Hemorrhagic transformation (HT) is a common complication in patients with acute ischemic stroke. It occurs when peripheral blood extravasates across a disrupted blood brain barrier (BBB) into the brain following ischemic stroke. Preventing HT is important as it worsens stroke outcome and increases mortality. Factors associated with increased risk of HT include stroke severity, reperfusion therapy (thrombolysis and thrombectomy), hypertension, hyperglycemia, and age. Inflammation and the immune system are important contributors to BBB disruption and HT and are associated with many of the risk factors for HT. In this review, we present the relationship of inflammation and immune activation to HT in the context of reperfusion therapy, hypertension, hyperglycemia, and age. Differences in inflammatory pathways relating to HT are discussed. The role of inflammation to stratify the risk of HT and therapies targeting the immune system to reduce the risk of HT are presented.
Embolic stroke of unknown source (ESUS) represents one in five ischemic strokes. Ipsilateral non-stenotic carotid plaques are identified in 40% of all ESUS. In this narrative review, we summarize the evidence supporting the potential causal relationship between ESUS and non-stenotic carotid plaques; discuss the remaining challenges in establishing the causal link between non-stenotic plaques and ESUS and describe biomarkers of potential interest for future research. In support of the causal relationship between ESUS and non-stenotic carotid plaques, studies have shown that plaques with high-risk features are five times more prevalent in the ipsilateral vs. the contralateral carotid and there is a lower incidence of atrial fibrillation during follow-up in patients with ipsilateral non-stenotic carotid plaques. However, non-stenotic carotid plaques with or without high-risk features often coexist with other potential etiologies of stroke, notably atrial fibrillation (8.5%), intracranial atherosclerosis (8.4%), patent foramen ovale (5–9%), and atrial cardiopathy (2.4%). Such puzzling clinical associations make it challenging to confirm the causal link between non-stenotic plaques and ESUS. There are several ongoing studies exploring whether select protein and RNA biomarkers of plaque progression or vulnerability could facilitate the reclassification of some ESUS as large vessel strokes or help to optimize secondary prevention strategies.
Purpose of review Diagnosis of stroke and understanding the mechanism of stroke is critical to implement optimal treatment. RNA expressed in peripheral blood cells is emerging as a precision biomarker to aid in stroke diagnosis and prediction of stroke cause. In this review, we summarize available data regarding the role of RNA to predict stroke, the rationale for these changes, and a discussion of novel mechanistic insight and clinical applications. Recent findings Differences in RNA gene expression in blood have been identified in patients with stroke, including differences to distinguish ischemic from hemorrhagic stroke, and differences between cardioembolic, large vessel atherosclerotic, and small vessel lacunar stroke cause. Gene expression differences show promise as novel stroke biomarkers to predict stroke of unclear cause (cryptogenic stroke). The differences in RNA expression provide novel insight to stroke mechanism, including the role of immune response and thrombosis in human stroke. Important insight to regulation of gene expression in stroke and its causes are being acquired, including alternative splicing, noncoding RNA, and microRNA. Summary Improved diagnosis of stroke and determination of stroke cause will improve stroke treatment and prevention. RNA biomarkers show promise to aid in the diagnosis of stroke and cause determination, as well as providing novel insight to mechanism of stroke in patients. While further study is required, an RNA profile may one day be part of the stroke armamentarium with utility to guide acute stroke therapy and prevention strategies and refine stroke phenotype.
Background and Purpose: With advancing age, alterations occur to the immune system, including an increase in inflammation (inflammaging) and a reduced ability to respond to new immune challenges. The role of an aging immune system in patients with ischemic stroke remains unclear, although age is an important determinant of stroke risk and outcome. This study assessed the aging immune system in patients with acute ischemic stroke by differences in leukocyte gene expression in relationship to age. Methods: Peripheral blood RNA from 2 cohorts with acute ischemic stroke was measured by whole-genome microarray, and genes associated with advancing age were identified (false discovery rate-corrected P <0.05, partial correlation coefficient <|0.3|). Genes were characterized by pathway analysis and compared with age-associated genes from nonstroke studies (n=3974). Results: There were 166 genes associated with age in cohort 1 (derivation cohort, n=94). Sixty-nine of these age-associated genes were verified in cohort 2 (validation cohort, n=79). Identified genes included a decrease in CR2 , CD27 , CCR7 , and NT5E . Genes were associated with altered B-cell receptor signaling, lymphocyte proliferation, and leukocyte homeostasis. Forty-three of the 69 age-associated genes in stroke were also associated with age in nonstroke studies. Conclusions: A relationship between leukocyte gene expression and age in patients with ischemic stroke was identified. The changes include alterations to the adaptive humoral immune system, which may influence age-related stroke risk and outcome.
Collaborative learning involves an interdependence between success of the individual and success of the group, requiring both personal preparation and teamwork. Asynchronous work, in combination with group interaction and problem solving, differentiates collaborative learning from other interactive teaching methods. In this study, three professors and five student participants individually reflected on a past collaborative learning experience that they considered successful. Reflections were coded using thematic analysis. Themes that emerged from participant’s descriptions of successful collaborative learning were: (a) familiarity with collaborative learning, (b) relationships, (c) benefits, (d) motivations, and (e) design and process. Furthermore, a phenomenographic theoretical framework revealed that a participant’s prior experiences generated significant variation in what characteristics they described as promoting success in collaborative learning. Past experiences that can generate this variation include training in educational theory, participation in and familiarity with related research, the individual’s role, prior experience with collaborative learning as a student, and advocacy by one’s professor before participation in collaborative learning. Our findings can inform educational practice, improving the implementation of collaborative learning pedagogies.
Background and ObjectivesThrombosis is central to the pathogenesis of acute ischemic stroke, with higher thrombin generation being associated with increased stroke risk. The immune system may contribute to thrombin generation in stroke and thus may offer novel strategies for stroke prevention. This study addresses the research question regarding the relationship of thrombin generation to leukocyte gene expression in patients with acute ischemic stroke.MethodsWe isolated RNA from whole blood and examined the relationship to thrombin generation capacity in patients with acute ischemic stroke. Due to its effects on thrombin generation, patients on anticoagulants were excluded from the study. The relationship of gene expression with peak thrombin was evaluated by analysis of covariance across peak thrombin quartiles adjusted for sex and age.ResultsIn 97 patients with acute ischemic stroke, peak thrombin was variable, ranging from 252.0 to 752.4 nM. Increased peak thrombin was associated with differences in thromboinflammatory leukocyte gene expression, including a decrease in ADAM metallopeptidase with thrombospondin type 1 motif 13 and an increase in nuclear factor κB (NF-κB)–activating protein, protein disulfide isomerase family A member 5, and tissue factor pathway inhibitor 2. Pathways associated with peak thrombin included interleukin 6 signaling, thrombin signaling, and NF-κB signaling. A linear discriminant analysis model summarizing the immune activation associated with peak thrombin in a first cohort of stroke could distinguish patients with low peak thrombin from high peak thrombin in a second cohort of 112 patients with acute ischemic stroke.DiscussionThe identified genes and pathways support a role of the immune system contributing to thrombus formation in patients with stroke. These may have relevance to antithrombotic strategies for stroke prevention.
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