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Zhang Y, Luo X, Song X, Li J, Liu Y, Wang L, Tan G. Efficacy of Human Urinary Kallidinogenase in Real-world Patients With Acute Ischemic Stroke: A Matched Comparison. Neurologist 2025:00127893-990000000-00195. [PMID: 40387155 DOI: 10.1097/nrl.0000000000000623] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 05/20/2025]
Abstract
OBJECTIVES We aimed to investigate the efficacy and safety of human urinary kallidinogenase (HUK) in real-world patients with acute ischemic stroke (AIS). METHODS AIS patients with prospective follow-up between April 2019 and June 2022 were enrolled in this study. Based on their treatment, the eligible patients were separated into 2 groups: the HUK group and the non-HUK group. Propensity score matching (PSM) analysis was used to reduce the biases from the unequal distribution of initial characteristics. The validated clinical composite scoring system was used to evaluate the neurological recovery. The safety outcomes include stroke recurrence, all-cause mortality, and major complications. RESULTS A total of 312 patients were enrolled in each of the 2 groups, and there were no significant differences in baseline characteristics between them. After treatment, both groups of AIS patients achieved favorable neurological outcomes. The National Institute of Health Stroke Scale (NIHSS) scores at discharge (3.47±3.41 vs. 4.37±2.85) demonstrated better neurological recovery in the HUK group. At the 90-day assessment, patients in the HUK group exhibited a higher incidence of favorable functional outcome (modified Rankin Scale score of 0 to 2, 74.68% vs. 60.58%), and lower risk of stroke recurrence (2.88% vs. 6.73%). The all-cause mortality (1.60% vs. 2.24%) was not significantly different between both groups. CONCLUSIONS HUK improved neurological and functional outcomes in patients with AIS in a large real-world population and had an acceptable safety profile.
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Affiliation(s)
- Yue Zhang
- Department of Neurology, The Second Hospital of Hebei Medical University
| | - Xintong Luo
- Department of Neurology, HeBei General Hospital
| | - Xiujuan Song
- Department of Neurology, The Second Hospital of Hebei Medical University
| | - Jiamin Li
- Department of Neurology, Shijiazhuang People's Hospital
| | - Yonggang Liu
- Department of Neurology, Baoding No. 1 Central Hospital, Hebei, China
| | - Lina Wang
- Department of Neurology, The Second Hospital of Hebei Medical University
| | - Guojun Tan
- Department of Neurology, The Second Hospital of Hebei Medical University
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Jiang Z, Huang J, Hu S, Xiang R, Ran L, Chen Y, Xie D, Long P, Li X, Yuan Y. Quantitative histopathological analysis of thrombi retrieved by mechanical thrombectomy and their association with stroke aetiology. Stroke Vasc Neurol 2025:svn-2024-003543. [PMID: 40102019 DOI: 10.1136/svn-2024-003543] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Accepted: 01/12/2025] [Indexed: 03/20/2025] Open
Abstract
BACKGROUND AND PURPOSE Approximately 25% of acute large vessel occlusive (LVO) ischaemic strokes are of unknown thrombotic origin, and there is a need to establish the aetiology to guide subsequent preventative measures. The aim of this study was to quantify thrombus composition in patients with LVO and explore associations between thrombus composition and stroke aetiology. METHODS Thrombi were extracted from 132 patients with acute ischaemic stroke. Erythrocytes, leucocytes and F+P (fibrin+platelet) proportions were assessed in tissue sections stained with H&E, while CD3+ T cells and neutrophil extracellular traps (NETs) were quantified in immunohistochemistry-stained sections. Thrombus components, clinical parameters and interventional variables were compared between different stroke subtypes defined by Trial of ORG 10172 in Acute Stroke Treatment criteria. RESULTS F+P composition was significantly higher (p<0.001) and erythrocyte proportions were significantly lower (p<0.001) in cardioembolic thrombi than in large artery atherosclerosis thrombi. The composition of thrombi from undetermined aetiology strokes resembled that from cardioembolic strokes. CD3+ T cell and NET proportions were not significantly different between stroke subtypes. CD3+ density per unit area was associated with the occlusive site, being significantly higher in the anterior circulation than the posterior circulation (p=0.004). Cardioembolic strokes were more common in the anterior circulation than large artery atherosclerosis strokes (p=0.002). Recanalisation time was significantly longer for large artery atherosclerosis emboli than for cardioembolic emboli (p=0.032). CONCLUSION There is significant heterogeneity in thrombus composition among different stroke subtypes. The quantitative assessment of thrombus composition may be a useful biomarker of stroke aetiology, and strokes of undetermined aetiology may be more likely to have a cardioembolic origin.
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Affiliation(s)
- Zhiyi Jiang
- Neurology, Third Xiangya Hospital of Central South University, Changsha, Hunan, China
- Department of Sports Medicine, The Xiangya Hospital, Central South University, Changsha, China
| | - Juan Huang
- Neurology, Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Shuntong Hu
- Neurology, Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Ruping Xiang
- Department of Neurology, The Fourth Hospital of Changsha, Changsha, China
| | - Longfeng Ran
- Department of Neurology, The Chengdu First People's Hospital, Chengdu, China
| | - Yiwei Chen
- Neurology, Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Dujie Xie
- Neurology, Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Panyao Long
- Neurology, Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Xiaobo Li
- Neurology, Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Yi Yuan
- Neurology, Third Xiangya Hospital of Central South University, Changsha, Hunan, China
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Single C, Mengel A, Laichinger K, Sartor‐Pfeiffer J, Selo N, Hennersdorf F, Bender B, Deb‐Chatterji M, Thomalla G, Mbroh J, Poli S, Ziemann U, Ernemann U, Feil K, German Stroke Registry—Endovascular Treatment (GSR). Sex-Related Differences in Outcomes of Endovascular Treatment in Large Vessel Occlusion Stroke-Analyses From the German Stroke Registry-Endovascular Treatment. Eur J Neurol 2025; 32:e70092. [PMID: 40008680 PMCID: PMC11863069 DOI: 10.1111/ene.70092] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2024] [Revised: 01/07/2025] [Accepted: 02/10/2025] [Indexed: 02/27/2025]
Abstract
BACKGROUND Sex-related differences in acute ischemic stroke may affect outcomes, yet evidence remains inconsistent. This large-scale study investigated sex-related differences in clinical presentation, peri-interventional parameters, and outcomes after endovascular thrombectomy (EVT) for large vessel occlusion (LVO) using data from the German Stroke Registry-Endovascular Treatment (GSR-ET). METHODS We analyzed 11.896 EVT patients (52.2% female) from the GSR-ET (June 2015-December 2021) comparing clinical characteristics, treatment details, and outcomes by sex. Two propensity score matchings (PSM) were applied: (1) logistic regression model with a caliper width of 0.1 on age, pre-stroke modified Rankin Scale (pmRS), and National Institutes of Health Stroke Scale at admission, and (2) 1:1 nearest neighbor matching with a caliper of 0.01. Primary outcomes were good (mRS 0-2) and excellent (mRS 0-1) outcomes at discharge and 90-day follow-up. RESULTS Women were older (76.3 ± 12.7 vs. 70.2 ± 12.9 years, p < 0.001) and had higher pre-stroke disability (median pmRS 0 (0, 2) vs. 0 (0, 1), p < 0.001). Cardioembolic strokes were more frequent in women, even after PSM. Despite this, women had better odds of achieving good outcomes at discharge (adjusted OR 1.20, 95% CI 1.04-1.38, p = 0.013), but not at follow-up (OR 0.91, 95% CI 0.78-1.05, p = 0.193). Both PSM analyses confirmed these findings. CONCLUSIONS While women demonstrated better short-term functional outcomes after EVT, these benefits diminished in follow-up. The persistence of cardioembolic stroke in women suggests potential sex-specific mechanisms. Understanding and addressing sex-related differences in stroke is essential to optimize acute stroke care and improve outcomes. Future studies should explore biological and socio-economic factors influencing sex-related differences. TRIAL REGISTRATION ClinicalTrials.gov identifier: NCT03356392.
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Affiliation(s)
- Constanze Single
- Department of Neurology & StrokeEberhard‐Karls UniversityTübingenGermany
| | - Annerose Mengel
- Department of Neurology & StrokeEberhard‐Karls UniversityTübingenGermany
- Hertie Institute for Clinical Brain ResearchEberhard‐Karls UniversityTübingenGermany
| | - Kornelia Laichinger
- Department of Neurology & StrokeEberhard‐Karls UniversityTübingenGermany
- Hertie Institute for Clinical Brain ResearchEberhard‐Karls UniversityTübingenGermany
| | - Jennifer Sartor‐Pfeiffer
- Department of Neurology & StrokeEberhard‐Karls UniversityTübingenGermany
- Hertie Institute for Clinical Brain ResearchEberhard‐Karls UniversityTübingenGermany
| | - Nadja Selo
- Department of NeuroradiologyEberhard‐Karls UniversityTübingenGermany
| | | | - Benjamin Bender
- Department of NeuroradiologyEberhard‐Karls UniversityTübingenGermany
| | | | - Götz Thomalla
- Department of NeurologyUniversity Medical Center Hamburg‐EppendorfHamburgGermany
| | - Joshua Mbroh
- Department of Neurology & StrokeEberhard‐Karls UniversityTübingenGermany
- Hertie Institute for Clinical Brain ResearchEberhard‐Karls UniversityTübingenGermany
| | - Sven Poli
- Department of Neurology & StrokeEberhard‐Karls UniversityTübingenGermany
- Hertie Institute for Clinical Brain ResearchEberhard‐Karls UniversityTübingenGermany
| | - Ulf Ziemann
- Department of Neurology & StrokeEberhard‐Karls UniversityTübingenGermany
- Hertie Institute for Clinical Brain ResearchEberhard‐Karls UniversityTübingenGermany
| | - Ulrike Ernemann
- Department of NeuroradiologyEberhard‐Karls UniversityTübingenGermany
| | - Katharina Feil
- Department of Neurology & StrokeEberhard‐Karls UniversityTübingenGermany
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Liu M, Liu S, Bai Y, Zhang M, Zhang D, Sun R, Wang G, Ma Y. Res@LDH: A Novel Nanohybrid Therapeutic for Ischemia-Reperfusion Injury with Dual Reactive Oxygen Species Scavenging Efficiency. Biomater Res 2024; 28:0108. [PMID: 39628470 PMCID: PMC11612122 DOI: 10.34133/bmr.0108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Revised: 10/10/2024] [Accepted: 10/30/2024] [Indexed: 12/06/2024] Open
Abstract
Ischemic stroke poses a global health challenge, necessitating effective therapeutic interventions given the limited time window for thrombolytic therapy. Here, we present Res@LDH, a novel nanohybrid therapeutic agent boasting a dual reactive oxygen species scavenging efficiency of approximately 90%. Comprising Ge-containing layered double hydroxide nanosheets (Ge-LDH) as a drug nanocarrier and resveratrol as a neuroprotective agent, Res@LDH demonstrates enhanced permeability across the blood-brain barrier, ensuring high biocompatibility and stability. We explored the potential of Res@LDH in mitigating oxidative stress injury induced by middle cerebral artery occlusion and reperfusion in mice, as well as H2O2-induced cytotoxicity in HT22 cells. Our experiments unveil Res@LDH's capacity to ameliorate neurological deficits, reduce the infarction volume, mitigate blood-brain barrier disruption, exhibit a robust antioxidant activity, and dampen the release of proinflammatory cytokines. Moreover, Res@LDH treatment markedly attenuates microglial and astrocytic activation. Leveraging a pioneering synthetic approach harnessing Ge-LDH and resveratrol, Res@LDH emerges as a promising strategy for addressing ischemia-reperfusion injury, offering a concise solution to current therapeutic challenges.
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Affiliation(s)
- Min Liu
- Department of Anesthesiology, Beijing Tongren Hospital,
Capital Medical University, Beijing 100730, China
| | - Siyuan Liu
- Department of Anesthesiology,
Affiliated Hospital of Nantong University, Nantong 226001, China
| | - Yafan Bai
- Department of Anesthesiology, Beijing Tongren Hospital,
Capital Medical University, Beijing 100730, China
| | - Mingru Zhang
- Department of Anesthesiology, Beijing Tongren Hospital,
Capital Medical University, Beijing 100730, China
| | - Duo Zhang
- School of Science,
China University of Geosciences, Beijing (CUGB), Beijing 100083, China
| | - Ruijin Sun
- School of Science,
China University of Geosciences, Beijing (CUGB), Beijing 100083, China
| | - Guyan Wang
- Department of Anesthesiology, Beijing Tongren Hospital,
Capital Medical University, Beijing 100730, China
| | - Yulong Ma
- Department of Anesthesiology,
The First Medical Center of Chinese PLA General Hospital, Beijing 100853, China
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Stoll G, Nieswandt B, Schuhmann MK. Ischemia/reperfusion injury in acute human and experimental stroke: focus on thrombo-inflammatory mechanisms and treatments. Neurol Res Pract 2024; 6:57. [PMID: 39582054 PMCID: PMC11587771 DOI: 10.1186/s42466-024-00355-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2024] [Accepted: 10/26/2024] [Indexed: 11/26/2024] Open
Abstract
BACKGROUND Despite high recanalization rates of > 90% after endovascular thrombectomy (EVT) clinical outcome in around 50% of treated acute ischemic stroke (AIS) patients is still poor. Novel treatments augmenting the beneficial effects of recanalization are eagerly awaited, but this requires mechanistic insights to explain and overcome futile recanalization. MAIN BODY At least two mechanisms contribute to futile recanalization after cerebral large vessel occlusions (LVO): (i) the no reflow phenomenon as evidenced by randomly distributed areas without return of blood flow despite reperfusion of large cerebral arteries, and (ii) ischemia/reperfusion (I/R) injury, the paradoxically harmful aspect of blood flow return in transiently ischemic organs. There is accumulating evidence from experimental stroke models that platelets and leukocytes interact and partly obstruct the microvasculature under LVO, and that platelet-driven inflammation (designated thrombo-inflammation) extends into the reperfusion phase and causes I/R injury. Blocking of platelet glycoprotein receptors (GP) Ib and GPVI ameliorated inflammation and I/R injury providing novel therapeutic options. Recently, MRI studies confirmed a significant, up to 40% infarct expansion after recanalization in AIS thereby proofing the existance of I/R injury in the human brain. Moreover, analysis of minute samples of ischemic arterial blood aspirated directly from the pial cerebral collateral circulation under LVO during the routine EVT procedure confirmed platelet activation and platelet-driven leukocyte accumulation in AIS and, thus, the principal transferability of pathophysiological stroke mechanisms from rodents to man. Two recently published clinical phase 1b/2a trials targeted (thrombo-) inflammation in AIS: The ACTIMIS trial targeting platelet GPVI by glenzocimab provided encouraging safety signals in AIS similar to the ApTOLL trial targeting toll-like receptor 4, a central receptor guiding stroke-induced innate immunity. However, both studies were not powered to show clinical efficacy. CONCLUSIONS The fact that the significance of I/R injury in AIS has recently been formally established and given the decisive role of platelet-leukocytes interactions herein, new avenues for adjunct stroke treatments emerge. Adjusted study designs to increase the probability of success are of outmost importance and we look forward from what can be learned from the so far unpublished, presumbably negative ACTISAFE and MOST trials.
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Affiliation(s)
- Guido Stoll
- Institute of Experimental Biomedicine I, University Hospital Wurzburg, Josef-Schneider-Str. 2, 97080, Wurzburg, Germany.
| | - Bernhard Nieswandt
- Institute of Experimental Biomedicine I, University Hospital Wurzburg, Josef-Schneider-Str. 2, 97080, Wurzburg, Germany
- Rudolf Virchow Center, Center for Integrative and Translational Biomaging, University of Wurzburg, Josef-Schneider-Str. 2, 97080, Wurzburg, Germany
| | - Michael K Schuhmann
- Department of Neurology, University Hospital Wurzburg, Josef-Schneider-Str. 11, 97080, Wurzburg, Germany
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Singh N, Kenney CC, Butcher KS, Buck B, Barber PA, Field TS, Choi PM, Yu AYX, Kleinig T, Appireddy R, Molina CA, Muir KW, Hill MD, Coutts SB. A Randomized Controlled Trial of Tenecteplase Versus Standard of Care for Minor Ischemic Stroke with Proven Occlusion (TEMPO-2): Rational and design of a multicenter, randomized open-label clinical trial. Int J Stroke 2024; 19:817-822. [PMID: 38676572 PMCID: PMC11298112 DOI: 10.1177/17474930241253702] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2024] [Accepted: 04/22/2024] [Indexed: 04/29/2024]
Abstract
BACKGROUND Almost half of acute ischemic stroke patients present with mild symptoms and there are large practice variations in their treatment globally. Individuals with an intracranial occlusion who present with minor stroke are at an increased risk of early neurological deterioration and poor outcomes. Individual patient data meta-analysis in the subgroup of patients with minor deficits showed benefit of alteplase in improving outcomes; however, this benefit has not been seen with intravenous alteplase in published randomized trials. DESIGN TEMPO-2 (A Randomized Controlled Trial of Tenecteplase Versus Standard of Care for Minor Ischemic Stroke With Proven Occlusion) is a prospective, open label with blinded outcome assessment, randomized controlled trial, designed to test the superiority of intravenous tenecteplase (0.25 mg/kg) over nonthrombolytic standard of care, with an estimated sample size of 1274 patients. Adult patients presenting with acute ischemic stroke with the National Institutes of Health Stroke Scale (NIHSS) ⩽ 5 and visible arterial occlusion or perfusion deficit within 12 h of onset are randomized to receive either tenecteplase (0.25 mg/kg) or standard of care. The primary outcome is return to baseline neurological functioning, measured by the modified Rankin scale (mRS) at 90 days. Safety outcomes include death and symptomatic hemorrhage (intra or extra-cranial). Other secondary outcomes include mRS 0-1, mRS 0-2, ordinal shift analysis of the mRS, partial, and full recanalization on follow-up computed tomography angiogram. CONCLUSION Results of this trial will aid in determining whether there is benefit of using tenecteplase (0.25 mg/kg) in treating patients presenting with minor stroke who are at high risk of developing poor outcomes due to presence of an intracranial occlusion. DATA ACCESS STATEMENT Data will be available upon reasonable request.
