• Assessment of cardiovascular risk.

      Cooney, Marie Therese; Cooney, Helen C; Dudina, Alexandra; Graham, Ian M; Department of Cardiology, Adelaide Meath Hospital, Tallaght, Dublin, 24, Ireland. therese.cooney@yahoo.com (Current hypertension reports, 2010-10)
      Atherosclerotic cardiovascular disease (CVD) is the most common cause of death worldwide. Usually atherosclerosis is caused by the combined effects of multiple risk factors. For this reason, most guidelines on the prevention of CVD stress the assessment of total CVD risk. The most intensive risk factor modification can then be directed towards the individuals who will derive the greatest benefit. To assist the clinician in calculating the effects of these multiple interacting risk factors, a number of risk estimation systems have been developed. This review address several issues regarding total CVD risk assessment: Why should total CVD risk be assessed? What risk estimation systems are available? How well do these systems estimate risk? What are the advantages and disadvantages of the current systems? What are the current limitations of risk estimation systems and how can they be resolved? What new developments have occurred in CVD risk estimation?
    • Elevated active secretory sphingomyelinase in antineutrophil cytoplasmic antibody-associated primary systemic vasculitis.

      Kiprianos, Allan P; Morgan, Matthew D; Little, Mark A; Harper, Lorraine; Bacon, Paul A; Young, Stephen P (2012-06)
    • Homocysteine increases the risk associated with hyperlipidaemia.

      Daly, Caroline; Fitzgerald, Anthony P; O'Callaghan, Patrick; Collins, Patrick; Cooney, Marie Therese; Graham, Ian M; Royal Brompton Hospital, Sydney St, London, UK. (European journal of cardiovascular prevention and rehabilitation : official journal of the European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology, 2009-04)
      The European Concerted Action Project 'Homocysteine and Vascular Disease' showed that an elevated homocysteine is associated with a substantially increased risk of cardiovascular disease, and particularly when combined with other factors such as smoking, hypertension and hypercholesterolaemia. The purpose of this study was to examine the potential interactions between homocysteine and individual lipid subfractions. In addition, it was hypothesized that HDL cholesterol may protect against hyperhomocysteinaemia because HDL cholesterol is associated with the enzyme paroxonase, which reduces oxidization of homocysteine to the harmful metabolite, homocysteine thiolactonase.
    • How much does HDL cholesterol add to risk estimation? A report from the SCORE Investigators.

      Cooney, Marie Therese; Dudina, Alexandra; De Bacquer, Dirk; Fitzgerald, Anthony; Conroy, Ronan; Sans, Susana; Menotti, Alessandro; De Backer, Guy; Jousilahti, Pekka; Keil, Ulrich; et al. (2009-06)
      Systematic COronary Risk Evaluation (SCORE), the risk estimation system recommended by the European guidelines on cardiovascular disease prevention, estimates 10-year risk of cardiovascular disease mortality based on age, sex, country of origin, systolic blood pressure, smoking status and either total cholesterol (TC) or TC/high-density lipoprotein cholesterol (HDL-C) ratio. As, counterintuitively, these two systems perform very similarly, we have investigated whether incorporating HDL-C and TC as separate variables improves risk estimation.
    • Lack of significant metabolic abnormalities in mice with liver-specific disruption of 11β-hydroxysteroid dehydrogenase type 1.

