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Rayman M.P.,University of Surrey | Blundell-Pound G.,University of Surrey | Pastor-Barriuso R.,CIBER ISCIII | Guallar E.,Johns Hopkins University | And 3 more authors.
PLoS ONE | Year: 2012

Background: Evidence that selenium affects the risk of type-2 diabetes is conflicting, with observational studies and a few randomized trials showing both lower and higher risk linked to the level of selenium intake and status. We investigated the effect of selenium supplementation on the risk of type-2 diabetes in a population of relatively low selenium status as part of the UK PRECISE (PREvention of Cancer by Intervention with SElenium) pilot study. Plasma adiponectin concentration, a recognised independent predictor of type-2 diabetes risk and known to be correlated with circulating selenoprotein P, was the biomarker chosen. Methods: In a randomized, double-blind, placebo-controlled trial, five hundred and one elderly volunteers were randomly assigned to a six-month intervention with 100, 200 or 300 μg selenium/d as high-selenium or placebo yeast. Adiponectin concentration was measured by ELISA at baseline and after six months of treatment in 473 participants with one or both plasma samples available. Results: Mean (SD) plasma selenium concentration was 88.5 ng/g (19.1) at baseline and increased significantly in the selenium-treatment groups. In baseline cross-sectional analyses, the fully adjusted geometric mean of plasma adiponectin was 14% lower (95% CI, 0-27%) in the highest than in the lowest quartile of plasma selenium (P for linear trend = 0.04). In analyses across randomized groups, however, selenium supplementation had no effect on adiponectin levels after six months of treatment (P = 0.96). Conclusions: These findings are reassuring as they did not show a diabetogenic effect of a six-month supplementation with selenium in this sample of elderly individuals of relatively low selenium status. Trial Registration: Controlled-Trials.com ISRCTN25193534. © 2012 Rayman et al.


Juraschek S.P.,Johns Hopkins Medical Institutions | Guallar E.,Johns Hopkins Medical Institutions | Guallar E.,National Center for Cardiovascular Research | Appel L.J.,Johns Hopkins Medical Institutions | Miller III E.R.,Johns Hopkins Medical Institutions
American Journal of Clinical Nutrition | Year: 2012

Background: In observational studies, increased vitamin C intake, vitamin C supplementation, and higher blood concentrations of vitamin C are associated with lower blood pressure (BP). However, evidence for blood pressure-lowering effects of vitamin C in clinical trials is inconsistent. Objective: The objective was to conduct a systematic review and meta-analysis of clinical trials that examined the effects of vitamin C supplementation on BP. Design: We searched Medline, EMBASE, and Central databases from 1966 to 2011. Prespecified inclusion criteria were as follows: 1) use of a randomized controlled trial design; 2) trial reported effects on systolic BP (SBP) or diastolic BP (DBP) or both; 3) trial used oral vitamin C and concurrent control groups; and 4) trial had a minimum duration of 2 wk. BP effects were pooled by random-effects models, with trials weighted by inverse variance. Results: Twenty-nine trials met eligibility criteria for the primary analysis. The median dose was 500 mg/d, the median duration was 8 wk, and trial sizes ranged from 10 to 120 participants. The pooled changes in SBP and DBP were -3.84 mm Hg (95% CI: -5.29, -2.38 mm Hg; P < 0.01) and -1.48 mm Hg (95% CI: -2.86, -0.10 mm Hg; P = 0.04), respectively. In trials in hypertensive participants, corresponding reductions in SBP and DBP were -4.85 mm Hg (P < 0.01) and -1.67 mm Hg (P = 0.17). After the inclusion of 9 trials with imputed BP effects, BP effects were attenuated but remained significant. Conclusions: In short-term trials, vitamin C supplementation reduced SBP and DBP. Long-term trials on the effects of vitamin C supplementation on BP and clinical events are needed. © 2012 American Society for Nutrition.


Hernaez R.,Washington Hospital Center | Bonekamp S.,Johns Hopkins University | Kamel I.,Johns Hopkins University | Brancati F.L.,Johns Hopkins University | And 3 more authors.
Hepatology | Year: 2011

Ultrasonography is a widely accessible imaging technique for the detection of fatty liver, but the reported accuracy and reliability have been inconsistent across studies. We aimed to perform a systematic review and meta-analysis of the diagnostic accuracy and reliability of ultrasonography for the detection of fatty liver. We used MEDLINE and Embase from October 1967 to March 2010. Studies that provided cross-tabulations of ultrasonography versus histology or standard imaging techniques, or that provided reliability data for ultrasonography, were included. Study variables were independently abstracted by three reviewers and double checked by one reviewer. Forty-nine (4720 participants) studies were included for the meta-analysis of diagnostic accuracy. The overall sensitivity, specificity, positive likelihood ratio, and negative likelihood ratio of ultrasound for the detection of moderate-severe fatty liver, compared to histology (gold standard), were 84.8% (95% confidence interval: 79.5-88.9), 93.6% (87.2-97.0), 13.3 (6.4-27.6), and 0.16 (0.12-0.22), respectively. The area under the summary receiving operating characteristics curve was 0.93 (0.91-0.95). Reliability of ultrasound for the detection of fatty liver showed kappa statistics ranging from 0.54 to 0.92 for intrarater reliability and from 0.44 to 1.00 for interrater reliability. Sensitivity and specificity of ultrasound was similar to that of other imaging techniques (i.e., computed tomography or magnetic resonance imaging). Statistical heterogeneity was present even after stratification for multiple clinically relevant characteristics. Conclusion: Ultrasonography allows for reliable and accurate detection of moderate-severe fatty liver, compared to histology. Because of its low cost, safety, and accessibility, ultrasound is likely the imaging technique of choice for screening for fatty liver in clinical and population settings. © 2011 American Association for the Study of Liver Diseases.


