Retinal Microvascular Changes in Subtypes of Ischemic Stroke

Aims: Retinal microvasculature shares prominent similarities with the brain vasculature. We aimed to assess the association between retinal microvasculature and subtypes of ischemic stroke.Method: We consecutively enrolled ischemic stroke patients within 7 days of onset, who met the criteria of subtype of atherothrombosis (AT), small artery disease (SAD), or cardioembolism (CE) according to a modified version of the Trial of Org 10172 in Acute Stroke Treatment (NEW-TOAST). Digital fundus photographs were taken within 72 h of hospital admission using a digital camera (Topcon TRC-50DX), and fundus photographs were semi-automatically measured by software (Canvus 14 and NeuroLucida) for retinal vasculature parameters.Results: A total of 141 patients were enrolled, including 72 with AT, 54 with SAD, and 15 with CE. AT subtype patients had the widest mean venular diameter within 0.5–1.0 disk diameter (MVD0.5−1.0DD) followed by SAD and CE subtypes (86.37 ± 13.49 vs. 83.55 ± 11.54 vs. 77.90 ± 8.50, respectively, P = 0.047); CE subtype patients had the highest mean arteriovenous ratio within 0.5–1.0 disk diameter (MAVR0.5−1.0DD) followed by the AT and SAD subtype groups (0.97 ± 0.03 vs. 0.89 ± 0.99 vs. 0.89 ± 0.11, respectively, P = 0.010); SAD subtype patients were found with the highest mean venular tortuosity within 0.0–2.0 disk diameter (MVT0.0−2.0DD) followed by the AT and CE subtypes (1.0294 ± 0.0081 vs. 1.0259 ± 0.0084 vs. 1.0243 ± 0.0066, respectively, P = 0.024). After adjusting for clinic characteristics, MVD0.5−1.0DD was significantly different among AT, SAD, and CE subtypes (P = 0.033). By receiver operating characteristic curve analysis, MVD0.5−1.0DD predicted the AT subtype (area 0.690, 95% confidence interval, 0.566–0.815), with a cutoff value of 82.23 μm (sensitivity 61.1%, specificity 73.3%).Conclusion: Retinal MVD0.5−1.0DD (>82.23 μm) might be associated with the AT stroke subtype; however, we need large-scale prospective studies in future to explore the underlying mechanism and causal explanation for this finding.

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Abstract 3884: Stroke Subtypes in Hispanic Patients in the NINDS Stroke Genetics Network (SiGN): A Comparison of Two Classification Systems

Stroke ◽

10.1161/str.43.suppl_1.a3884 ◽

2012 ◽

Vol 43 (suppl_1) ◽

Author(s):

Michael Katsnelson ◽

Tatjana Rundek ◽

Ralph Sacco ◽

Hannah Gardener ◽

Shaneela Malik ◽

...

Keyword(s):