      Lavery, Gareth G; Zielinska, Agnieszka E; Gathercole, Laura L; Hughes, Beverly; Semjonous, Nina; Guest, Phillip; Saqib, Khalid; Sherlock, Mark; Reynolds, Gary; Morgan, Stuart A; et al. (Endocrinology, 2012-07)
      Glucocorticoids (GC) are implicated in the development of metabolic syndrome, and patients with GC excess share many clinical features, such as central obesity and glucose intolerance. In patients with obesity or type 2 diabetes, systemic GC concentrations seem to be invariably normal. Tissue GC concentrations determined by the hypothalamic-pituitary-adrenal (HPA) axis and local cortisol (corticosterone in mice) regeneration from cortisone (11-dehydrocorticosterone in mice) by the 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) enzyme, principally expressed in the liver. Transgenic mice have demonstrated the importance of 11β-HSD1 in mediating aspects of the metabolic syndrome, as well as HPA axis control. In order to address the primacy of hepatic 11β-HSD1 in regulating metabolism and the HPA axis, we have generated liver-specific 11β-HSD1 knockout (LKO) mice, assessed biomarkers of GC metabolism, and examined responses to high-fat feeding. LKO mice were able to regenerate cortisol from cortisone to 40% of control and had no discernible difference in a urinary metabolite marker of 11β-HSD1 activity. Although circulating corticosterone was unaltered, adrenal size was increased, indicative of chronic HPA stimulation. There was a mild improvement in glucose tolerance but with insulin sensitivity largely unaffected. Adiposity and body weight were unaffected as were aspects of hepatic lipid homeostasis, triglyceride accumulation, and serum lipids. Additionally, no changes in the expression of genes involved in glucose or lipid homeostasis were observed. Liver-specific deletion of 11β-HSD1 reduces corticosterone regeneration and may be important for setting aspects of HPA axis tone, without impacting upon urinary steroid metabolite profile. These discordant data have significant implications for the use of these biomarkers of 11β-HSD1 activity in clinical studies. The paucity of metabolic abnormalities in LKO points to important compensatory effects by HPA activation and to a crucial role of extrahepatic 11β-HSD1 expression, highlighting the contribution of cross talk between GC target tissues in determining metabolic phenotype.
    • Neurological signs and involuntary movements in schizophrenia: intrinsic to and informative on systems pathobiology.

      Whitty, Peter F; Owoeye, Olabisi; Waddington, John L; Department of Psychiatry, The Adelaide and Meath Hospital, Tallaght, Dublin,, Ireland. (2012-02-01)
      While it has long been considered whether the pathobiology of schizophrenia extends beyond its defining symptoms to involve diverse domains of abnormality, in the manner of a systemic disease, studies of neuromotor dysfunction have been confounded by treatment with antipsychotic drugs. This challenge has been illuminated by a new generation of studies on first-episode schizophrenia before initiation of antipsychotic treatment and by opportunities in developing countries to study chronically ill patients who have remained antipsychotic naive due to limitations in provision of psychiatric care. Building from studies in antipsychotic-naive patients, this article reviews 2 domains of neuromotor dysfunction in schizophrenia: neurological signs and involuntary movements. The presence and characteristics of neurological signs in untreated vis-a-vis treated psychosis indicate a vulnerability marker for schizophrenia and implicate disruption to neuronal circuits linking the basal ganglia, cerebral cortex, and cerebellum. The presence and characteristics of involuntary movements in untreated vis-a-vis treated psychosis indicate an intrinsic feature of the disease process and implicate dysfunction in cortical-basal ganglia-cortical circuitry. These neuromotor disorders of schizophrenia join other markers of subtle but pervasive cerebral and extracerebral, systemic dysfunction, and complement current concepts of schizophrenia as a disorder of developmentally determined cortical-basal ganglia-thalamo-cortical/cerebellar network disconnectivity.
    • A novel surrogate index for hepatic insulin resistance.

      Vangipurapu, J; Stančáková, A; Kuulasmaa, T; Paananen, J; Kuusisto, J; Ferrannini, E; Laakso, M; Department of Medicine, University of Eastern Finland, Kuopio University Hospital, 70210, Kuopio, Finland. (Diabetologia, 2011-03)
      In epidemiological and genetic studies surrogate indices are needed to investigate insulin resistance in different insulin-sensitive tissues. Our objective was to develop a surrogate index for hepatic insulin resistance.
    • Platelet degranulation and monocyte-platelet complex formation are increased in the acute and convalescent phases after ischaemic stroke or transient ischaemic attack.