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Affiliation(s)
- Nishita Singh
- Neurology Division, Department of Internal Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, MB, Canada
| | - Carol C Kenney
- Departments of Neurosciences, Radiology and Community Health Sciences, University of Calgary, Calgary, AB, Canada
| | - Ken S Butcher
- School of Clinical Medicine, University of New South Wales, Sydney, NSW, Australia
| | - Brian Buck
- Division of Neurology, Department of Medicine, University of Alberta, Edmonton, AB, Canada
| | - Philip A Barber
- Departments of Neurosciences, Radiology and Community Health Sciences, University of Calgary, Calgary, AB, Canada
| | - Thalia S Field
- Vancouver Stroke Program, Division of Neurology, Department of Medicine, The University of British Columbia, Vancouver, BC, Canada
| | - Philip M Choi
- Department of Neurosciences, Box Hill Hospital, Faculty of Medicine, Nursing and Health Sciences, Monash University, Box Hill, VIC, Australia
| | - Amy YX Yu
- Division of Neurology, Department of Medicine, University of Toronto and Sunnybrook Health Sciences Centre, Toronto, ON, Canada
| | - Timothy Kleinig
- Department of Neurology, Royal Adelaide Hospital, Adelaide, SA, Australia
| | - Ramana Appireddy
- Division of Neurology, Department of Medicine, Queen’s University, Kingston, ON, Canada
| | | | - Keith W Muir
- School of Psychology & Neuroscience, University of Glasgow, Queen Elizabeth University Hospital, Glasgow, UK
| | - Michael D Hill
- Departments of Neurosciences, Radiology and Community Health Sciences, University of Calgary, Calgary, AB, Canada
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Departments of Medicine and Radiology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Shelagh B Coutts
- Departments of Neurosciences, Radiology and Community Health Sciences, University of Calgary, Calgary, AB, Canada
- Department of Community Health Sciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
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Jacqmarcq C, Picot A, Flon J, Lebrun F, Martinez de Lizarrondo S, Naveau M, Bernay B, Goux D, Rubio M, Malzert-Fréon A, Michel A, Proamer F, Mangin P, Gauberti M, Vivien D, Bonnard T. MRI-based microthrombi detection in stroke with polydopamine iron oxide. Nat Commun 2024; 15:5070. [PMID: 38871729 DOI: 10.1038/s41467-024-49480-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Accepted: 06/05/2024] [Indexed: 06/15/2024] Open
Abstract
In acute ischemic stroke, even when successful recanalization is obtained, downstream microcirculation may still be obstructed by microvascular thrombosis, which is associated with compromised brain reperfusion and cognitive decline. Identifying these microthrombi through non-invasive methods remains challenging. We developed the PHySIOMIC (Polydopamine Hybridized Self-assembled Iron Oxide Mussel Inspired Clusters), a MRI-based contrast agent that unmasks these microthrombi. In a mouse model of thromboembolic ischemic stroke, our findings demonstrate that the PHySIOMIC generate a distinct hypointense signal on T2*-weighted MRI in the presence of microthrombi, that correlates with the lesion areas observed 24 hours post-stroke. Our microfluidic studies reveal the role of fibrinogen in the protein corona for the thrombosis targeting properties. Finally, we observe the biodegradation and biocompatibility of these particles. This work demonstrates that the PHySIOMIC particles offer an innovative and valuable tool for non-invasive in vivo diagnosis and monitoring of microthrombi, using MRI during ischemic stroke.
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Affiliation(s)
- Charlène Jacqmarcq
- Normandie University, UNICAEN, Université Caen Normandie, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), GIP Cyceron, Institute Blood and Brain @ Caen-Normandie (BB@C), Caen, France
| | - Audrey Picot
- Normandie University, UNICAEN, Université Caen Normandie, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), GIP Cyceron, Institute Blood and Brain @ Caen-Normandie (BB@C), Caen, France
| | - Jules Flon
- Normandie University, UNICAEN, Université Caen Normandie, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), GIP Cyceron, Institute Blood and Brain @ Caen-Normandie (BB@C), Caen, France
| | - Florent Lebrun
- Normandie University, UNICAEN, Université Caen Normandie, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), GIP Cyceron, Institute Blood and Brain @ Caen-Normandie (BB@C), Caen, France
| | - Sara Martinez de Lizarrondo
- Normandie University, UNICAEN, Université Caen Normandie, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), GIP Cyceron, Institute Blood and Brain @ Caen-Normandie (BB@C), Caen, France
| | - Mikaël Naveau
- Normandie University, UNICAEN, Université Caen Normandie, CNRS UMS 3408, Caen, France
| | - Benoît Bernay
- Normandie University, UNICAEN, Université Caen Normandie, SF 4206 ICORE, Plateforme Proteogen, Caen, France
| | - Didier Goux
- Normandie University, UNICAEN, Université Caen Normandie, US EMerode, CMAbio3: Centre de Microscopie Appliquée à la Biologie, Caen, France
| | - Marina Rubio
- Normandie University, UNICAEN, Université Caen Normandie, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), GIP Cyceron, Institute Blood and Brain @ Caen-Normandie (BB@C), Caen, France
| | - Aurélie Malzert-Fréon
- Normandie University, UNICAEN, Université Caen Normandie, EA 4258, CERMN: Centre d'études et de recherche sur le médicament de Normandie, Caen, France
| | - Anita Michel
- University of Strasbourg, INSERM, EFS Grand-Est, BPPS UMR-S1255, FMTS, F-67065, Strasbourg, France
| | - Fabienne Proamer
- University of Strasbourg, INSERM, EFS Grand-Est, BPPS UMR-S1255, FMTS, F-67065, Strasbourg, France
| | - Pierre Mangin
- University of Strasbourg, INSERM, EFS Grand-Est, BPPS UMR-S1255, FMTS, F-67065, Strasbourg, France
| | - Maxime Gauberti
- Normandie University, UNICAEN, Université Caen Normandie, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), GIP Cyceron, Institute Blood and Brain @ Caen-Normandie (BB@C), Caen, France
- Centre Hospitalier Universitaire Caen, Department of Diagnostic Imaging and Interventional Radiology, Caen, France
| | - Denis Vivien
- Normandie University, UNICAEN, Université Caen Normandie, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), GIP Cyceron, Institute Blood and Brain @ Caen-Normandie (BB@C), Caen, France.
- Centre Hospitalier Universitaire Caen, Department of Clinical Research, Caen, France.
| | - Thomas Bonnard
- Normandie University, UNICAEN, Université Caen Normandie, INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders (PhIND), GIP Cyceron, Institute Blood and Brain @ Caen-Normandie (BB@C), Caen, France.
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Aziz YN, Sucharew H, Stanton RJ, Alwell K, Ferioli S, Khatri P, Adeoye O, Flaherty ML, Mackey J, De Los Rios La Rosa F, Martini SR, Mistry EA, Coleman E, Jasne AS, Slavin SJ, Walsh K, Star M, Ridha M, Ades LMC, Haverbusch M, Demel SL, Woo D, Kissela BM, Kleindorfer DO. Racial Disparities in Blood Pressure at Time of Acute Ischemic Stroke Presentation: A Population Study. J Am Heart Assoc 2024; 13:e032645. [PMID: 38700029 PMCID: PMC11179936 DOI: 10.1161/jaha.123.032645] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/13/2023] [Accepted: 04/10/2024] [Indexed: 05/05/2024]
Abstract
BACKGROUND Hypertension is a stroke risk factor with known disparities in prevalence and management between Black and White patients. We sought to identify if racial differences in presenting blood pressure (BP) during acute ischemic stroke exist. METHODS AND RESULTS Adults with acute ischemic stroke presenting to an emergency department within 24 hours of last known normal during study epochs 2005, 2010, and 2015 within the Greater Cincinnati/Northern Kentucky Stroke Study were included. Demographics, histories, arrival BP, National Institutes of Health Stroke Scale score, and time from last known normal were collected. Multivariable linear regression was used to determine differences in mean BP between Black and White patients, adjusting for age, sex, National Institutes of Health Stroke Scale score, history of hypertension, hyperlipidemia, smoking, stroke, body mass index, and study epoch. Of 4048 patients, 853 Black and 3195 White patients were included. In adjusted analysis, Black patients had higher presenting systolic BP (161 mm Hg [95% CI, 159-164] versus 158 mm Hg [95% CI, 157-159], P<0.01), diastolic BP (86 mm Hg [95% CI, 85-88] versus 83 mm Hg [95% CI, 82-84], P<0.01), and mean arterial pressure (111 mm Hg [95% CI, 110-113] versus 108 mm Hg [95% CI, 107-109], P<0.01) compared with White patients. In adjusted subanalysis of patients <4.5 hours from last known normal, diastolic BP (88 mm Hg [95% CI, 86-90] versus 83 mm Hg [95% CI, 82-84], P<0.01) and mean arterial pressure (112 mm Hg [95% CI, 110-114] versus 108 mm Hg [95% CI, 107-109], P<0.01) were also higher in Black patients. CONCLUSIONS This population-based study suggests differences in presenting BP between Black and White patients during acute ischemic stroke. Further study is needed to determine whether these differences influence clinical decision-making, outcome, or clinical trial eligibility.
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Affiliation(s)
- Yasmin N. Aziz
- Department of Neurology and Rehabilitation MedicineUniversity of CincinnatiCincinnatiOH
| | - Heidi Sucharew
- Department of Emergency MedicineUniversity of CincinnatiCincinnatiOH
| | - Robert J. Stanton
- Department of Neurology and Rehabilitation MedicineUniversity of CincinnatiCincinnatiOH
| | - Kathleen Alwell
- Department of Neurology and Rehabilitation MedicineUniversity of CincinnatiCincinnatiOH
| | - Simona Ferioli
- Department of Neurology and Rehabilitation MedicineUniversity of CincinnatiCincinnatiOH
| | - Pooja Khatri
- Department of Neurology and Rehabilitation MedicineUniversity of CincinnatiCincinnatiOH
| | - Opeolu Adeoye
- Department of Emergency MedicineWashington UniversitySt LouisMO
| | - Matthew L. Flaherty
- Department of Neurology and Rehabilitation MedicineUniversity of CincinnatiCincinnatiOH
| | - Jason Mackey
- Department of NeurologyIndiana UniversityIndianapolisIN
| | | | - Sharyl R. Martini
- Department of NeurologyMichael E. DeBakey VA Medical CenterHoustonTX
| | - Eva A. Mistry
- Department of Neurology and Rehabilitation MedicineUniversity of CincinnatiCincinnatiOH
| | | | | | | | - Kyle Walsh
- Department of Neurology and Rehabilitation MedicineUniversity of CincinnatiCincinnatiOH
| | | | - Mohamed Ridha
- Department of NeurologyThe Ohio State UniversityColumbusOH
| | - Laura M. C. Ades
- Department of NeurologyNYU Grossman School of MedicineBrooklynNY
| | - Mary Haverbusch
- Department of Neurology and Rehabilitation MedicineUniversity of CincinnatiCincinnatiOH
| | - Stacie L. Demel
- Department of Neurology and Rehabilitation MedicineUniversity of CincinnatiCincinnatiOH
| | - Daniel Woo
- Department of Neurology and Rehabilitation MedicineUniversity of CincinnatiCincinnatiOH
| | - Brett M. Kissela
- Department of Neurology and Rehabilitation MedicineUniversity of CincinnatiCincinnatiOH
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9
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Bielawski PB, Zhang I, Correa-Paz C, Campos F, Migliavacca M, Polo E, Del Pino P, Pelaz B, Vivien D, Maysinger D. Modulation of Abundance and Location of High-Mobility Group Box 1 in Human Microglia and Macrophages under Oxygen-Glucose Deprivation. ACS Pharmacol Transl Sci 2024; 7:680-692. [PMID: 38481701 PMCID: PMC10928888 DOI: 10.1021/acsptsci.3c00271] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2023] [Revised: 01/03/2024] [Accepted: 02/12/2024] [Indexed: 03/01/2025]
Abstract
While stroke represents one of the main causes of death worldwide, available effective drug treatment options remain limited to classic thrombolysis with recombinant tissue plasminogen activator (rtPA) for arterial-clot occlusion. Following stroke, multiple pathways become engaged in producing a vicious proinflammatory cycle through the release of damage-associated molecular patterns (DAMPs) such as high-mobility group box 1 (HMGB1) and heat shock protein 70 kDa (HSP72). HMGB1, in particular, can activate proinflammatory cytokine production when acetylated (AcHMGB1), a form that prefers cytosolic localization and extracellular release. This study aimed at determining how HMGB1 and HSP72 are modulated and affected following treatment with the anti-inflammatory compound resveratrol and novel platelet membrane-derived nanocarriers loaded with rtPA (CSM@rtPA) recently developed by our group for ischemic artery recanalization. Under ischemic conditions of oxygen-glucose deprivation (OGD), nuclear abundance of HMGB1 and AcHMGB1 in microglia and macrophages decreased, whereas treatment with CSM@rtPA did not alter nuclear or cytosolic abundance. Resveratrol treatment markedly increased the cytosolic abundance of HSP72 in microglia. Using proximity ligation assays, we determined that HSP72 interacted with HMGB1 and with acetylated HMGB1. The interaction was differentially affected under the OGD conditions. Resveratrol treatment under the OGD further decreased HSP72-HMGB1 interactions, whereas, in contrast, treatment increased HSP72-AcHMGB1 interactions in microglia. This study points out a salient molecular interaction suited for a two-pronged nanotherapeutic intervention in stroke: enhancement of rtPA's thrombolytic activity and modulation of cytosolic interactions between HMGB1 and HSP72 by resveratrol.
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Affiliation(s)
- Patrick-Brian Bielawski
- Department
of Pharmacology and Therapeutics, McGill
University, Montreal, QC H3G 1Y6, Canada
| | - Issan Zhang
- Department
of Pharmacology and Therapeutics, McGill
University, Montreal, QC H3G 1Y6, Canada
| | - Clara Correa-Paz
- Translational
Stroke Laboratory Group (TREAT), Clinical Neurosciences Research Laboratory
(LINC), Health Research Institute of Santiago
de Compostela (IDIS), Santiago
de Compostela 15706, Spain
| | - Francisco Campos
- Translational
Stroke Laboratory Group (TREAT), Clinical Neurosciences Research Laboratory
(LINC), Health Research Institute of Santiago
de Compostela (IDIS), Santiago
de Compostela 15706, Spain
| | - Martina Migliavacca
- Center
for Research in Biological Chemistry and Molecular Materials (CiQUS), University of Santiago de Compostela (USC), Santiago de Compostela 15782, Spain
| | - Ester Polo
- Center
for Research in Biological Chemistry and Molecular Materials (CiQUS), University of Santiago de Compostela (USC), Santiago de Compostela 15782, Spain
| | - Pablo Del Pino
- Center
for Research in Biological Chemistry and Molecular Materials (CiQUS), University of Santiago de Compostela (USC), Santiago de Compostela 15782, Spain
| | - Beatriz Pelaz
- Center
for Research in Biological Chemistry and Molecular Materials (CiQUS), University of Santiago de Compostela (USC), Santiago de Compostela 15782, Spain
| | - Denis Vivien
- UNICAEN,
INSERM UMR-S U1237, Physiopathology and Imaging of Neurological Disorders
(PhIND), GIP Cyceron, Institut Blood and Brain @ Caen-Normandie (BB@C), Normandie University, 14000 Caen, France
- Department
of Clinical Research, Caen Normandie University
Hospital, 14000 Caen, France
| | - Dusica Maysinger
- Department
of Pharmacology and Therapeutics, McGill
University, Montreal, QC H3G 1Y6, Canada
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10
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Kong J, Zou R, Chu R, Hu N, Liu J, Sun Y, Ge X, Mao M, Yu H, Wang Y. An Ultrasmall Cu/Cu 2O Nanoparticle-Based Diselenide-Bridged Nanoplatform Mediating Reactive Oxygen Species Scavenging and Neuronal Membrane Enhancement for Targeted Therapy of Ischemic Stroke. ACS NANO 2024; 18:4140-4158. [PMID: 38134247 DOI: 10.1021/acsnano.3c08734] [Citation(s) in RCA: 20] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/24/2023]
Abstract
Ischemic stroke is one of the major causes of death and disability worldwide, and an effective and timely treatment of ischemic stroke has been a challenge because of the narrow therapeutic window and the poor affinity with thrombus of the thrombolytic agent. In this study, rPZDCu, a multifunctional nanoparticle (NP) with the effects of thrombolysis, reactive oxygen species (ROS) scavenging, and neuroprotection, was synthesized based on an ultrasmall Cu4.6O NP, the thrombolytic agent rt-PA, and docosahexaenoic acid (DHA), which is a major component of the neuronal membrane. rPZDCu showed strong thrombus-targeting ability, which was achieved by the platelet cell membrane coating on the NP surface, and a good thrombolytic effect in both the common carotid artery clot model and embolic middle cerebral artery occlusion (MCAO) model of rats. Furthermore, rPZDCu exhibited a good escape from the phagocytosis of macrophages, effective promotion of the polarization of microglia, and efficient recovery of neurobiological and behavioral functions in the embolic MCAO model of rats. This is a heuristic report of (1) the Cu0/Cu+ NP for the treatments of brain diseases, (2) the integration of DHA and ROS scavengers for central nervous system therapies, and (3) diselenide-based ROS-responsive NPs for ischemic stroke treatments. This study also offers an example of cell membrane-camouflaged stimuli-responsive nanomedicine for brain-targeting drug delivery.
