Publications
415 results found
Leadbeater PDM, Kirkby NS, Thomas S, et al., 2011, Aspirin has little additional anti-platelet effect in healthy volunteers receiving prasugrel, Journal of Thrombosis and Haemostasis, Vol: 9, Pages: 2050-2056, ISSN: 1538-7836
Summary. Background: Strong P2Y12 blockade, as can be achieved with novel anti‐platelet agents such as prasugrel, has been shown in vitro to inhibit both ADP and thromboxane A2‐mediated pathways of platelet aggregation, calling into question the need for the concomitant use of aspirin. Objective: The present study investigated the hypothesis that aspirin provides little additional anti‐aggregatory effect in a group of healthy volunteers taking prasugrel. Study participants/methods: In all, 9 males, aged 18 to 40 years, enrolled into the 21‐day study. Prasugrel was loaded at 60 mg on day 1 and maintained at 10 mg until day 21. At day 8, aspirin 75 mg was introduced and the dose increased to 300 mg on day 15. On days 0, 7, 14 and 21, platelet function was assessed by aggregometry, response to treatments was determined by VerifyNow™ and urine samples were collected for quantification of prostanoid metabolites. Results: At day 7, aggregation responses to a range of platelet agonists were reduced and there was only a small further inhibition of aggregation to TRAP‐6, collagen and epinephrine at days 14 and 21, when aspirin was included with prasugrel. Urinary prostanoid metabolites were unaffected by prasugrel, and were reduced by the addition of aspirin, independent of dose. Conclusions: In healthy volunteers, prasugrel produces a strong anti‐aggregatory effect, which is little enhanced by the addition of aspirin. The addition of aspirin as a dual‐therapy with potent P2Y12 receptor inhibitors warrants further investigation.
Leadbeater PDM, Kirkby NS, Thomas S, et al., 2011, URINARY PROSTANOID METABOLITES IN HEALTHY VOLUNTEERS TAKING PRASUGREL AND ASPIRIN, HEART, Vol: 97, Pages: 16-16, ISSN: 1355-6037
Kirkby NS, Leadbeater PDM, Chan MV, et al., 2011, INHIBITION OF ADP- AND THROMBOXANE-DEPENDENT PATHWAYS OF PLATELET AGGREGATION BY THE P2Y12 ANTAGONISTS, TICAGRELOR AND PRASUGREL, HEART, Vol: 97, Pages: 9-9, ISSN: 1355-6037
Kirkby NS, Leadbeater PDM, Chan MV, et al., 2011, Antiplatelet effects of aspirin vary with level of P2Y(12) receptor blockade supplied by either ticagrelor or prasugrel, Journal of Thrombosis and Haemostasis, Vol: 9, Pages: 2103-2105, ISSN: 1538-7836
Pathan N, Burmester M, Adamovic T, et al., 2011, Intestinal injury and endotoxemia in children undergoing surgery for congenital heart disease, American Journal of Respiratory & Critical Care Medicine, Vol: 184, Pages: 1261-1269, ISSN: 1073-449X
RATIONALE: Children with congenital heart disease are at risk of gut barrier dysfunction and translocation of gut bacterial antigens into the bloodstream. This may contribute to inflammatory activation and organ dysfunction postoperatively.OBJECTIVES: To investigate the role of intestinal injury and endotoxemia in the pathogenesis of organ dysfunction after surgery for congenital heart disease.METHODS: We analyzed blood levels of intestinal fatty acid binding protein and endotoxin (endotoxin activity assay) alongside global transcriptomic profiling and assays of monocyte endotoxin receptor expression in children undergoing surgery for congenital heart disease.MEASUREMENTS AND MAIN RESULTS: Levels of intestinal fatty acid binding protein and endotoxin were greater in children with duct-dependent cardiac lesions. Endotoxemia was associated with severity of vital organ dysfunction and intensive care stay. We identified activation of pathogen-sensing, antigen-processing, and immune-suppressing pathways at the genomic level postoperatively and down-regulation of pathogen-sensing receptors on circulating immune cells.CONCLUSIONS: Children undergoing surgery for congenital heart disease are at increased risk of intestinal mucosal injury and endotoxemia. Endotoxin activity correlates with a number of outcome variables in this population, and may be used to guide the use of gut-protective strategies.
