Life after stroke in Appalachia

Objective The purpose of this study was to describe the structure of meaning in the experience of surviving stroke for adults living in Appalachia. Methods This qualitative phenomenological study includes a sample of 6 adult survivors of ischemic stroke who were discharged from either a community or university hospital to home in the Appalachian region. Data was collected through semi-structured interviews, transcribed, and analyzed thematically by two investigators. The explicated themes were verified by the survivors as representative of their experience. Results Five main themes emerged: 1) Frustration with new physical and functional impairment, 2) Negative emotions including anger, guilt, loneliness, and depression 3) Need for accessible support, 4) Longing for home during recovery and, 5) Stepping forward after stroke which included sub-themes of perseverance, acceptance, and retraining. Anger was described as contributing to delayed recover and emotional lability was described as a source of anger. The familiarity of home was viewed as key to reestablishing control over one\u27s life. Survivors described how they developed perseverance to move forward and emphasized that willingness to participate in retraining led to adapting to impairments. Acceptance was described as letting go of prior expectations of self and others so one could live in the present

Monocyte-lymphocyte cross-communication via soluble CD163 directly links innate immune system activation and adaptive immune system suppression following ischemic stroke

CD163 is a scavenger receptor expressed on innate immune cell populations which can be shed from the plasma membrane via the metalloprotease ADAM17 to generate a soluble peptide with lympho-inhibitory properties. The purpose of this study was to investigate CD163 as a possible effector of stroke-induced adaptive immune system suppression. Liquid biopsies were collected from ischemic stroke patients (n = 39), neurologically asymptomatic controls (n = 20), and stroke mimics (n = 20) within 24 hours of symptom onset. Peripheral blood ADAM17 activity and soluble CD163 levels were elevated in stroke patients relative to non-stroke control groups, and negatively associated with post-stroke lymphocyte counts. Subsequent in vitro experiments suggested that this stroke-induced elevation in circulating soluble CD163 likely originates from activated monocytic cells, as serum from stroke patients stimulated ADAM17-dependant CD163 shedding from healthy donor-derived monocytes. Additional in vitro experiments demonstrated that stroke-induced elevations in circulating soluble CD163 can elicit direct suppressive effects on the adaptive immune system, as serum from stroke patients inhibited the proliferation of healthy donor-derived lymphocytes, an effect which was attenuated following serum CD163 depletion. Collectively, these observations provide novel evidence that the innate immune system employs protective mechanisms aimed at mitigating the risk of post-stroke autoimmune complications driven by adaptive immune system overactivation, and that CD163 is key mediator of this phenomenon

Machine-Learning Approach Identifies a Pattern of Gene Expression in Peripheral Blood that can Accurately Detect Ischaemic Stroke

Early and accurate diagnosis of stroke improves the probability of positive outcome. The objective of this study was to identify a pattern of gene expression in peripheral blood that could potentially be optimised to expedite the diagnosis of acute ischaemic stroke (AIS). A discovery cohort was recruited consisting of 39 AIS patients and 24 neurologically asymptomatic controls. Peripheral blood was sampled at emergency department admission, and genome-wide expression profiling was performed via microarray. A machine-learning technique known as genetic algorithm k-nearest neighbours (GA/kNN) was then used to identify a pattern of gene expression that could optimally discriminate between groups. This pattern of expression was then assessed via qRT-PCR in an independent validation cohort, where it was evaluated for its ability to discriminate between an additional 39 AIS patients and 30 neurologically asymptomatic controls, as well as 20 acute stroke mimics. GA/kNN identified 10 genes (ANTXR2, STK3, PDK4, CD163, MAL, GRAP, ID3, CTSZ, KIF1B and PLXDC2) whose coordinate pattern of expression was able to identify 98.4% of discovery cohort subjects correctly (97.4% sensitive, 100% specific). In the validation cohort, the expression levels of the same 10 genes were able to identify 95.6% of subjects correctly when comparing AIS patients to asymptomatic controls (92.3% sensitive, 100% specific), and 94.9% of subjects correctly when comparing AIS patients with stroke mimics (97.4% sensitive, 90.0% specific). The transcriptional pattern identified in this study shows strong diagnostic potential, and warrants further evaluation to determine its true clinical efficacy

Life after stroke in Appalachia

Objective: The purpose of this study was to describe the structure of meaning in the experience of surviving stroke for adults living in Appalachia. Methods: This qualitative phenomenological study includes a sample of 6 adult survivors of ischemic stroke who were discharged from either a community or university hospital to home in the Appalachian region. Data was collected through semi-structured interviews, transcribed, and analyzed thematically by two investigators. The explicated themes were verified by the survivors as representative of their experience. Results: Five main themes emerged: 1) Frustration with new physical and functional impairment, 2) Negative emotions including anger, guilt, loneliness, and depression 3) Need for accessible support, 4) Longing for home during recovery and, 5) Stepping forward after stroke which included sub-themes of perseverance, acceptance, and retraining. Anger was described as contributing to delayed recover and emotional lability was described as a source of anger. The familiarity of home was viewed as key to reestablishing control over one's life. Survivors described how they developed perseverance to move forward and emphasized that willingness to participate in retraining led to adapting to impairments. Acceptance was described as letting go of prior expectations of self and others so one could live in the present

