Oxygen-sensitive outcomes and gene expression in acute ischemic stroke.
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ABSTRACT:
SUBMITTER: Rink C
PROVIDER: S-EPMC2913550 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Introduction: Ischemic stroke remains one of the most debilitating diseases and is the fifth leading cause of death in the US. The ability to predict stroke outcomes within the acute period of stroke would be essential for care planning and rehabilitation. The Blood and Clot Thrombectomy Registry and Collaboration (BACTRAC; clinicaltrials.gov NCT03153683) study collects arterial blood immediately distal and proximal to the intracranial thrombus at the time of mechanical thrombectomy. These blood samples are an innovative resource in evaluating acute gene expression changes at the time of ischemic stroke. The purpose of this study was to identify inflammatory genes and important immune factors during mechanical thrombectomy for emergent large vessel occlusion (ELVO) and which patient demographics were predictors for stroke outcomes (infarct and/or edema volume) in acute ischemic stroke patients. Methods: The BACTRAC study is a non-probability sampling of male and female subjects (≥18 year old) treated with mechanical thrombectomy for ELVO. We evaluated 28 subjects (66 ± 15.48 years) relative concentrations of mRNA for gene expression in 84 inflammatory molecules in arterial blood distal and proximal to the intracranial thrombus who underwent thrombectomy. We used the machine learning method, Random Forest to predict which inflammatory genes and patient demographics were important features for infarct and edema volumes. To validate the overlapping genes with outcomes, we perform ordinary least squares regression analysis. Results: Machine learning analyses demonstrated that the genes and subject factors CCR4, IFNA2, IL-9, CXCL3, Age, T2DM, IL-7, CCL4, BMI, IL-5, CCR3, TNFα, and IL-27 predicted infarct volume. The genes and subject factor IFNA2, IL-5, CCL11, IL-17C, CCR4, IL-9, IL-7, CCR3, IL-27, T2DM, and CSF2 predicted edema volume. The overlap of genes CCR4, IFNA2, IL-9, IL-7, IL-5, CCR3, and IL-27 with T2DM predicted both infarct and edema volumes. These genes relate to a microenvironment for chemoattraction and proliferation of autoimmune cells, particularly Th2 cells and neutrophils. Conclusions: Machine learning algorithms can be employed to develop prognostic predictive biomarkers for stroke outcomes in ischemic stroke patients, particularly in regard to identifying acute gene expression changes that occur during stroke.
| S-EPMC6974670 | biostudies-literature
Project description:To investigate the neuroprotective effects of Ginkgolide B (GB) against ischemic stroke-induced injury in vivo and in vitro, and further explore the possible mechanisms concerned.Transient middle cerebral artery occlusion (tMCAO) mice and oxygen-glucose deprivation/reoxygenation (OGD/R)-treated N2a cells were used to explore the neuroprotective effects of GB. The expression of brain-derived neurotrophic factor (BDNF) was detected via Western blot and qRT-PCR.GB treatment (4 mg/kg, i. p., bid) significantly reduced neurological deficits, water content, and cerebral infarct volume in tMCAO mice. GB also significantly increased Bcl-2/Bax ratio, reduced the expression of caspase-3, and protected against OGD/R-induced neuronal apoptosis. Meanwhile, GB caused the up-regulation of BDNF protein in vivo and in vitro.Our data suggest that GB might protect the brain against ischemic insult partly via modulating BDNF expression.