Kirkby NS, Leadbeater PDM, Chan M, et al., 2011, Aspirin augments the anti-platelet effects of partial but not complete P2Y<sub>12</sub> receptor blockade by ticagrelor, JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Vol: 9, Pages: 780-780, ISSN: 1538-7933
Kirkby NS, Singhal R, Mitchell JA, et al., 2011, Synergistic inhibition of platelet aggregation by nitric oxide and prostacyclin is potentiated by P2Y<sub>12</sub> blockade, JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Vol: 9, Pages: 780-781, ISSN: 1538-7933
Leadbeater PDM, Farndale RW, Mitchell JA, et al., 2011, The effect of stir-speed on GPVI-dependent platelet aggregation, JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Vol: 9, Pages: 528-529, ISSN: 1538-7933
Leadbeater PDM, Mitchell JA, Warner TD, 2011, The effect of time on platelet aggregation assessed by light transmission, JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Vol: 9, Pages: 779-779, ISSN: 1538-7933
Leadbeater PDM, Mitchell JA, Warner TD, 2011, The effect of stir-speed and time on TP-receptor induced platelet aggregation in the presence of aspirin and P2Y<sub>12</sub> receptor blockade, JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Vol: 9, Pages: 779-780, ISSN: 1538-7933
Reed DM, Foldes G, Gatheral T, et al., 2011, ENDOTHELIN-1 RELEASE FROM HUMAN EMBRYONIC STEM CELL DERIVED-ENDOTHELIAL CELLS (HESC-EC): COMPARISONS WITH HUMAN ENDOTHELIAL CELLS, 10th World Congress on Inflammation, Publisher: BIRKHAUSER VERLAG AG, Pages: 224-224, ISSN: 1023-3830
Reed DM, Foldes G, Badiger RV, et al., 2011, TLR3 AND INTERFERON FUNCTION IN HUMAN EMBRYONIC STEM CELL-DERIVED ENDOTHELIAL CELLS (HESC-EC): RELEVANCE TO VIRAL IMMUNITY, Heart
Wright WR, Kirkby NS, Harrington LS, et al., 2011, ROLE OF COX-1 AND COX-2 IN THE RELEASE OF PROSTANOIDS IN MURINE LUNG AND ISOLATED LUNG FIBROBLASTS, 10th World Congress on Inflammation, Publisher: BIRKHAUSER VERLAG AG, Pages: 232-232, ISSN: 1023-3830
Kirkby NS, Harrington LS, Lundberg MH, et al., 2011, CONTRIBUTION OF COX1 AND COX2 TO PROSTACYCLIN RELEASE BY HEALTHY MOUSE TISSUES, 10th World Congress on Inflammation, Publisher: BIRKHAUSER VERLAG AG, Pages: 116-117, ISSN: 1023-3830
Armstrong PC, Kirkby NS, Zain ZN, et al., 2011, Thrombosis is reduced by inhibition of COX-1, but unaffected by inhibition of COX-2, in an acute model of platelet activation in the mouse, PLoS ONE, Vol: 6, ISSN: 1932-6203
Harrington LS, Lundberg MH, Waight M, et al., 2011, Reduced endothelial dependent vasodilation in vessels from TLR4<SUP>-/-</SUP> mice is associated with increased superoxide generation, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, Vol: 408, Pages: 511-515, ISSN: 0006-291X
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- Citations: 8
Armstrong PCJ, Leadbeater PD, Chan MV, et al., 2011, In the presence of strong P2Y<sub>12</sub> receptor blockade, aspirin provides little additional inhibition of platelet aggregation, JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Vol: 9, Pages: 552-561, ISSN: 1538-7933
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- Citations: 141
Miragoli M, Moshkov A, Novak P, et al., 2011, Scanning ion conductance microscopy: a convergent high-resolution technology for multi-parametric analysis of living cardiovascular cells, Journal of the Royal Society Interface, Vol: 8, Pages: 913-925, ISSN: 1742-5662