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Affiliation(s)
- Jianglong Kong
- College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou 310058, China
| | - Rui Zou
- Department of Nuclear Medicine, the Third Affiliated Hospital of Sun Yat-Sen University, Guangzhou 510630, People's Republic of China
| | - Runxuan Chu
- National Pharmaceutical Engineering Research Center, China State Institute of Pharmaceutical Industry, Shanghai 201203, People's Republic of China
| | - Nan Hu
- Changchun Institute of Technology, Changchun 130012, People's Republic of China
| | - Jiawen Liu
- College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou 310058, China
| | - Yuting Sun
- College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou 310058, China
| | - Xiaohan Ge
- College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou 310058, China
| | - Meiru Mao
- College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou 310058, China
| | - Hongrui Yu
- College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou 310058, China
| | - Yi Wang
- College of Biosystems Engineering and Food Science, Zhejiang University, Hangzhou 310058, China
- Ningbo Research Institute, Zhejiang University, Ningbo 315100, People's Republic of China
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11
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Dammavalam V, Lin S, Nessa S, Daksla N, Stefanowski K, Costa A, Bergese S. Neuroprotection during Thrombectomy for Acute Ischemic Stroke: A Review of Future Therapies. Int J Mol Sci 2024; 25:891. [PMID: 38255965 PMCID: PMC10815099 DOI: 10.3390/ijms25020891] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 01/08/2024] [Accepted: 01/09/2024] [Indexed: 01/24/2024] Open
Abstract
Stroke is a major cause of death and disability worldwide. Endovascular thrombectomy has been impactful in decreasing mortality. However, many clinical results continue to show suboptimal functional outcomes despite high recanalization rates. This gap in recanalization and symptomatic improvement suggests a need for adjunctive therapies in post-thrombectomy care. With greater insight into ischemia-reperfusion injury, recent preclinical testing of neuroprotective agents has shifted towards preventing oxidative stress through upregulation of antioxidants and downstream effectors, with positive results. Advances in multiple neuroprotective therapies, including uric acid, activated protein C, nerinetide, otaplimastat, imatinib, verapamil, butylphthalide, edaravone, nelonemdaz, ApTOLL, regional hypothermia, remote ischemic conditioning, normobaric oxygen, and especially nuclear factor erythroid 2-related factor 2, have promising evidence for improving stroke care. Sedation and blood pressure management in endovascular thrombectomy also play crucial roles in improved stroke outcomes. A hand-in-hand approach with both endovascular therapy and neuroprotection may be the key to targeting disability due to stroke.
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Affiliation(s)
- Vikalpa Dammavalam
- Department of Neurology, Stony Brook University Hospital, Stony Brook, NY 11794, USA; (V.D.); (K.S.)
| | - Sandra Lin
- Department of Anesthesiology, Stony Brook University Hospital, Stony Brook, NY 11794, USA; (S.L.); (N.D.); (A.C.)
| | - Sayedatun Nessa
- Department of Neurology, Stony Brook University Hospital, Stony Brook, NY 11794, USA; (V.D.); (K.S.)
| | - Neil Daksla
- Department of Anesthesiology, Stony Brook University Hospital, Stony Brook, NY 11794, USA; (S.L.); (N.D.); (A.C.)
| | - Kamil Stefanowski
- Department of Neurology, Stony Brook University Hospital, Stony Brook, NY 11794, USA; (V.D.); (K.S.)
| | - Ana Costa
- Department of Anesthesiology, Stony Brook University Hospital, Stony Brook, NY 11794, USA; (S.L.); (N.D.); (A.C.)
| | - Sergio Bergese
- Department of Anesthesiology, Stony Brook University Hospital, Stony Brook, NY 11794, USA; (S.L.); (N.D.); (A.C.)
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12
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Skolarus LE, Bailey S, Corches CL, Sales AE, Lin CC, Bi R, Springer MV, Oliver A, Robles MC, Brooks T, Tupper M, Jaggi M, Al-Qasmi M, Trevithick BA, Barber K, Majjhoo A, Zimmerman MA, Meurer WJ, Brown DL, Morgenstern LB, Burke JF. Association of the Stroke Ready Community-Based Participatory Research Intervention With Incidence of Acute Stroke Thrombolysis in Flint, Michigan. JAMA Netw Open 2023; 6:e2321558. [PMID: 37399011 PMCID: PMC10318478 DOI: 10.1001/jamanetworkopen.2023.21558] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Accepted: 05/17/2023] [Indexed: 07/04/2023] Open
Abstract
Importance Acute stroke treatment rates in the US lag behind those in other high-income nations. Objective To assess whether a hospital emergency department (ED) and community intervention was associated with an increased proportion of patients with stroke receiving thrombolysis. Design, Setting, and Participants This nonrandomized controlled trial of the Stroke Ready intervention took place in Flint, Michigan, from October 2017 to March 2020. Participants included adults living in the community. Data analysis was completed from July 2022 to May 2023. Intervention Stroke Ready combined implementation science and community-based participatory research approaches. Acute stroke care was optimized in a safety-net ED, and then a community-wide, theory-based health behavior intervention, including peer-led workshops, mailers, and social media, was conducted. Main Outcomes and Measures The prespecified primary outcome was the proportion of patients hospitalized with ischemic stroke or transient ischemic attack from Flint who received thrombolysis before and after the intervention. The association between thrombolysis and the Stroke Ready combined intervention, including the ED and community components, was estimated using logistic regression models, clustering at the hospital level and adjusting for time and stroke type. In prespecified secondary analyses, the ED and community intervention were explored separately, adjusting for hospital, time, and stroke type. Results In total, 5970 people received in-person stroke preparedness workshops, corresponding to 9.7% of the adult population in Flint. There were 3327 ischemic stroke and TIA visits (1848 women [55.6%]; 1747 Black individuals [52.5%]; mean [SD] age, 67.8 [14.5] years) among patients from Flint seen in the relevant EDs, including 2305 in the preintervention period from July 2010 to September 2017 and 1022 in the postintervention period from October 2017 to March 2020. The proportion of thrombolysis usage increased from 4% in 2010 to 14% in 2020. The combined Stroke Ready intervention was not associated with thrombolysis use (adjusted odds ratio [OR], 1.13; 95% CI, 0.74-1.70; P = .58). The ED component was associated with an increase in thrombolysis use (adjusted OR, 1.63; 95% CI, 1.04-2.56; P = .03), but the community component was not (adjusted OR, 0.99; 95% CI, 0.96-1.01; P = .30). Conclusions and Relevance This nonrandomized controlled trial found that a multilevel ED and community stroke preparedness intervention was not associated with increased thrombolysis treatments. The ED intervention was associated with increased thrombolysis usage, suggesting that implementation strategies in partnership with safety-net hospitals may increase thrombolysis usage. Trial Registration ClinicalTrials.gov Identifier: NCT036455900.
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Affiliation(s)
- Lesli E. Skolarus
- Davee Department of Neurology, Stroke and Vascular Neurology, Northwestern University, Chicago, Illinois
- Department of Neurology, University of Michigan, Ann Arbor
| | | | | | - Anne E. Sales
- Department of Family and Community Medicine, Sinclair School of Nursing, University of Missouri, Columbia
- VA Ann Arbor Healthcare System, Ann Arbor, Michigan
| | - Chun Chieh Lin
- Department of Neurology, University of Michigan, Ann Arbor
- Department of Neurology, Ohio State University, Columbus
| | - Ran Bi
- Department of Neurology, University of Michigan, Ann Arbor
| | | | | | | | - Tia Brooks
- Department of Neurology, University of Michigan, Ann Arbor
| | - Michael Tupper
- Department of Emergency Medicine, University of Michigan, Ann Arbor
- Department of Emergency Medicine, Hurley Medical Center, Flint, Michigan
| | - Michael Jaggi
- Department of Emergency Medicine, University of Michigan, Ann Arbor
- Department of Emergency Medicine, Hurley Medical Center, Flint, Michigan
| | - Mohammed Al-Qasmi
- Department of Emergency Medicine, Hurley Medical Center, Flint, Michigan
| | | | - Kimberly Barber
- Department of Clinical & Academic Research, Genesys Regional Medical Center, Grand Blanc, Michigan
| | - Aniel Majjhoo
- Department of Neurology, McLaren Flint Hospital, Flint, Michigan
| | | | | | - Devin L. Brown
- Department of Neurology, University of Michigan, Ann Arbor
| | - Lewis B. Morgenstern
- Department of Neurology, University of Michigan, Ann Arbor
- Department of Emergency Medicine, University of Michigan, Ann Arbor
- School of Public Health, University of Michigan, Ann Arbor
| | - James F. Burke
- Department of Neurology, University of Michigan, Ann Arbor
- Department of Neurology, Ohio State University, Columbus
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13
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Loppi SH, Tavera-Garcia MA, Becktel DA, Maiyo BK, Johnson KE, Nguyen TVV, Schnellmann RG, Doyle KP. Increased fatty acid metabolism and decreased glycolysis are hallmarks of metabolic reprogramming within microglia in degenerating white matter during recovery from experimental stroke. J Cereb Blood Flow Metab 2023; 43:1099-1114. [PMID: 36772984 PMCID: PMC10291449 DOI: 10.1177/0271678x231157298] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Revised: 12/22/2022] [Accepted: 01/20/2023] [Indexed: 02/12/2023]
Abstract
The goal of this study was to evaluate changes in metabolic homeostasis during the first 12 weeks of recovery in a distal middle cerebral artery occlusion mouse model of stroke. To achieve this goal, we compared the brain metabolomes of ipsilateral and contralateral hemispheres from aged male mice up to 12 weeks after stroke to that of age-matched naïve and sham mice. There were 707 biochemicals detected in each sample by liquid chromatography-mass spectroscopy (LC-MS). Mitochondrial fatty acid β-oxidation, indicated by acyl carnitine levels, was increased in stroked tissue at 1 day and 4 weeks following stroke. Glucose and several glycolytic intermediates were elevated in the ipsilateral hemisphere for 12 weeks compared to the aged naïve controls, but pyruvate was decreased. Additionally, itaconate, a glycolysis inhibitor associated with activation of anti-inflammatory mechanisms in myeloid cells, was higher in the same comparisons. Spatial transcriptomics and RNA in situ hybridization localized these alterations to microglia within the area of axonal degeneration. These results indicate that chronic metabolic differences exist between stroked and control brains, including alterations in fatty acid metabolism and glycolysis within microglia in areas of degenerating white matter for at least 12 weeks after stroke.
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Affiliation(s)
- Sanna H Loppi
- Department of Immunobiology, College of Medicine, University of Arizona, Tucson, Arizona, USA
| | - Marco A Tavera-Garcia
- Department of Immunobiology, College of Medicine, University of Arizona, Tucson, Arizona, USA
| | - Danielle A Becktel
- Department of Immunobiology, College of Medicine, University of Arizona, Tucson, Arizona, USA
| | - Boaz K Maiyo
- Department of Immunobiology, College of Medicine, University of Arizona, Tucson, Arizona, USA
| | - Kristos E Johnson
- Department of Immunobiology, College of Medicine, University of Arizona, Tucson, Arizona, USA
| | - Thuy-Vi V Nguyen
- Department of Neurology, College of Medicine, University of Arizona, Tucson, Arizona, USA
| | - Rick G Schnellmann
- Department of Pharmacology and Toxicology, College of Pharmacy, University of Arizona, Tucson, Arizona, USA
- BIO5 Institute, College of Medicine, University of Arizona, Tucson, Arizona, USA
| | - Kristian P Doyle
- Department of Immunobiology, College of Medicine, University of Arizona, Tucson, Arizona, USA
- Department of Neurology, College of Medicine, University of Arizona, Tucson, Arizona, USA
- BIO5 Institute, College of Medicine, University of Arizona, Tucson, Arizona, USA
- Arizona Center on Aging, College of Medicine, University of Arizona, Tucson, Arizona, USA
- Department of Psychology, College of Medicine, University of Arizona, Tucson, Arizona, USA
- Department of Neurosurgery, College of Medicine, University of Arizona, Tucson, Arizona, USA
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14
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Szepanowski RD, Haupeltshofer S, Vonhof SE, Frank B, Kleinschnitz C, Casas AI. Thromboinflammatory challenges in stroke pathophysiology. Semin Immunopathol 2023:10.1007/s00281-023-00994-4. [PMID: 37273022 DOI: 10.1007/s00281-023-00994-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Accepted: 04/27/2023] [Indexed: 06/06/2023]
Abstract
Despite years of encouraging translational research, ischemic stroke still remains as one of the highest unmet medical needs nowadays, causing a tremendous burden to health care systems worldwide. Following an ischemic insult, a complex signaling pathway emerges leading to highly interconnected thrombotic as well as neuroinflammatory signatures, the so-called thromboinflammatory cascade. Here, we thoroughly review the cell-specific and time-dependent role of different immune cell types, i.e., neutrophils, macrophages, T and B cells, as key thromboinflammatory mediators modulating the neuroinflammatory response upon stroke. Similarly, the relevance of platelets and their tight crosstalk with a variety of immune cells highlights the relevance of this cell-cell interaction during microvascular dysfunction, neovascularization, and cellular adhesion. Ultimately, we provide an up-to-date overview of therapeutic approaches mechanistically targeting thromboinflammation currently under clinical translation, especially focusing on phase I to III clinical trials.
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Affiliation(s)
- R D Szepanowski
- Department of Neurology, University Hospital Essen, Essen, Germany
- Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen, Germany
| | - S Haupeltshofer
- Department of Neurology, University Hospital Essen, Essen, Germany
- Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen, Germany
| | - S E Vonhof
- Department of Neurology, University Hospital Essen, Essen, Germany
- Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen, Germany
| | - B Frank
- Department of Neurology, University Hospital Essen, Essen, Germany
- Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen, Germany
| | - C Kleinschnitz
- Department of Neurology, University Hospital Essen, Essen, Germany.
- Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen, Germany.
| | - A I Casas
- Department of Neurology, University Hospital Essen, Essen, Germany
- Center for Translational Neuro- and Behavioral Sciences (C-TNBS), Essen, Germany
- Department of Pharmacology and Personalised Medicine, Faculty of Health, Medicine, and Life Sciences, Maastricht University, Maastricht, The Netherlands
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15
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Zhu Z, Muhammad B, Du B, Gu N, Meng TY, Kan S, Mu YF, Cheng YB, Zhu SG, Geng DQ. Elevated NT-proBNP predicts unfavorable outcomes in patients with acute ischemic stroke after thrombolytic therapy. BMC Neurol 2023; 23:203. [PMID: 37221489 DOI: 10.1186/s12883-023-03222-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2023] [Accepted: 04/20/2023] [Indexed: 05/25/2023] Open
Abstract
OBJECTIVE Few studies correlated n-terminal pro-brain natriuretic peptide (NT-proBNP) with early neurological deterioration (END) and prognosis of acute ischaemic stroke (AIS) patients with rt-PA intravenous thrombolysis. Therefore this study aimed to investigate the relationship between NT-proBNP and END, and prognosis after intravenous thrombolysis in patients with AIS. METHODS A total of 325 patients with AIS were enrolled. We performed the natural logarithm transformation on the NT-proBNP [ln(NT-proBNP)]. Univariate and multivariate logistic regression analyses were performed to assess the relationship between ln(NT-proBNP) and END, and prognosis and receiver operating characteristic (ROC) curves were used to show the sensitivity and specificity of NT-proBNP. RESULTS After thrombolysis, among 325 patients with AIS, 43 patients (13.2%) developed END. In addition, three months follow-up showed a poor prognosis in 98 cases (30.2%) and a good prognosis in 227 cases (69.8%). Multivariate logistic regression analysis showed that ln(NT-proBNP) was an independent risk factor for END (OR = 1.450,95%CI:1.072 ~ 1.963, P = 0.016) and poor prognosis at three months follow-up (OR = 1.767, 95%CI: 1.347 ~ 2.317, P < 0.001) respectively. According to ROC curve analysis, ln(NT-proBNP) (AUC 0.735, 95%CI: 0.674 ~0.796, P < 0.001) had a good predictive value for poor prognosis, with a predictive value of 5.12 and sensitivity and specificity of 79.59% and 60.35% respectively. When combined with NIHSS to predict END(AUC 0.718, 95%CI: 0.631 ~ 0.805, P < 0.001) and poor prognosis(AUC 0.780, 95%CI: 0.724 ~ 0.836, P < 0.001), the predictive value of the model is further improved. CONCLUSION NT-proBNP is independently associated with END and poor prognosis in patients with AIS following intravenous thrombolysis and has a particular predictive value for END and poor prognosis.
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Affiliation(s)
- Zhuang Zhu
- School of Clinical Medicine, Xuzhou Medical University, Xuzhou, 221000, China
- Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, China
| | - Bilal Muhammad
- Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, China
| | - Bo Du
- Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, China
| | - Ning Gu
- School of Clinical Medicine, Xuzhou Medical University, Xuzhou, 221000, China
- Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, China
| | - Tian-Yue Meng
- School of Clinical Medicine, Xuzhou Medical University, Xuzhou, 221000, China
- Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, China
| | - Shu Kan
- Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, China
| | - Ying-Feng Mu
- Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, China
| | - Yan-Bo Cheng
- Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, China
| | - Shi-Guang Zhu
- Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, China.
| | - De-Qin Geng
- Department of Neurology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, 221000, China.