Shifts in Leukocyte Counts Drive the Differential Expression of Transcriptional Stroke Biomarkers in Whole Blood

Our group recently identified a panel of ten genes whose RNA expression levels in whole blood have utility for detection of stroke. The purpose of this study was to determine the mechanisms by which these genes become differentially expressed during stroke pathology. First, we assessed the transcriptional distribution of the ten genes across the peripheral immune system by measuring their expression levels on isolated neutrophils, monocytes, B-lymphocytes, CD-4+ T-lymphocytes, CD-8+ T-lymphocytes, and NK-cells generated from the blood of healthy donors (n = 3). Then, we examined the relationship between the whole-blood expression levels of the ten genes and white blood cell counts in a cohort of acute ischemic stroke patients (n = 36) and acute stroke mimics (n = 15) recruited at emergency department admission. All ten genes displayed strong patterns of lineage-specific expression in our analysis of isolated leukocytes, and their whole-blood expression levels were correlated with white blood cell differential across the total patient population, suggesting that many of them are likely differentially expressed in whole blood during stroke as an artifact of stroke-induced shifts in leukocyte counts. Specifically, factor analysis inferred that over 50% of the collective variance in their whole-blood expression levels across the patient population was driven by underlying variance in white blood cell counts alone. However, the cumulative expression levels of the ten genes displayed a superior ability to discriminate between stroke patients and stroke mimics relative to white blood cell differential, suggesting that additional less prominent factors influence their expression levels which add to their diagnostic utility. These findings not only provide insight regarding this particular panel of ten genes, but also into the results of prior stroke transcriptomics studies performed in whole blood

Peripheral blood AKAP7 expression as an early marker for lymphocyte-mediated post-stroke blood brain barrier disruption

Our group recently identified 16 genes whose peripheral blood expression levels are differentially regulated in acute ischemic stroke. The purpose of this study was to determine whether the early expression levels of any of these 16 genes are predictive for post-stroke blood brain barrier (BBB) disruption. Transcriptional expression levels of candidate genes were measured in peripheral blood sampled from ischemic stroke patients at emergency department admission, and BBB permeability was assessed at 24 hour follow up via perfusion-weighted imaging. Early heightened expression levels of AKAP7, a gene encoding a protein kinase A-binding scaffolding molecule, were significantly associated with BBB disruption 24 hours post-hospital admission. We then determined that AKAP7 is predominantly expressed by lymphocytes in peripheral blood, and strongly co-expressed with ITGA3, a gene encoding the adhesion molecule integrin alpha 3. Subsequent in vitro experiments revealed that heightened expression of AKAP7 and ITGA3 in primary human lymphocytes is associated with a highly adherent phenotype. Collectively, our results suggest that AKAP7 expression levels may have clinical utility as a prognostic biomarker for post-stroke BBB complications, and are likely elevated early in patients who later develop post-stroke BBB disruption due to the presence of an invasive lymphocyte population in the peripheral blood

Neuroprotection for Ischemic Stroke: Moving Past Shortcomings and Identifying Promising Directions

The translation of neuroprotective agents for ischemic stroke from bench-to-bedside has largely failed to produce improved treatments since the development of tissue plasminogen activator (tPA). One possible reason for lack of translation is the failure to acknowledge the greatest risk factor for stroke, age, and other common comorbidities such as hypertension, obesity, and diabetes that are associated with stroke. In this review, we highlight both mechanisms of studying these factors and results of those that have been addressed. We also discuss the potential role of other lifestyle factors associated with an increased stroke risk such as sleep fragmentation and/or deprivation. Furthermore, many proposed therapeutic agents have targeted molecular mechanisms occurring soon after the onset of ischemia despite data indicating delayed patient presentation following ischemic stroke. Modulating inflammation has been identified as a promising therapeutic avenue consistent with preliminary success of ongoing clinical trials for anti-inflammatory compounds such as minocycline. We review the role of inflammation in stroke and in particular, the role of inflammatory cell recruitment and macrophage phenotype in the inflammatory process. Emerging evidence indicates an increasing role of neuro-immune crosstalk, which has led to increased interest in identification of peripheral biomarkers indicative of neural injury. It is our hope that identification and investigation of factors influencing stroke pathophysiology may lead to improved therapeutics