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Jaqueto M, Alfieri DF, de Araújo MCM, Fürstenberger Lehmann ALC, Flauzino T, Trevisan ER, Nagao MR, de Freitas LB, Colado Simão AN, Lozovoy MAB, Delfino VDA, Reiche EMV. Acute kidney injury is associated with soluble vascular cell adhesion molecule 1 levels and short-term mortality in patients with ischemic stroke. Clin Neurol Neurosurg 2024; 245:108470. [PMID: 39079288 DOI: 10.1016/j.clineuro.2024.108470] [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: 09/05/2023] [Revised: 06/27/2024] [Accepted: 07/26/2024] [Indexed: 09/10/2024]
Abstract
BACKGROUND The mechanisms that modulate the onset of acute kidney inlury (AKI) after ischemic stroke (IS) and valuable biomarkers to predict the occurrence and prognosis of AKI among patients with IS are missing. OBJECTIVE To evaluate the frequency of AKI and the prognostic validity of clinical and laboratory biomarkers in predicting AKI and short-term mortality after the IS. METHODS Ninety-five patients with IS were enrolled. Baseline IS severity was assessed using the National Institutes of Health Stroke Scale (NIHSS) and disability was determined after three-month follow-up using the modified Rankin Scale. Patients with IS were also categorized as survivors and non-survivors after the follow-up. Baseline data and laboratory biomarkers were obtained up to 24 h of the admission. RESULTS Fifteen (15.7 %) patients with IS presented AKI. The proportion of patients with vitamin D deficiency and the mortality were higher among those with AKI than those without AKI (p=0.011 and p-0.009, respectively). Patients with AKI showed higher disability and higher increased soluble vascular cellular adhesion molecule-1 (sVCAM-1) than those without AKI (p=0.029 and p=0.023, respectively). Logistic regression analysis showed that only sVCAM-1 was associated with the occurrence of AKI after IS [odds ratio (OR): 2.715, 95 % confidence intereval (CI): 1.12-6.67, p=0.027]. When both AKI and NIHSS were evaluated as explanatory variables, this panel showed an OR of 5.782 (95 % CI: 1.09-30.43, p<0.001) and correctly classified 83.6 % of cases. CONCLUSION In conclusion, sVCAM-1 levels showed a potential useful for prediction of AKI after IS.
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Affiliation(s)
- Marcel Jaqueto
- Department of Clinical Medicine, Health Science Center and Radiology Service of the University Hospital, State University of Londrina, Paraná, Brazil.
| | - Daniela Frizon Alfieri
- Department of Pharmaceutical Sciences, Health Sciences Center, State University of Londrina, Paraná, Brazil.
| | - Maria Caroline Martins de Araújo
- Laboratory of Research in Applied Immunology, Health Sciences Center, State University of Londrina, Paraná, Brazil; School of Medicine of Pontifical Catholic University of Paraná, Campus Londrina, Londrina, Paraná, Brazil.
| | - Ana Lucia Cruz Fürstenberger Lehmann
- Department of Clinical Medicine, Health Science Center and Radiology Service of the University Hospital, State University of Londrina, Paraná, Brazil.
| | - Tamires Flauzino
- Laboratory of Research in Applied Immunology, Health Sciences Center, State University of Londrina, Paraná, Brazil; School of Medicine of Pontifical Catholic University of Paraná, Campus Londrina, Londrina, Paraná, Brazil.
| | - Emmanuelle Roberto Trevisan
- Laboratory of Research in Applied Immunology, Health Sciences Center, State University of Londrina, Paraná, Brazil; School of Medicine of Pontifical Catholic University of Paraná, Campus Londrina, Londrina, Paraná, Brazil.
| | - Maisa Rocha Nagao
- Laboratory of Research in Applied Immunology, Health Sciences Center, State University of Londrina, Paraná, Brazil; School of Medicine of Pontifical Catholic University of Paraná, Campus Londrina, Londrina, Paraná, Brazil.
| | - Leonardo Bodner de Freitas
- Laboratory of Research in Applied Immunology, Health Sciences Center, State University of Londrina, Paraná, Brazil; School of Medicine of Pontifical Catholic University of Paraná, Campus Londrina, Londrina, Paraná, Brazil.
| | - Andrea Name Colado Simão
- Laboratory of Research in Applied Immunology, Health Sciences Center, State University of Londrina, Paraná, Brazil; School of Medicine of Pontifical Catholic University of Paraná, Campus Londrina, Londrina, Paraná, Brazil; Department of Pathology, Clinical Analysis, and Toxicology, Health Sciences Center, State University of Londrina, Londrina, Brazil.
| | - Marcell Alysson Batisti Lozovoy
- Laboratory of Research in Applied Immunology, Health Sciences Center, State University of Londrina, Paraná, Brazil; School of Medicine of Pontifical Catholic University of Paraná, Campus Londrina, Londrina, Paraná, Brazil; Department of Pathology, Clinical Analysis, and Toxicology, Health Sciences Center, State University of Londrina, Londrina, Brazil.
| | - Vinicius Daher Alvares Delfino
- Department of Clinical Medicine, Health Science Center and Radiology Service of the University Hospital, State University of Londrina, Paraná, Brazil.
| | - Edna Maria Vissoci Reiche
- Postgraduate Program of Clinical and Laboratory Pathophysiology, Health Sciences Center, State University of Londrina, Londrina, Paraná, Brazil; Pontificial Catholic University of Paraná, Campus Londrina, School of Medicine, Londrina, Paraná, Brazil.
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Lin S, Chunxiao W, Li S, Guimei Z, Yaru Z, Weijie Z, Yiming Q, Ruolin Z, Lingjie M, Yan Z. Relationship between thrombus vWF and NETs with clinical severity and peripheral blood immunocytes' indicators in patients with acute ischemic stroke. Interv Neuroradiol 2024:15910199241258374. [PMID: 38807555 PMCID: PMC11571128 DOI: 10.1177/15910199241258374] [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: 12/08/2023] [Accepted: 05/13/2024] [Indexed: 05/30/2024] Open
Abstract
OBJECTIVE To investigate the association between von Willebrand factor (vWF) and neutrophil extracellular traps (NETs) in thrombus with clinical severity and peripheral blood immunocytes' indicators in patients with early-stage acute ischemic stroke (AIS). METHODS A retrospective study was conducted using the clinical data of 66 patients with AIS who underwent endovascular mechanical thrombectomy and had their thrombus samples collected. The concentrations of vWF and NETs in the thrombus samples were quantitatively assessed. Peripheral blood samples taken in the early stages of the disease were analyzed for total white blood cell counts (WBC), ratios of neutrophils (NEU%), lymphocytes (LYM%), eosinophils (EOS%), and monocytes (MONO%). The severity of clinical symptoms in these patients was evaluated using the modified Rankin Scale (mRS), Essen Stroke Risk Score (ESRS), Barthel Index (BI), and National Institute of Health Stroke Scale (NIHSS). RESULTS Higher vWF levels in thrombus were associated with lower NIHSS scores, while higher NETs levels were associated with higher initial NIHSS scores. In the early stages of AIS, WBC count and vWF levels were negatively correlated, as well as NEU%. LYM% was positively correlated with vWF level; however, it was negatively correlated with NETs. EOS% was positively correlated with vWF levels. CONCLUSION In the early stages of AIS, a higher peripheral WBC count and NEU%, combined with decreased EOS% and LYM%, were significantly correlated with a lower vWF level in the thrombus, potentially indicating more severe symptoms. Consequently, the timely administration of vWF-targeted medications is recommended for such patients. Reduced LYM% is indicative of elevated NETs levels and correlated with more severe clinical symptoms. Therefore, the prompt initiation of NETs-targeted medication is warranted for these patients.