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16
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Prothymosin α Plays Role as a Brain Guardian through Ecto-F 1 ATPase-P2Y 12 Complex and TLR4/MD2. Cells 2023; 12:cells12030496. [PMID: 36766838 PMCID: PMC9914670 DOI: 10.3390/cells12030496] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 01/21/2023] [Accepted: 01/30/2023] [Indexed: 02/05/2023] Open
Abstract
Prothymosin alpha (ProTα) was discovered to be a necrosis inhibitor from the conditioned medium of a primary culture of rat cortical neurons under starved conditions. This protein carries out a neuronal cell-death-mode switch from necrosis to apoptosis, which is, in turn, suppressed by a variety of neurotrophic factors (NTFs). This type of NTF-assisted survival action of ProTα is reproduced in cerebral and retinal ischemia-reperfusion models. Further studies that used a retinal ischemia-reperfusion model revealed that ProTα protects retinal cells via ecto-F1 ATPase coupled with the Gi-coupled P2Y12 receptor and Toll-like receptor 4 (TLR4)/MD2 coupled with a Toll-IL-1 receptor domain-containing adaptor inducing IFN-β (TRIF). In cerebral ischemia-reperfusion models, ProTα has additional survival mechanisms via an inhibition of matrix metalloproteases in microglia and vascular endothelial cells. Heterozygous or conditional ProTα knockout mice show phenotypes of anxiety, memory learning impairment, and a loss of neurogenesis. There are many reports that ProTα has multiple intracellular functions for cell survival and proliferation through a variety of protein-protein interactions. Overall, it is suggested that ProTα plays a key role as a brain guardian against ischemia stress through a cell-death-mode switch assisted by NTFs and a role of neurogenesis.
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17
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Ueda H. Prothymosin α-derived hexapeptide prevents the brain damage and sequelae due to ischemia-hemorrhage. Peptides 2023; 160:170922. [PMID: 36496010 DOI: 10.1016/j.peptides.2022.170922] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/08/2022] [Revised: 12/05/2022] [Accepted: 12/07/2022] [Indexed: 12/12/2022]
Abstract
ProTα discovered as a necrosis-inhibitor from the conditioned medium of cortical culture also shows a potent survival action in brain and retinal ischemia/reperfusion models. The proposed mechanisms are the initial cell death mode switch from necrosis to apoptosis, which is subsequently inhibited by neurotrophic factors in vivo. It should be noted that ProTα and its derived hexapeptide P6Q completely suppress the cerebral hemorrhage induced by late tPA treatment (4.5 h) after the brain ischemia/reperfusion. Mechanisms underlying their beneficial actions may be related to the fact that ProTα inhibits the production of matrix metalloproteases (MMPs) in microglia and vascular endothelial cells. However, as P6Q inhibits MMPs in vascular endothelial cells, but not in microglia, the suppression of MMP production in endothelial cells seems to play major roles in the late tPA-induced hemorrhage. Although the tPA-treatments could enable the survival of patients with stroke, the post-stroke sequelae are the next clinical issues to be solved. The use of small peptide P6Q revealed the blockade of post-stroke pain, depression and memory-learning deficits in animal models. Furthermore, recent studies also showed that P6Q supplementation increased the viability of human induced pluripotent stem (iPS) cell-derived retinal pigment epithelium cell suspensions during the storage and P6Q attenuated the cisplatin-induced acute kidney injury.
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Affiliation(s)
- Hiroshi Ueda
- Department of Pharmacology and Therapeutic Innovation of Nagasaki University Graduate School of Biomedical Sciences, Nagasaki 852-8521, Japan; Graduate Institute of Pharmacology, National Defense Medical Center, Neihu, 114201 Taipei, Taiwan
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18
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Potemkin N, Clarkson AN. Non-coding RNAs in stroke pathology, diagnostics, and therapeutics. Neurochem Int 2023; 162:105467. [PMID: 36572063 DOI: 10.1016/j.neuint.2022.105467] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Revised: 12/18/2022] [Accepted: 12/19/2022] [Indexed: 12/24/2022]
Abstract
Ischemic stroke is a leading cause of death and disability worldwide. Methods to alleviate functional deficits after ischemic stroke focus on restoration of cerebral blood flow to the affected area. However, pharmacological or surgical methods such as thrombolysis and thrombectomy have a narrow effective window. Harnessing and manipulating neurochemical processes of recovery may provide an alternative to these methods. Recently, non-coding RNA (ncRNA) have been increasingly investigated for their contributions to the pathology of diseases and potential for diagnostic and therapeutic applications. Here we will review several ncRNA - H19, MALAT1, ANRIL, NEAT1, pseudogenes, small nucleolar RNA, piwi-interacting RNA and circular RNA - and their involvement in stroke pathology. We also examine these ncRNA as potential diagnostic biomarkers, particularly in circulating blood, and as targets for therapeutic interventions. An important aspect of this is a discussion of potential methods of treatment delivery to allow for targeting of interventions past the blood-brain barrier, including lipid nanoparticles, polymer nanoparticles, and viral and non-viral vectors. Overall, several long non-coding RNA (lncRNA) discussed here have strong implications for the development of pathology and functional recovery after ischemic stroke. LncRNAs H19 and ANRIL show potential as diagnostic biomarkers, while H19 and MALAT1 may prove to be effective therapeutics for both minimising damage as well as promoting recovery. Other ncRNA have also been implicated in ischemic stroke but are currently too poorly understood to make inferences for diagnosis or treatment. Whilst the field of ncRNAs is relatively new, significant work has already highlighted that ncRNAs represent a promising novel investigative tool for understanding stroke pathology, could be used as diagnostic biomarkers, and as targets for therapeutic interventions.
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Affiliation(s)
- Nikita Potemkin
- Department of Anatomy, Brain Health Research Centre and Brain Research New Zealand, University of Otago, Dunedin, 9054, New Zealand.
| | - Andrew N Clarkson
- Department of Anatomy, Brain Health Research Centre and Brain Research New Zealand, University of Otago, Dunedin, 9054, New Zealand.
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19
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Tang Y, Liu MS, Fu C, Li GQ. Sex-dependent association analysis between serum uric acid and spontaneous hemorrhagic transformation in patients with ischemic stroke. Front Neurol 2023; 14:1103270. [PMID: 36937530 PMCID: PMC10022728 DOI: 10.3389/fneur.2023.1103270] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2022] [Accepted: 02/07/2023] [Indexed: 03/06/2023] Open
Abstract
Objective The association between serum uric acid (UA) and spontaneous hemorrhagic transformation (HT) has been seldom studied, and the role of UA in spontaneous HT remains unclear. This study aims to investigate the sex-dependent association between UA and spontaneous HT in patients with ischemic stroke. Method We retrospectively included patients with ischemic stroke in a tertiary academic hospital between December 2016 and May 2020. Patients were included if they presented within 24 h after the onset of symptoms and did not receive reperfusion therapy. Spontaneous HT was determined by an independent evaluation of neuroimaging by three trained neurologists who were blinded to clinical data. A univariate analysis was performed to identify factors related to spontaneous HT. Four logistic regression models were established to adjust each factor and assess the association between UA and spontaneous HT. Results A total of 769 patients were enrolled (64.6% were male patients and 3.9% had HT). After adjusting the confounders with a P < 0.05 (model A) in the univariate analysis, the ratio of UA and its interquartile range (RUI) was independently associated with spontaneous HT in male patients (OR: 1.85; 95% CI: 1.07-3.19; P = 0.028), but not in female patients (OR: 1.39; 95% CI: 0.28-6.82; P = 0.685). In models B-D, the results remain consistent with model A after the adjustment for other potential confounders. Conclusions Higher serum UA was independently associated with a higher occurrence of spontaneous HT in male patients who were admitted within 24 h after the stroke onset without receiving reperfusion therapy.
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20
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Cai J, Ye Z, Hu Y, Yang J, Wu L, Yuan F, Zhang L, Chen Q, Zhang S. Identification of immunogenic cell death-related gene classification patterns and immune infiltration characterization in ischemic stroke based on machine learning. Front Cell Neurosci 2022; 16:1094500. [PMID: 36601430 PMCID: PMC9806121 DOI: 10.3389/fncel.2022.1094500] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Accepted: 12/01/2022] [Indexed: 12/23/2022] Open
Abstract
Ischemic stroke (IS) accounts for more than 80% of strokes and is one of the leading causes of death and disability in the world. Due to the narrow time window for treatment and the frequent occurrence of severe bleeding, patients benefit less from early intravenous thrombolytic drug therapy. Therefore, there is an urgent need to explore the molecular mechanisms poststroke to drive the development of new therapeutic approaches. Immunogenic cell death (ICD) is a type of regulatory cell death (RCD) that is sufficient to activate the adaptive immune response of immunocompetent hosts. Although there is growing evidence that ICD regulation of immune responses and immune responses plays an important role in the development of IS, the role of ICD in the pathogenesis of IS has rarely been explored. In this study, we systematically evaluated ICD-related genes in IS. The expression profiles of ICD-related genes in IS and normal control samples were systematically explored. We conducted consensus clustering, immune infiltration analysis, and functional enrichment analysis of IS samples using ICD differentially expressed genes. The results showed that IS patients could be classified into two clusters and that the immune infiltration profile was altered in different clusters. In addition, we performed machine learning to screen nine signature genes that can be used to predict the occurrence of disease. We also constructed nomogram models based on the nine risk genes (CASP1, CASP8, ENTPD1, FOXP3, HSP90AA1, IFNA1, IL1R1, MYD88, and NT5E) and explored the immune infiltration correlation, gene-miRNA, and gene-TF regulatory network of the nine risk genes. Our study may provide a valuable reference for further elucidation of the pathogenesis of IS and provide directions for drug screening, personalized therapy, and immunotherapy for IS.
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Affiliation(s)
- Jiayang Cai
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Zhang Ye
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Yuanyuan Hu
- Department of Ophthalmology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Ji’an Yang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Liquan Wu
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Fanen Yuan
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Li Zhang
- Department of Anesthesiology, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Qianxue Chen
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei, China
| | - Shenqi Zhang
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan, Hubei, China,Central Laboratory, Renmin Hospital of Wuhan University, Wuhan, Hubei, China,*Correspondence: Shenqi Zhang,
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21
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Griem-Krey N, Clarkson AN, Wellendorph P. CaMKIIα as a Promising Drug Target for Ischemic Grey Matter. Brain Sci 2022; 12:1639. [PMID: 36552099 PMCID: PMC9775128 DOI: 10.3390/brainsci12121639] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2022] [Revised: 11/26/2022] [Accepted: 11/28/2022] [Indexed: 12/02/2022] Open
Abstract
Ca2+/calmodulin-dependent protein kinase II (CaMKII) is a major mediator of Ca2+-dependent signaling pathways in various cell types throughout the body. Its neuronal isoform CaMKIIα (alpha) centrally integrates physiological but also pathological glutamate signals directly downstream of glutamate receptors and has thus emerged as a target for ischemic stroke. Previous studies provided evidence for the involvement of CaMKII activity in ischemic cell death by showing that CaMKII inhibition affords substantial neuroprotection. However, broad inhibition of this central kinase is challenging because various essential physiological processes like synaptic plasticity rely on intact CaMKII regulation. Thus, specific strategies for targeting CaMKII after ischemia are warranted which would ideally only interfere with pathological activity of CaMKII. This review highlights recent advances in the understanding of how ischemia affects CaMKII and how pathospecific pharmacological targeting of CaMKII signaling could be achieved. Specifically, we discuss direct targeting of CaMKII kinase activity with peptide inhibitors versus indirect targeting of the association (hub) domain of CaMKIIα with analogues of γ-hydroxybutyrate (GHB) as a potential way to achieve more specific pharmacological modulation of CaMKII activity after ischemia.
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Affiliation(s)
- Nane Griem-Krey
- Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark
| | - Andrew N. Clarkson
- Department of Anatomy, Brain Health Research Centre and Brain Research New Zealand, University of Otago, Dunedin 9016, New Zealand
| | - Petrine Wellendorph
- Department of Drug Design and Pharmacology, University of Copenhagen, 2100 Copenhagen, Denmark
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22
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Tinchon A, Freydl E, Fitzgerald RD, Duarte C, Weber M, Calabek-Wohinz B, Waiß C, Oberndorfer S. Real-time monitoring of intravenous thrombolysis in acute ischemic stroke using rotational thromboelastometry: a feasibility pilot study. J Neurol 2022; 269:6129-6138. [PMID: 35852602 PMCID: PMC9553850 DOI: 10.1007/s00415-022-11271-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 07/03/2022] [Accepted: 07/04/2022] [Indexed: 11/03/2022]
Abstract
INTRODUCTION Rotational thromboelastometry (ROTEM) records whole blood coagulation in vitro. Data on dynamic changes of clot patterns during intravenous thrombolysis (IVT) in acute ischemic stroke is scarce. We investigated the feasibility of ROTEM as a potential point-of-care assessment tool for IVT. METHODS In this prospective pilot study, patients with acute stroke symptoms received IVT. Whole blood coagulation was tracked on the ROTEM analyzer. Blood samples were analyzed before, and then 2, 15, 30 and 60 min after beginning IVT. In vitro clots (iCLs) were described by their maximum clot firmness (MCF), the time needed to reach MCF (MCF-t), as well as the area under the curve (AR10). National Institutes of Health Stroke Scale (NIHSS) was used as early clinical outcome parameter. RESULTS We analyzed 288 iCLs from 12 patients undergoing IVT. In all iCLs, an early fibrinolysis (91% within the first 10 min) was detected during IVT. Three different curve progression patterns were observed: a low-responder pattern with a continuous clot increase, a high-responder pattern with a sustained clot decrease or total clotting suppression and an intermediate-responder pattern with alternating clot characteristics. There was a difference among these groups in early clinical outcome (AR10 and MCF each p = 0.01, MCF-t p = 0.02, Kruskal-Wallis Test). CONCLUSION The fibrinolysis patterns determined using ROTEM allow for the monitoring of IVT in patients with acute ischemic stroke. This pilot study found a correlation between the in vitro fibrinolysis patterns and early clinical outcomes. These findings support a potential for individualization of IVT in the future.
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Affiliation(s)
- Alexander Tinchon
- Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500, Krems, Austria.
- Department of Neurology, University Hospital St. Pölten, Dunant-Platz 1, 3100, St. Pölten, Austria.
- Karl Landsteiner Institute of Clinical Neurology and Neuropsychology, University Hospital St. Pölten, Dunant-Platz 1, 3100, St. Pölten, Austria.
| | - Elisabeth Freydl
- Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500, Krems, Austria
- Department of Neurology, University Hospital St. Pölten, Dunant-Platz 1, 3100, St. Pölten, Austria
- Karl Landsteiner Institute of Clinical Neurology and Neuropsychology, University Hospital St. Pölten, Dunant-Platz 1, 3100, St. Pölten, Austria
| | - Robert D Fitzgerald
- Karl Landsteiner Institute of Anesthesiology and Intensive Care Medicine, Clinic of Hietzing, Wolkersbergenstrasse 1, 1130, Vienna, Austria
| | - Christina Duarte
- Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500, Krems, Austria
- Department of Neurology, University Hospital St. Pölten, Dunant-Platz 1, 3100, St. Pölten, Austria
| | - Michael Weber
- Department of General Health Studies, Division Biostatistics and Data Science, Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500, Krems, Austria
| | - Bernadette Calabek-Wohinz
- Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500, Krems, Austria
- Department of Neurology, University Hospital St. Pölten, Dunant-Platz 1, 3100, St. Pölten, Austria
- Karl Landsteiner Institute of Clinical Neurology and Neuropsychology, University Hospital St. Pölten, Dunant-Platz 1, 3100, St. Pölten, Austria
| | - Christoph Waiß
- Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500, Krems, Austria
- Karl Landsteiner Institute of Clinical Neurology and Neuropsychology, University Hospital St. Pölten, Dunant-Platz 1, 3100, St. Pölten, Austria
| | - Stefan Oberndorfer
- Karl Landsteiner University of Health Sciences, Dr. Karl-Dorrek-Straße 30, 3500, Krems, Austria
- Department of Neurology, University Hospital St. Pölten, Dunant-Platz 1, 3100, St. Pölten, Austria
- Karl Landsteiner Institute of Clinical Neurology and Neuropsychology, University Hospital St. Pölten, Dunant-Platz 1, 3100, St. Pölten, Austria
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23
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Chen F, Zhang L, Bai X, Wang X, Geng Z. Clinical Application of Thromboelastography in Acute Ischemic Stroke. Clin Appl Thromb Hemost 2022; 28:10760296221131801. [PMID: 36285384 PMCID: PMC9608017 DOI: 10.1177/10760296221131801] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/05/2022] Open
Abstract
Acute ischemic stroke (AIS), characterized by high morbidity and mortality, has imposed a considerable burden on society. Despite rapid development in the treatment of AIS, there is still a high risk of recurrence. Furthermore, there is a time delay in waiting for the results of conventional coagulation tests in candidate patients for intravenous thrombolysis therapy. Heterogeneous responses to antiplatelet, intravascular thrombolysis, and endovascular therapies also worsen the situation. Thromboelastography (TEG), as a global and portable detection method for hemostasis, facilitates clinicians in disease monitoring, treatment evaluation, and prognosis prediction in AIS. In this narrative review, we provided a comprehensive summary of the clinical application of TEG in ischemic stroke and gave insights to further studies.
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Affiliation(s)
- Feng Chen
- Department of Neurology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Liren Zhang
- Department of Neurology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiaolin Bai
- Department of Neurology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Xiuzhe Wang
- Department of Neurology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China,Zhi Geng, 600 Yishan Road, Xuhui District, Shanghai, 200233 China.