Risk Factors ◽

Ischemic Stroke ◽

Classification Systems ◽

Blood Collection ◽

Large Artery ◽

Stroke Subtype ◽

Reliable Determination ◽

Stroke Treatment ◽

Stroke Subtypes ◽

Small Artery Occlusion

Objectives: Identification of gene variants of stroke subtypes is important for the development of tailored ischemic stroke therapies among various ethnic groups. Valid and reliable determination of ischemic stroke subtype is essential for achieving this goal and to standardize a classification scheme across multi-center studies and different populations. Causative Classification System for Ischemic Stroke (CCS) is a novel computerized subclassification tool developed to improve reliability and accuracy of classifying stroke types. The CCS algorithm relies on both phenotypic and causative stroke variables. A Hispanic subset of the SiGN, an important and distinct target population with greater risk of certain stroke subtypes, was evaluated with Trial of Org 10172 in Acute Stroke Treatment (TOAST) and CCS and the agreement between the two classification systems was analyzed. Methods: Over 6000 subjects at 15 sites across US and Europe were enrolled, with TOAST and CCS locally adjudicated. Blood collection and central data quality control (10% central readjudication) were performed on all participants. A subset of Hispanics was analyzed for the purpose of this study and the agreement between the TOAST and CCS were assessed by kappa statistic. Findings: Hispanics (n=595, 10.9%) compared to non-Hispanics (n=5457) were more likely to be younger (63.7 vs. 64.0), male (55% vs. 46%) and have fewer of the traditional stroke risk factors HTN (54% vs. 64%), Afib (11% vs. 14%), DM(23% vs. 25%), CAD(16% vs. 20%) and smoking(19% vs. 22%). While the TOAST showed no differences between stroke subtypes for Hispanic vs. non-Hispanics, in CCS, Hispanics were classified with more of large vessel (22% vs. 20%), cardioembolic (37% vs. 30%) and small vessel strokes (13% vs. 9%) and fewer with undetermined etiology (28% vs. 40%) as compared to non-Hispanics. TOAST and CCS offered moderate correlation across all stroke types in Hispanics: kappa of 0.66 for large artery atherosclerosis, 0.58 for cardioembolic, and 0.58 for small artery occlusion. Conclusion: CCS offers a more sensitive and accurate system for subphenotyping of strokes in Hispanics who tended to have relatively fewer risk factors and unclassified strokes. Further studies correlating the two classification systems and their relation to genotyping data are warranted.

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DNA Content in Ischemic Stroke Thrombi Can Help Identify Cardioembolic Strokes Among Strokes of Undetermined Cause

Stroke ◽

10.1161/strokeaha.120.029134 ◽

2020 ◽

Vol 51 (9) ◽

pp. 2810-2816

Author(s):

Lucas Di Meglio ◽

Jean-Philippe Desilles ◽

Mialitiana Solonomenjanahary ◽

Julien Labreuche ◽

Véronique Ollivier ◽

...

Keyword(s):

Ischemic Stroke ◽

Dna Content ◽

Operating Characteristic ◽

Characteristic Curve ◽

Embolic Stroke ◽

Unique Identifier ◽

Stroke Treatment ◽

Glycoprotein Vi ◽

Biochemical Assays ◽

Toast Classification

Background and Purpose: Identification of acute ischemic stroke (AIS) cause is crucial for guidance of secondary prevention. Previous studies have yielded inconsistent results regarding possible correlations between AIS cause and thrombus composition, as assessed by semiquantitative histological analysis. Here, we performed a correlation analysis between AIS cause and AIS thrombus cellular composition and content, as assessed using quantitative biochemical assays. Methods: Homogenates of 250 patients with AIS thrombi were prepared by mechanical grinding. Platelet, red blood cell, and leukocyte content of AIS thrombi were estimated by quantification of GP (glycoprotein) VI, heme, and DNA in thrombus homogenates. AIS cause was defined as cardioembolic, noncardioembolic, or embolic stroke of undetermined source, according to the TOAST classification (Trial of ORG 10172 in Acute Stroke Treatment). Results: Cardioembolic thrombi were richer in DNA (35.8 versus 13.8 ng/mg, P <0.001) and poorer in GPVI (0.104 versus 0.117 ng/mg, P =0.045) than noncardioembolic ones. The area under the receiver operating characteristic curve of DNA content to discriminate cardioembolic thrombi from noncardioembolic was 0.72 (95% CI, 0.63–0.81). With a threshold of 44.7 ng DNA/mg thrombus, 47% of thrombi from undetermined cause would be classified as cardioembolic with a specificity of 90%. Conclusions: Thrombus DNA content may provide an accurate biomarker for identification of cardioembolic thrombi in patients with AIS with embolic stroke of undetermined source. Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT03268668.

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Exome Array Analysis of Early-Onset Ischemic Stroke

Stroke ◽

10.1161/strokeaha.120.031357 ◽

2020 ◽

Vol 51 (11) ◽

pp. 3356-3360

Author(s):

Thomas Jaworek ◽

Kathleen A. Ryan ◽

Brady J. Gaynor ◽

Patrick F. McArdle ◽

Oscar C. Stine ◽

...