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Affiliation(s)
- Shi Lin
- Cognitive Center, Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Wei Chunxiao
- Cognitive Center, Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Sun Li
- Cognitive Center, Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Zhang Guimei
- Cognitive Center, Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Zhang Yaru
- Department of Neurology and National Center for Neurological Diseases, Huashan Hospital, Shanghai, China
| | - Zhai Weijie
- Cognitive Center, Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Qi Yiming
- Cognitive Center, Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Zhou Ruolin
- Cognitive Center, Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Meng Lingjie
- Cognitive Center, Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, China
| | - Zhang Yan
- Cognitive Center, Department of Neurology, The First Hospital of Jilin University, Jilin University, Changchun, China
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Machado FJDM, Marta-Enguita J, Gómez SU, Rodriguez JA, Páramo-Fernández JA, Herrera M, Zandio B, Aymerich N, Muñoz R, Bermejo R, Marta-Moreno J, López B, González A, Roncal C, Orbe J. Transcriptomic Analysis of Extracellular Vesicles in the Search for Novel Plasma and Thrombus Biomarkers of Ischemic Stroke Etiologies. Int J Mol Sci 2024; 25:4379. [PMID: 38673963 PMCID: PMC11050408 DOI: 10.3390/ijms25084379] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Revised: 04/10/2024] [Accepted: 04/10/2024] [Indexed: 04/28/2024] Open
Abstract
Accurate etiologic diagnosis provides an appropriate secondary prevention and better prognosis in ischemic stroke (IS) patients; still, 45% of IS are cryptogenic, urging us to enhance diagnostic precision. We have studied the transcriptomic content of plasma extracellular vesicles (EVs) (n = 21) to identify potential biomarkers of IS etiologies. The proteins encoded by the selected genes were measured in the sera of IS patients (n = 114) and in hypertensive patients with (n = 78) and without atrial fibrillation (AF) (n = 20). IGFBP-2, the most promising candidate, was studied using immunohistochemistry in the IS thrombi (n = 23) and atrium of AF patients (n = 13). In vitro, the IGFBP-2 blockade was analyzed using thromboelastometry and endothelial cell cultures. We identified 745 differentially expressed genes among EVs of cardioembolic, atherothrombotic, and ESUS groups. From these, IGFBP-2 (cutoff > 247.6 ng/mL) emerged as a potential circulating biomarker of embolic IS [OR = 8.70 (1.84-41.13) p = 0.003], which was increased in patients with AF vs. controls (p < 0.001) and was augmented in cardioembolic vs. atherothrombotic thrombi (p < 0.01). Ex vivo, the blockage of IGFBP-2 reduced clot firmness (p < 0.01) and lysis time (p < 0.001) and in vitro, diminished endothelial permeability (p < 0.05) and transmigration (p = 0.06). IGFBP-2 could be a biomarker of embolic IS and a new therapeutic target involved in clot formation and endothelial dysfunction.
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Affiliation(s)
- Florencio J. D. M. Machado
- Laboratory of Atherothrombosis, Cima Universidad de Navarra, 31008 Pamplona, Spain; (F.J.D.M.M.); (J.M.-E.); (S.U.G.); (J.A.R.); (J.A.P.-F.); (C.R.)
- Instituto de Investigación Sanitaria de Navarra IdiSNA, 31008 Pamplona, Spain; (M.H.); (B.L.)
| | - Juan Marta-Enguita
- Laboratory of Atherothrombosis, Cima Universidad de Navarra, 31008 Pamplona, Spain; (F.J.D.M.M.); (J.M.-E.); (S.U.G.); (J.A.R.); (J.A.P.-F.); (C.R.)
- Instituto de Investigación Sanitaria de Navarra IdiSNA, 31008 Pamplona, Spain; (M.H.); (B.L.)
- Red de Investigación Cooperativa Orientada a Resultados en Salud (RICORS)-Ictus, Instituto Salud Carlos III, 28029 Madrid, Spain; (B.Z.); (N.A.); (R.M.); (J.M.-M.)
| | - Susan U. Gómez
- Laboratory of Atherothrombosis, Cima Universidad de Navarra, 31008 Pamplona, Spain; (F.J.D.M.M.); (J.M.-E.); (S.U.G.); (J.A.R.); (J.A.P.-F.); (C.R.)
| | - Jose A. Rodriguez
- Laboratory of Atherothrombosis, Cima Universidad de Navarra, 31008 Pamplona, Spain; (F.J.D.M.M.); (J.M.-E.); (S.U.G.); (J.A.R.); (J.A.P.-F.); (C.R.)
- Instituto de Investigación Sanitaria de Navarra IdiSNA, 31008 Pamplona, Spain; (M.H.); (B.L.)
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - José Antonio Páramo-Fernández
- Laboratory of Atherothrombosis, Cima Universidad de Navarra, 31008 Pamplona, Spain; (F.J.D.M.M.); (J.M.-E.); (S.U.G.); (J.A.R.); (J.A.P.-F.); (C.R.)
- Instituto de Investigación Sanitaria de Navarra IdiSNA, 31008 Pamplona, Spain; (M.H.); (B.L.)
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Hematology Department, Clinica Universidad de Navarra, 31008 Pamplona, Spain
| | - María Herrera
- Instituto de Investigación Sanitaria de Navarra IdiSNA, 31008 Pamplona, Spain; (M.H.); (B.L.)
- Red de Investigación Cooperativa Orientada a Resultados en Salud (RICORS)-Ictus, Instituto Salud Carlos III, 28029 Madrid, Spain; (B.Z.); (N.A.); (R.M.); (J.M.-M.)
- Neurology Department, Hospital Universitario de Navarra, 31008 Pamplona, Spain
| | - Beatriz Zandio
- Red de Investigación Cooperativa Orientada a Resultados en Salud (RICORS)-Ictus, Instituto Salud Carlos III, 28029 Madrid, Spain; (B.Z.); (N.A.); (R.M.); (J.M.-M.)
