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      Dynamic change of neutrophil to lymphocyte ratio and hemorrhagic transformation after thrombolysis in stroke

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          Abstract

          Background

          The neutrophil to lymphocyte ratio (NLR) has been shown to predict short- and long-term outcomes in ischemic stroke patients. We sought to explore the temporal profile of the plasma NLR in stroke patients treated with intravenous thrombolysis (IVT) and its relationship with intracranial bleeding complications after thrombolysis.

          Methods

          A total of 189 ischemic stroke patients were prospectively enrolled. Blood samples for leukocyte, neutrophil, and lymphocyte counts were obtained at admission and at 3–6, 12–18, and 36–48 h after IVT. Head CT was performed on admission and repeated after 36–48 h, and a CT scan was done immediately in case of clinical worsening. Hemorrhagic events were categorized as symptomatic intracranial hemorrhage (sICH) and parenchymal hematomas (PH) according to previously published criteria.

          Results

          An increasing trend in the NLR was observed after stroke, and the NLR was higher in patients who developed PH or sICH at 3–6, 12–18, and 36–48 h after IVT ( P < 0.01) than in those without PH or sICH. The optimal cutoff value for the serum NLR as an indicator for auxiliary diagnosis of PH and sICH was 10.59 at 12–18 h. Furthermore, the NLR obtained at 12–18-h post-treatment was independently associated with PH (adjusted odds ratio [OR] 1.14) and sICH (adjusted OR 1.14). In addition, patients with a NLR ≥10.59 had an 8.50-fold greater risk for PH (95 % confidence interval [CI] 2.69–26.89) and a 7.93-fold greater risk for sICH (95 % CI 2.25–27.99) than patients with a NLR <10.59.

          Conclusions

          NLR is a dynamic variable, and its variation is associated with HT after thrombolysis in stroke patients.

          Electronic supplementary material

          The online version of this article (doi:10.1186/s12974-016-0680-x) contains supplementary material, which is available to authorized users.

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          Most cited references25

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          Targeting neutrophils in ischemic stroke: translational insights from experimental studies.

          Neutrophils have key roles in ischemic brain injury, thrombosis, and atherosclerosis. As such, neutrophils are of great interest as targets to treat and prevent ischemic stroke. After stroke, neutrophils respond rapidly promoting blood-brain barrier disruption, cerebral edema, and brain injury. A surge of neutrophil-derived reactive oxygen species, proteases, and cytokines are released as neutrophils interact with cerebral endothelium. Neutrophils also are linked to the major processes that cause ischemic stroke, thrombosis, and atherosclerosis. Thrombosis is promoted through interactions with platelets, clotting factors, and release of prothrombotic molecules. In atherosclerosis, neutrophils promote plaque formation and rupture by generating oxidized-low density lipoprotein, enhancing monocyte infiltration, and degrading the fibrous cap. In experimental studies targeting neutrophils can improve stroke. However, early human studies have been met with challenges, and suggest that selective targeting of neutrophils may be required. Several properties of neutrophil are beneficial and thus may important to preserve in patients with stroke including antimicrobial, antiinflammatory, and neuroprotective functions.
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            Hemorrhagic transformation after ischemic stroke in animals and humans.

            Hemorrhagic transformation (HT) is a common complication of ischemic stroke that is exacerbated by thrombolytic therapy. Methods to better prevent, predict, and treat HT are needed. In this review, we summarize studies of HT in both animals and humans. We propose that early HT ( 18 to 24 hours after stroke) that relates to ischemia activation of brain proteases (MMP-2, MMP-3, MMP-9, and endogenous tissue plasminogen activator), neuroinflammation, and factors that promote vascular remodeling (vascular endothelial growth factor and high-moblity-group-box-1). Processes that mediate BBB repair and reduce HT risk are discussed, including transforming growth factor beta signaling in monocytes, Src kinase signaling, MMP inhibitors, and inhibitors of reactive oxygen species. Finally, clinical features associated with HT in patients with stroke are reviewed, including approaches to predict HT by clinical factors, brain imaging, and blood biomarkers. Though remarkable advances in our understanding of HT have been made, additional efforts are needed to translate these discoveries to the clinic and reduce the impact of HT on patients with ischemic stroke.
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              Neutrophil recruitment to the brain in mouse and human ischemic stroke.