Cardiovascular diseases are complex pathologies that include alterations of various cell functions at the levels of intact tissue, single cells and subcellular signalling compartments. Conventional techniques to study these processes are extremely divergent and rely on a combination of individual methods, which usually provide spatially and temporally limited information on single parameters of interest. This review describes scanning ion conductance microscopy (SICM) as a novel versatile technique capable of simultaneously reporting various structural and functional parameters at nanometre resolution in living cardiovascular cells at the level of the whole tissue, single cells and at the subcellular level, to investigate the mechanisms of cardiovascular disease. SICM is a multimodal imaging technology that allows concurrent and dynamic analysis of membrane morphology and various functional parameters (cell volume, membrane potentials, cellular contraction, single ion-channel currents and some parameters of intracellular signalling) in intact living cardiovascular cells and tissues with nanometre resolution at different levels of organization (tissue, cellular and subcellular levels). Using this technique, we showed that at the tissue level, cell orientation in the inner and outer aortic arch distinguishes atheroprone and atheroprotected regions. At the cellular level, heart failure leads to a pronounced loss of T-tubules in cardiac myocytes accompanied by a reduction in Z-groove ratio. We also demonstrated the capability of SICM to measure the entire cell volume as an index of cellular hypertrophy. This method can be further combined with fluorescence to simultaneously measure cardiomyocyte contraction and intracellular calcium transients or to map subcellular localization of membrane receptors coupled to cyclic adenosine monophosphate production. The SICM pipette can be used for patch-clamp recordings of membrane potential and single channel currents. In conclusio
Potter CMF, Lundberg MH, Harrington LS, et al., 2011, Role of Shear Stress in Endothelial Cell Morphology and Expression of Cyclooxygenase Isoforms, ARTERIOSCLEROSIS THROMBOSIS AND VASCULAR BIOLOGY, Vol: 31, Pages: 384-U314, ISSN: 1079-5642
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- Citations: 62
Foldes G, Ali NN, Randi A, et al., 2011, PATHOGEN SENSING PATHWAYS IN HUMAN STEM CELL-DERIVED ENDOTHELIAL CELLS, Publisher: LIPPINCOTT WILLIAMS & WILKINS, Pages: 4-4, ISSN: 1073-2322
Cartwright N, Noulin N, Couillin L, et al., 2010, Macrophage Sensing of Lps <i>in vivo</i> is Not Required for the Induction of Systemic Inflammation, CIRCULATION, Vol: 122, ISSN: 0009-7322
Warner TD, Armstrong PCJ, Curzen NP, et al., 2010, Dual antiplatelet therapy in cardiovascular disease: does aspirin increase clinical risk in the presence of potent P2Y<sub>12</sub> receptor antagonists?, HEART, Vol: 96, Pages: 1693-1694, ISSN: 1355-6037
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- Citations: 40
Mitchell JA, Badiger R, Tietz A, et al., 2010, INTERFERON (IFN) ALPHA PREPARATIONS ACTIVATE HUMAN LUNG MICROVASCULAR ENDOTHELIAL CELLS TO RELEASE THE CHEMOKINE IP10, 61st Annual Meeting of the American-Association-for-the-Study-of-Liver-Diseases, Publisher: WILEY-BLACKWELL, Pages: 809A-810A, ISSN: 0270-9139
Moreno L, McMaster SK, Gatheral T, et al., 2010, Nucleotide oligomerization domain 1 is a dominant pathway for NOS2 induction in vascular smooth muscle cells: comparison with Toll-like receptor 4 responses in macrophages, BRITISH JOURNAL OF PHARMACOLOGY, Vol: 160, Pages: 1997-2007, ISSN: 0007-1188