| S-EPMC5544371 | biostudies-other
Project description:Aim: The atherogenic index of plasma (AIP) was significantly related to adverse outcomes in patients with cardiovascular disease. Our aim was to investigate the association between AIP and adverse outcomes in acute ischemic stroke. Methods: Patients with acute ischemic stroke (AIS) admitted between 2015 and 2018 were prospectively enrolled in this study. Functional outcomes were evaluated by the modified Rankin Scale (mRS). Poor outcomes were defined as mRS 3-6. The relationship of AIP with the risk of outcomes was analyzed by multivariate logistic regression models. Results: A total of 1,463 patients with AIS within 24 h of symptom onset were enrolled. The poor outcome group had a significantly higher level of AIP [0.09 (-0.10 to 0.27) vs. 0.04 (-0.09 to 0.18), p < 0.001] compared with the good outcome group. Multivariable logistic regression analysis showed that higher AIP was associated with poor outcomes in all the stroke patients (OR 1.84, 95% CI, 1.23-2.53, p = 0.007), which was more evident in patients with large-artery atherosclerosis subtype (OR 1.90, 95% CI, 1.53-2.62, p = 0.002), but not in the other subtypes. Receiver operating curve (ROC) analysis revealed that the best predictive cutoff value of AIP was 0.112, with a sensitivity of 70.8% and a specificity of 59.2%, and the area under the ROC curves for AIP was 0.685. Conclusion: AIP may be an important and independent predictor of the outcome of dysfunction in patients with AIS, especially the stroke subtype of large-artery atherosclerosis.
| S-EPMC8542679 | biostudies-literature
Project description:It is uncertain whether previous ischemic stroke within 3 months of receiving intravenous thrombolysis (tPA [tissue-type plasminogen activator]) for acute ischemic stroke (AIS) is associated with an increased risk of adverse outcomes.Using administrative claims data, we identified adults with AIS who received intravenous tPA at California, New York, and Florida hospitals from 2005 to 2013. Our primary outcome was intracerebral hemorrhage, and our secondary outcomes were unfavorable discharge disposition and inpatient mortality. We used logistic regression to compare rates of outcomes in patients with and without previous ischemic stroke within 3 months of intravenous tPA for AIS.We identified 36 599 AIS patients treated with intravenous tPA, of whom 568 (1.6%) had a previous ischemic stroke in the past 3 months. Of all patients who received intravenous tPA, the rate of intracerebral hemorrhage was 4.9% (95% confidence interval [CI], 4.7%-5.1%), and death occurred in 10.7% (95% CI, 10.4%-11.0%). After adjusting for demographics, vascular risk factors, and the Elixhauser Comorbidity Index, previous ischemic stroke within 3 months of thrombolysis for AIS was not associated with an increased risk of intracerebral hemorrhage (odds ratio, 0.9; 95% CI, 0.6-1.4; P=0.62), but was associated with an increased risk of death (odds ratio, 1.5; 95% CI, 1.2-1.9; P=0.001) and unfavorable discharge disposition (odds ratio, 1.3; 95% CI, 1.0-1.7; P=0.04).Among patients who receive intravenous tPA for AIS, recent ischemic stroke is not associated with an increased risk of intracerebral hemorrhage but is associated with a higher risk of death and unfavorable discharge disposition.
| S-EPMC5663184 | biostudies-literature
Project description:Acute ischemic stroke (AIS) is a primary cause of mortality and morbidity worldwide. Currently, no clinically approved immune intervention is available for AIS treatment, partly due to the lack of relevant patient classification based on the peripheral immunity status of patients with AIS. In this study, we adopted the consensus clustering approach to classify patients with AIS into molecular subgroups based on the transcriptomic profiles of peripheral blood, and we identified three distinct AIS molecular subgroups and 8 modules in each subgroup by the weighted gene co-expression network analysis. Remarkably, the pre-ranked gene set enrichment analysis revealed that the co-expression modules with subgroup I-specific signature genes significantly overlapped with the differentially expressed genes in AIS patients with hemorrhagic transformation (HT). With respect to subgroup II, exclusively male patients with decreased proteasome activity were identified. Intriguingly, the majority of subgroup III was composed of female patients who showed a comparatively lower level of AIS-induced immunosuppression (AIIS). In addition, we discovered a non-linear relationship between female age and subgroup-specific gene expression, suggesting a gender- and age-dependent alteration of peripheral immunity. Taken together, our novel AIS classification approach could facilitate immunomodulatory therapies, including the administration of gender-specific therapeutics, and attenuation of the risk of HT and AIIS after ischemic stroke.