Keyword(s):

Ischemic Stroke ◽

Early Onset ◽

Large Scale ◽

Genome Wide Association Study ◽

Meta Analysis ◽

Population Level ◽

Small Vessel ◽

Stroke Treatment ◽

Functional Variants ◽

Individual Snps

Background and Purpose: The genetic contribution to ischemic stroke may include rare- or low-frequency variants of high-penetrance and large-effect sizes. Analyses focusing on early-onset disease, an extreme-phenotype, and on the exome, the protein-coding portion of genes, may increase the likelihood of identifying such rare functional variants. To evaluate this hypothesis, we implemented a 2-stage discovery and replication design, and then addressed whether the identified variants also associated with older-onset disease. Methods: Discovery was performed in UMD-GEOS Study (University of Maryland-Genetics of Early-Onset Stroke), a biracial population-based study of first-ever ischemic stroke cases 15 to 49 years of age (n=723) and nonstroke controls (n=726). All participants had prior GWAS (Genome Wide Association Study) and underwent Illumina exome-chip genotyping. Logistic-regression was performed to test single-variant associations with all-ischemic stroke and TOAST (Trial of ORG 10172 in Acute Stroke Treatment) subtypes in Whites and Blacks. Population level results were combined using meta-analysis. Gene-based aggregation testing and meta-analysis were performed using seqMeta. Covariates included age and gender, and principal-components for population structure. Pathway analyses were performed across all nominally associated genes for each stroke outcome. Replication was attempted through lookups in a previously reported meta-analysis of early-onset stroke and a large-scale stroke genetics study consisting of primarily older-onset cases. Results: Gene burden tests identified a significant association with NAT10 in small-vessel stroke ( P =3.79×10 − 6 ). Pathway analysis of the top 517 genes ( P <0.05) from the gene-based analysis of small-vessel stroke identified several signaling and metabolism-related pathways related to neurotransmitter, neurodevelopmental notch-signaling, and lipid/glucose metabolism. While no individual SNPs reached chip-wide significance ( P <2.05×10 −7 ), several were near, including an intronic variant in LEXM (rs7549251; P =4.08×10 − 7 ) and an exonic variant in TRAPPC11 (rs67383011; P =5.19×10 − 6 ). Conclusions: Exome-based analysis in the setting of early-onset stroke is a promising strategy for identifying novel genetic risk variants, loci, and pathways.

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Abstract 2597: Centralized and Study-specific Phenotyping in a Large-scale Stroke Genetics Study: An Analysis from the NINDS Stroke Genetics Network (SiGN)

Stroke ◽

10.1161/str.43.suppl_1.a2597 ◽

2012 ◽

Vol 43 (suppl_1) ◽

Author(s):

Bradford B Worrall ◽

Alejandro Rabinstein ◽

Dale M Gamble ◽

Kevin M Barrett ◽

Shaneela Malik ◽

...

Keyword(s):

Ischemic Stroke ◽

Large Scale ◽

Association Studies ◽

Web Based ◽

Stroke Treatment ◽

Automated Algorithm ◽

Genome Association ◽

Whole Genome Association ◽

Toast Classification ◽

User Friendly

Background: The Stroke Genetics Network (SiGN) funded by the NINDS aims to identify genetic risk factors in ischemic stroke using whole-genome association studies (GWAS). High quality phenotyping is crucial to successful application of GWAS. As a heterogenous disorder, stroke poses specific challenges. The Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification is a broadly used, but its validity is challenged especially when performed by multiple investigators with differing interpretations of the system. The Causative Classification System for Ischemic Stroke (CCS) system is a new, web-based, and computerized algorithm that integrates clinical, diagnostic, and etiologic stroke characteristics in an evidence-based manner ( ccs.mgh.harvard.edu ) to generate subtypes. Methods: In planning the SiGN proposal, a sample of 20 coded charts were collected from a subset of participating studies to assess feasibility of central adjudication and comparability to study-specific TOAST. Two central adjudicators reviewed all records and generated TOAST and CCS subtypes. These were compared to study-specific TOAST subtype and the CCS phenotype generated for SiGN by local trained adjudicators. CCS data is now available for 7134 included cases using both a 5 and a 7 category system as defined in the table . Results: All 4 phenotypes were available for 115 ischemic stroke cases from 6 studies in SiGN. Basic demographics were 54% women, 63% white, and median age between 65-74. Table 1 provides the agreement between the various subtypes. Table 2 describes the types of disagreement. Conclusions: Central adjudication with only two adjudicators and curated medical records yielded more consistent subtyping independent of phenotyping system. The agreement for TOAST was higher than published rates by independent groups (∼0.50). In contrast, the agreement for CCS was lower than previously published (0.85-0.95). Site adjudicators' familiarity with TOAST and inexperience with CCS may contribute. Although CCS is an automated algorithm and has a number of user friendly features, our findings suggest that formal training and certification process before starting to use CCS may be worthwhile to achieve optimal benefit from the system.