Xiuzhe Wang, 600 Yishan Road, Xuhui District, Shanghai, 200233 China
| | - Zhi Geng
- Department of Neurology, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
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24
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Lylyk P, Cirio J, Toranzo C, Aiello E, Valencia J, Paredes-Fernández D. Mechanical thrombectomy for acute ischemic stroke due to large vessel occlusion in Argentina: An economic analysis. J Stroke Cerebrovasc Dis 2022; 31:106595. [PMID: 35716524 DOI: 10.1016/j.jstrokecerebrovasdis.2022.106595] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/03/2022] [Revised: 05/11/2022] [Accepted: 06/06/2022] [Indexed: 11/17/2022] Open
Abstract
OBJECTIVES Mechanical thrombectomy (MT) after intravenous thrombolysis (IV-tPA) is an effective and cost-saving treatment for stroke due to large vessel occlusion. However, rates of MT use are low in Argentina. This study was designed to estimate the economic value and the budget impact of incorporating MT after thrombolysis, simulating scenarios from Argentinian compulsory social health insurance (Obras Sociales) and private insurances (Empresas de Medicina Prepaga). MATERIALS AND METHODS We adapted a previously published cost-utility and budget-impact (CUA and BIA) model to the Argentinian setting. The CUA was carried out for a lifetime horizon with efficacy inputs from the SWIFT PRIME clinical trial. For seven possible health states, we identified local costs (Argentinian Pesos AR$), utility (QALY), and transition/distribution probabilities (5% discounted rate) and performed deterministic and probabilistic sensitivity analyses. The BIA was based on a six-step approach and a static model for a five-year horizon, and two scenarios (staggered growth and no growth). RESULTS Despite higher incremental procedure costs, IV-tPA and MT was dominant over IV-tPA alone (AR$1,049,062 overall savings). Cost-effectiveness remained in the deterministic sensitivity analysis (100% probability of cost-effectiveness). Increased MT procedure volume resulted in savings in years three (0.96%), four (2.6%), and five (4.4%). By year five, 1,280 patients were treated with MT (versus 480) with overall savings of 1.8% (AR$817,244,417). CONCLUSIONS MT after IV-tPA is cost-effective in Argentina. Savings offset the incremental hospitalization and long-term costs from the third year onwards. With increased, access the superior efficacy of MT mitigates future disability and comorbidity, reducing overall expenses.
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Affiliation(s)
- Pedro Lylyk
- Instituto Médico ENERI - Equipo de Neurocirugía Endovascular y Radiología Intervencionista, Buenos Aires, Argentina; Stroke Unit, Clínica La Sagrada Familia, Buenos Aires, Argentina
| | - Juan Cirio
- Instituto Médico ENERI - Equipo de Neurocirugía Endovascular y Radiología Intervencionista, Buenos Aires, Argentina; Stroke Unit, Clínica La Sagrada Familia, Buenos Aires, Argentina
| | - Carlos Toranzo
- Instituto Médico ENERI - Equipo de Neurocirugía Endovascular y Radiología Intervencionista, Buenos Aires, Argentina; Stroke Unit, Clínica La Sagrada Familia, Buenos Aires, Argentina
| | | | - Juan Valencia
- Health Economics, Policy and Reimbursement, Medtronic Latin-America, USA
| | - Daniela Paredes-Fernández
- Health Economics, Policy and Reimbursement, Medtronic South Latin-America, 532 Rosario Norte Street, Las Condes, Chile.
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25
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Branyan TE, Selvamani A, Park MJ, Korula KE, Kosel KF, Srinivasan R, Sohrabji F. Functional Assessment of Stroke-Induced Regulation of miR-20a-3p and Its Role as a Neuroprotectant. Transl Stroke Res 2022; 13:432-448. [PMID: 34570349 PMCID: PMC9046320 DOI: 10.1007/s12975-021-00945-x] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2021] [Revised: 08/12/2021] [Accepted: 09/07/2021] [Indexed: 12/14/2022]
Abstract
MicroRNAs have gained popularity as a potential treatment for many diseases, including stroke. This study identifies and characterizes a specific member of the miR-17-92 cluster, miR-20a-3p, as a possible stroke therapeutic. A comprehensive microRNA screening showed that miR-20a-3p was significantly upregulated in astrocytes of adult female rats, which typically have better stroke outcomes, while it was profoundly downregulated in astrocytes of middle-aged females and adult and middle-aged males, groups that typically have more severe stroke outcomes. Assays using primary human astrocytes and neurons show that miR-20a-3p treatment alters mitochondrial dynamics in both cell types. To assess whether stroke outcomes could be improved by elevating astrocytic miR-20a-3p, we created a tetracycline (Tet)-induced recombinant adeno-associated virus (rAAV) construct where miR-20a-3p was located downstream a glial fibrillary acidic protein promoter. Treatment with doxycycline induced miR-20-3p expression in astrocytes, reducing mortality and modestly improving sensory motor behavior. A second Tet-induced rAAV construct was created in which miR-20a-3p was located downstream of a neuron-specific enolase (NSE) promoter. These experiments demonstrate that neuronal expression of miR-20a-3p is vastly more neuroprotective than astrocytic expression, with animals receiving the miR-20a-3p vector showing reduced infarction and sensory motor improvement. Intravenous injections, which are a therapeutically tractable treatment route, with miR-20a-3p mimic 4 h after middle cerebral artery occlusion (MCAo) significantly improved stroke outcomes including infarct volume and sensory motor performance. Improvement was not observed when miR-20a-3p was given immediately or 24 h after MCAo, identifying a unique delayed therapeutic window. Overall, this study identifies a novel neuroprotective microRNA and characterizes several key pathways by which it can improve stroke outcomes.
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Affiliation(s)
- Taylor E Branyan
- Women's Health in Neuroscience Program, Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center College of Medicine, Bryan, TX, 77807, USA
- Texas A&M Institute for Neuroscience, College Station, TX, 77840, USA
| | - Amutha Selvamani
- Women's Health in Neuroscience Program, Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center College of Medicine, Bryan, TX, 77807, USA
| | - Min Jung Park
- Women's Health in Neuroscience Program, Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center College of Medicine, Bryan, TX, 77807, USA
| | - Kriti E Korula
- Women's Health in Neuroscience Program, Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center College of Medicine, Bryan, TX, 77807, USA
| | - Kelby F Kosel
- Women's Health in Neuroscience Program, Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center College of Medicine, Bryan, TX, 77807, USA
| | - Rahul Srinivasan
- Women's Health in Neuroscience Program, Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center College of Medicine, Bryan, TX, 77807, USA
- Texas A&M Institute for Neuroscience, College Station, TX, 77840, USA
| | - Farida Sohrabji
- Women's Health in Neuroscience Program, Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center College of Medicine, Bryan, TX, 77807, USA.
- Texas A&M Institute for Neuroscience, College Station, TX, 77840, USA.
- Department of Neuroscience and Experimental Therapeutics, Texas A&M Health Science Center College of Medicine, 8447 Riverside Pkwy, Bryan, TX, 77807, USA.
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26
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Zhou Y, Zhang Y, Cui M, Zhang Y, Shang X. Prognostic value of the systemic inflammation response index in patients with acute ischemic stroke. Brain Behav 2022; 12:e2619. [PMID: 35588444 PMCID: PMC9226852 DOI: 10.1002/brb3.2619] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/19/2021] [Revised: 04/21/2022] [Accepted: 04/27/2022] [Indexed: 11/12/2022] Open
Abstract
OBJECTIVES Inflammation plays an essential role in acute ischemic stroke (AIS). Recent studies have recognized the systemic inflammation response index (SIRI) as a useful index to indicate inflammation status and predict the prognosis of multiple diseases. However, the relationship between SIRI and AIS prognosis is unclear. Our study is aimed to investigate the association between SIRI and the prognosis of AIS. METHODS Our study prospectively recruited 287 consecutive patients with first-ever stroke within 72 h after stroke. Demographic and clinical information was collected at baseline. The functional prognosis was assessed 3 months after AIS using the modified Rankin Scale (mRS). A poor outcome was defined as mRS > 2. SIRI was calculated as neutrophil × monocyte/lymphocyte count. Univariate and multivariate analyses were introduced to identify the association between SIRI and AIS prognosis. Receiver operating characteristic curve and reclassification analyses were used to evaluate the predictive value of SIRI for AIS prognosis. RESULTS The patients with poor prognosis account for 27.5% of all participants. After fully adjusting for all covariates, each standard deviation increment of SIRI caused 58.9% additional risk for poor prognosis after AIS. When dividing SIRI into quartiles, the fourth quartile had a 6.152 times risk than the first quartile. Moreover, after adding SIRI into established clinical risk factors, AUC showed a significant improvement (0.829 vs. 0.790, p for comparison = .016). Consistently, category-free net reclassification index (NRI, 0.761, 95% CI: 0.517-1.004, p < .001) and integrated discrimination index (IDI, 0.093, 95% CI: 0.0512-0.134, p < .001) confirmed the improvement by SIRI to predict poor prognosis of AIS, CONCLUSION: SIRI is an independent prognostic indicator for AIS. Elevated SIRI is associated with poor functional outcome of AIS. Our findings suggest the usefulness of SIRI to refine the risk stratification of unfavorable prognosis of AIS.
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Affiliation(s)
- Yaping Zhou
- Department of Neurology, The First Hospital of China Medical University, Shenyang, China.,Department of Rehabilitation Medicine, Affiliated Tenth People's Hospital of Tongji University, Shanghai Tenth People's Hospital, Shanghai, China
| | - Yidi Zhang
- Department of Neurology, The First Hospital of China Medical University, Shenyang, China
| | - Mingming Cui
- Department of Neurology, The First Hospital of China Medical University, Shenyang, China
| | - Yuming Zhang
- Department of Neurology, The First Hospital of China Medical University, Shenyang, China
| | - Xiuli Shang
- Department of Neurology, The First Hospital of China Medical University, Shenyang, China
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27
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Liu J, Wang Y, Li J, Zhang S, Wu Q, Wei C, Cui T, Wu B, Willey JZ, Liu M. Treatment and Outcomes of Thrombolysis Related Hemorrhagic Transformation: A Multi-Center Study in China. Front Aging Neurosci 2022; 14:847648. [PMID: 35462687 PMCID: PMC9021791 DOI: 10.3389/fnagi.2022.847648] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 03/15/2022] [Indexed: 12/03/2022] Open
Abstract
Objective To investigate the current management of thrombolysis related hemorrhagic transformation (HT) in real-world practice, and whether these treatments would reduce the risk of 3-month death and hematoma expansion after HT. Methods A multicenter retrospective study was performed in three comprehensive stroke centers in China (West China Hospital, The First People’s Hospital of Ziyang, and Mianyang Central Hospital) between January 1st 2012 and December 31th 2020. Participants were patients diagnosed with HT after intravenous thrombolytics on brain computed tomography (CT) within 36 h after stroke onset. The treatment after thrombolysis related HT included aggressive therapy (procoagulant, neurosurgical treatment) and dehydration therapy (mannitol or glycerin and fructose). The primary clinical outcome was 3-month death. The primary radiographic outcome was hematoma expansion, defined as a 33% increase in the hematoma volume using the (A × B × C)/2 method on follow-up imaging. Results Of 538 patients with ischemic stroke receiving thrombolysis included during the study period, 94 patients (17.4%) were diagnosed with HT, 50% (47/94) of whom were symptomatic HT. The 3-month death was 31.5% (29/92), with two patients having been lost to follow up. A total of 68 patients (72.3%) had follow-up brain CT scans after HT detection for evaluating hematoma expansion, of whom 14.7% (10/68) had hematoma expansion. Among the 10 patients with hematoma expansion, 7 patients were from symptomatic HT group, and 3 patients were from the asymptomatic hematoma group. In regard to escalation in therapy, six patients received neurosurgical treatment and three patients had a fresh frozen plasma infusion. In addition, dehydration therapy was the most common management after HT diagnosis [87.2% (82 of 94)]. In the multivariable models, refusing any treatment after HT diagnosis was the sole factor associated with increased 3-month death (odds ratio, 13.6; 95% CI, 3.98–56.9) and hematoma expansion risk (odds ratio, 8.54; 95% CI, 1.33–70.1). In regard to the effects of aggressive therapy, a non-significant association of receiving hemostatic/neurosurgery therapy with a lower 3-month death and hematoma expansion risk was observed (all P > 0.05). Conclusion Refusing any treatment after HT detection had a significant trend of increasing 3-month death and hematoma expansion risk after HT. Our finding of hematoma expansion among patients with asymptomatic HT in non-western populations suggests an opportunity for intervention. Very few patients after thrombolysis related HT diagnosis received procoagulant or neurosurgical therapies. Large multicenter studies enrolling diverse populations are needed to examine the efficacy of these therapies on different HT subtypes.
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Affiliation(s)
- Junfeng Liu
- Department of Neurology, Center of Cerebrovascular Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Yanan Wang
- Department of Neurology, Center of Cerebrovascular Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Jing Li
- Department of Neurology, The First People’s Hospital of Ziyang, Ziyang, China
| | - Shanshan Zhang
- Department of Neurology, Mianyang Central Hospital, Mianyang, China
| | - Qian Wu
- Department of Neurology, Center of Cerebrovascular Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Chenchen Wei
- Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Ting Cui
- Department of Neurology, Center of Cerebrovascular Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Bo Wu
- Department of Neurology, Center of Cerebrovascular Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Joshua Z. Willey
- Department of Neurology, Columbia University Irving Medical Center, New York, NY, United States
| | - Ming Liu
- Department of Neurology, Center of Cerebrovascular Diseases, West China Hospital, Sichuan University, Chengdu, China
- *Correspondence: Ming Liu,
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De Meyer SF, Langhauser F, Haupeltshofer S, Kleinschnitz C, Casas AI. Thromboinflammation in Brain Ischemia: Recent Updates and Future Perspectives. Stroke 2022; 53:1487-1499. [PMID: 35360931 DOI: 10.1161/strokeaha.122.038733] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
Despite decades of promising preclinical validation and clinical translation, ischemic stroke still remains as one of the leading causes of death and disability worldwide. Within its complex pathophysiological signatures, thrombosis and inflammation, that is, thromboinflammation, are highly interconnected processes leading to cerebral vessel occlusion, inflammatory responses, and severe neuronal damage following the ischemic event. Hence, we here review the most recent updates on thromboinflammatory-dependent mediators relevant after stroke focusing on recent discoveries on platelet modulation, a potential regulation of the innate and adaptive immune system in thromboinflammation, utterly providing a thorough up-to-date overview of all therapeutic approaches currently undergoing clinical trial.
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Affiliation(s)
- Simon F De Meyer
- Laboratory for Thrombosis Research, KU Leuven Campus Kulak Kortrijk, Belgium (S.F.D.M.)
| | - Friederike Langhauser
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, Germany (F.L., S.H., C.K., A.I.C.)
| | - Steffen Haupeltshofer
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, Germany (F.L., S.H., C.K., A.I.C.)
| | - Christoph Kleinschnitz
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, Germany (F.L., S.H., C.K., A.I.C.)
| | - Ana I Casas
- Department of Neurology and Center for Translational Neuro- and Behavioral Sciences (C-TNBS), University Hospital Essen, Germany (F.L., S.H., C.K., A.I.C.).,Department of Pharmacology and Personalised Medicine, Faculty of Health, Medicine, and Life Sciences, Maastricht University, the Netherlands (A.I.C.)
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Liu J, Tao W, Wang Z, Chen X, Wu B, Liu M. Radiomics-based prediction of hemorrhage expansion among patients with thrombolysis/thrombectomy related-hemorrhagic transformation using machine learning. Ther Adv Neurol Disord 2022; 14:17562864211060029. [PMID: 35173809 PMCID: PMC8842178 DOI: 10.1177/17562864211060029] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2021] [Accepted: 10/28/2021] [Indexed: 02/05/2023] Open
Abstract
Introduction: Patients with hemorrhagic transformation (HT) were reported to have
hemorrhage expansion. However, identification these patients with high risk
of hemorrhage expansion has not been well studied. Objectives: We aimed to develop a radiomic score to predict hemorrhage expansion after HT
among patients treated with thrombolysis/thrombectomy during acute phase of
ischemic stroke. Methods: A total of 104 patients with HT after reperfusion treatment from the West
China hospital, Sichuan University, were retrospectively included in this
study between 1 January 2012 and 31 December 2020. The preprocessed initial
non-contrast-enhanced computed tomography (NECT) imaging brain images were
used for radiomic feature extraction. A synthetic minority oversampling
technique (SMOTE) was applied to the original data set. The after-SMOTE data
set was randomly split into training and testing cohorts with an 8:2 ratio
by a stratified random sampling method. The least absolute shrinkage and
selection operator (LASSO) regression were applied to identify candidate
radiomic features and construct the radiomic score. The performance of the
score was evaluated by receiver operating characteristic (ROC) analysis and
a calibration curve. Decision curve analysis (DCA) was performed to evaluate
the clinical value of the model. Results: Among the 104 patients, 17 patients were identified with hemorrhage expansion
after HT detection. A total of 154 candidate predictors were extracted from
NECT images and five optimal features were ultimately included in the
development of the radiomic score by using logistic regression
machine-learning approach. The radiomic score showed good performance with
high area under the curves in both the training data set (0.91, sensitivity:
0.83; specificity: 0.89), test data set (0.87, sensitivity: 0.60;
specificity: 0.85), and original data set (0.82, sensitivity: 0.77;
specificity: 0.78). The calibration curve and DCA also indicated that there
was a high accuracy and clinical usefulness of the radiomic score for
hemorrhage expansion prediction after HT. Conclusions: The currently established NECT-based radiomic score is valuable in predicting
hemorrhage expansion after HT among patients treated with reperfusion
treatment after ischemic stroke, which may aid clinicians in determining
patients with HT who are most likely to benefit from anti-expansion
treatment.