| S-EPMC9388856 | biostudies-literature
Project description:BackgroundAbnormal electrolytes were closely related to the prognosis of various diseases, the prognostic role of electrolytes in stroke has not been investigated well. We aimed to investigate the association between electrolytes and clinical outcomes in patients with acute ischemic stroke (AIS) or transient ischemic attack (TIA).MethodsData were recruited from the China National Stroke Registry III study. Patients were classified into three groups according to tertiles and the normal range of each electrolyte. Multivariable logistic and Cox proportional hazards regressions were adopted to explore the associations of electrolytes with poor functional outcomes [modified Rankin Scale (mRS) 3-6/2-6] and all-cause death at 3 months and 1 year.ResultsA total of 10,299 eligible patients were enrolled. After adjusted for confounding factors, the first tertile electrolytes were associated with increased risk of poor functional outcome (mRS score 3-6) at 1 year, the adjusted odds ratios (95% confidence intervals) were 1.33 (1.14-1.55) for potassium, 1.41 (1.20-1.60) for sodium, 1.27 (1.08-1.48) for chloride, compared with the second tertile. Similar results were found when poor functional outcome was defined as mRS score 2-6 and all-cause death. However, almost no significant association was present of calcium with these outcomes. All results were consistent when each electrolyte was classified into three groups according to the normal range and the outcomes timepoint was set at 3 months.ConclusionsLower levels of potassium, sodium, chloride but not calcium were associated with higher risk of poor functional outcomes and death in patients with AIS or TIA.
| S-EPMC8339832 | biostudies-literature
Project description:BackgroundThis study identified early immune gene responses in peripheral blood associated with 90-day ischemic stroke (IS) outcomes.MethodsPeripheral blood samples from the CLEAR trial IS patients at ≤ 3 h, 5 h, and 24 h after stroke were compared to vascular risk factor matched controls. Whole-transcriptome analyses identified genes and networks associated with 90-day IS outcome assessed using the modified Rankin Scale (mRS) and the NIH Stroke Scale (NIHSS).ResultsThe expression of 467, 526, and 571 genes measured at ≤ 3, 5 and 24 h after IS, respectively, were associated with poor 90-day mRS outcome (mRS ≥ 3), while 49, 100 and 35 genes at ≤ 3, 5 and 24 h after IS were associated with good mRS 90-day outcome (mRS ≤ 2). Poor outcomes were associated with up-regulated genes or pathways such as IL-6, IL-7, IL-1, STAT3, S100A12, acute phase response, P38/MAPK, FGF, TGFA, MMP9, NF-kB, Toll-like receptor, iNOS, and PI3K/AKT. There were 94 probe sets shared for poor outcomes vs. controls at all three time-points that correlated with 90-day mRS; 13 probe sets were shared for good outcomes vs. controls at all three time-points; and 46 probe sets were shared for poor vs. good outcomes at all three time-points that correlated with 90-day mRS. Weighted Gene Co-Expression Network Analysis (WGCNA) revealed modules significantly associated with 90-day outcome for mRS and NIHSS. Poor outcome modules were enriched with up-regulated neutrophil genes and with down-regulated T cell, B cell and monocyte-specific genes; and good outcome modules were associated with erythroblasts and megakaryocytes. Finally, genes identified by genome-wide association studies (GWAS) to contain significant stroke risk loci or loci associated with stroke outcome including ATP2B, GRK5, SH3PXD2A, CENPQ, HOXC4, HDAC9, BNC2, PTPN11, PIK3CG, CDK6, and PDE4DIP were significantly differentially expressed as a function of stroke outcome in the current study.ConclusionsThis study suggests the immune response after stroke may impact functional outcomes and that some of the early post-stroke gene expression markers associated with outcome could be useful for predicting outcomes and could be targets for improving outcomes.
