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      Serum Uric Acid Levels and Cerebral Microbleeds in Patients with Acute Ischemic Stroke

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          Abstract

          Unlike experimental studies indicating a neuroprotective property of uric acid, clinical studies have shown that elevated levels of uric acid are associated with a risk of ischemic stroke. However, the association of uric acid with cerebral hemorrhage has seldom been tested. We aimed to elucidate the association between uric acid and cerebral microbleeds (CMBs), a hemorrhage-prone cerebral microangiopathy. Seven hundred twenty-four patients with ischemic stroke who were consecutively admitted to our hospital were included in this study. We collected demographic, clinical, and laboratory data, including uric acid level, and examined the presence of CMBs using T2*-weighted gradient-echo MRI. We used logistic regression analysis to examine an independent association between uric acid and CMBs. Two-hundred twenty-six patients had CMBs (31.2%). After adjusting for possible confounders, elevated uric acid was independently associated with the presence of CMBs (the highest quartile vs. lowest quartile, adjusted odd ratio [OR], 1.98; 95% confidence interval [CI], 1.16–3.39). This association retained in patients with deep or infratentorial CMBs (with or without lobar CMBs) but not among those with lobar CMBs. In addition, this association was robust among patients with hypertension (the highest quartile vs. lowest quartile, adjusted OR, 2.74; 95% CI, 1.43–5.24). In contrast, we did not find the association in patients without hypertension. We demonstrated that serum uric acid is independently associated with the presence of CMBs. In particular, the relation between uric acid and CMBs was robust in hypertensive patients.

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          Most cited references37

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          Serum uric acid and risk for cardiovascular disease and death: the Framingham Heart Study.

          Hyperuricemia is associated with risk for cardiovascular disease and death. However, the role of uric acid independent of established risk factors is uncertain. To examine the relation of serum uric acid level to incident coronary heart disease, death from cardiovascular disease, and death from all causes. Community-based, prospective observational study. Framingham, Massachusetts. 6763 Framingham Heart Study participants (mean age, 47 years). Serum uricacid level at baseline (1971 to 1976); event rates per 1000 person-years by sex-specific uric acid quintile. During 117,376 person-years of follow-up, 617 coronary heart disease events, 429 cardiovascular disease deaths, and 1460 deaths from all causes occurred. In men, after adjustment for age, elevated serum uric acid level was not associated with increased risk for an adverse outcome. In women, after adjustment for age, uric acid level was predictive of coronary heart disease (P = 0.002), death from cardiovascular disease (P = 0.009), and death from all causes (P = 0.03). After additional adjustment for cardiovascular disease risk factors, uric acid level was no longer associated with coronary heart disease, death from cardiovascular disease, or death from all causes. In a stepwise Cox model, diuretic use was identified as the covariate responsible for rendering serum uric acid a statistically nonsignificant predictor of outcomes. These findings indicate that uric acid does not have a causal role in the development of coronary heart disease, death from cardiovascular disease, or death from all causes. Any apparent association with these outcomes is probably due to the association of uric acid level with other risk factors.
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            Prevalence and risk factors of cerebral microbleeds: the Rotterdam Scan Study.

            Cerebral microbleeds are focal deposits of hemosiderin that can be visualized with MRI. Little is known on their prevalence in the general population and on their etiology. It has been suggested that, in analogy to spontaneous intracranial hemorrhage, the etiology of microbleeds differs according to their location in the brain, with lobar microbleeds being caused by cerebral amyloid angiopathy and deep or infratentorial microbleeds resulting from hypertension and atherosclerosis. We investigated the prevalence of and risk factors for microbleeds in the general population aged 60 years and older. This study is based on 1,062 persons (mean age 69.6 years) from the population-based Rotterdam Scan Study. MRI was performed at 1.5 T and included a sequence optimized to increase the conspicuity of microbleeds. We assessed the relation of APOE genotype, cardiovascular risk factors, and markers of small vessel disease to the presence and location of microbleeds with multiple logistic regression. Overall prevalence of cerebral microbleeds was high and increased with age from 17.8% in persons aged 60-69 years to 38.3% in those over 80 years. APOE epsilon 4 carriers had significantly more often strictly lobar microbleeds than noncarriers. In contrast, cardiovascular risk factors and presence of lacunar infarcts and white matter lesions were associated with microbleeds in a deep or infratentorial location but not in a lobar location. The prevalence of cerebral microbleeds is high. Our data support the hypothesis that strictly lobar microbleeds are related to cerebral amyloid angiopathy, whereas microbleeds in a deep or infratentorial location result from hypertensive or atherosclerotic microangiopathy.
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              Uric acid stimulates monocyte chemoattractant protein-1 production in vascular smooth muscle cells via mitogen-activated protein kinase and cyclooxygenase-2.

              Previous studies have reported that uric acid stimulates vascular smooth muscle cell (VSMC) proliferation in vitro. We hypothesized that uric acid may also have direct proinflammatory effects on VSMCs. Crystal- and endotoxin-free uric acid was found to increase VSMC monocyte chemoattractant protein-1 (MCP-1) expression in a time- and dose-dependent manner, peaking at 24 hours. Increased mRNA and protein expression occurred as early as 3 hours after uric acid incubation and was partially dependent on posttranscriptional modification of MCP-1 mRNA. In addition, uric acid activated the transcription factors nuclear factor-kappaB and activator protein-1, as well as the MAPK signaling molecules ERK p44/42 and p38, and increased cyclooxygenase-2 (COX-2) mRNA expression. Inhibition of p38 (with SB 203580), ERK 44/42 (with UO126 or PD 98059), or COX-2 (with NS398) each significantly suppressed uric acid-induced MCP-1 expression at 24 hours, implicating these pathways in the response to uric acid. The ability of both n-acetyl-cysteine and diphenyleneionium (antioxidants) to inhibit uric acid-induced MCP-1 production suggested involvement of intracellular redox pathways. Uric acid regulates critical proinflammatory pathways in VSMCs, suggesting it may have a role in the vascular changes associated with hypertension and vascular disease.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2013
                25 January 2013
                : 8
                : 1
                : e55210
                Affiliations
                [1 ]Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea
                [2 ]Clinical Research Center for Stroke, Clinical Research Institute, Seoul National University Hospital, Seoul, Republic of Korea
                [3 ]Department of Neurology, Seoul National University Bundang Hospital, Gyeonggi-do, Republic of Korea
                Kaohsiung Chang Gung Memorial Hospital, Taiwan
                Author notes

                Competing Interests: The authors have declared that no competing interests exist.

                Conceived and designed the experiments: WSR SHL. Performed the experiments: BJK CKK. Analyzed the data: WSR. Contributed reagents/materials/analysis tools: SHL. Wrote the paper: WSR SHL.

                Article
                PONE-D-12-25492
                10.1371/journal.pone.0055210
                3555938
                23372838
                7868e7d8-48fd-4440-acc4-1592432334e2
                Copyright @ 2013

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 9 August 2012
                : 22 December 2012
                Page count
                Pages: 6
                Funding
                This study was supported by grants of the Korea Health 21 R&D Project, Ministry of Health and Welfare (A111014), and by Basic Science Research Program through the National Research Foundation of Korea funded by Ministry of Education, Science, and Technology (2011-0026315). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
                Categories
                Research Article
                Biology
                Neuroscience
                Neuroimaging
                Fmri
                Computational Neuroscience
                Medicine
                Cardiovascular
                Hypertension
                Stroke
                Neurology
                Cerebrovascular Diseases
                Ischemic Stroke
                Hemorrhagic Stroke
                Neuroimaging

                Uncategorized
                Uncategorized

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