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Affiliation(s)
- Junfeng Liu
- Center of Cerebrovascular Diseases, Department of Neurology, West China Hospital, Sichuan University, Chengdu, China
| | - Wendan Tao
- Center of Cerebrovascular Diseases, Department of Neurology, West China Hospital, Sichuan University, Chengdu, China
| | - Zhetao Wang
- Department of Radiology, West China Hospital, Sichuan University, Chengdu, China
| | - Xinyue Chen
- CT collaboration, Siemens Healthineers,China
| | - Bo Wu
- Center of Cerebrovascular Diseases, Department of Neurology, West China Hospital, Sichuan University, Chengdu, China
| | - Ming Liu
- Center of Cerebrovascular Diseases, Department of Neurology, West China Hospital, Sichuan University, No. 37 Guo Xue Xiang, Chengdu 610041, China
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El Khoury C, Aboa‐Eboule C, Fraticelli L, Claustre C, Bischoff M, Blanc‐Lasserre K, Buisson M, Cakmak S, Cho T, Ferroud‐Plattet B, Guerrier O, Philippeau F, Serre P, Mechtouff L, Nighoghossian N, Ruzteroltz T, Vallet A, Ong E, Derex L, RESCUE‐RESUVal group. Temporal trends in reperfusion therapy for patients with acute ischemic stroke. J Am Coll Emerg Physicians Open 2022; 3:e12654. [PMID: 35079735 PMCID: PMC8769069 DOI: 10.1002/emp2.12654] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Revised: 11/25/2021] [Accepted: 12/28/2021] [Indexed: 11/25/2022] Open
Abstract
OBJECTIVES To analyze the temporal trends in thrombolysis rates after implementation of a regional emergency network for acute ischemic stroke (AIS). METHODS We conducted a retrospective study based on a prospective multicenter observational registry. The AIS benefited from reperfusion therapy included in 1 of the 5 primary stroke units or 1 comprehensive stroke center and 37 emergency departments were included using a standardized case report form. The population covers 3 million inhabitants. RESULTS In total, 32,319 AIS was reported in the regional hospitalization database of which 2215 thrombolyzed AIS patients were included in the registry and enrolled in this study. The annual incidence rate of thrombolysis continuously and significantly increased from 2010 to 2018 (10.2% to 17.3%, P-trend = 0.0013). The follow-up of the onset-to-door and the door-to-needle delays over the study period showed stable rates, as did the all-cause mortality rate at 3-months (13.2%). CONCLUSION Although access to stroke thrombolysis has increased linearly since 2010, the 3-month functional outcome has not evolved as favorably. Further efforts must focus on reducing hospital delays.
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Affiliation(s)
- Carlos El Khoury
- Auvergne Rhône‐Alpes Agency for HealthRESCUe NetworkLyonFrance
- Clinical Research Unit and Emergency DepartmentMédipôle Hôpital MutualisteLyonFrance
| | | | - Laurie Fraticelli
- Auvergne Rhône‐Alpes Agency for HealthRESCUe NetworkLyonFrance
- Health, Systemic, ProcessEA 4129 Research UnitUniversity Claude Bernard Lyon 1LyonFrance
| | | | - Magali Bischoff
- Auvergne Rhône‐Alpes Agency for HealthRESCUe NetworkLyonFrance
| | | | - Marielle Buisson
- Hospices Civils de LyonCardiologic Hospital Louis PradelLyonFrance
| | | | - Tee‐hi Cho
- Stroke UnitPierre Wertheimer HospitalLyonFrance
| | | | | | | | - Patrice Serre
- Auvergne Rhône‐Alpes Agency for HealthRESCUe NetworkLyonFrance
- Department of Emergency MedicineBourg‐en‐Bresse HospitalBourg‐en‐BresseFrance
| | - Laura Mechtouff
- Auvergne Rhône‐Alpes Agency for HealthRESCUe NetworkLyonFrance
| | | | | | | | - Elodie Ong
- Auvergne Rhône‐Alpes Agency for HealthRESCUe NetworkLyonFrance
| | - Laurent Derex
- Auvergne Rhône‐Alpes Agency for HealthRESCUe NetworkLyonFrance
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Liu R, Song P, Gu X, Liang W, Sun W, Hua Q, Zhang Y, Qiu Z. Comprehensive Landscape of Immune Infiltration and Aberrant Pathway Activation in Ischemic Stroke. Front Immunol 2022; 12:766724. [PMID: 35140708 PMCID: PMC8818702 DOI: 10.3389/fimmu.2021.766724] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2021] [Accepted: 12/16/2021] [Indexed: 11/24/2022] Open
Abstract
Ischemic stroke (IS) is a multifactorial disease caused by the interaction of multiple environmental and genetic risk factors, and it is the most common cause of disability. The immune microenvironment and inflammatory response participate in the whole process of IS occurrence and development. Therefore, the rational use of relevant markers or characteristic pathways in the immune microenvironment will become one of the important therapeutic strategies for the treatment of IS. We collected peripheral blood samples from 10 patients diagnosed with IS at the First Affiliated Hospital of Gannan Medical University and First Affiliated Hospital, Jinan" University, and from 10 normal people. The GSE16561 dataset was downloaded from the Gene Expression Omnibus (GEO) database. xCell, gene set enrichment analysis (GSEA), single-sample GSEA (ssGSEA) and immune-related gene analysis were used to evaluate the differences in the immune microenvironment and characteristic pathways between the IS and control groups of the two datasets. xCell analysis showed that the IS-24h group had significantly reduced central memory CD8+ T cell, effector memory CD8+ T cell, B cell and Th1 cell scores and significantly increased M1 macrophage and macrophage scores. GSEA showed that the IS-24h group had significantly increased inflammation-related pathway activity(myeloid leukocyte activation, positive regulation of tumor necrosis factor biosynthetic process, myeloid leukocyte migration and leukocyte chemotaxis), platelet-related pathway activity(platelet activation, signaling and aggregation; protein polymerization; platelet degranulation; cell-cell contact zone) and pathology-related pathway activity (ERBB signaling pathway, positive regulation of ERK1 and ERK2 cascade, vascular endothelial growth factor receptor signaling pathway, and regulation of MAP kinase activity). Immune-related signature analysis showed that the macrophage signature, antigen presentation-related signature, cytotoxicity-related signature, B cell-related signature and inflammation-related signature were significantly lower in the IS-24h group than in the control group. In this study, we found that there were significant differences in the immune microenvironment between the peripheral blood of IS patients and control patients, as shown by the IS group having significantly reduced CD8+ Tcm, CD8+ Tem, B cell and Th1 cell scores and significantly increased macrophage and M1 macrophage scores. Additionally, inflammation-related, pathological, and platelet-related pathway activities were significantly higher in the IS group than in the control group.
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Affiliation(s)
- Rongrong Liu
- Department of Neurology and Stroke Center, The First Affiliated Hospital, Jinan University, Guangzhou, China
- Department of Oncology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Department of Neurology, Ganzhou People’s Hospital, Ganzhou, China
- Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
- Clinical Neuroscience Institute, Jinan University, Guangzhou, China
| | - Pingping Song
- Department of Neurology and Stroke Center, The First Affiliated Hospital, Jinan University, Guangzhou, China
- Clinical Neuroscience Institute, Jinan University, Guangzhou, China
| | - Xunhu Gu
- Department of Neurology, The Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Weidong Liang
- Department of Oncology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- Department of Anesthesiology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Wei Sun
- Department of Neurology and Stroke Center, The First Affiliated Hospital, Jinan University, Guangzhou, China
- Clinical Neuroscience Institute, Jinan University, Guangzhou, China
| | - Qian Hua
- Department of Oncology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
| | - Yusheng Zhang
- Department of Neurology and Stroke Center, The First Affiliated Hospital, Jinan University, Guangzhou, China
- Clinical Neuroscience Institute, Jinan University, Guangzhou, China
- *Correspondence: Yusheng Zhang, ; Zhengang Qiu,
| | - Zhengang Qiu
- Department of Oncology, The First Affiliated Hospital of Gannan Medical University, Ganzhou, China
- *Correspondence: Yusheng Zhang, ; Zhengang Qiu,
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Sanders CB, Knisely K, Rathfoot C, Edrissi C, Nathaniel T. Acute Ischemic Stroke and Heart Failure: Stroke Risk Factors Associated with Exclusion from Thrombolytic Therapy. Clin Appl Thromb Hemost 2022; 28:10760296221116347. [PMID: 36278505 PMCID: PMC9596934 DOI: 10.1177/10760296221116347] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2022] [Revised: 06/22/2022] [Accepted: 07/11/2022] [Indexed: 11/05/2022] Open
Abstract
Objective: Acute ischemic stroke (AIS) patients with congestive heart failure (HF) that present with various risk factors are less likely to receive recombinant tissue plasminogen activator (rtPA). The risk factors associated with excluding AIS patients with congestive heart failure (AIS-HF) from rtPA therapy have not been fully established. Methods: Retrospective data for 5469 AIS patients comprised of 590 AIS patients with HF and 4879 AIS patients without HF were collected from a regional stroke registry between January 2010 and June 2016. Baseline risk factors were analyzed using logistic regression analysis to determine the risk factors associated with rtPA exclusion in AIS-HF patients. Results: In the adjusted analysis, AIS-HF patients that that did not receive rtPA were more likely to be older (OR = 0.982, 95% CI, 0.966-1, P = .020), presented with coronary artery disease (OR = 0.618, 95% CI, 0.391-0.98, P = .040), and with an elevated INR (OR = 0.326, 95% CI, 0.129-0.82, P = .018). AIS-HF patients that were included for rtPA therapy were more likely to show improvement in ambulatory status (OR = 1.69, 95% CI, 1.058-2.7, P = .028). The discriminating power of the model was strong with an area under the curve (AUROC) = 0.668 (95% CI, 0.611-0.724, P < .001). Conclusion: Our study establishes the associations between stroke risk factors and exclusion from rtPA therapy. This finding suggests the need to develop management strategies for older HF patients with carotid artery disease and an elevated INR to improve their eligibility for rtPA treatment following an acute ischemic stroke.
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Affiliation(s)
| | - Krista Knisely
- School of Medicine Greenville, University of South Carolina, Greenville, SC, USA
| | - Chase Rathfoot
- School of Medicine Greenville, University of South Carolina, Greenville, SC, USA
| | - Camron Edrissi
- School of Medicine Greenville, University of South Carolina, Greenville, SC, USA
| | - Thomas Nathaniel
- School of Medicine Greenville, University of South Carolina, Greenville, SC, USA
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Dose-Response Relationship and Threshold Drug Dosage Identification for a Novel Hybrid Mechanical-Thrombolytic System with an Ultra-Low Dose Patch. Cell Mol Bioeng 2021; 14:627-637. [PMID: 34900015 DOI: 10.1007/s12195-021-00683-y] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2020] [Accepted: 05/31/2021] [Indexed: 10/21/2022] Open
Abstract
Introduction Ischemic stroke treatment has advanced in the last two decades and intravenous thrombolysis is now considered the standard of care for selected patients. Recanalization can also be achieved by mechanical endovascular treatment for patients with large vessel occlusions. Complicating treatment-related symptomatic intracerebral hemorrhage and prolonged needle-to-recanalization times have been identified as major determinants of poor three-month functional outcomes. A hybrid mechanical-thrombolytic system with a patch imbued with an ultra-low dose of thrombolytic agents loaded onto a stent-retriever has been developed. Methods In this study, the in situ dose-response relationship of the thrombolytic patch imbued with up to 1000 IU of urokinase plasminogen activator (uPA) was quantified using Raman spectroscopy. Results Thrombi of up to 400 μm thickness dissolved within 15 min when patches imbued with < 1% of the conventional thrombolysis therapy dosage were applied. The results demonstrated that low-dose thrombolytic patches can dissolve normal clots compressed in the blood vessel in a short time. 500 IU is the threshold uPA dosage in the thrombolytic patch that most effectively dissolves the clots. Conclusion This study suggests that a novel endovascular stent-retriever loaded with an ultra-low drug dose fibrinolytic patch may be a suitable treatment for patients who are ineligible for conventional thrombolytic therapy.
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Yang Y, Xie D, Zhang Y. Increased Platelet-to-Lymphocyte Ratio is an Independent Predictor of Hemorrhagic Transformation and In-Hospital Mortality Among Acute Ischemic Stroke with Large-Artery Atherosclerosis Patients. Int J Gen Med 2021; 14:7545-7555. [PMID: 34754227 PMCID: PMC8570380 DOI: 10.2147/ijgm.s329398] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2021] [Accepted: 10/01/2021] [Indexed: 12/28/2022] Open
Abstract
Background The platelet-to-lymphocyte ratio (PLR) is an inflammation marker of acute ischemic stroke, but its significance in patients with hemorrhage transformation (HT) after acute ischemic stroke with large-artery atherosclerosis (AIS-LAA) is unclear, and we also identified the relationship between PLR and in-hospital mortality of HT after AIS-LAA. Methods This was a retrospective analysis of patients with AIS-LAA. The PLR was calculated according to platelet and lymphocyte counts on admission. HT was defined on follow-up magnetic resonance imaging or computed tomography when neurologic deterioration worsened during hospitalization. The univariate analysis and multivariate logistic regression were performed to assess the association of PLR, HT and in-hospital mortality of HT after AIS-LAA. Results We included 328 Chinese AIS-LAA patients (mean age 67.2±11.1 years; 70.4% male). HT occurred in 38 patients (11.6%). After multivariate regression analyses, NRL (odds ratio [OR] 1.354, 95% confidence interval [CI] 1.176–1.559, P<0.001) and PLR (odds ratio [OR] 3.869, 95% confidence interval [CI] 2.233–5.702, P<0.001) were independently associated with HT after AIS-LAA. The area under the ROC curve (AUC) value of PLR (0.72, 95% CI (0.64–0.80), P<0.001) tested a greater discriminatory ability compared with neutrophil-lymphocyte ratio (NLR) (0.67, 95% CI (0.58–0.76), P<0.001). Meanwhile, PLR was found to be significantly related to HT after AIS-LAA, including in subtypes of artery-to-artery embolization (aOR 1.699, 95% CI 1.298–3.215, P<0.001), in-situ thrombosis (aOR4.499, 95% CI 1.344–9.054, P<0.001) and branch atheromatous disease (aOR3.239, 95% CI 1.098–8.354, P<0.001). Increased PLR predicts high in-hospital mortality of HT after AIS-LAA (OR 1.041, 95% CI (1.006–1.077), P=0.020; aOR 1.053, 95% CI (1.004–1.104), P=0.034). Conclusion High PLR is associated with greater risk of HT in AIS-LAA patients, including in artery-to-artery embolization, in-situ thrombosis and branch atheromatous disease. Meanwhile, increased PLR predicts high in-hospital mortality of HT after AIS-LAA.
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Affiliation(s)
- Yi Yang
- Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Dan Xie
- Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China
| | - Yongbo Zhang
- Department of Neurology, Beijing Friendship Hospital, Capital Medical University, Beijing, People's Republic of China
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Yuan J, Li L, Yang Q, Ran H, Wang J, Hu K, Pu W, Huang J, Wen L, Zhou L, Jiang Y, Xiong X, Zhang J, Zhou Z. Targeted Treatment of Ischemic Stroke by Bioactive Nanoparticle-Derived Reactive Oxygen Species Responsive and Inflammation-Resolving Nanotherapies. ACS NANO 2021; 15:16076-16094. [PMID: 34606239 DOI: 10.1021/acsnano.1c04753] [Citation(s) in RCA: 78] [Impact Index Per Article: 19.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/13/2023]
Abstract
Stroke is a primary cause of death and disability worldwide, while effective and safe drugs remain to be developed for its clinical treatment. Herein, we report bioactive nanoparticle-derived multifunctional nanotherapies for ischemic stroke, which are engineered from a pharmacologically active oligosaccharide material (termed as TPCD) prepared by covalently conjugating a radical-scavenging compound (Tempol) and a hydrogen-peroxide-eliminating moiety of phenylboronic acid pinacol ester (PBAP) on β-cyclodextrin. Of note, combined functional moieties of Tempol and PBAP on β-cyclodextrin contribute to antioxidative and anti-inflammatory activities of TPCD. Cellularly, TPCD nanoparticles (i.e., TPCD NPs) reduced oxygen-glucose deprivation-induced overproduction of oxidative mediators, increased antioxidant enzyme expression, and suppressed microglial-mediated inflammation, thereby inhibiting neuronal apoptosis. After intravenous (i.v.) delivery, TPCD NPs could efficiently accumulate at the cerebral ischemic injury site of mice with middle cerebral artery occlusion (MCAO), showing considerable distribution in cells relevant to the pathogenesis of stroke. Therapeutically, TPCD NPs significantly decreased infarct volume and accelerated recovery of neurological function in MCAO mice. Mechanistically, efficacy of TPCD NPs is achieved by its antioxidative, anti-inflammatory, and antiapoptotic effects. Furthermore, TPCD NPs can function as a reactive oxygen species labile nanovehicle to efficiently load and triggerably release an inflammation-resolving peptide Ac2-26, giving rise to an inflammation-resolving nanotherapy (i.e., ATPCD NP). Compared to TPCD NP, ATPCD NP demonstrated notably enhanced in vivo efficacies, largely resulting from its additional inflammation-resolving activity. Consequently, TPCD NP-derived nanomedicines can be further developed as promising targeted therapies for stroke and other inflammation-associated cerebrovascular diseases.