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- Citations: 21
Foeldes G, Liu A, Badiger R, et al., 2010, Innate Immunity in Human Embryonic Stem Cells: Comparison with Adult Human Endothelial Cells, PLOS ONE, Vol: 5, ISSN: 1932-6203
Treatment of human disease with human embryonic stem cell (hESC)-derived cells is now close to reality, but little is known of their responses to physiological and pathological insult. The ability of cells to respond via activation of Toll like receptors (TLR) is critical in innate immune sensing in most tissues, but also extends to more general danger sensing, e.g. of oxidative stress, in cardiomyocytes. We used biomarker release and gene-array analysis to compare responses in hESC before and after differentiation, and to those in primary human endothelial cells. The presence of cardiomyocytes and endothelial cells was confirmed in differentiated cultures by immunostaining, FACS-sorting and, for cardiomyocytes, beating activity. Undifferentiated hESC did not respond with CXCL8 release to Gram positive or Gram negative bacteria, or a range of PAMPs (pathogen associated molecular patterns) for TLRs 1-9 (apart from flagellin, an activator of TLR5). Surprisingly, lack of TLR-dependent responses was maintained over 4 months of differentiation of hESC, in cultures which included cardiomyocytes and endothelial cells. In contrast, primary cultures of human aortic endothelial cells (HAEC) demonstrated responses to a broad range of PAMPs. Expression of downstream TLR signalling pathways was demonstrated in hESC, and IL-1β, TNFα and INFγ, which bypass the TLRs, stimulated CXCL8 release. NFκB pathway expression was also present in hESC and NFκB was able to translocate to the nucleus. Low expression levels of TLRs were detected in hESC, especially TLRs 1 and 4, explaining the lack of response of hESC to the main TLR signals. TLR5 levels were similar between differentiated hESC and HAEC, and siRNA knockdown of TLR5 abolished the response to flagellin. These findings have potential implications for survival and function of grafted hESC-derived cells.
Hansel TT, Kropshofer H, Singer T, et al., 2010, The safety and side effects of monoclonal antibodies, NATURE REVIEWS DRUG DISCOVERY, Vol: 9, Pages: 325-338, ISSN: 1474-1776
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- Citations: 682
Harrington LS, Moreno L, Reed A, et al., 2010, The PPARβ/δAgonist GW0742 Relaxes Pulmonary Vessels and Limits Right Heart Hypertrophy in Rats with Hypoxia-Induced Pulmonary Hypertension, PLOS ONE, Vol: 5, ISSN: 1932-6203
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- Citations: 40
Armstrong PCJ, Dhanji A-RA, Tucker AT, et al., 2010, Reduction of platelet thromboxane A<sub>2</sub> production <i>ex vivo</i> and <i>in vivo</i> by clopidogrel therapy, JOURNAL OF THROMBOSIS AND HAEMOSTASIS, Vol: 8, Pages: 613-615, ISSN: 1538-7933
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- Citations: 70
Mitchell JA, Sorrentino R, Cartwright N, et al., 2010, Toll-like receptor 2 as therapeutic target in lung disease, NEW DRUGS AND TARGETS FOR ASTHMA AND COPD, Editors: Hansel, Publisher: KARGER, Pages: 69-72, ISBN: 978-3-8055-9566-7
Wiegman CH, Moriceau NOJ, Paul-Clark MJ, et al., 2010, Effect Of Short-term (3 Day) Cigarette Smoke-exposure In Mice On Histone Deacetylase (HDAC)2 And Hypoxia Inducible Factor (HIF)-1α Function, AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE, Vol: 181, ISSN: 1073-449X
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