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Smyth D.G.,William Harvey Research Institute
Journal of Molecular Endocrinology | Year: 2016

Many important fields of research had a humble origin. In the distant past, A J P Martin’s discovery that amino acids could be separated by paper chromatography and Moore and Stein’s use of columns for quantitative amino acid analysis provided the first steps towards the determination of structure in complex biologically active molecules. They opened the door to reveal the essential relationship that exists between structure and function. In molecular endocrinology, for example, striking advances have been made by chemists with their expertise in the identification of structure working with biologists who contributed valuable knowledge and experience. Advantage was gained from the convergence of different background, and it is notable that the whole is greater than the sum. In the determination of structure, it may be recalled that four of the world’s great pioneers (Archibald Martin, Rodney Porter, Fred Sanger and Vincent du Vigneaud) were acknowledged for their fundamental contributions when individually they were awarded the Nobel Prize. They foresaw that the identification of structure would prove of outstanding importance in the future. Indeed, study of the structures of β-endorphin and enkephalin and the different forms of opiate activity they engender has led to a transformation in our understanding of chemical transmission in the brain. © 2016 Society for Endocrinology Published by Bioscientifica Ltd.

Ortega-Gomez A.,Institute for Cardiovascular Prevention | Perretti M.,William Harvey Research Institute | Soehnlein O.,Institute for Cardiovascular Prevention
EMBO Molecular Medicine | Year: 2013

Resolution of inflammation is a coordinated and active process aimed at restoration of tissue integrity and function. This review integrates the key molecular and cellular mechanisms of resolution. We describe how abrogation of chemokine signalling blocks continued neutrophil tissue infiltration and how apoptotic neutrophils attract monocytes and macrophages to induce their clearance. Uptake of apoptotic neutrophils by macrophages reprograms macrophages towards a resolving phenotype, a key event to restore tissue homeostasis. Finally, we highlight the therapeutic potential that derives from understanding the mechanisms of resolution. © 2013.

McGettigan P.,William Harvey Research Institute | Henry D.,Institute for Clinical Evaluative science | Henry D.,University of Toronto | Henry D.,University of Newcastle
PLoS Medicine | Year: 2013

Background: Certain non-steroidal anti-inflammatory drugs (NSAIDs) (e.g., rofecoxib [Vioxx]) increase the risk of heart attack and stroke and should be avoided in patients at high risk of cardiovascular events. Rates of cardiovascular disease are high and rising in many low- and middle-income countries. We studied the extent to which evidence on cardiovascular risk with NSAIDs has translated into guidance and sales in 15 countries. Methods and Findings: Data on the relative risk (RR) of cardiovascular events with individual NSAIDs were derived from meta-analyses of randomised trials and controlled observational studies. Listing of individual NSAIDs on Essential Medicines Lists (EMLs) was obtained from the World Health Organization. NSAID sales or prescription data for 15 low-, middle-, and high-income countries were obtained from Intercontinental Medical Statistics Health (IMS Health) or national prescription pricing audit (in the case of England and Canada). Three drugs (rofecoxib, diclofenac, etoricoxib) ranked consistently highest in terms of cardiovascular risk compared with nonuse. Naproxen was associated with a low risk. Diclofenac was listed on 74 national EMLs, naproxen on just 27. Rofecoxib use was not documented in any country. Diclofenac and etoricoxib accounted for one-third of total NSAID usage across the 15 countries (median 33.2%, range 14.7-58.7%). This proportion did not vary between low- and high-income countries. Diclofenac was by far the most commonly used NSAID, with a market share close to that of the next three most popular drugs combined. Naproxen had an average market share of less than 10%. Conclusions: Listing of NSAIDs on national EMLs should take account of cardiovascular risk, with preference given to low risk drugs. Diclofenac has a risk very similar to rofecoxib, which was withdrawn from worldwide markets owing to cardiovascular toxicity. Diclofenac should be removed from EMLs. Please see later in the article for the Editors' Summary. © 2013 McGettigan, Henry.

Yaqoob M.M.,William Harvey Research Institute
Current Opinion in Nephrology and Hypertension | Year: 2010

Purpose of review: Chronic kidney disease progressively impairs the ability of kidneys to excrete hydrogen ions owing to the reduced capacity of the kidney to synthesize ammonia resulting in metabolic acidosis. There is good experimental evidence that metabolic acidosis contributes to protein energy wasting disorder and progression of chronic kidney disease (CKD). However, there was a lack of robust clinical evidence to support these experimental observations. Recent findings: Three recent publications have confirmed the experimental evidence and the only randomized controlled study of its kind has suggested that the correction of acidosis by sodium bicarbonate in patients with advanced CKD is associated with attenuation of the rate of decline of renal function, reduction in the incidence of end stage renal disease and improvement of nutritional parameters. Summary: In light of these recent studies, it appears that this cheap and simple strategy, which is in line with current renal recommendations, has the potential of translating into significant economic, quality of life and clinical outcome benefits in an expanding pool of patients with CKD. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Wolff C.B.,William Harvey Research Institute
Advances in Experimental Medicine and Biology | Year: 2013

Autoregulation of blood flow to most individual organs is well known. The balance of oxygen supply relative to the rate of oxygen consumption ensures normal function. There is less reserve as regards oxygen supply than for any other necessary metabolite or waste product so oxygen supply is flow dependent. Reduced rate of supply compromises tissue oxygenation long before any other substance. The present report reiterates evidence from earlier studies demonstrating that the rate of oxygen delivery (DO2), for most individual tissues, is well sustained at a value bearing a ratio to oxygen consumption (VO2) which is specific for the organ concerned. For the brain DO2 is sustained at approximately three times the rate of oxygen consumption and for exercising skeletal muscle (below the anaerobic threshold), a ratio close to 1.5. The tissue-specific ratios are sustained in the face of alterations in local VO2 and lowered arterial oxygen content (CaO2). Tolerance varies between different organs. Hence, the role of the circulation is predominantly one of ensuring an adequate supply of oxygen. The precise values of the individual tissue DO2:VO 2 ratios apply within physiological ranges which require further investigation. © 2013 Springer Science+Business Media New York.

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