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    ABSTRACT: The risk of acute myocardial infarction in firefighters is increased during fire suppression duties, and is likely to reflect a combination of factors including extreme physical exertion and heat exposure. We assess the effects of physical exertion and heat exposure on vascular function and thrombosis in firefighters.
    Journal of the American College of Cardiology 01/2014; 63(12):A1.
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    ABSTRACT: To determine the optimal T1 mapping approach to assess myocardial fibrosis at 3T. T1 mapping was performed at 3T using the modified look-locker-inversion sequence in 20 healthy volunteers and 20 patients with aortic stenosis (AS). Pre- and post-contrast myocardial T1, the partition coefficient (λ; ΔRmyocardium/ΔRblood, where ΔR = 1/post-contrast T1 - 1/pre-contrast T1), and extracellular volume fraction [ECV; λ (1 - haematocrit)] were assessed. After establishing the optimal time point and myocardial region for analysis, we compared the reproducibility of these T1 measures and their ability to differentiate asymptomatic patients with AS from healthy volunteers. There was no segmental variation across the ventricle in any of the T1 measures evaluated. λ and ECV did not vary with time, while post-contrast T1 was relatively constant between 15 and 30 min. Thus, mid-cavity myocardium at 20 min was used for subsequent analyses. ECV displayed excellent intra-, inter-observer, and scan-rescan reproducibility [intra-class correlation coefficients (ICC) 1.00, 0.97, and 0.96, respectively], as did λ (ICC 0.99, 0.94, 0.93, respectively). Moreover, ECV and λ were both higher in patients with AS compared with controls (ECV 28.3 ± 1.7 vs. 26.0 ± 1.6%, P < 0.001; λ 0.46 ± 0.03 vs. 0.44 ± 0.03, P = 0.02), with the former offering improved differentiation. In comparison, scan-rescan reproducibilities for pre- and post-contrast myocardial T1 were only modest (ICC 0.72 and 0.56) with no differences in values observed between cases and controls (both P> 0.05). ECV appears to be the most promising measure of diffuse myocardial fibrosis at 3T based upon its superior reproducibility and ability to differentiate disease from health.
    European Heart Journal – Cardiovascular Imaging 11/2013;
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    ABSTRACT: Therapeutic inhibition of neutrophil-derived elastases holds promise with powerful treatment effects observed in various preclinical models of lung, bowel and skin inflammation and ischaemia-reperfusion injury relevant to myocardial infarction, stroke and transplant medicine. This brief review considers recent studies eliciting the complex interaction between neutrophil-derived elastases and endogenous inhibitors that determines elastase-mediated inflammation in humans. Translating results of preclinical studies with neutrophil elastase inhibitors remains challenging. Future clinical studies will harness developments in drug delivery and utilize more specific markers of neutrophil elastase activity to inform on the efficacy of inhibition. A summary of recently published and ongoing clinical trials with synthetic inhibitors sivelestat and AZD9668 and recombinant elafin is provided. Clinical trials with neutrophil elastase inhibitors in lung and cardiovascular disease are ongoing, and future studies will incorporate novel delivery approaches and be directed by specific markers of neutrophil-derived elastase activity to target inhibition to the sites of inflammatory tissue injury.
    Current opinion in hematology 11/2013;
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    ABSTRACT: The use of non-invasive imaging to identify ruptured or high-risk coronary atherosclerotic plaques would represent a major clinical advance for prevention and treatment of coronary artery disease. We used combined PET and CT to identify ruptured and high-risk atherosclerotic plaques using the radioactive tracers (18)F-sodium fluoride ((18)F-NaF) and (18)F-fluorodeoxyglucose ((18)F-FDG). In this prospective clinical trial, patients with myocardial infarction (n=40) and stable angina (n=40) underwent (18)F-NaF and (18)F-FDG PET-CT, and invasive coronary angiography. (18)F-NaF uptake was compared with histology in carotid endarterectomy specimens from patients with symptomatic carotid disease, and with intravascular ultrasound in patients with stable angina. The primary endpoint was the comparison of (18)F-fluoride tissue-to-background ratios of culprit and non-culprit coronary plaques of patients with acute myocardial infarction. In 37 (93%) patients with myocardial infarction, the highest coronary (18)F-NaF uptake was seen in the culprit plaque (median maximum tissue-to-background ratio: culprit 1·66 [IQR 1·40-2·25] vs highest non-culprit 1·24 [1·06-1·38], p<0·0001). By contrast, coronary (18)F-FDG uptake was commonly obscured by myocardial uptake and where discernible, there were no differences between culprit and non-culprit plaques (1·71 [1·40-2·13] vs 1·58 [1·28-2·01], p=0·34). Marked (18)F-NaF uptake occurred at the site of all carotid plaque ruptures and was associated with histological evidence of active calcification, macrophage infiltration, apoptosis, and necrosis. 18 (45%) patients with stable angina had plaques with focal (18)F-NaF uptake (maximum tissue-to-background ratio 1·90 [IQR 1·61-2·17]) that were associated with more high-risk features on intravascular ultrasound than those without uptake: positive remodelling (remodelling index 1·12 [1·09-1·19] vs 1·01 [0·94-1·06]; p=0·0004), microcalcification (73% vs 21%, p=0·002), and necrotic core (25% [21-29] vs 18% [14-22], p=0·001). (18)F-NaF PET-CT is the first non-invasive imaging method to identify and localise ruptured and high-risk coronary plaque. Future studies are needed to establish whether this method can improve the management and treatment of patients with coronary artery disease. Chief Scientist Office Scotland and British Heart Foundation.