              Neutrophils are rapidly recruited in response to local tissue infection or inflammation. Stroke triggers a strong inflammatory reaction but the relevance of neutrophils in the ischemic brain is not fully understood, particularly in the absence of reperfusion. We investigated brain neutrophil recruitment in two murine models of permanent ischemia induced by either cauterization of the distal portion of the middle cerebral artery (c-MCAo) or intraluminal MCA occlusion (il-MCAo), and three fatal cases of human ischemic stroke. Flow cytometry analyses revealed progressive neutrophil recruitment after c-MCAo, lesser neutrophil recruitment following il-MCAo, and absence of neutrophils after sham operation. Confocal microscopy identified neutrophils in the leptomeninges from 6 h after the occlusion, in the cortical basal lamina and cortical Virchow-Robin spaces from 15 h, and also in the cortical brain parenchyma at 24 h. Neutrophils showed signs of activation including histone-3 citrullination, chromatin decondensation, and extracellular projection of DNA and histones suggestive of extracellular trap formation. Perivascular neutrophils were identified within the entire cortical infarction following c-MCAo. After il-MCAo, neutrophils prevailed in the margins but not the center of the cortical infarct, and were intraluminal and less abundant in the striatum. The lack of collaterals to the striatum and a collapsed pial anastomotic network due to brain edema in large hemispheric infarctions could impair neutrophil trafficking in this model. Neutrophil extravasation at the leptomeninges was also detected in the human tissue. We concluded that neutrophils extravasate from the leptomeningeal vessels and can eventually reach the brain in experimental animal models and humans with prolonged arterial occlusion.
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                Author and article information

                Contributors
                guozhiliang3@163.com
                yushuhong11@163.com
                xiaolulu1107@126.com
                1252356496@qq.com
                yeruid@gmail.com
                zhengp@unimelb.edu.au
                dql.nju@gmail.com
                sunwen_neuro@yeah.net
                zhouyisheng@hotmail.com
                wspsmmu@163.com
                +86 25 84801861 , zwsemail@sina.com
                +86 25 80860124 , xfliu2@vip.163.com
                Journal
                J Neuroinflammation
                J Neuroinflammation
                Journal of Neuroinflammation
                BioMed Central (London )
                1742-2094
                26 August 2016
                26 August 2016
                2016
                : 13
                : 1
                : 199
                Affiliations
                [1 ]Department of Neurology, Jinling Hospital, Medical School of Nanjing University, 305 E Zhongshan Rd, Nanjing, 210002 Jiangsu Province China
                [2 ]Department of Neurology, Second Affiliated Hospital of Soochow University, Suzhou, 215004 China
                [3 ]Department of Medicine, Royal Melbourne Hospital, University of Melbourne, Melbourne, Australia
                [4 ]Department of Radiology, Jinling Hospital, Medical School of Nanjing University, Nanjing, 210002 China
                [5 ]Department of Neurology, PLA 123 Hospital, 1052 Yanshan Road, Yuhui District, Bengbu, 233000 China
                Article
                680
                10.1186/s12974-016-0680-x
                5000487
                27561990
                2f611caa-d4d1-4010-a3fc-32e5fb17e3f7
                © The Author(s). 2016

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 15 December 2015
                : 18 August 2016
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China;
                Award ID: 81171099
                Award ID: 81501193
                Award Recipient :
                Funded by: FundRef http://dx.doi.org/10.13039/501100001809, National Natural Science Foundation of China (CN);
                Award ID: 81471182
                Award Recipient :
                Categories
                Research
                Custom metadata
                © The Author(s) 2016

                Neurosciences
                neutrophil to lymphocyte ratio (nlr),ischemic stroke,thrombolysis,hemorrhagic transformation,biomarker

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