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      The Sustained Increase of Plasma Fibrinogen During Ischemic Stroke Predicts Worse Outcome Independently of Baseline Fibrinogen Level

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          Abstract

          Hyperfibrinogenemia at the beginning of ischemic stroke is associated with poor outcome. We hypothesized that the sustained increase of plasma fibrinogen during stroke predicts outcome independently of baseline fibrinogen concentration. We included 266 patients with first-ever ischemic stroke in whom plasma fibrinogen level was measured on days 1, 7, and 14. The sustained fibrinogen’s increase was defined as the persistent elevation of fibrinogen’s concentration on days 7 and 14 by at least 20 % compared to the level on day 1. The functional outcome on day 30 was assessed using modified Rankin Scale (mRS). Favorable outcome was defined as mRS 0–1. The sustained increase of fibrinogen was found in 17 % of patients. On multivariate logistic regression analysis adjusted for age, NIHSS score, baseline fibrinogen >2.66 mmol/L, presence of infection, and hyperglycemia, the sustained fibrinogen’s level was associated with reduced chance of favorable outcome (OR: 0.17, 95 % CI: 0.06–0.48, P < 0.01).

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          C-reactive protein in ischemic stroke: an independent prognostic factor.

          There is growing evidence of the prognostic importance of C-reactive protein (CRP) in ischemic stroke. However, the independent value of CRP at different stages after stroke has not been established. Therefore, we assessed the prognostic values of CRP in ischemic stroke. We also compared the relation of CRP at admission and discharge with 1-year outcome. One hundred ninety-three patients were included in a derivation set (n=128) and a validation set (n=65). Serum CRP was measured, within 24 hours after index ischemic stroke, within 48 to 72 hours, and at hospital discharge. We examined the association between the level of CRP at different stages after stroke and outcome. We adjusted for the possible confounding effect using a multivariate Cox proportional hazard model. A cutoff point of 1.5 mg/dL for CRP at discharge provided optimum sensitivity and specificity for adverse outcome, based on the receiver operator curves. CRP at admission (hazard ratio [HR] 2.78, 95% CI 1.45 to 5.33; P=0.0021) and discharge (HR 9.42, 95% CI 4.27 to 19.05; P<0.0001) were predictors of the combined end point of new vascular events or death at 1 year. CRP at hospital discharge was the strongest independent marker of adverse outcome (HR 7.42, 95% CI 2.75 to 20.03; P=0.0001). These results were confirmed in the validation set (HR 15.66, 95% CI 3.36 to 72.97; P=0.0005). CRP is a marker of increased 1-year risk in ischemic stroke. CRP at discharge is better related to later outcome and could be of greater utility for risk stratification. These findings are consistent with the hypothesis that elevated CRP may predict future cardiovascular events or death.
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            Severe hypertriglyceridemia with insulin resistance is associated with systemic inflammation: reversal with bezafibrate therapy in a randomized controlled trial.

            To determine whether hypertriglyceridemia is associated with systemic inflammation, which may contribute to the increased cardiovascular risk in patients who have hypertriglyceridemia. In addition, we investigated whether fibrates reverse this inflammatory state. Serum lipid levels, body mass index, insulin resistance, and inflammatory parameters were compared between 18 patients who had severe hypertriglyceridemia without cardiovascular disease and 20 normolipidemic controls. We measured the ex vivo production capacity of tumor necrosis factor (TNF)-alpha and interleukin (IL)-6 after whole-blood stimulation with lipopolysaccharide, as well as circulating levels of C-reactive protein and fibrinogen. A randomized controlled trial was conducted to determine whether bezafibrate (400 mg administered daily for 6 weeks) affected these parameters in hypertriglyceridemic patients. When compared with normolipidemic controls, hypertriglyceridemic patients had significantly lower high-density lipoprotein (HDL) cholesterol and higher triglyceride levels, body mass index, and insulin resistance. In addition, hypertriglyceridemic patients had a significantly higher production capacity of TNF-alpha (mean difference, 11 700 pg/mL; 95% confidence interval [CI]: 7800 to 15,700 pg/mL]) and IL-6 (mean difference, 20,400 pg/mL; 95% CI: 7800 to 32,900 pg/mL), and higher levels of C-reactive protein (mean difference, 0.8 mg/L; 95% CI: 0.1 to 2.4 mg/L) and fibrinogen (mean difference, 0.8 g/dL; 95% CI: 0.3 to 1.3 g/dL). Bezafibrate therapy significantly increased HDL cholesterol levels, reduced triglyceride and insulin resistance levels, and reduced production capacity of TNF-alpha and IL-6, as well as levels of C-reactive protein and fibrinogen. Systemic inflammation is present in patients who have the clinical phenotype that is associated with severe hypertriglyceridemia, and may contribute to the increased risk of cardiovascular disease in these patients. Bezafibrate has anti-inflammatory effects in these patients.
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              The immune system in stroke: clinical challenges and their translation to experimental research.

              Stroke represents an unresolved challenge for both developed and developing countries and has a huge socio-economic impact. Although considerable effort has been made to limit stroke incidence and improve outcome, strategies aimed at protecting injured neurons in the brain have all failed. This failure is likely to be due to both the incompleteness of modelling the disease and its causes in experimental research, and also the lack of understanding of how systemic mechanisms lead to an acute cerebrovascular event or contribute to outcome. Inflammation has been implicated in all forms of brain injury and it is now clear that immune mechanisms profoundly influence (and are responsible for the development of) risk and causation of stroke, and the outcome following the onset of cerebral ischemia. Until very recently, systemic inflammatory mechanisms, with respect to common comorbidities in stroke, have largely been ignored in experimental studies. The main aim is therefore to understand interactions between the immune system and brain injury in order to develop novel therapeutic approaches. Recent data from clinical and experimental research clearly show that systemic inflammatory diseases -such as atherosclerosis, obesity, diabetes or infection - similar to stress and advanced age, are associated with dysregulated immune responses which can profoundly contribute to cerebrovascular inflammation and injury in the central nervous system. In this review, we summarize recent advances in the field of inflammation and stroke, focusing on the challenges of translation between pre-clinical and clinical studies, and potential anti-inflammatory/immunomodulatory therapeutic approaches.
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                Author and article information

                Contributors
                +48-12-4248600 , +48-12-4248626 , dziedzic@cm-uj.krakow.pl
                Journal
                Inflammation
                Inflammation
                Inflammation
                Springer US (Boston )
                0360-3997
                1573-2576
                16 February 2014
                16 February 2014
                2014
                : 37
                : 1142-1147
                Affiliations
                Department of Neurology, Jagiellonian University Medical College, ul. Botaniczna 3, 31-503 Kraków, Poland
                Article
                9838
                10.1007/s10753-014-9838-9
                4077303
                24531853
                b55f41c9-b775-4163-9b74-6631808f0333
                © The Author(s) 2014

                Open Access This article is distributed under the terms of the Creative Commons Attribution License which permits any use, distribution, and reproduction in any medium, provided the original author(s) and the source are credited.

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                © Springer Science+Business Media New York 2014

                Immunology
                fibrinogen,inflammation,outcome,stroke,brain infarction
                Immunology
                fibrinogen, inflammation, outcome, stroke, brain infarction

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