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Blocking PSD-93-CX3CL1 Interaction Promotes the Phenotypic Transformation of Microglia During Acute Ischemic Stroke

10.21203/rs.3.rs-687096/v1 ◽

2021 ◽

Author(s):

qingxiu zhang ◽

xiaowei cao ◽

hui yang ◽

xiaomei Liu ◽

shiying Lou ◽

...

Keyword(s):

Ischemic Stroke ◽

White Matter ◽

Acute Ischemic Stroke ◽

Neuroprotective Effect ◽

Underlying Mechanism ◽

White Matter Injury ◽

Tetrazolium Chloride ◽

Stroke Treatment ◽

Microglial Polarization ◽

M1 Type

Abstract BackgroundPostsynaptic density 93 (PSD-93) plays an important role in ischemic brain injury by mediating neurotoxicity and neuroinflammation. Different photypes of microglia perform an important role in ischemic crerbral injury and repair. Blocking the combination of PSD-93 and CX3C chemokine ligand 1 (CX3CL1) is beneficial in acute ischemic stroke, but the underlying mechanism remains unclear. MethodsMiddle cerebral artery occlusion (MCAO) model was established in male C57BL/6 mice. The peptide Tat-CX3CL1 (357-395aa) which disturbing the interaction of PSD-93 and CX3CL1 was used in this study to explore the mechanism of its neuroprotective effect. The production and secretion of cytokines associated with M1 and M2 type of microglia was detected by PCR and ELISA, respectively. Neurologic damage was evaluated by behavior, triphenyl tetrazolium chloride staining, and brain water content. MBP and SMI32 double immunostaining were used to detect white matter injury and double staining for Iba1 and CD68 to assess M1 type microglia polarization. ResultsThe cytokines level of M1 phenotype cytokines was increased at 6 h after stroke and peaked at 24 h after perfusion. However, the cytokines level of M2 phenotype was decreased at 6 h and 24 h following reperfusion. The Tat-CX3CL1 (357-395aa) facilitated microglial polarization from M1 type to M2 type by reducing the production of soluble CX3CL1. Furthermore, ADAM17 inhibitor GW280264x could restrain the polarization of microglia from M1 to M2 via reducing soluble CX3CL1 formation. Moreover, Tat-CX3CL1 (357-395aa) attenuated long-term cognitive deficits and improved white matter integrity. ConclusionsBlocking the binding between CX3CL1 and PSD-93 by Tat-CX3CL1 (357-395aa) could facilitate the functional recovery after ischemic stroke by promoting M1 to M2 microglial polarization transformation. Tat-CX3CL1 (357-395aa) may be a potent agent for ischemic stroke treatment.

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Racial Differences by Ischemic Stroke Subtype: A Comprehensive Diagnostic Approach

Stroke Research and Treatment ◽

10.1155/2012/735097 ◽

2012 ◽

Vol 2012 ◽

pp. 1-6

Author(s):

Sarah Song ◽

Richard E. Burgess ◽

Chelsea S. Kidwell

Keyword(s):