- Neurology Department, Hospital Universitario de Navarra, 31008 Pamplona, Spain
| | - Nuria Aymerich
- Red de Investigación Cooperativa Orientada a Resultados en Salud (RICORS)-Ictus, Instituto Salud Carlos III, 28029 Madrid, Spain; (B.Z.); (N.A.); (R.M.); (J.M.-M.)
- Neurology Department, Hospital Universitario de Navarra, 31008 Pamplona, Spain
| | - Roberto Muñoz
- Red de Investigación Cooperativa Orientada a Resultados en Salud (RICORS)-Ictus, Instituto Salud Carlos III, 28029 Madrid, Spain; (B.Z.); (N.A.); (R.M.); (J.M.-M.)
- Neurology Department, Hospital Universitario de Navarra, 31008 Pamplona, Spain
| | - Rebeca Bermejo
- Neurointervencionist Radiology, Hospital Universitario de Navarra, 31008 Pamplona, Spain;
| | - Javier Marta-Moreno
- Red de Investigación Cooperativa Orientada a Resultados en Salud (RICORS)-Ictus, Instituto Salud Carlos III, 28029 Madrid, Spain; (B.Z.); (N.A.); (R.M.); (J.M.-M.)
- Neurology Department, Hospital Universitario Miguel Servet, Instituto de Investigación Sanitaria de Aragón (IIS-Aragon), 50009 Zaragoza, Spain
| | - Begoña López
- Instituto de Investigación Sanitaria de Navarra IdiSNA, 31008 Pamplona, Spain; (M.H.); (B.L.)
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Cardiovascular Diseases Program, Cima Universidad de Navarra, 31008 Pamplona, Spain
| | - Arantxa González
- Instituto de Investigación Sanitaria de Navarra IdiSNA, 31008 Pamplona, Spain; (M.H.); (B.L.)
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain
- Cardiovascular Diseases Program, Cima Universidad de Navarra, 31008 Pamplona, Spain
- Department of Pathology, Anatomy and Physiology, Universidad de Navarra, 31008 Pamplona, Spain
| | - Carmen Roncal
- Laboratory of Atherothrombosis, Cima Universidad de Navarra, 31008 Pamplona, Spain; (F.J.D.M.M.); (J.M.-E.); (S.U.G.); (J.A.R.); (J.A.P.-F.); (C.R.)
- Instituto de Investigación Sanitaria de Navarra IdiSNA, 31008 Pamplona, Spain; (M.H.); (B.L.)
- Centro de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV), Instituto de Salud Carlos III, 28029 Madrid, Spain
| | - Josune Orbe
- Laboratory of Atherothrombosis, Cima Universidad de Navarra, 31008 Pamplona, Spain; (F.J.D.M.M.); (J.M.-E.); (S.U.G.); (J.A.R.); (J.A.P.-F.); (C.R.)
- Instituto de Investigación Sanitaria de Navarra IdiSNA, 31008 Pamplona, Spain; (M.H.); (B.L.)
- Red de Investigación Cooperativa Orientada a Resultados en Salud (RICORS)-Ictus, Instituto Salud Carlos III, 28029 Madrid, Spain; (B.Z.); (N.A.); (R.M.); (J.M.-M.)
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Hansra GK, Jayasena T, Hosoki S, Poljak A, Lam BCP, Rust R, Sagare A, Zlokovic B, Thalamuthu A, Sachdev PS. Fluid biomarkers of the neurovascular unit in cerebrovascular disease and vascular cognitive disorders: A systematic review and meta-analysis. CEREBRAL CIRCULATION - COGNITION AND BEHAVIOR 2024; 6:100216. [PMID: 38510579 PMCID: PMC10951911 DOI: 10.1016/j.cccb.2024.100216] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/10/2023] [Revised: 01/30/2024] [Accepted: 02/16/2024] [Indexed: 03/22/2024]
Abstract
Background The disruption of the neurovascular unit (NVU), which maintains the integrity of the blood brain barrier (BBB), has been identified as a critical mechanism in the development of cerebrovascular and neurodegenerative disorders. However, the understanding of the pathophysiological mechanisms linking NVU dysfunction to the disorders is incomplete, and reliable blood biomarkers to measure NVU dysfunction are yet to be established. This systematic review and meta-analysis aimed to identify biomarkers associated with BBB dysfunction in large vessel disease, small vessel disease (SVD) and vascular cognitive disorders (VCD). Methods A literature search was conducted in PubMed, EMBASE, Scopus and PsychINFO to identify blood biomarkers related to dysfunction of the NVU in disorders with vascular pathologies published until 20 November 2023. Studies that assayed one or more specific markers in human serum or plasma were included. Quality of studies was assessed using the Newcastle-Ottawa Quality Assessment Scale. Effects were pooled and methodological heterogeneity examined using the random effects model. Results A total of 112 studies were included in this review. Where study numbers allowed, biomarkers were analysed using random effect meta-analysis for VCD (1 biomarker; 5 studies) and cerebrovascular disorders, including stroke and SVD (9 biomarkers; 29 studies) while all remaining biomarkers (n = 17 biomarkers; 78 studies) were examined through qualitative analysis. Results of the meta-analysis revealed that cerebrospinal fluid/serum albumin quotient (Q-Alb) reliably differentiates VCD patients from healthy controls (MD = 2.77; 95 % CI = 1.97-3.57; p < 0.0001) while commonly measured biomarkers of endothelial dysfunction (VEGF, VCAM-1, ICAM-1, vWF and E-selectin) and neuronal injury (NfL) were significantly elevated in vascular pathologies. A qualitative assessment of non-meta-analysed biomarkers revealed NSE, NfL, vWF, ICAM-1, VCAM-1, lipocalin-2, MMP-2 and MMP-9 levels to be upregulated in VCD, although these findings were not consistently replicated. Conclusions This review identifies several promising biomarkers of NVU dysfunction which require further validation. A panel of biomarkers representing multiple pathophysiological pathways may offer greater discriminative power in distinguishing possible disease mechanisms of VCD.