      McCabe, Dominick J H; Harrison, Paul; Mackie, Ian J; Sidhu, Paul S; Purdy, Gordon; Lawrie, Andrew S; Watt, Hilary; Brown, Martin M; Machin, Samuel J; Stroke Research Unit, Department of Headache, Brain Injury and Rehabilitation, Institute of Neurology, The National Hospital for Neurology and Neurosurgery, University College London, London, UK. d.mccabe@ion.ucl.ac.uk (British journal of haematology, 2004-06)
      Flow cytometric studies suggest that platelets are activated in ischaemic stroke or transient ischaemic attack (TIA). However, few studies have measured circulating leucocyte-platelet complexes in this patient population. Whole blood flow cytometry was used to quantify the expression of CD62P-, CD63-, and PAC1-binding, and the percentages of leucocyte-platelet complexes in acute (1-27 d, n = 79) and convalescent (79-725 d, n = 70) ischaemic cerebrovascular disease (CVD) patients compared with controls without CVD (n = 27). We performed a full blood count, and measured plasma levels of soluble P-selectin, soluble E-selectin, and von Willebrand factor antigen (VWF:Ag) as additional markers of platelet and/or endothelial cell activation. The median percentage CD62P expression and the median percentage monocyte-platelet complexes were higher in both acute and convalescent CVD patients than controls (P
    • Re-evaluating the Rose approach: comparative benefits of the population and high-risk preventive strategies.

      Cooney, Marie-Therese; Dudina, Alexandra; Whincup, Peter; Capewell, Simon; Menotti, Alessandro; Jousilahti, Pekka; Njølstad, Inger; Oganov, Raphel; Thomsen, Troels; Tverdal, Aage; et al. (European journal of cardiovascular prevention and rehabilitation : official journal of the European Society of Cardiology, Working Groups on Epidemiology & Prevention and Cardiac Rehabilitation and Exercise Physiology, 2009-10)
      Options for the prevention of cardiovascular disease, the greatest global cause of death, include population preventive measures (the Rose approach), or specifically seeking out and managing high-risk cases. However, the likely benefit of a population approach has been recently questioned.
    • Risk stratification in cardiovascular disease primary prevention - scoring systems, novel markers, and imaging techniques.

      Zannad, Faiez; De Backer, Guy; Graham, Ian; Lorenz, Matthias; Mancia, Giuseppe; Morrow, David A; Reiner, Zeljko; Koenig, Wolfgang; Dallongeville, Jean; Macfadyen, Robert J; et al. (Fundamental & clinical pharmacology, 2012-04)
      The aim of this paper is to review and discuss current methods of risk stratification for cardiovascular disease (CVD) prevention, emerging biomarkers, and imaging techniques, and their relative merits and limitations. This report is based on discussions that took place among experts in the area during a special CardioVascular Clinical Trialists workshop organized by the European Society of Cardiology Working Group on Cardiovascular Pharmacology and Drug Therapy in September 2009. Classical risk factors such as blood pressure and low-density lipoprotein cholesterol levels remain the cornerstone of risk estimation in primary prevention but their use as a guide to management is limited by several factors: (i) thresholds for drug treatment vary with the available evidence for cost-effectiveness and benefit-to-risk ratios; (ii) assessment may be imprecise; (iii) residual risk may remain, even with effective control of dyslipidemia and hypertension. Novel measures include C-reactive protein, lipoprotein-associated phospholipase A(2) , genetic markers, and markers of subclinical organ damage, for which there are varying levels of evidence. High-resolution ultrasound and magnetic resonance imaging to assess carotid atherosclerotic lesions have potential but require further validation, standardization, and proof of clinical usefulness in the general population. In conclusion, classical risk scoring systems are available and inexpensive but have a number of limitations. Novel risk markers and imaging techniques may have a place in drug development and clinical trial design. However, their additional value above and beyond classical risk factors has yet to be determined for risk-guided therapy in CVD prevention.
    • Thyroid dysfunction in Down's syndrome and screening for hypothyroidism in children and adolescents using capillary TSH measurement.

      Murphy, J; Philip, M; Macken, S; Meehan, J; Roche, E; Mayne, P D; O'Regan, M; Hoey, H M C V; Department of Paediatrics, University of Dublin, Trinity College, Tallaght, Dublin, Ireland. murphyj6@tcd.ie (Journal of pediatric endocrinology & metabolism : JPEM, 2008-02)
      Thyroid dysfunction is more common in individuals with Down's syndrome (DS) than in the general population, whose clinical features can mask the presenting signs and symptoms of hypothyroidism. Biochemical screening is necessary; however, venepuncture may be difficult.