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Affiliation(s)
- Jichao Yuan
- Department of Neurology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Lanlan Li
- Department of Pharmaceutics, College of Pharmacy, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Qinghua Yang
- Department of Pharmaceutics, College of Pharmacy, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Hong Ran
- Department of Neurology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Jie Wang
- Department of Neurology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Kaiyao Hu
- Department of Pharmaceutics, College of Pharmacy, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Wendan Pu
- Department of Pharmaceutics, College of Pharmacy, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Jialu Huang
- Department of Neurology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Lan Wen
- Department of Neurology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Linke Zhou
- Department of Neurology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Ying Jiang
- Department of Neurology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Xiaoxing Xiong
- Department of Neurosurgery, Renmin Hospital of Wuhan University, Wuhan 430060, China
| | - Jianxiang Zhang
- Department of Pharmaceutics, College of Pharmacy, Third Military Medical University (Army Medical University), Chongqing 400038, China
- State Key Laboratory of Trauma, Burn and Combined Injury, Third Military Medical University (Army Medical University), Chongqing 400038, China
| | - Zhenhua Zhou
- Department of Neurology, Southwest Hospital, Third Military Medical University (Army Medical University), Chongqing 400038, China
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Rech MA, Donahey E, DeMott JM, Coles LL, Peksa GD. The impact of antihypertensive use in the treatment of acute ischemic stroke in patients receiving alteplase. Am J Emerg Med 2021; 50:93-96. [PMID: 34329955 DOI: 10.1016/j.ajem.2021.07.037] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2021] [Revised: 06/30/2021] [Accepted: 07/09/2021] [Indexed: 10/20/2022] Open
Abstract
BACKGROUND Treatment of acute ischemic stroke (AIS) with intravenous alteplase within 4.5 h of symptom onset is associated with neurologic improvement. High baseline blood pressure (BP) and BP variability during the first 24 h of AIS is associated with increased early adverse events and death. The purpose of this study is to characterize the incidence of poor neurologic outcome in patients treated with alteplase for AIS who received antihypertensive medications prior to and within the first 24 h following alteplase administration compared with patients who did not. METHODS This was a multicenter, retrospective cohort of patients >18 years diagnosed with AIS from January 1, 2011 through December 31, 2015 who received one or more antihypertensive medication in the first 24 h of AIS in patients receiving alteplase compared to controls. The primary endpoint was poor neurologic outcome at 90 days, according to modified Rankin Scale ≥3. Univariate analysis was conducted using Chi-square, Fisher's exact test, or Mann-Whitney U test. Multivariable logistic regression was conducted to determine independent predictors of poor outcome. RESULTS Of the 587 patients evaluated, 351 (59.7%) were included, of which 127 (36.2%) received antihypertensive(s). More patients in the antihypertensive treatment group had a history of hypertension (88.2% vs. 69.6%, p < 0.01), diabetes (37% vs. 25.5%, p = 0.03) and chronic kidney disease (19.7% vs. 8.5%, p < 0.01). Intravenous push labetalol was most commonly administered (81.2%), followed by nicardipine (44.1%), and hydralazine (22%). More patients in the antihypertensive treatment group experienced poor neurologic outcome at 90 days (53.5% vs. 38.8%, p < 0.01), however, this finding was not observed after multivariable logistic regression. CONCLUSION Antihypertensive treatment in the first 24 h of AIS was associated with poor neurologic outcomes at 90 days. However, after controlling for other clinical factors in a multivariable logistic regression, this association was no longer observed.
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Affiliation(s)
- Megan A Rech
- Department of Emergency Medicine, Stritch School of Medicine, Loyola University Chicago, 2160 S 1st Ave, Maywood, IL 60153, United States of America.
| | - Elisabeth Donahey
- Department of Pharmacy, Loyola University Medical Center, 2160 S 1st Ave, Maywood, IL 60153, United States of America.
| | - Joshua M DeMott
- Rush University Medical Center, Chicago IL, 1653 W Congress Pkwy, Chicago, IL 60612, United States of America.
| | - Laura L Coles
- Novant Health Forsyth Medical Center, 3333 Silas Creek Pkwy, Winston-Salem, NC 27103, United States of America
| | - Gary D Peksa
- Rush University Medical Center, Chicago IL, 1653 W Congress Pkwy, Chicago, IL 60612, United States of America.
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Four Decades of Ischemic Penumbra and Its Implication for Ischemic Stroke. Transl Stroke Res 2021; 12:937-945. [PMID: 34224106 DOI: 10.1007/s12975-021-00916-2] [Citation(s) in RCA: 50] [Impact Index Per Article: 12.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 05/10/2021] [Accepted: 05/12/2021] [Indexed: 12/15/2022]
Abstract
The ischemic penumbra defined four decades ago has been the main battleground of ischemic stroke. The evolving ischemic penumbra concept has been providing insight for the development of vascular and cellular approaches as well as diagnostic tools for the treatment of ischemic stroke. rt-PA thrombolytic therapy to prevent the transition of ischemic penumbra to core has been approved for acute ischemic stroke within 3 h and was later recommended to extend to 4.5 h after symptom onset. Mechanical thrombectomy was introduced for the treatment of acute ischemic stroke with a therapeutic window of up to 24 h after stroke onset. Multiple modalities brain imaging techniques have been developed that provide guidance to define ischemic penumbra for reperfusion therapy in clinical practice. Cellular and molecular dissection of ischemic penumbra has been providing targets for the development of neuroprotective therapy for ischemic stroke. However, the dynamic nature of ischemic penumbra implicates that infarct core eventually expands into penumbra over time without reperfusion, dictating relative short therapeutic windows and limiting the impact of current reperfusion intervention. Entering the 5th decade since the introduction, ischemic penumbra remains the main focus of ischemic stroke research and clinical practice. In this review, we summarized the evolving ischemic penumbra concept and its implication in the development of vascular and cellular interventions as well as diagnostic tools for acute ischemic stroke. In addition, we discussed future perspectives on expansion of the campaign beyond ischemic penumbra to develop treatment for ischemic stroke.
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Liu J, Wang Y, Jin Y, Guo W, Song Q, Wei C, Li J, Zhang S, Liu M. Prediction of Hemorrhagic Transformation After Ischemic Stroke: Development and Validation Study of a Novel Multi-biomarker Model. Front Aging Neurosci 2021; 13:667934. [PMID: 34122045 PMCID: PMC8193036 DOI: 10.3389/fnagi.2021.667934] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Accepted: 04/27/2021] [Indexed: 02/05/2023] Open
Abstract
Objectives: We aimed to develop and validate a novel multi-biomarker model for predicting hemorrhagic transformation (HT) risk after acute ischemic stroke (AIS). Methods: We prospectively included patients with AIS admitted within 24 h of stroke from January 1st 2016 to January 31st 2019. A panel of 17 circulating biomarkers was measured and analyzed in this cohort. We assessed the ability of individual circulating biomarkers and the combination of multiple biomarkers to predict any HT, symptomatic HT (sHT) and parenchymal hematoma (PH) after AIS. The strategy of multiple biomarkers in combination was then externally validated in an independent cohort of 288 Chinese patients. Results: A total of 1207 patients with AIS (727 males; mean age, 67.2 ± 13.9 years) were included as a derivation cohort, of whom 179 patients (14.8%) developed HT. The final multi-biomarker model included three biomarkers [platelets, neutrophil-to-lymphocyte ratios (NLR), and high-density lipoprotein (HDL)] from different pathways, showing a good performance for predicting HT in both the derivation cohort (c statistic = 0·64, 95% CI 0·60–0·69), and validation cohort (c statistic = 0·70, 95% CI 0·58–0·82). Adding these three biomarkers simultaneously to the basic model with conventional risk factors improved the ability of HT reclassification [net reclassification improvement (NRI) 65.6%, P < 0.001], PH (NRI 64.7%, P < 0.001), and sHT (NRI 71.3%, P < 0.001). Conclusion: This easily applied multi-biomarker model had a good performance for predicting HT in both the derivation and external validation cohorts. Incorporation of biomarkers into clinical decision making may help to identify patients at high risk of HT after AIS and warrants further consideration.
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Affiliation(s)
- Junfeng Liu
- Department of Neurology, Center of Cerebrovascular Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Yanan Wang
- Department of Neurology, Center of Cerebrovascular Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Yuxi Jin
- West China School of Medicine, Sichuan University, Chengdu, China
| | - Wen Guo
- Department of Neurology, Center of Cerebrovascular Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Quhong Song
- Department of Neurology, Center of Cerebrovascular Diseases, West China Hospital, Sichuan University, Chengdu, China
| | - Chenchen Wei
- Department of Neurology, Center of Cerebrovascular Diseases, West China Hospital, Sichuan University, Chengdu, China.,Department of Neurology, The Affiliated Hospital of Qingdao University, Qingdao, China
| | - Jing Li
- Department of Neurology, The First People's Hospital of Ziyang, Ziyang, China
| | - Shanshan Zhang
- Department of Neurology, Mianyang Central Hospital, Mianyang, China
| | - Ming Liu
- Department of Neurology, Center of Cerebrovascular Diseases, West China Hospital, Sichuan University, Chengdu, China
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Abstract
Objectives: Concise “synthetic” review of the state of the art of management of acute ischemic stroke. Data Sources: Available literature on PubMed. Study Selection: We selected landmark studies, recent clinical trials, observational studies, and professional guidelines on the management of stroke including the last 10 years. Data Extraction: Eligible studies were identified and results leading to guideline recommendations were summarized. Data Synthesis: Stroke mortality has been declining over the past 6 decades, and as a result, stroke has fallen from the second to the fifth leading cause of death in the United States. This trend may follow recent advances in the management of stroke, which highlight the importance of early recognition and early revascularization. Recent studies have shown that early recognition, emergency interventional treatment of acute ischemic stroke, and treatment in dedicated stroke centers can significantly reduce stroke-related morbidity and mortality. However, stroke remains the second leading cause of death worldwide and the number one cause for acquired long-term disability, resulting in a global annual economic burden. Conclusions: Appropriate treatment of ischemic stroke is essential in the reduction of mortality and morbidity. Management of stroke involves a multidisciplinary approach that starts and extends beyond hospital admission.
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Lee EJ, Kim SJ, Bae J, Lee EJ, Kwon OD, Jeong HY, Kim Y, Jeong HB. Impact of onset-to-door time on outcomes and factors associated with late hospital arrival in patients with acute ischemic stroke. PLoS One 2021; 16:e0247829. [PMID: 33765030 PMCID: PMC7993794 DOI: 10.1371/journal.pone.0247829] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Accepted: 02/14/2021] [Indexed: 11/19/2022] Open
Abstract
Background and purpose Previous studies have reported that early hospital arrival improves clinical outcomes in patients with acute ischemic stroke; however, whether early arrival is associated with favorable outcomes regardless of reperfusion therapy and the type of stroke onset time is unclear. Thus, we investigated the impact of onset-to-door time on outcomes and evaluated the predictors of pre-hospital delay after ischemic stroke. Methods Consecutive acute ischemic stroke patients who arrived at the hospital within five days of onset from September 2019 to May 2020 were selected from the prospective stroke registries of Seoul National University Hospital and Chung-Ang University Hospital of Seoul, Korea. Patients were divided into early (onset-to-door time, ≤4.5 h) and late (>4.5 h) arrivers. Multivariate analyses were performed to assess the effect of early arrival on clinical outcomes and predictors of late arrival. Results Among the 539 patients, 28.4% arrived early and 71.6% arrived late. Early hospital arrival was significantly associated with favorable outcomes (three-month modified Rankin Scale [mRS]: 0−2, adjusted odds ratio [aOR]: 2.03, 95% confidence interval: [CI] 1.04–3.96) regardless of various confounders, including receiving reperfusion therapy and type of stroke onset time. Furthermore, a lower initial National Institute of Health Stroke Scale (NIHSS) score (aOR: 0.94, 95% CI: 0.90–0.97), greater pre-stroke mRS score (aOR: 1.58, 95% CI: 1.18–2.13), female sex (aOR: 1.71, 95% CI: 1.14–2.58), unclear onset time, and ≤6 years of schooling (aOR: 1.76, 95% CI: 1.03–3.00 compared to >12 years of schooling) were independent predictors of late arrival. Conclusions Thus, the onset-to-door time of≤4.5 h is crucial for better clinical outcome, and lower NIHSS score, greater pre-stroke mRS score, female sex, unclear onset times, and ≤6 years of schooling were independent predictors of late arrival. Therefore, educating about the importance of early hospital arrival after acute ischemic stroke should be emphasized. More strategic efforts are needed to reduce the prehospital delay by understanding the predictors of late arrival.
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Affiliation(s)
- Eung-Joon Lee
- Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Seung Jae Kim
- Department of Family Medicine, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
- International Healthcare Center, Seoul St. Mary’s Hospital, College of Medicine, The Catholic University of Korea, Seoul, Republic of Korea
| | - Jeonghoon Bae
- Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Eun Ji Lee
- Department of Radiology, Soonchunhyang University Seoul Hospital, Seoul, Republic of Korea
| | - Oh Deog Kwon
- Republic of Korea Navy 2 Fleet Medical Corps, Pyeongtaek-si, Gyeonggi-do, Republic of Korea
| | - Han-Yeong Jeong
- Department of Neurology, Seoul National University Hospital, Seoul, Republic of Korea
| | - Yongsung Kim
- Department of Neurology, Chung-Ang University Hospital, Seoul, Republic of Korea
| | - Hae-Bong Jeong
- Department of Neurology, Chung-Ang University Hospital, Seoul, Republic of Korea
- * E-mail:
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Combination of Polyethylene Glycol-Conjugated Urokinase Nanogels and Urokinase for Acute Ischemic Stroke Therapeutic Implications. Transl Stroke Res 2020; 12:844-857. [DOI: 10.1007/s12975-020-00865-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/07/2020] [Revised: 09/17/2020] [Accepted: 10/11/2020] [Indexed: 12/25/2022]
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The use of transcranial ultrasound and clinical assessment to diagnose ischaemic stroke due to large vessel occlusion in remote and rural areas. PLoS One 2020; 15:e0239653. [PMID: 33007053 PMCID: PMC7531787 DOI: 10.1371/journal.pone.0239653] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Accepted: 09/07/2020] [Indexed: 12/12/2022] Open
Abstract
Rapid endovascular thrombectomy, which can only be delivered in specialist centres, is the most effective treatment for acute ischaemic stroke due to large vessel occlusion (LVO). Pre-hospital selection of these patients is challenging, especially in remote and rural areas due to long transport times and limited access to specialist clinicians and diagnostic facilities. We investigated whether combined transcranial ultrasound and clinical assessment (“TUCA” model) could accurately triage these patients and improve access to thrombectomy. We recruited consecutive patients within 72 hours of suspected stroke, and performed non-contrast transcranial colour-coded ultrasonography within 24 hours of brain computed tomography. We retrospectively collected clinical information, and used hospital discharge diagnosis as the “gold standard”. We used binary regression for diagnosis of haemorrhagic stroke, and an ordinal regression model for acute ischaemic stroke with probable LVO, without LVO, transient ischaemic attacks (TIA) and stroke mimics. We calculated sensitivity, specificity, positive and negative predictive values and performed a sensitivity analysis. We recruited 107 patients with suspected stroke from July 2017 to December 2019 at two study sites: 13/107 (12%) with probable LVO, 50/107 (47%) with acute ischaemic stroke without LVO, 18/107 (17%) with haemorrhagic stroke, and 26/107 (24%) with stroke mimics or TIA. The model identified 55% of cases with probable LVO who would have correctly been selected for thrombectomy and 97% of cases who would not have required this treatment (sensitivity 55%, specificity 97%, positive and negative predictive values 75% and 93%, respectively). Diagnostic accuracy of the proposed model was superior to the clinical assessment alone. These data suggest that our model might be a useful tool to identify pre-hospital patients requiring mechanical thrombectomy, however a larger sample is required with the use of CT angiogram as a reference test.
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Branyan TE, Sohrabji F. Sex differences in stroke co-morbidities. Exp Neurol 2020; 332:113384. [PMID: 32585156 PMCID: PMC7418167 DOI: 10.1016/j.expneurol.2020.113384] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2020] [Revised: 06/06/2020] [Accepted: 06/15/2020] [Indexed: 12/12/2022]
Abstract
Males and females possess distinct biological differences that manifest in diverse risk profiles for acute and chronic diseases. A well-documented example of this is ischemic stroke. It has been demonstrated that older females have greater prevalence of, and worse outcome after, ischemic stroke than do males and younger females. Loss of estrogen after menopause is heavily implicated as a contributing factor for this phenomenon; however, there is mounting evidence to suggest that certain risk factors tend to occur more often in older females, such as hypertension and atrial fibrillation, while others more adversely affect females than they do males, such as diabetes and smoking. Sex-specific risk factors, such as oral contraceptive use and menopause, could also contribute to the discrepancy in stroke prevalence and outcome. Additionally, there is evidence to suggest that females tend to present with more nontraditional symptoms of acute stroke than do males, making it more difficult for clinicians to correctly identify the occurrence of a stroke, which may delay the administration of thrombolytic intervention. Finally, certain sociodemographic factors, such as the fact that females were more likely to live alone prior to stroke, may contribute to poorer recovery in females. This review will explore the various co-morbidities and sociodemographic factors that contribute to the greater prevalence of and poorer outcome after stroke in older females and will highlight the critical need for considering sex as a predisposing biological variable in stroke studies.
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Affiliation(s)
- Taylor E Branyan
- Women's Health in Neuroscience Program, Department of Neuroscience and Experimental Therapeutics, Texas A&M HSC College of Medicine, Bryan, TX 77807, USA; Texas A&M Institute for Neuroscience, College Station, TX 77840, USA
| | - Farida Sohrabji
- Women's Health in Neuroscience Program, Department of Neuroscience and Experimental Therapeutics, Texas A&M HSC College of Medicine, Bryan, TX 77807, USA; Texas A&M Institute for Neuroscience, College Station, TX 77840, USA.
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44
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Increased intracranial hemorrhage of mechanical thrombectomy in acute ischemic stroke patients with atrial fibrillation. J Thromb Thrombolysis 2020; 51:536-544. [PMID: 32918671 DOI: 10.1007/s11239-020-02269-3] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
The impact of atrial fibrillation (AF) on outcomes of mechanical thrombectomy (MT) for acute ischemic stroke (AIS) is controversial, and with a paucity of evidence base. This study aimed to investigate the potential association between AF and outcomes after MT in AIS patients. A post-hoc analysis of a multi-center prospective clinical trial was conducted. Before and after propensity score matching (PSM), the clinical features were compared between patients with and without AF. Multivariable logistic regression and mediation analyses were performed to assess the relationship between AF and ICH. Of the total 245 patients, 123 patients were included in the AF group. After PSM, the AF group showed more retrieval attempts (P = 0.004), comparable favorable outcome (P = 0.493), and mortality (P = 0.362) at 90 days. Multivariate analysis revealed that AF was significantly associated with increased risk for ICH (OR 2.198; 95%CI 1.099-4.395; P = 0.026). INR and retrieval attempts were found to act as partial mediations. In the subgroup with lower INR, AF still had a significant association with ICH (OR 2.496; 95%CI 1.331-4.679; P = 0.004). In AIS patients undergoing MT, AF was associated with more retrieval attempts and higher risk of any ICH. Of note, the effect of AF on the increased risk of ICH was partly attributable to the adjusted anticoagulation status and more retrieval attempts. It is crucial to elaborately prevent ICH after thrombectomy for stroke patients with AF.