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Affiliation(s)
- Gurpreet Kaur Hansra
- Centre for Healthy Brain Ageing, Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Australia
| | - Tharusha Jayasena
- Centre for Healthy Brain Ageing, Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Australia
| | - Satoshi Hosoki
- Centre for Healthy Brain Ageing, Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Australia
- Department of Neurology, National Cerebral and Cardiovascular Centre, Suita, Japan
| | - Anne Poljak
- Centre for Healthy Brain Ageing, Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Australia
- Bioanalytical Mass Spectrometry Facility, Mark Wainwright Analytical Centre, University of New South Wales, NSW, Australia
| | - Ben Chun Pan Lam
- Centre for Healthy Brain Ageing, Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Australia
- School of Psychology and Public Health, La Trobe University, Melbourne, Australia
| | - Ruslan Rust
- Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Abhay Sagare
- Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Berislav Zlokovic
- Department of Physiology and Neuroscience, Zilkha Neurogenetic Institute, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Anbupalam Thalamuthu
- Centre for Healthy Brain Ageing, Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Australia
| | - Perminder S. Sachdev
- Centre for Healthy Brain Ageing, Discipline of Psychiatry and Mental Health, School of Clinical Medicine, University of New South Wales, Sydney, Australia
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Yan X, Xia P, Tong H, Lan C, Wang Q, Zhou Y, Zhu H, Jiang C. Development and Validation of a Dynamic Nomogram for Predicting 3-Month Mortality in Acute Ischemic Stroke Patients with Atrial Fibrillation. Risk Manag Healthc Policy 2024; 17:145-158. [PMID: 38250220 PMCID: PMC10799644 DOI: 10.2147/rmhp.s442353] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 01/11/2024] [Indexed: 01/23/2024] Open
Abstract
Background Acute ischemic stroke (AIS) in patients with atrial fibrillation (AF) carries a substantial risk of mortality, emphasizing the need for effective risk assessment and timely interventions. This study aimed to develop and validate a practical dynamic nomogram for predicting 3-month mortality in AIS patients with AF. Methods AIS patients with AF were enrolled and randomly divided into training and validation cohorts. The nomogram was developed based on independent risk factors identified by multivariate logistic regression analysis. The prediction performance of the nomogram was evaluated using the area under the receiver operating characteristic curve (AUC-ROC), calibration plots, decision curve analysis (DCA), and Kaplan-Meier survival analysis. Results A total of 412 patients with AIS and AF entered final analysis, 288 patients in the training cohort and 124 patients in the validation cohort. The nomogram was developed using age, baseline National Institutes of Health Stroke Scale score, early introduction of novel oral anticoagulants, and pneumonia as independent risk factors. The nomogram exhibited good discrimination both in the training cohort (AUC, 0.851; 95% CI, 0.802-0.899) and the validation cohort (AUC, 0.811; 95% CI, 0.706-0.916). The calibration plots, DCA and Kaplan-Meier survival analysis demonstrated that the nomogram was well calibrated and clinically useful, effectively distinguishing the 3-month survival status of patients with AIS and AF, respectively. The dynamic nomogram can be obtained at the website: https://yanxiaodi.shinyapps.io/3-monthmortality/. Conclusion The dynamic nomogram represents the first predictive model for 3-month mortality and may contribute to managing the mortality risk of patients with AIS and AF.
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Affiliation(s)
- Xiaodi Yan
- Department of Pharmacy, Nanjing Drum Tower Hospital, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, People’s Republic of China
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, People’s Republic of China
| | - Peng Xia
- Department of Pharmacy, Nanjing Drum Tower Hospital, School of Pharmacy, Nanjing Medical University, Nanjing, Jiangsu, People’s Republic of China
| | - Hanwen Tong
- Department of Emergency Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China
| | - Chen Lan
- Department of Pharmacy, Nanjing Drum Tower Hospital, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, People’s Republic of China
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, People’s Republic of China
| | - Qian Wang
- Department of Pharmacy, Nanjing Drum Tower Hospital, School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, People’s Republic of China
- School of Basic Medicine and Clinical Pharmacy, China Pharmaceutical University, Nanjing, Jiangsu, People’s Republic of China
| | - Yujie Zhou
- Department of Respiratory Critical Care Medicine, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China
| | - Huaijun Zhu
- Department of Pharmacy, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China
| | - Chenxiao Jiang
- Department of Pharmacy, Nanjing Drum Tower Hospital, Affiliated Hospital of Medical School, Nanjing University, Nanjing, Jiangsu, People’s Republic of China
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He C, Chu J, Li Y, Dang Y, Xue K, Cai C. Reassessing the Risk of Venous Thromboembolism (VTE) Events in Women. Clin Appl Thromb Hemost 2024; 30:10760296241305108. [PMID: 39648738 PMCID: PMC11626654 DOI: 10.1177/10760296241305108] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 11/11/2024] [Accepted: 11/19/2024] [Indexed: 12/10/2024] Open
Abstract
This research aims to reassess women's risk of venous thromboembolism (VTE) events. We conducted an in-depth analysis of the environmental risk factors associated with VTE and their interactions with gender while also exploring the genetic underpinnings of the disease. VTE is identified as a multifactorial condition influenced by a combination of genetic, non-predisposing, and predisposing environmental factors. We further investigated the genetic basis of VTE, focusing on the identification and analysis of risk loci, as well as gene interaction networks and genetic analyses, which offer significant insights into the pathogenesis of VTE. Recognizing the critical role of gender in assessing VTE risk and developing prevention strategies, this research underscores the necessity of adopting an integrated perspective that accounts for individual vulnerabilities at both genetic and environmental levels to formulate effective preventive measures.
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Affiliation(s)
- Changhuai He
- Department of Hepatobiliary Surgery, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, China
| | - Jie Chu
- Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yiqing Li
- Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yiping Dang
- Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Kaming Xue
- Department of Integrated Traditional Chinese and Western Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chuanqi Cai
- Department of Vascular Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Brinholi FF, Michelin AP, Matsumoto AK, de O Semeão L, Almulla AF, Supasitthumrong T, Tunvirachaisakul C, Barbosa DS, Maes M. Paraoxonase 1 status is a major Janus-faced component of mild and moderate acute ischemic stroke and consequent disabilities. Metab Brain Dis 2023; 38:2115-2131. [PMID: 37204661 DOI: 10.1007/s11011-023-01232-4] [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: 03/23/2023] [Accepted: 05/09/2023] [Indexed: 05/20/2023]
Abstract
AIMS This study aims to examine the associations between paraoxonase 1 (PON)1 status and acute ischemic stroke (AIS) and consequent disabilities. METHODS This study recruited 122 patients with AIS and 40 healthy controls and assessed the Q192R gene variants, arylesterase (AREase) and chloromethyl phenylacetate (CMPAase) activities, and high-density lipoprotein cholesterol (HDLc) in baseline conditions. AREase and CMPAase were measured 3 months later. The National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin score (mRS) were assessed at baseline and 3 and 6 months later. RESULTS Reduced CMPAase and increased AREase activities are significantly associated with AIS and mRS and NIHSS scores (baseline and 3 and 6 months later). The best predictor of AIS/disabilities was a decrease in the z-unit-based composite zCMPAase-zAREase score. Serum high density lipoprotein cholsterol (HDLc) was significantly correlated with CMPAase, but not AREase, activity and a lowered zCMPAase + zHDLc score was the second best predictor of AIS/disabilities. Regression analysis showed that 34.7% of the variance in baseline NIHSS was explained by zCMPAase-zAREase and zCMPAase + zHDLc composites, HDLc, and hypertension. Neural network analysis showed that stroke was differentiated from controls with an area under the ROC curve of 0.975 using both new composite scores, PON1 status, hypertension, dyslipidemia, previous stroke as body mass index. The PON1 Q192R genotype has many significant direct and mediated effects on AIS/disabilities, however, its overall effect was not significant. DISCUSSION PON1 status and the CMPAase-HDLc complex play key roles in AIS and its disabilities at baseline and 3 and 6 months later.