Herranz B.,National Center for Cardiovascular Research | Marquez S.,University of Alcalá | Guijarro B.,University of Alcalá | Aracil E.,Ramon y Cajal Hospital | And 5 more authors.
Circulation Research | Year: 2012

Rationale: Atherosclerotic lesions develop in regions of disturbed flow, whereas laminar flow protects from atherogenesis; however, the mechanisms involved are not completely elucidated. Integrins are mechanosensors of shear stress in endothelial cells, and integrin-linked kinase (ILK) is important for blood vessel integrity and cardiovascular development. Objectives: To explore the role of ILK in vascular function by studying conditionally ILK-deficient (cKO) mice and human atherosclerotic arteries. RESULTS:: ILK expression was detected in the endothelial cell layer of nonatherosclerotic vessels but was absent from the endothelium of atherosclerotic arteries. Live ultrasound imaging revealed that acetylcholine-mediated vasodilatation was impaired in cKO mice. These mice exhibited lowered agonist-induced nitric oxide synthase (NOS) activity and decreased cyclic guanosine monophosphate and nitrite production. ILK deletion caused endothelial NOS (eNOS) uncoupling, reflected in reduced tetrahydrobiopterin (BH4) levels, increased BH2 levels, decreased dihydrofolate reductase expression, and increased eNOS-dependent generation of superoxide accompanied by extensive vascular protein nitration. ILK reexpression prevented eNOS uncoupling in cKO cells, whereas superoxide formation was unaffected by ILK depletion in eNOS-KO cells, indicating eNOS as a primary source of superoxide anion. eNOS and ILK coimmunoprecipitated in aortic lysates from control animals, and eNOS-ILK-shock protein 90 interaction was detected in human normal mammary arteries but was absent from human atherosclerotic carotid arteries. eNOS-ILK interaction in endothelial cells was prevented by geldanamycin, suggesting heat shock protein 90 as a binding partner. Conclusions: Our results identify ILK as a regulatory partner of eNOS in vivo that prevents eNOS uncoupling, and suggest ILK as a therapeutic target for prevention of endothelial dysfunction related to shear stress-induced vascular diseases. © 2011 American Heart Association, Inc.


Sanz G.,National Center for Cardiovascular Research | Fuster V.,National Center for Cardiovascular Research | Fuster V.,Mount Sinai School of Medicine
Mount Sinai Journal of Medicine | Year: 2012

Cardiovascular-disease prevention is often inadequate due to several factors. Lack of professional adherence to guidelines, unaffordable medication, and lack of patients' adherence to treatment are the most important. It has been suggested that an affordable, fixed-dose combination drug containing evidence-based active compounds could improve cardiovascular prevention by improving patients' adherence to treatment. The available evidence suggests that the polypill strategy can achieve this objective and it will gain a place in the therapeutic armamentarium for the prevention of cardiovascular events in patients at high risk. © 2012 Mount Sinai School of Medicine.


Kovacic J.C.,Mount Sinai School of Medicine | Fuster V.,Mount Sinai School of Medicine | Fuster V.,National Center for Cardiovascular Research
Mount Sinai Journal of Medicine | Year: 2012

The involvement of vascular factors in Alzheimer dementia was first appreciated over 100 years ago. Recently, significant advances in our understanding of these brain-vascular relationships have taken place. Vascular cognitive impairment is now recognized as a distinct group of interrelated vascular-based neurological insults that can accumulate and lead to dementia. Importantly, the pathology of vascular cognitive impairment extends far beyond brain destruction wrought by major stroke. Other subtle changes may also arise that contribute to vascular cognitive impairment and dementia, including subclinical stroke, white-matter changes such as hyperintensities and lipohyalinosis, small lacunar infarcts, cerebral hypoperfusion, and compromise of the blood-brain barrier. In this review we critically examine the emerging body of evidence that relates atherosclerotic risk factors, brain functioning, and Alzheimer disease. © 2012 Mount Sinai School of Medicine.