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45
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Wang Y, Qiu K, Song Q, Cheng Y, Liu J, Liu M. AST to ALT ratio and risk of hemorrhagic transformation in patients with acute ischemic stroke. Neurol Res 2020; 42:980-986. [PMID: 32697140 DOI: 10.1080/01616412.2020.1796403] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Hemorrhagic transformation (HT) is a common complication of ischemic stroke. We performed this study to determine whether aspartate aminotransferase (AST) to alanine aminotransferase (ALT) ratio (AAR) was related to HT, as well as compare the predictive values of AAR, ALT and AST for HT in patients with ischemic stroke. METHODS We included ischemic stroke patients within 7 days of onset. HT was identified by a follow-up imaging examination. Univariate and multivariate logistic regression models were performed to assess the association between AAR and HT. Net reclassification index (NRI) was calculated to assess the ability of AAR, AST and ALT to reclassify risks of HT. RESULTS A total of 2042 (median age: 69 years; 63.2% males) patients were included in this study, of whom 232 (11.4%) were identified as HT. The receiver-operating characteristic curve analysis showed that the optimal cut-off value for AAR to predict HT was 1.22. Higher AAR (≥1.22) was an independent predictor associated with HT (OR 1.44, 95%CI 1.06-1.97, P = 0.02) after adjusting for covariates. A U-shaped dose-effect relationship was found between AAR level and HT in logistic regression model with restricted cubic splines. In addition, adding AAR to a model containing conventional risk factors significantly improved predictive power for HT (NRI: 15.4%, P = 0.027), but not for ALT (NRI: 10.3%, P = 0.141) or AST (NRI: 8.3%, P = 0.237). CONCLUSIONS Higher AAR was associated with an increased risk of HT after ischemic stroke. In addition, AAR might be a better biomarker for predicting HT than ALT or AST.
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Affiliation(s)
- Yanan Wang
- Department of Neurology, West China Hospital, Sichuan University , Sichuan, China
| | - Ke Qiu
- West China School of Medicine, Sichuan University , Sichuan, China
| | - Quhong Song
- Department of Neurology, West China Hospital, Sichuan University , Sichuan, China
| | - Yajun Cheng
- Department of Neurology, West China Hospital, Sichuan University , Sichuan, China
| | - Junfeng Liu
- Department of Neurology, West China Hospital, Sichuan University , Sichuan, China
| | - Ming Liu
- Department of Neurology, West China Hospital, Sichuan University , Sichuan, China
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Wang X, Carcel C, Wang R, Li J, Bae HJ, Wang Y, Wang A, Wang Y, Toyoda K, Sui Y, Lee TH, Navarro JC, Sun MC, Anderson CS, Sharma V, Sandset EC, Woodward M. Worse prognosis in women, compared with men, after thrombolysis: An individual patient data pooling study of Asian acute stroke registries. Int J Stroke 2020; 16:784-791. [PMID: 32638639 DOI: 10.1177/1747493020938307] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
BACKGROUND AND PURPOSE To examine sex differences in disease profiles and short-term outcomes after acute ischemic stroke treated with recombinant tissue plasminogen activator. METHODS Eight national and regional stroke registries contributed individual participant data from mainland China, Japan, Philippines, Singapore, South Korea and Taiwan in 2005-2018. The primary outcome was ordinal-modified Rankin scale at 90 days. Key safety outcome was symptomatic intracerebral hemorrhage (sICH). RESULTS Of 4453 patients included in the analyses, 1692 (36.3%) were women who were older, more likely to have a more severe neurological deficit, history of hypertension and atrial fibrillation, and a cardioembolic stroke compared to men. Women were more likely than men to have unfavorable shift of modified Rankin scale (fully adjusted odds ratio) (women vs. men) 1.14, 95% confidence interval 1.02-1.28). There was no significant sex difference for death 1.05 (0.84-1.31) or sICH (1.17, 0.89-1.54). Women were more likely to have unfavorable functional outcome with increasing age (P = 0.022 for interaction). In the age groups 70-80 and ≥80 years, women had a worse functional outcome compared to men (1.22, 1.02-1.47 and 1.43, and 1.06-1.92, respectively). CONCLUSION In this pooled data from Asian acute stroke registries, women had poorer prognosis than men after receiving recombinant tissue plasminogen activator for acute ischemic stroke, which worsened with age. Women older than 70 appear to have a worse outcome than men which could be explained by greater stroke severity, more AF, and cardioembolic stroke.
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Affiliation(s)
- Xia Wang
- The George Institute for Global Health, University of New South Wales, NSW, Australia
| | - Cheryl Carcel
- The George Institute for Global Health, University of New South Wales, NSW, Australia.,Sydney School of Public Health, University of Sydney, NSW, Australia
| | - Ruigang Wang
- North China University of Science and Technology Affiliated Hospital, HeBei Province, Tangshan, China
| | - Jingwei Li
- Department of Cardiology, People's Liberation Army General Hospital, Beijing, China.,Department of Cardiology, Xinqiao Hospital, Third Military Medical University, Chongqing, China
| | - Hee-Joon Bae
- Department of Neurology and Cerebrovascular Center, Seoul National University, Bundang Hospital, Seongnam-si, Gyeonggi-do, Republic of Korea
| | - Yilong Wang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Anxin Wang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Yongjun Wang
- Department of Neurology, Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Kazunori Toyoda
- Department of Cerebrovascular Medicine, National Cerebral and Cardiovascular Centre, Osaka, Japan
| | - Yi Sui
- Shenyang First People's Hospital, Shenyang Medical College Affiliated Shenyang Brain Hospital, Shenyang Brain Institute, Shenyang Clinical Research Center for Neurological Disorders, Shenyang, China
| | - Tsong-Hai Lee
- Department of Neurology, Chang Gung Memorial Hospital, Linkou Medical Center and College of Medicine, Chang Gung University, Taoyuan
| | - Jose C Navarro
- Stroke Services, Department of Neurology, Jose R. Reyes Memorial Medical Center, Manila, Philippines
| | - Mu-Chien Sun
- Department of Neurology, Changhua Christian Hospital, Changhua
| | - Craig S Anderson
- The George Institute for Global Health, University of New South Wales, NSW, Australia.,The George Institute China at Peking University Health Science Center, Beijing, PR China.,Neurology Department, Royal Prince Alfred Hospital, Sydney Health Partners, Sydney, NSW, Australia.,Health Heart Research Center, Beijing, China
| | - Vijay Sharma
- Division of Neurology, National University Hospital, Singapore.,Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Else C Sandset
- Department of Neurology, Oslo University Hospital, Oslo, Norway.,Norwegian Air Ambulance Foundation, Oslo, Norway
| | - Mark Woodward
- The George Institute for Global Health, University of New South Wales, NSW, Australia.,The George Institute for Global Health, University of Oxford, Oxford, UK.,Department of Epidemiology, Johns Hopkins University, Baltimore, MD, USA
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Rebchuk AD, O’Neill ZR, Szefer EK, Hill MD, Field TS. Health Utility Weighting of the Modified Rankin Scale: A Systematic Review and Meta-analysis. JAMA Netw Open 2020; 3:e203767. [PMID: 32347948 PMCID: PMC7191324 DOI: 10.1001/jamanetworkopen.2020.3767] [Citation(s) in RCA: 38] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
IMPORTANCE The utility-weighted modified Rankin Scale (UW-mRS) has been proposed as a patient-centered alternative primary outcome for stroke clinical trials. However, to date, there is no clear consensus on an approach to weighting the mRS. OBJECTIVE To characterize the between-study variability in utility weighting of the mRS in a population of patients who experienced stroke and its implications when applied to the results of a clinical trial. DATA SOURCES In this systematic review and meta-analysis, MEDLINE, Embase, and PsycINFO were searched from January 1987 through May 2019 using major search terms for stroke, health utility, and mRS. STUDY SELECTION Original research articles published in English were reviewed. Included were studies with participants 18 years or older with ischemic or hemorrhagic stroke, transient ischemic attack, or subarachnoid hemorrhage, with mRS scores and utility weights evaluated concurrently. A total of 5725 unique articles were identified. Of these, 283 met criteria for full-text review, and 24 were included in the meta-analysis. DATA EXTRACTION AND SYNTHESIS PRISMA guidelines for systematic review were followed. Data extraction was performed independently by multiple researchers. Data were pooled using mixed models. MAIN OUTCOMES AND MEASURES The mean utility weights and 95% CIs were calculated for each mRS score and health utility scale. Geographic differences in weighting for the EuroQoL 5-dimension (EQ-5D) and Stroke Impact Scale-based UW-mRS were explored using inverse variance-weighted linear models. The results of 18 major acute stroke trials cited in current guidelines were then reanalyzed using the UW-mRS weighting scales identified in the systematic review. RESULTS The meta-analysis included 22 389 individuals; the mean (SD) age of participants was 65.9 (4.0) years, and the mean (SD) proportion of male participants was 58.2% (7.5%). For all health utility scales evaluated, statistically significant differences were observed between the mean utility weights by mRS score. For studies using an EQ-5D-weighted mRS, between-study variance was higher for worse (mRS 2-5) compared with better (mRS 0-1) scores. Of the 18 major acute stroke trials with reanalyzed results, 3 had an unstable outcome when using different UW-mRSs. CONCLUSIONS AND RELEVANCE Multiple factors, including cohort-specific characteristics and health utility scale selection, can influence mRS utility weighting. If the UW-mRS is selected as a primary outcome, the approach to weighting may alter the results of a clinical trial. Researchers using the UW-mRS should prospectively and concurrently obtain mRS scores and utility weights to characterize study-specific outcomes.
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Affiliation(s)
- Alexander D. Rebchuk
- Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada
| | - Zoe R. O’Neill
- Faculty of Medicine, McGill University, Montreal, Quebec, Canada
| | | | - Michael D. Hill
- Hotchkiss Brain Institute, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
- Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, Alberta, Canada
| | - Thalia S. Field
- Faculty of Medicine, The University of British Columbia, Vancouver, British Columbia, Canada
- Djavad Mowafaghian Centre for Brain Health, The University of British Columbia, Vancouver, British Columbia, Canada
- Vancouver Stroke Program, The University of British Columbia, Vancouver, British Columbia, Canada
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48
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Kollikowski AM, Schuhmann MK, Nieswandt B, Müllges W, Stoll G, Pham M. Local Leukocyte Invasion during Hyperacute Human Ischemic Stroke. Ann Neurol 2020; 87:466-479. [PMID: 31899551 DOI: 10.1002/ana.25665] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2019] [Revised: 12/27/2019] [Accepted: 12/30/2019] [Indexed: 12/21/2022]
Abstract
OBJECTIVE Bridging the gap between experimental stroke and patients by ischemic blood probing during the hyperacute stage of vascular occlusion is crucial to assess the role of inflammation in human stroke and for the development of adjunct treatments beyond recanalization. METHODS We prospectively observed 151 consecutive ischemic stroke patients with embolic large vessel occlusion of the anterior circulation who underwent mechanical thrombectomy. In all these patients, we attempted microcatheter aspiration of 3 different arterial blood samples: (1) within the core of the occluded vascular compartment and controlled by (2) carotid and (3) femoral samples obtained under physiological flow conditions. Subsequent laboratory analyses comprised leukocyte counting and differentiation, platelet counting, and the quantification of 13 proinflammatory human chemokines/cytokines. RESULTS Forty patients meeting all clinical, imaging, interventional, and laboratory inclusion criteria could be analyzed, showing that the total number of leukocytes significantly increased under the occlusion condition. This increase was predominantly driven by neutrophils. Significant increases were also apparent for lymphocytes and monocytes, accompanied by locally elevated plasma levels of the T-cell chemoattractant CXCL-11. Finally, we found evidence that short-term clinical outcome (National Institute of Health Stroke Scale at 72 hours) was negatively associated with neutrophil accumulation. INTERPRETATION We provide the first direct human evidence that neutrophils, lymphocytes, and monocytes, accompanied by specific chemokine upregulation, accumulate in the ischemic vasculature during hyperacute stroke and may affect outcome. These findings strongly support experimental evidence that immune cells contribute to acute ischemic brain damage and indicate that ischemic inflammation initiates already during vascular occlusion. Ann Neurol 2020;87:466-479.
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Affiliation(s)
| | | | - Bernhard Nieswandt
- Institute of Experimental Biomedicine, University Hospital and Rudolf Virchow Center, University of Würzburg, Würzburg, Germany
| | - Wolfgang Müllges
- Department of Neurology, University Hospital of Würzburg, Würzburg, Germany
| | - Guido Stoll
- Department of Neurology, University Hospital of Würzburg, Würzburg, Germany
| | - Mirko Pham
- Department of Neuroradiology, University Hospital of Würzburg, Würzburg, Germany
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49
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Vaughan BC, Jones MER, Browne IL, Olshavsky JM, Schultz RD. Selective retrograde cerebral cooling in complete cerebral circulatory arrest. Brain Circ 2019; 5:234-240. [PMID: 31950100 PMCID: PMC6950516 DOI: 10.4103/bc.bc_60_19] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2019] [Revised: 12/09/2019] [Accepted: 12/16/2019] [Indexed: 01/01/2023] Open
Abstract
BACKGROUND AND PURPOSE: Cerebral hypothermia is a known neuroprotectant with promising applications in the treatment of ischemic events. Although systemic cooling is standard in post-cardiac arrest care, the deleterious effects of whole-body cooling have precluded it from translation into a viable treatment option for acute ischemic stroke (AIS). Selective cerebral cooling has been proposed as a method to minimize these risks while granting the neuroprotection of therapeutic hypothermia in AIS. METHODS: In a porcine model (n = 3), the efficacy of selective retrograde cerebral cooling through the internal jugular vein was evaluated in the setting of complete cerebral circulatory arrest. Furthermore, a novel endovascular device and cooling system enabling selective retrograde cerebral cooling were studied in a normothermic perfused cadaver. RESULTS AND CONCLUSION: Neurologic assessment of animals receiving this therapy reflected substantial neuroprotection in animals undergoing both 15 min and 30 min of otherwise catastrophic complete cerebral circulatory arrest. The novel endovascular device and cooling system were validated in human anatomy, demonstrating successful cerebral cooling, and feasibility of this mechanism of selective retrograde cerebral cooling.
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Affiliation(s)
| | - Melissa E R Jones
- Voyage Biomedical Inc., Berkeley, CA, United States.,Undergraduate Medical Education, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Ikennah L Browne
- Voyage Biomedical Inc., Berkeley, CA, United States.,Department of Surgery, Division of General Surgery, University of Calgary, Calgary, AB, Canada
| | | | - Robert D Schultz
- Voyage Biomedical Inc., Berkeley, CA, United States.,Section of Cardiac Surgery, Libin Cardiovascular Institute of Alberta, University of Calgary, Calgary, AB, Canada
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50
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Halder SK, Matsunaga H, Ueda H. Prothymosin alpha and its mimetic hexapeptide improve delayed tissue plasminogen activator-induced brain damage following cerebral ischemia. J Neurochem 2019; 153:772-789. [PMID: 31454420 DOI: 10.1111/jnc.14858] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2018] [Revised: 04/13/2019] [Accepted: 08/22/2019] [Indexed: 12/14/2022]
Abstract
Tissue plasminogen activator (tPA) administration beyond 4.5 h of stroke symptoms is beneficial for patients but has an increased risk of cerebral hemorrhage. Thus, increasing the therapeutic window of tPA is important for stroke recovery. We previously showed that prothymosin alpha (ProTα) or its mimetic hexapeptide (P6Q) has anti-ischemic activity. Here, we examined the beneficial effects of ProTα or P6Q against delayed tPA-induced brain damage following middle cerebral artery occlusion (MCAO) or photochemically induced thrombosis in mice. Brain hemorrhage was observed by tPA administration during reperfusion at 4.5 and 6 h after MCAO. Co-administration of ProTα with tPA at 4.5 h inhibited hemorrhage and motor dysfunction 2-4 days, but not 7 days after MCAO. ProTα administration at 2 and 4.5 h after MCAO significantly inhibited tPA (4.5 h)-induced motor dysfunction and death more than 7 days. Administration of tPA caused the loss of tight junction proteins, zona occulden-1 and occludin, and up-regulation of matrix metalloproteinase-2/9, in a ProTα-reversible manner. P6Q administration abolished tPA (4.5 h)-induced hemorrhage and reversed tPA (6 h)-induced vascular damage and matrix metalloproteinase-2 and 9 up-regulation. Twice administrations of P6Q at 2 h alone and 6 h with tPA significantly improved motor dysfunction more than 7 days. In photochemically induced thrombosis ischemia, similar vascular leakage and neuronal damage (infarction and motor dysfunction) by late tPA (4.5 or 6 h) were also inhibited by P6Q. Thus, these studies suggest that co-administration with ProTα or P6Q would be beneficial to inhibit delayed tPA-induced hemorrhagic mechanisms in acute ischemic stroke.
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Affiliation(s)
- Sebok Kumar Halder
- Department of Pharmacology and Therapeutic Innovation, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Hayato Matsunaga
- Department of Pharmacology and Therapeutic Innovation, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
| | - Hiroshi Ueda
- Department of Pharmacology and Therapeutic Innovation, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan
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