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Affiliation(s)
- Francis F Brinholi
- Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina, Brazil
| | - Ana Paula Michelin
- Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina, Brazil
| | - Andressa K Matsumoto
- Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina, Brazil
| | - Laura de O Semeão
- Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina, Brazil
| | - Abbas F Almulla
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Rd., Phayathai Road, Pathumwan, Bangkok, 10330, Thailand
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf, Iraq
| | - Thitiporn Supasitthumrong
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Rd., Phayathai Road, Pathumwan, Bangkok, 10330, Thailand
| | - Chavit Tunvirachaisakul
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Rd., Phayathai Road, Pathumwan, Bangkok, 10330, Thailand
| | - Décio S Barbosa
- Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina, Brazil
| | - Michael Maes
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Rd., Phayathai Road, Pathumwan, Bangkok, 10330, Thailand.
- Department of Psychiatry, Medical University of Plovdiv, Plovdiv, Bulgaria.
- Kyung Hee University, 26 Kyungheedae-ro, Dongdaemun-gu, Seoul, 02447, Korea.
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8
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Fuellen G, Walter U, Henze L, Böhmert J, Palmer D, Lee S, Schmitt CA, Rudolf H, Kowald A. Protein Biomarkers in Blood Reflect the Interrelationships Between Stroke Outcome, Inflammation, Coagulation, Adhesion, Senescence and Cancer. Cell Mol Neurobiol 2023; 43:1413-1424. [PMID: 35953740 PMCID: PMC9371377 DOI: 10.1007/s10571-022-01260-1] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 07/08/2022] [Indexed: 11/11/2022]
Abstract
The most important predictors for outcomes after ischemic stroke, that is, for health deterioration and death, are chronological age and stroke severity; gender, genetics and lifestyle/environmental factors also play a role. Of all these, only the latter can be influenced after the event. Recurrent stroke may be prevented by antiaggregant/anticoagulant therapy, angioplasty of high-grade stenoses, and treatment of cardiovascular risk factors. Blood cell composition and protein biomarkers such as C-reactive protein or interleukins in serum are frequently considered as biomarkers of outcome. Here we aim to provide an up-to-date protein biomarker signature that allows a maximum of mechanistic understanding, to predict health deterioration following stroke. We thus surveyed protein biomarkers that were reported to be predictive for outcome after ischemic stroke, specifically considering biomarkers that predict long-term outcome (≥ 3 months) and that are measured over the first days following the event. We classified the protein biomarkers as immune‑inflammatory, coagulation-related, and adhesion-related biomarkers. Some of these biomarkers are closely related to cellular senescence and, in particular, to the inflammatory processes that can be triggered by senescent cells. Moreover, the processes that underlie inflammation, hypercoagulation and cellular senescence connect stroke to cancer, and biomarkers of cancer-associated thromboembolism, as well as of sarcopenia, overlap strongly with the biomarkers discussed here. Finally, we demonstrate that most of the outcome-predicting protein biomarkers form a close-meshed functional interaction network, suggesting that the outcome after stroke is partially determined by an interplay of molecular processes relating to inflammation, coagulation, cell adhesion and cellular senescence.
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Affiliation(s)
- Georg Fuellen
- Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center and Centre for Transdisciplinary Neurosciences Rostock and Research Focus Oncology, Rostock and Ageing of Individuals and Society, Interdisciplinary Faculty, Rostock University, Rostock, Germany.
| | - Uwe Walter
- Department of Neurology, Rostock University Medical Center and Centre for Transdisciplinary Neurosciences Rostock, Rostock, Germany
| | - Larissa Henze
- Department of Medicine, Clinic III, Hematology, Oncology, Palliative Medicine, Rostock University Medical Center and Research Focus Oncology, Rostock, Germany
| | - Jan Böhmert
- Department of Neurology, Rostock University Medical Center and Centre for Transdisciplinary Neurosciences Rostock, Rostock, Germany
| | - Daniel Palmer
- Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center and Centre for Transdisciplinary Neurosciences Rostock and Research Focus Oncology, Rostock and Ageing of Individuals and Society, Interdisciplinary Faculty, Rostock University, Rostock, Germany
| | - Soyoung Lee
- Medical Department of Hematology, Oncology and Tumor Immunology, and Molekulares Krebsforschungszentrum - MKFZ, Charité - Universitätsmedizin, Campus Virchow Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Robert-Rössle-Straße 10, 13125, Berlin, Germany
- Johannes Kepler University, Altenbergerstraße 69, 4040, Linz, Austria
- Institute of Tumor Biology, Kepler University Hospital, Krankenhausstraße 9, 4021, Linz, Austria
| | - Clemens A Schmitt
- Medical Department of Hematology, Oncology and Tumor Immunology, and Molekulares Krebsforschungszentrum - MKFZ, Charité - Universitätsmedizin, Campus Virchow Klinikum, Augustenburger Platz 1, 13353, Berlin, Germany
- Max-Delbrück-Center for Molecular Medicine in the Helmholtz Association, Robert-Rössle-Straße 10, 13125, Berlin, Germany
- Johannes Kepler University, Altenbergerstraße 69, 4040, Linz, Austria
- Department of Hematology and Oncology, Kepler University Hospital, Krankenhausstraße 9, 4021, Linz, Austria
| | - Henrik Rudolf
- Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center and Centre for Transdisciplinary Neurosciences Rostock and Research Focus Oncology, Rostock and Ageing of Individuals and Society, Interdisciplinary Faculty, Rostock University, Rostock, Germany
| | - Axel Kowald
- Institute for Biostatistics and Informatics in Medicine and Ageing Research, Rostock University Medical Center and Centre for Transdisciplinary Neurosciences Rostock and Research Focus Oncology, Rostock and Ageing of Individuals and Society, Interdisciplinary Faculty, Rostock University, Rostock, Germany.