Ischemic Stroke ◽

Racial Differences ◽

Classification Systems ◽

High Rate ◽

Urban Hospital ◽

Stroke Patients ◽

Stroke Subtype ◽

Stroke Treatment ◽

Significant Difference ◽

Ischemic Stroke Subtype

Background. Previous studies have suggested that black populations have more small-vessel and fewer cardioembolic strokes. We sought to analyze racial differences in ischemic stroke subtype employing a comprehensive diagnostic workup with magnetic resonance-imaging-(MRI-) based evaluation including diffusion-weighted imaging (DWI).Methods. 350 acute ischemic stroke patients admitted to an urban hospital with standardized comprehensive diagnostic evaluations were retrospectively analyzed. Ischemic stroke subtype was determined by three Trial of Org 10172 in Acute Stroke Treatment (TOAST) classification systems.Results. We found similar proportions of cardioembolic and lacunar strokes in the black and white cohort. The only subtype category with a significant difference by race was “stroke of other etiology,” more common in whites. Black stroke patients were more likely to have an incomplete evaluation, but this did not reach significance.Conclusions. We found similar proportions by race of cardioembolic and lacunar strokes when employing a full diagnostic evaluation including DWI MRI. The relatively high rate of cardioembolism may have been underappreciated in black stroke patients when employing a CT approach to stroke subtype diagnosis. Further research is required to better understand the racial differences in frequency of “stroke of other etiology” and explore disparities in the extent of diagnostic evaluations.

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Assessment of quality of life in patients with the effects of transient ischemic stroke

East European Journal of Neurology ◽

10.33444/2411-5797.2016.6(12).37-39 ◽

2016 ◽

pp. 37-39

Author(s):

A. Babirad

Keyword(s):

Quality Of Life ◽

Ischemic Stroke ◽

Large Scale ◽

Cerebrovascular Diseases ◽

Control Measures ◽

Sociological Research ◽

Cerebrovascular Events ◽

Sf 36 ◽

Angioplasty And Stenting

Cerebrovascular diseases are a problem of the world today, and according to the forecast, the problem of the near future arises. The main risk factors for the development of ischemic disorders of the cerebral circulation include oblique and aging, arterial hypertension, smoking, diabetes mellitus and heart disease. An effective strategy for the prevention of cerebrovascular events is based on the implementation of large-scale risk control measures, including the use of antiagregant and anticoagulant therapy, invasive interventions such as atheromectomy, angioplasty and stenting. In this connection, the efforts of neurologists, cardiologists, angiosurgery, endocrinologists and other specialists are the basis for achieving an acceptable clinical outcome. A review of the SF-36 method for assessing the quality of life in patients with the effects of transient ischemic stroke is presented. The assessment of quality of life is recognized in world medical practice and research, an indicator that is also used to assess the quality of the health system and in general sociological research.

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Identification of N-Substituted Triazolo-azetidines as Novel Antibacterials using pDualrep2 HTS Platform

Combinatorial Chemistry & High Throughput Screening ◽

10.2174/1386207322666190412165316 ◽

2019 ◽

Vol 22 (5) ◽

pp. 346-354

Author(s):

Yan A. Ivanenkov ◽

Renat S. Yamidanov ◽

Ilya A. Osterman ◽

Petr V. Sergiev ◽

Vladimir A. Aladinskiy ◽

...

Keyword(s):

Antibacterial Activity ◽

Large Scale ◽

Underlying Mechanism ◽

Luciferase Assay ◽

Reporter System ◽

E Coli ◽

Starting Point ◽

High Concentrations ◽

Mic Value

Aim and Objective: Antibiotic resistance is a serious constraint to the development of new effective antibacterials. Therefore, the discovery of the new antibacterials remains one of the main challenges in modern medicinal chemistry. This study was undertaken to identify novel molecules with antibacterial activity. Materials and Methods: Using our unique double-reporter system, in-house large-scale HTS campaign was conducted for the identification of antibacterial potency of small-molecule compounds. The construction allows us to visually assess the underlying mechanism of action. After the initial HTS and rescreen procedure, luciferase assay, C14-test, determination of MIC value and PrestoBlue test were carried out. Results: HTS rounds and rescreen campaign have revealed the antibacterial activity of a series of Nsubstituted triazolo-azetidines and their isosteric derivatives that has not been reported previously. Primary hit-molecule demonstrated a MIC value of 12.5 µg/mL against E. coli Δ tolC with signs of translation blockage and no SOS-response. Translation inhibition (26%, luciferase assay) was achieved at high concentrations up to 160 µg/mL, while no activity was found using C14-test. The compound did not demonstrate cytotoxicity in the PrestoBlue assay against a panel of eukaryotic cells. Within a series of direct structural analogues bearing the same or bioisosteric scaffold, compound 2 was found to have an improved antibacterial potency (MIC=6.25 µg/mL) close to Erythromycin (MIC=2.5-5 µg/mL) against the same strain. In contrast to the parent hit, this compound was more active and selective, and provided a robust IP position. Conclusion: N-substituted triazolo-azetidine scaffold may be used as a versatile starting point for the development of novel active and selective antibacterial compounds.