Sillesen H.,Copenhagen University | Fuster V.,Mount Sinai Medical Center | Fuster V.,National Center for Cardiovascular Research
Mount Sinai Journal of Medicine | Year: 2012

Atherosclerosis is the leading cause of death and disabling disease. Whereas risk factors are well known and constitute therapeutic targets, they are not useful for prediction of risk of future myocardial infarction, stroke, or death. Therefore, methods to identify atherosclerosis itself have been tested and found useful (ie, coronary calcium detection by computed tomography scanning, reduction in ankle-brachial index, and ultrasound scanning of the carotid arteries). This review will focus on the latter technique. Detection of thickened carotid intima-media by ultrasound has been used in many large epidemiological studies, but although it has been found to be associated with increased risk of cardiovascular death, its clinical utility is limited. Detection of carotid plaque has, on the other hand, been found to be associated with a substantial risk of future events. Similarly, detection of plaque in the femoral arteries is associated with increased risk, and plaque in the femoral as well as carotid arteries predicts even higher risk. Furthermore, quantification of plaque size (plaque area), such as quantification of amount of coronary calcium on computed tomography scanning, improves predictability-the larger the plaques, the higher the risk. So far, studies using ultrasound all have been performed with 2-dimensional ultrasound imaging. Recently, 3-dimensional ultrasound imaging has been introduced, which allows for more accurate quantification of atherosclerosis. Small studies pioneering its use have indicated the utility of measuring changes in vessel-wall volume and plaque volume with respect to treatment effect. The High-Risk Plaque Initiative BioImage Study is currently investigating the predictive value of total carotid plaque volume with respect to prediction of future cardiovascular events. © 2012 Mount Sinai School of Medicine.


Sanz G.,National Center for Cardiovascular Research
Current Cardiovascular Risk Reports | Year: 2011

In spite of major advances in the diagnosis and treatment of cardiovascular diseases, they remain the primary cause of death worldwide. Furthermore, the burden of disease is increasing steadily, particularly in emerging countries. Inappropriate prescription, unaffordable cost of medication, and lack of adherence to treatment all contribute to the failure of cardiovascular prevention. In addition, identification of patients at high risk of new ischemic events by means of the available scores is relatively inefficient, as most events occur in individuals with only modest elevations of risk factors. The concept of a fixed-dose combination or "polypill" has emerged recently as a potential strategy for improving cardiovascular disease burden. It is argued that such an approach will make unnecessary patient identification while reducing cost and improving adherence to medication. Several polypills are being developed and some of them are undergoing clinical testing. © 2010 Springer Science+Business Media, LLC.


Fernandez-Messina L.,Hospital Of La Princesa | Fernandez-Messina L.,National Center for Cardiovascular Research | Gutierrez-Vazquez C.,National Center for Cardiovascular Research | Rivas-Garcia E.,Hospital Of La Princesa | And 3 more authors.
Biology of the Cell | Year: 2015

The immune system is composed of different cell types localised throughout the organism to sense and respond to pathological situations while maintaining homeostasis under physiological conditions. Intercellular communication between immune cells is essential to coordinate an effective immune response and involves both cell contact dependent and independent processes that ensure the transfer of information between bystander and distant cells. There is a rapidly growing body of evidence on the pivotal role of extracellular vesicles (EVs) in cell communication and these structures are emerging as important mediators for immune modulation upon delivery of their molecular cargo. In the last decade, EVs have been shown to be efficient carriers of genetic information, including microRNAs (miRNAs), that can be transferred between cells and regulate gene expression and function on the recipient cell. Here, we review the current knowledge of intercellular functional transfer of EV-delivered miRNAs and their putative role in immune regulation. © 2015 Société Française des Microscopies and Société de Biologie Cellulaire de France.


Kelly B.B.,Institute of Medicine | Narula J.,Mount Sinai Medical Center | Fuster V.,Mount Sinai Medical Center | Fuster V.,National Center for Cardiovascular Research
Mount Sinai Journal of Medicine | Year: 2012

Cardiovascular disease is the leading cause of death worldwide, affecting not only high-income but also low- and middle-income countries. Nearly 80 percent of all estimated cardiovascular disease-related deaths worldwide now occur in low- and middle-income countries, where nearly 30 percent of all deaths are attributable to cardiovascular disease. The health burden of cardiovascular disease and other chronic diseases is also accompanied by a significant deleterious economic impact at the level of both national economies and households. The global trends in the health and economic burden of cardiovascular disease provide a compelling argument in support of prioritizing urgent yet carefully planned efforts to prevent and control cardiovascular disease worldwide-and especially in low- and middle-income countries. After decades of escalating efforts to draw attention to the high burden of cardiovascular disease and other chronic diseases, this critically important issue is now emerging as a more central part of the global health and development agenda. The breadth of behavioral, biological, social, environmental, and systems-level factors that contribute to cardiovascular disease necessitates multisectoral approaches across the lifecourse that promote healthful lifestyles, reduce risk, and reduce cardiovascular-disease morbidity and mortality through the delivery of quality health care services. Given that the complex interactions among the determinants of cardiovascular disease vary in different contexts, real progress in control efforts will come through approaches that are driven by a country's disease burden and risk profile, capacities, resources, and priorities-approaches that are led by a country's key decision-makers and stakeholders, including governments, civil society, the private sector, and communities. Many countries are already establishing efforts to address chronic diseases. In addition to these locally driven efforts, success will require active engagement and sustained action from a wide array of stakeholders operating at global and regional levels. © 2012 Mount Sinai School of Medicine.

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