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9
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de Araújo MCM, Alfieri DF, Lehmann ALCF, Luz TF, Trevisani ER, Nagao MR, de Freitas LB, Simão ANC, Reiche EMV. Baseline severity and soluble vascular cell adhesion molecule 1 (sVCAM-1) as biomarker predictors of short-term mortality in acute ischemic stroke. Metab Brain Dis 2023; 38:657-670. [PMID: 36409382 DOI: 10.1007/s11011-022-01116-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 10/28/2022] [Indexed: 11/22/2022]
Abstract
The aim was to investigate the association between plasma levels of cellular adhesion molecules (CAMs) and risk factors, subtypes, severity and short-term mortality of acute ischemic stroke (IS), and to identify a panel of biomarkers to predict short-term mortality after IS. The prospective study evaluated 132 IS patients within 24 h of their hospital admission. The baseline IS severity was assessed using the National Institutes Health Stroke Scale (NIHSS) and categorized as mild (NIHSS < 5), moderate (NIHSS 5-14) and severe (NIHSS ≥ 15). After three-month follow-up, the disability was assessed using the modified Rankin Scale (mRS); moreover, the patients were classified as survivors and non-survivors. Baseline inflammatory and anti-inflammatory cytokines and soluble CAMs were evaluated. Twenty-nine (21.9%) IS patients were non-survivors and showed higher NIHSS and soluble vascular cellular adhesion molecule 1 (sVCAM-1) than the survivors. The sVCAM-1 levels positively correlated with age, homocysteine, severity, and disability. The model #3 combining sVCAM-1 and NIHSS showed better results to predict short-term mortality with an area under the curve receiving operating characteristics (AUC/ROC) of 0.8841 [95% confidence interval (CI): 0.795-0.941] than the models with sVCAM-1 and NIHSS alone, with positive predictive value of 68.0%, negative predictive value of 91.3%, and accuracy of 86.5%. In conclusion, the combined model with baseline severity of IS and sVCAM-1 levels can early predict the prognosis of IS patients who may benefit with therapeutic measures of personalized therapy that taken into account these biomarkers. Moreover, this result suggests that VCAM-1 might be a potential target for the therapeutic strategies in IS.
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Affiliation(s)
- Maria Caroline Martins de Araújo
- Clinical and Laboratory Pathophysiology Postgraduate Program, Health Sciences Center, State University of Londrina, Paraná, Brazil
| | - Daniela Frizon Alfieri
- Department of Pharmaceutical Sciences, Health Sciences Center, State University of Londrina, Paraná, Brazil
| | - Ana Lucia Cruz Fürstenberger Lehmann
- Department of Clinical Medicine, Health Science Center and Radiology Service of the University Hospital, State University of Londrina, Paraná, Brazil
| | - Tamires Flauzino Luz
- Laboratory of Research in Applied Immunology, Health Sciences Center, State University of Londrina, Paraná, Brazil
| | - Emmanuelle Roberto Trevisani
- Laboratory of Research in Applied Immunology, Health Sciences Center, State University of Londrina, Paraná, Brazil
| | - Maisa Rocha Nagao
- Laboratory of Research in Applied Immunology, Health Sciences Center, State University of Londrina, Paraná, Brazil
| | - Leonardo Bodner de Freitas
- Laboratory of Research in Applied Immunology, Health Sciences Center, State University of Londrina, Paraná, Brazil
| | - Andrea Name Colado Simão
- Laboratory of Research in Applied Immunology, Health Sciences Center, State University of Londrina, Paraná, Brazil
- Department of Pathology, Clinical Analysis, and Toxicology, Health Sciences Center, State University of Londrina, Av. Robert Koch, 60, Londrina, Paraná, CEP 86.038-440, Brazil
| | - Edna Maria Vissoci Reiche
- Laboratory of Research in Applied Immunology, Health Sciences Center, State University of Londrina, Paraná, Brazil.
- Department of Pathology, Clinical Analysis, and Toxicology, Health Sciences Center, State University of Londrina, Av. Robert Koch, 60, Londrina, Paraná, CEP 86.038-440, Brazil.
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10
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Stroke mortality prediction using machine learning: systematic review. J Neurol Sci 2023; 444:120529. [PMID: 36580703 DOI: 10.1016/j.jns.2022.120529] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2022] [Revised: 11/30/2022] [Accepted: 12/18/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND AND AIMS Accurate prognostication of stroke may help in appropriate therapy and rehabilitation planning. In the past few years, several machine learning (ML) algorithms were applied for prediction of stroke outcomes. We aimed to examine the performance of machine learning-based models for the prediction of mortality after stroke, as well as to identify the most prominent factors for mortality. MATERIALS AND METHODS We searched MEDLINE/PubMed and Web of Science databases for original publications on machine learning applications in stroke mortality prediction, published between January 1, 2011, and October 27, 2022. Risk of bias and applicability were evaluated using the tailored QUADAS-2 tool. RESULTS Of the 1015 studies retrieved, 28 studies were included. Twenty-Five studies were retrospective. The ML models demonstrated a favorable range of AUC for mortality prediction (0.67-0.98). In most of the articles, the models were applied for short-term post stroke mortality. The number of explanatory features used in the models to predict mortality ranged from 5 to 200, with substantial overlap in the variables included. Age, high BMI and high NIHSS score were identified as important predictors for mortality. Almost all studies had a high risk of bias in at least one category and concerns regarding applicability. CONCLUSION Using machine learning, data available at the time of admission may aid in stroke mortality prediction. Notwithstanding, current research is based on few preliminary works with high risk of bias and high heterogeneity. Thus, future prospective, multicenter studies with standardized reports are crucial to firmly establish the usefulness of the algorithms in stroke prognostication.
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11
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Maes M, Brinholi FF, Michelin AP, Matsumoto AK, de Oliveira Semeão L, Almulla AF, Supasitthumrong T, Tunvirachaisakul C, Barbosa DS. In Mild and Moderate Acute Ischemic Stroke, Increased Lipid Peroxidation and Lowered Antioxidant Defenses Are Strongly Associated with Disabilities and Final Stroke Core Volume. Antioxidants (Basel) 2023; 12:188. [PMID: 36671047 PMCID: PMC9854933 DOI: 10.3390/antiox12010188] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2022] [Revised: 01/06/2023] [Accepted: 01/06/2023] [Indexed: 01/15/2023] Open
Abstract
In acute ischemic stroke (AIS), there are no data on whether oxidative stress biomarkers have effects above and beyond known risk factors and measurements of stroke volume. This study was conducted in 122 mild-moderate AIS patients and 40 controls and assessed the modified ranking scale (mRS) at baseline, and 3 and 6 months later. We measured lipid hydroperoxides (LOOH), malondialdehyde (MDA), advanced oxidation protein products, paraoxonase 1 (PON1) activities and PON1 Q192R genotypes, high density lipoprotein cholesterol (HDL), sulfhydryl (-SH) groups), and diffusion-weighted imaging (DWI) stroke volume and fluid-attenuated inversion recovery (FLAIR) signal intensity. We found that (a) AIS is characterized by lower chloromethyl acetate CMPAase PON1 activity, HDL and -SH groups and increased LOOH and neurotoxicity (a composite of LOOH, inflammatory markers and glycated hemoglobin); (b) oxidative and antioxidant biomarkers strongly and independently predict mRS scores 3 and 6 months later, DWI stroke volume and FLAIR signal intensity; and (c) the PON1 Q192R variant has multiple effects on stroke outcomes that are mediated by its effects on antioxidant defenses and lipid peroxidation. Lipid peroxidation and lowered -SH and PON1-HDL activity are drug targets to prevent AIS and consequent neurodegenerative processes and increased oxidative reperfusion mediators due to ischemia-reperfusion injury.