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Dl-3-n-Butylphthalide (NBP): A Promising Therapeutic Agent for Ischemic Stroke

CNS & Neurological Disorders - Drug Targets ◽

10.2174/1871527317666180612125843 ◽

2018 ◽

Vol 17 (5) ◽

pp. 338-347 ◽

Cited By ~ 34

Author(s):

Shan Wang ◽

Fei Ma ◽

Longjian Huang ◽

Yong Zhang ◽

Yuchen Peng ◽

...

Keyword(s):

Ischemic Stroke ◽

Complex Disease ◽

Time Window ◽

Recombinant Tissue Plasminogen Activator ◽

Research Progress ◽

Apium Graveolens ◽

Synthetic Compound ◽

Stroke Treatment ◽

Single Target ◽

Anti Oxidant

Background and Objective: Stroke is a leading cause of morbidity and mortality in both developed and developing countries all over the world. The only drug for ischemic stroke approved by FDA is recombinant tissue plasminogen activator (rtPA). However, only 2-5% stroke patients receive rtPAs treatment due to its strict therapeutic time window. As ischemic stroke is a complex disease involving multiple mechanisms, medications with multi-targets may be more powerful compared with single-target drugs. Dl-3-n-Butylphthalide (NBP) is a synthetic compound based on l-3-n- Butylphthalide that is isolated from seeds of Apium graveolens. The racemic 3-n-butylphthalide (dl- NBP) was approved by Food and Drug Administration of China for the treatment of ischemic stroke in 2002. A number of clinical studies indicated that NBP not only improved the symptoms of ischemic stroke, but also contributed to the long-term recovery. The potential mechanisms of NBP for ischemic stroke treatment may target different pathophysiological processes, including anti-oxidant, antiinflammation, anti-apoptosis, anti-thrombosis, and protection of mitochondria et al. Conclusion: In this review, we have summarized the research progress of NBP for the treatment of ischemic stroke during the past two decades.

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A Novel Method to Predict Drug-Target Interactions Based on Large-Scale Graph Representation Learning

Cancers ◽

10.3390/cancers13092111 ◽

2021 ◽

Vol 13 (9) ◽

pp. 2111

Author(s):

Bo-Wei Zhao ◽

Zhu-Hong You ◽

Lun Hu ◽

Zhen-Hao Guo ◽

Lei Wang ◽

...

Keyword(s):

Drug Target ◽

Large Scale ◽

Computational Models ◽

Structural Information ◽

Characteristic Curve ◽

Representation Learning ◽

Graph Representation ◽

Convolutional Network ◽

Novel Method

Identification of drug-target interactions (DTIs) is a significant step in the drug discovery or repositioning process. Compared with the time-consuming and labor-intensive in vivo experimental methods, the computational models can provide high-quality DTI candidates in an instant. In this study, we propose a novel method called LGDTI to predict DTIs based on large-scale graph representation learning. LGDTI can capture the local and global structural information of the graph. Specifically, the first-order neighbor information of nodes can be aggregated by the graph convolutional network (GCN); on the other hand, the high-order neighbor information of nodes can be learned by the graph embedding method called DeepWalk. Finally, the two kinds of feature are fed into the random forest classifier to train and predict potential DTIs. The results show that our method obtained area under the receiver operating characteristic curve (AUROC) of 0.9455 and area under the precision-recall curve (AUPR) of 0.9491 under 5-fold cross-validation. Moreover, we compare the presented method with some existing state-of-the-art methods. These results imply that LGDTI can efficiently and robustly capture undiscovered DTIs. Moreover, the proposed model is expected to bring new inspiration and provide novel perspectives to relevant researchers.

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