical Benefits Scheme, the Australian Government subsidises the cost of a large range of medicines. This study assesses the income‐related distribution of Pharmaceutical Benefits Scheme resources using patient‐level data from Medicare Australia and concentration indices. We find that use of, and government expenditure for, Pharmaceutical Benefits Scheme‐subsidised drugs is progressive in that more resources flow to lower income groups, even after adjusting for differences in medical need, as measured by age, sex, self‐assessed health and clinically assessed comorbidities. Of the major drug classes, cardiovascular drugs contributed substantially to the overall progressivity of Pharmaceutical Benefits Scheme subsidies, accounting for almost 50 per cent
Off-Hour Admission and Outcomes in Patients with Acute Intracerebral Hemorrhage in the INTERACT2 Trial.
No full textInternational audienceConflicting data exist of an association between off-hour (weekend, holiday, or night-time) hospital admission and adverse outcome in intracerebral hemorrhage (ICH). We determined the association between off-hour admissions and poor clinical outcome, and of any differential effect of early intensive blood pressure (BP) lowering treatment between off- and on-hour admissions, among participants of the Intensive BP Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2). Subsidiary analysis of INTERACT2, a multinational, multicenter, clinical trial of patients with spontaneous ICH with elevated systolic BP, randomly assigned to intensive (target systolic BP <140 mm Hg) or guideline-based (<180 mm Hg) BP management. Primary outcome was death or major disability (modified Rankin scale of 3-6) at 90 days. Off-hour admission was defined as night-time (4:30 p.m. to 8:30 a.m.) on weekdays, weekends (Saturday and Sunday), and public holidays in each participating country. Of 2,794 patients with information on the primary outcome, 1,770 (63%) were admitted to study centers during off-hours. Off-hour admission was not associated with risk of poor outcome at 90 days (53% off-hour vs. 55% on-hour; p = 0.49), even after adjustment for comorbid risk factors (odds ratio 0.92; 95% CI 0.76-1.12). Consistency exists in the effects of intensive BP lowering between off- and on-hour admission (p = 0.85 for homogeneity). Off-hour admission was not associated with increased risks of death or major disability among trial protocol participants with acute ICH. Intensive BP lowering can provide similar treatment effect irrespective of admission hours
The business of product innovation : international empirical evidence
No full textIt is so widely recognized that innovation is a key driver of economic growth that it is cliché to say so. This article studies product innovation by firms with data from 68 countries, covering more than 25,000 firms in eight manufacturing sectors. The author assesses the predictions of inter-disciplinary research on innovation by firms. The econometric evidence suggests that globalization and local knowledge increase the likelihood that firms will introduce new products. By contrast, domestic regulatory impediments to competition are not robustly correlated with product innovation.E-Business,Innovation,Microfinance,Education for Development (superceded),Statistical&Mathematical Sciences