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Affiliation(s)
- Michael Maes
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Rd., Phayathai Road, Pathumwan, Bangkok 10330, Thailand
- Cognitive Fitness and Technology Research Unit, Faculty of Medicine, Chulalongkorn University, Bangkok 10330, Thailand
- Department of Psychiatry, Medical University of Plovdiv, 4000 Plovdiv, Bulgaria
- Research Institute, Medical University Plovdiv, 4000 Plovdiv, Bulgaria
- Deakin University, IMPACT-the Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Barwon Health, Geelong, VIC 3220, Australia
| | - Francis F. Brinholi
- Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina 86057-970, PR, Brazil
| | - Ana Paula Michelin
- Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina 86057-970, PR, Brazil
| | - Andressa K. Matsumoto
- Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina 86057-970, PR, Brazil
| | - Laura de Oliveira Semeão
- Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina 86057-970, PR, Brazil
| | - Abbas F. Almulla
- Medical Laboratory Technology Department, College of Medical Technology, The Islamic University, Najaf 54001, Iraq
| | - Thitiporn Supasitthumrong
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Rd., Phayathai Road, Pathumwan, Bangkok 10330, Thailand
| | - Chavit Tunvirachaisakul
- Department of Psychiatry, Faculty of Medicine, Chulalongkorn University, 1873 Rama 4 Rd., Phayathai Road, Pathumwan, Bangkok 10330, Thailand
| | - Decio S. Barbosa
- Health Sciences Graduate Program, Health Sciences Center, State University of Londrina, Londrina 86057-970, PR, Brazil
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12
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Maes MHJ, Stoyanov D. False dogmas in mood disorders research: Towards a nomothetic network approach. World J Psychiatry 2022; 12:651-667. [PMID: 35663296 PMCID: PMC9150032 DOI: 10.5498/wjp.v12.i5.651] [Citation(s) in RCA: 25] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/11/2021] [Revised: 10/07/2021] [Accepted: 04/25/2022] [Indexed: 02/06/2023] Open
Abstract
The current understanding of major depressive disorder (MDD) and bipolar disorder (BD) is plagued by a cacophony of controversies as evidenced by competing schools to understand MDD/BD. The DSM/ICD taxonomies have cemented their status as the gold standard for diagnosing MDD/BD. The aim of this review is to discuss the false dogmas that reign in current MDD/BD research with respect to the new, data-driven, machine learning method to model psychiatric illness, namely nomothetic network psychiatry (NNP). This review discusses many false dogmas including: MDD/BD are mind-brain disorders that are best conceptualized using a bio-psycho-social model or mind-brain interactions; mood disorders due to medical disease are attributable to psychosocial stress or chemical imbalances; DSM/ICD are the gold standards to make the MDD/BD diagnosis; severity of illness should be measured using rating scales; clinical remission should be defined using threshold values on rating scale scores; existing diagnostic BD boundaries are too restrictive; and mood disorder spectra are the rule. In contrast, our NNP models show that MDD/BD are not mind-brain or psycho-social but systemic medical disorders; the DSM/ICD taxonomies are counterproductive; a shared core, namely the reoccurrence of illness (ROI), underpins the intertwined recurrence of depressive and manic episodes and suicidal behaviors; mood disorders should be ROI-defined; ROI mediates the effects of nitro-oxidative stress pathways and early lifetime trauma on the phenome of mood disorders; severity of illness and treatment response should be delineated using the NNP-derived causome, pathway, ROI and integrated phenome scores; and MDD and BD are the same illness.
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Affiliation(s)
- Michael HJ Maes
- Department of Psychiatry, Chulalongkorn University, Bangkok 10330, Thailand
| | - Drozdstoy Stoyanov
- Department of Psychiatry, Medical University Plovdiv, Plovdiv 4000, Bulgaria
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13
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The Assessment of Endovascular Therapies in Ischemic Stroke: Management, Problems and Future Approaches. J Clin Med 2022; 11:jcm11071864. [PMID: 35407472 PMCID: PMC8999747 DOI: 10.3390/jcm11071864] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2022] [Revised: 03/18/2022] [Accepted: 03/25/2022] [Indexed: 02/06/2023] Open
Abstract
Ischemic stroke accounts for over 80% of all strokes and is one of the leading causes of mortality and permanent disability worldwide. Intravenous administration of recombinant tissue plasminogen activator (rt-PA) is an approved treatment strategy for acute ischemic stroke of large arteries within 4.5 h of onset, and mechanical thrombectomy can be used for large arteries occlusion up to 24 h after onset. Improving diagnostic work up for acute treatment, reducing onset-to-needle time and urgent radiological access angiographic CT images (angioCT) and Magnetic Resonance Imaging (MRI) are real problems for many healthcare systems, which limits the number of patients with good prognosis in real world compared to the results of randomized controlled trials. The applied endovascular procedures demonstrated high efficacy, but some cellular mechanisms, following reperfusion, are still unknown. Changes in the morphology and function of mitochondria associated with reperfusion and ischemia-reperfusion neuronal death are still understudied research fields. Moreover, future research is needed to elucidate the relationship between continuously refined imaging techniques and the variable structure or physical properties of the clot along with vascular permeability and the pleiotropism of ischemic reperfusion lesions in the penumbra, in order to define targeted preventive procedures promoting long-term health benefits.