| S-EPMC9869610 | biostudies-literature
Project description:The cardiovascular safety and efficacy of linagliptin, a dipeptidyl peptidase-4 inhibitor, in patients with type 2 diabetes mellitus (T2DM) after acute coronary syndrome (ACS) or acute ischemic stroke (AIS) are unclear. The aim of our real-world cohort study was to evaluate the cardiovascular outcomes of linagliptin in patients with T2DM after ACS or AIS.An open observational noncrossover retrospective cohort study was conducted between June 1, 2012 and December 31, 2013 utilizing Taiwan National Health Insurance Research Database. A total of 1203 patients with T2DM after ACS or AIS were selected as the study cohort. Cardiovascular safety and efficacy of linagliptin were evaluated by comparing outcomes of 401 subjects receiving linagliptin after ACS or AIS to 802 matched control subjects not receiving any incretin-based therapy after ACS or AIS. The primary composite outcome included cardiovascular death, non-fatal myocardial infarction and non-fatal ischemic stroke.The primary composite outcome after 15-month follow-up was 7% (28 patients) in the linagliptin group compared with 6.1% (49 patients) in the control group [hazard ratio (HR) 1.06; 95% confidence interval (CI) .66-1.68]. The linagliptin group also had similar risks of all-cause mortality, hospitalization for heart failure, percutaneous coronary intervention and coronary artery bypass grafting compared to the control group in terms of the secondary outcomes.In T2DM patients after ACS or AIS, treatment with linagliptin was not associated with increased risks of cardiovascular death, non-fatal myocardial infarction, or non-fatal ischemic stroke.
| S-EPMC5753457 | biostudies-other
Project description:BackgroundmicroRNA (miRNA) are important regulators of gene expression. In patients with ischemic stroke we have previously shown that differences in immune cell gene expression are present. In this study we sought to determine the miRNA that are differentially expressed in peripheral blood cells of patients with acute ischemic stroke and thus may regulate immune cell gene expression.MethodsmiRNA from peripheral blood cells of forty-eight patients with ischemic stroke and vascular risk factor controls were compared. Differentially expressed miRNA in patients with ischemic stroke were determined by microarray with qRT-PCR confirmation. The gene targets and pathways associated with ischemic stroke that may be regulated by the identified miRNA were characterized.ResultsIn patients with acute ischemic stroke, miR-122, miR-148a, let-7i, miR-19a, miR-320d, miR-4429 were decreased and miR-363, miR-487b were increased compared to vascular risk factor controls. These miRNA are predicted to regulate several genes in pathways previously identified by gene expression analyses, including toll-like receptor signaling, NF-κβ signaling, leukocyte extravasation signaling, and the prothrombin activation pathway.ConclusionsSeveral miRNA are differentially expressed in blood cells of patients with acute ischemic stroke. These miRNA may regulate leukocyte gene expression in ischemic stroke including pathways involved in immune activation, leukocyte extravasation and thrombosis.
| S-EPMC4050059 | biostudies-literature
Project description:Background: Post-ischemic inflammatory response might be affected by many factors. We chose leukocyte count as a marker of inflammatory response and investigated whether the effects of leukocyte count on the clinical outcomes in acute ischemic stroke patients are different according to different factors. Methods: We derived data from the China National Stroke Registry II. Patients with ischemic stroke were classified into four groups by leukocyte count quartiles within the first 24 h after admission. Adverse clinical outcomes were defined as recurrent stroke, all-cause death, and poor functional outcomes (3 ? mRS ? 5) at 3-months and 1-year follow-up. The subgroup factors were age, sex, history of hypertension, history of diabetes, history of previous stroke, or transient ischemic attack and smoking status. We assessed the association between leukocyte count and adverse clinical outcomes and evaluated this association in different subgroups. Results: A total of 14,678 patients were included. Patients in higher quartiles were likely to be younger, male, smokers, and drinkers, and to have a shorter time from symptom onset to arrival, a more proportion of history of diabetes, atrial fibrillation, and hypertension, and a higher severity of stroke. Higher quartiles were associated with elevated risk of adverse clinical outcomes at 3-months and 1-year follow-up. Leukocyte count had a moderate accuracy to predict clinical outcomes. There was no difference in the relationship between leukocyte count and adverse clinical outcomes across subgroups such as age, sex, history of hypertension, and smoking. The effect of leukocyte count on all-cause death was pronounced among patients with previous stroke or transient ischemic attack, and the effect of leukocyte count on short-term poor functional outcomes was also pronounced among patients without diabetes. Conclusions: Leukocyte count is associated with short-term and long-term clinical outcomes of acute ischemic stroke and may have predictive value, especially in patients with certain specific characteristics.
| S-EPMC6988785 | biostudies-literature