    The Lancet 11/2013;
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    ABSTRACT: While glucocorticoids (GC) are known to be present in the zebrafish embryo little is known about their physiological roles at this stage. We hypothesised that GC play key roles in stress response, hatching and swim activity during early development. To test this, whole embryo cortisol (WEC) and corticosteroid-related genes were measured in embryos from 6 to 120 hours post fertilisation (hpf) by ELISA. Stress response was assessed by change in WEC following stirring, hypoxia or brief electrical impulses applied to the bathing water. The impact of pharmacological and molecular glucocorticoid manipulation on the stress-response, spontaneous hatching and swim activity at different stages of development was also assessed. WEC levels demonstrated a biphasic pattern during development with a decrease from 0 to 36 hpf followed by a progressive increase towards 120hpf. This was accompanied by a significant and sustained increase in the expression of genes encoding cyp11b1 (glucocorticoid biosynthesis), 11βhsd2 (glucocorticoid metabolism) and gr (glucocorticoid receptor) from 48 to 120hpf. Metyrapone (Met) an inhibitor of 11β hydroxylase (encoded by cyp11b1) and cyp11b1 morpholino knockdown significantly reduced basal and stress-induced WEC levels at 72 and 120hpf but not at 24 hpf. Spontaneous hatching and swim activity were significantly affected by manipulation of GC action from approximately 48 hpf onwards. We have identified a number of key roles of GC in zebrafish embryos contributing to adaptive physiological responses under adverse conditions. The ability to alter GC action in the zebrafish embryo also highlights its potential value for GC research.
    The Journal of Physiology 10/2013;
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    ABSTRACT: Some clinicians assess the efficacy of pralidoxime in organophosphorus (OP) poisoned patients by measuring reactivation of butyrylcholinesterase (BuChE). However, the degree of BuChE inhibition varies by OP insecticide and it is unclear how well oximes reactivate BuChE in vivo. We aimed to assess the usefulness of BuChE activity to monitor pralidoxime treatment by studying its reactivation after pralidoxime administration to patients with laboratory-proven World Health Organization (WHO) Class II OP insecticide poisoning. Patient data were derived from two studies, a cohort study (using a bolus treatment of 1 g pralidoxime chloride) and a randomized controlled trial (RCT) (comparing 2 g pralidoxime over 20 min, followed by an infusion of 0.5 g/h, with placebo). Two grams of pralidoxime variably reactivated BuChE in patients poisoned by two diethyl-OP insecticides, chlorpyrifos and quinalphos; however, unlike AChE reactivation, this reactivation was not sustained. It did not reactivate BuChE inhibited by the dimethyl OPs dimethoate or fenthion. The 1 g dose produced no reactivation. Pralidoxime produced variable reactivation of BuChE in WHO Class II OP poisoned patients according to the pralidoxime dose administered, OP ingested, and individual patient. The use of BuChE assays for monitoring the effect of pralidoxime treatment is unlikely to be clinically useful.
    Toxicological Sciences 09/2013;
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    Journal of the American College of Cardiology 09/2013;
  • Circulation Cardiovascular Imaging 09/2013; 6(5):e29.
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    ABSTRACT: Valvular heart disease is a major cause of morbidity and mortality, and with an aging population, its prevalence is increasing. Here, we review the evolving use of positron emission tomography/computed tomography in valvular heart disease, with particular focus on calcific aortic stenosis and infective endocarditis. In principle, the activity of any pathological process can be studied, as long as an appropriate radiotracer can be developed. We will review some of the early data using established tracers in the above and other conditions, providing discussion as to the future research and clinical roles of these techniques. Furthermore, we will discuss the potential impact of novel tracers that are currently under development or testing in preclinical models. It is hoped that such advanced imaging might improve the diagnosis, treatment and outlook for patients with valvular heart disease.
    Future Cardiology 09/2013; 9(5):657-67.
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    Heart (British Cardiac Society) 08/2013;
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