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14
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Li G, Wang C, Wang S, Hao Y, Xiong Y, Zhao X. Clinical Significance and Dynamic Change of Coagulation Parameters in Ischemic Stroke Patients Treated with Intravenous Thrombolysis. Clin Appl Thromb Hemost 2022; 28:10760296221121287. [PMID: 36040718 PMCID: PMC9434657 DOI: 10.1177/10760296221121287] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/27/2022] Open
Abstract
Objective Investigations on coagulation parameters including fibrinogen (Fbg),
fibrinogen degradation products (FDP), and D-dimer in ischemic stroke
patients treated with intravenous thrombolysis are insufficient. We aimed to
investigate the association between in-hospital clinical outcomes and the
coagulation parameters at different time points in ischemic stroke patients
treated with intravenous tissues plasminogen activator (IV tPA). Methods We retrospectively enrolled patients who received IV tPA therapy within 4.5 h
from symptoms onset. Demographics, clinical characteristics, imaging
measures, and the discharge mRS score were collected. Multivariable logistic
regression analyses were performed to test whether coagulation parameters
were independent predictors for the in-hospital clinical outcomes. We also
employed machine learning models to investigate whether coagulation
parameters were able to improve the prediction of favorable functional
outcomes. Results One hundred and fifty-two patients treated with IV tPA were included. Among
the coagulation parameters, low D-dimers at 48 h proved to be an independent
predictor of favorable functional outcome (adjusted odd ratio 0.24, 95%
confidential intervals 0.06-0.92, P = 0.04). The AUC of D-dimer at 48 h to
predict favorable functional outcome was 0.73 (0.60-0.87) and the optimal
cut-off value was 0.92 (sensitivity 0.69, specificity 0.78). Machine
learning models with D-dimer at 48 h had superior performance in predicting
favorable functional outcomes and among the input variables in the machine
learning models, D-dimer at 48 h showed the highest weight in predicting mRS
0-1 at discharge (38.44%). Conclusion Increased levels of D-dimer at 48 h was associated with lower proportion of
favorable functional outcomes in acute ischemic stroke patients with
intravenous thrombolysis.
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Affiliation(s)
- Guangshuo Li
- Department of Neurology, 105738Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Chuanying Wang
- Department of Neurology, 105738Beijing Tiantan Hospital, Capital Medical University, Beijing, China
| | - Shang Wang
- Department of Neurology, 105738Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Yahui Hao
- China National Clinical Research Center for Neurological Diseases, Beijing, China
| | - Yunyun Xiong
- Department of Neurology, 105738Beijing Tiantan Hospital, Capital Medical University, Beijing, China.,China National Clinical Research Center for Neurological Diseases, Beijing, China.,Chinese Institute for Brain Research, China
| | - Xingquan Zhao
- Department of Neurology, 105738Beijing Tiantan Hospital, Capital Medical University, Beijing, China
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15
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New Drug Targets to Prevent Death Due to Stroke: A Review Based on Results of Protein-Protein Interaction Network, Enrichment, and Annotation Analyses. Int J Mol Sci 2021; 22:ijms222212108. [PMID: 34829993 PMCID: PMC8619767 DOI: 10.3390/ijms222212108] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2021] [Revised: 10/30/2021] [Accepted: 11/03/2021] [Indexed: 02/07/2023] Open
Abstract
This study used established biomarkers of death from ischemic stroke (IS) versus stroke survival to perform network, enrichment, and annotation analyses. Protein-protein interaction (PPI) network analysis revealed that the backbone of the highly connective network of IS death consisted of IL6, ALB, TNF, SERPINE1, VWF, VCAM1, TGFB1, and SELE. Cluster analysis revealed immune and hemostasis subnetworks, which were strongly interconnected through the major switches ALB and VWF. Enrichment analysis revealed that the PPI immune subnetwork of death due to IS was highly associated with TLR2/4, TNF, JAK-STAT, NOD, IL10, IL13, IL4, and TGF-β1/SMAD pathways. The top biological and molecular functions and pathways enriched in the hemostasis network of death due to IS were platelet degranulation and activation, the intrinsic pathway of fibrin clot formation, the urokinase-type plasminogen activator pathway, post-translational protein phosphorylation, integrin cell-surface interactions, and the proteoglycan-integrin extracellular matrix complex (ECM). Regulation Explorer analysis of transcriptional factors shows: (a) that NFKB1, RELA and SP1 were the major regulating actors of the PPI network; and (b) hsa-mir-26-5p and hsa-16-5p were the major regulating microRNA actors. In conclusion, prevention of death due to IS should consider that current IS treatments may be improved by targeting VWF, the proteoglycan-integrin-ECM complex, TGF-β1/SMAD, NF-κB/RELA and SP1.
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16
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Zhang Z, Mei Y, Xiong M, Lu F, Zhao X, Zhu J, He B. Genetic Variation of Inflammatory Genes to Ischemic Stroke Risk in a Chinese Han Population. Pharmgenomics Pers Med 2021; 14:977-986. [PMID: 34413669 PMCID: PMC8370589 DOI: 10.2147/pgpm.s320483] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2021] [Accepted: 07/21/2021] [Indexed: 01/01/2023] Open
Abstract
Background Inflammation proteins play an important role in stroke occurrence. IL1A, IL1B, PTGS2, MMP2, and MMP9 were the mediators involved in the immune response, and the association of these genetic variations with ischemic stroke (IS) risk was still unclear. Methods To investigate the susceptibility of genetic variations of IL1A, IL1B, PTGS2, MMP2, and MMP9 to IS risk, we performed a case–control study involving 299 patients and 300 controls in a Chinese population. Thirteen genetic variations of investigated genes of all participants were genotyped using an improved multiplex ligase detection–reaction technique. Results No SNP in all genes showed an association with overall IS. However, in subgroup analysis, PTGS2 rs689466 (dominant model: CT vs TT – ORadjusted= 2.51, 95% CI: 1.22–5.16, p = 0.012; co-dominant model: CT/CC vs TT – ORadjusted= 2.53, 95% CI: 1.26–5.07, p = 0.009; additive model – ORadjusted= 2.26, 95% CI: 1.19–4.28, p = 0.013) and rs5275 (dominant model: GG vs AA – ORadjusted= 0.31, 95% CI: 0.12–0.80, p = 0.016; co-dominant model: GA/GG vs AA – ORadjusted= 0.45, 95% CI: 0.21–0.95, p = 0.036; additive model – ORadjusted= 0.60, 95% CI: 0.39–0.92, p = 0.020) were associated with IS type of small-vessel occlusion. Conclusion Our study suggested that PTGS2 rs689466 C and rs5275 A were potentially associated with IS subtype of small-vessel occlusion. Our result should be confirmed with further large sample sized studies.
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Affiliation(s)
- Zhongqiu Zhang
- School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, Jiangsu Province, People's Republic of China.,Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu Province, People's Republic of China
| | - Yanping Mei
- Department of Laboratory Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu Province, People's Republic of China
| | - Mengqiu Xiong
- Department of Laboratory Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu Province, People's Republic of China
| | - Fang Lu
- School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, Jiangsu Province, People's Republic of China.,Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu Province, People's Republic of China
| | - Xianghong Zhao
- School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, Jiangsu Province, People's Republic of China.,Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu Province, People's Republic of China
| | - Junrong Zhu
- School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, Jiangsu Province, People's Republic of China.,Department of Pharmacy, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu Province, People's Republic of China
| | - Bangshun He
- School of Basic Medicine & Clinical Pharmacy, China Pharmaceutical University, Nanjing, 211198, Jiangsu Province, People's Republic of China.,Department of Laboratory Medicine, Nanjing First Hospital, Nanjing Medical University, Nanjing, 210006, Jiangsu Province, People's Republic of China
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