A New NF-κB Inhibitor, MEDS-23, Reduces the Severity of Adverse Post-Ischemic Stroke Outcomes in Rats

Aim: Nuclear factor kappa B (NF-κB) is known to play an important role in the inflammatory process which takes place after ischemic stroke. The major objective of the present study was to examine the effects of MEDS-23, a potent inhibitor of NF-κB, on clinical outcomes and brain inflammatory markers in post-ischemic stroke rats. Main methods: Initially, a Toxicity Experiment was performed to determine the appropriate dose of MEDS-23 for use in animals, as MEDS-23 was analyzed in vivo for the first time. We used the middle cerebral artery occlusion (MCAO) model for inducing ischemic stroke in rats. The effects of MEDS-23 (at 10 mg/kg, ip) on post-stroke outcomes (brain inflammation, fever, neurological deficits, mortality, and depression- and anxiety-like behaviours) was tested in several efficacy experiments. Key findings: MEDS-23 was found to be safe and significantly reduced the severity of some adverse post-stroke outcomes such as fever and neurological deficits. Moreover, MEDS-23 significantly decreased prostaglandin E2 levels in the hypothalamus and hippocampus of post-stroke rats, but did not prominently alter the levels of interleukin-6 and tumor necrosis factor-α. Significance: These results suggest that NF-κB inhibition is a potential therapeutic strategy for the treatment of ischemic stroke.

Trends in clinical prediction models of stroke outcomes research outputs: a bibliometric analysis

Stroke is one of the leading causes of death and disability globally. Clinical models have been reported to predict stroke outcomes and thus, potentially guide clinical decisions. This study aimed to describe the global trends of research in clinical prediction models of stroke outcomes. A bibliometric analysis was conducted on clinical prediction models of stroke outcomes publications reported in Scopus from 2010 to 2019. Bibliographic data were extracted, quantitatively analysed, and visualized using VOSviewer software. A total of 6,364 publications were included in the final analysis. The number of published studies had steadily increased since 2010. “Stroke” and “Journal of Stroke and Cerebrovascular Diseases” were the journal with the most publications and citations. The most cited publications were by Lip et al. (2010) and Berkhemer et al. (2015). The United States of America (USA), China together with their institutions contributed most to the pool of publications in the field. Our study showed a steady increasing research activity in the clinical prediction of stroke outcomes since 2010, with saturation in recent years. The top articles were published in high-quality stroke-related journals and by high-income countries. There is a need to reinforce research capacities in the field by developing collaborative networks.

Mitochondrial DNA Copy Number as a Marker and Mediator of Stroke Prognosis: Observational and Mendelian Randomization Analyses

Background:Low buffy coat mitochondrial DNA copy number (mtDNA-CN) is associated with incident risk of stroke and post-stroke mortality; however, its prognostic utility has not been extensively explored.Objective:To investigate whether low buffy coat mtDNA-CN is a marker and causal determinant of post-stroke outcomes using epidemiological and genetic studies.Methods:First, we performed association testing between baseline buffy coat mtDNA-CN measurements and 1-month post-stroke outcomes in 3498 acute, first stroke cases from 25 countries from the international, multicenter case-control study, “Importance of Conventional and Emerging Risk Factors of Stroke in Different Regions and Ethnic Groups of the World” (INTERSTROKE). Then, we performed two-sample Mendelian Randomization analyses to evaluate potential causative effects of low mtDNA-CN on 3-month modified Rankin Scale (mRS). Genetic variants associated with mtDNA-CN levels were derived from the UKBiobank study (N=383476), and corresponding effects on 3-month mRS were ascertained from the Genetics of Ischemic Stroke funCtional Outcome study (GISCOME; N=6021).Results:A 1-standard deviation (SD) lower mtDNA-CN at baseline was associated with stroke severity (baseline mRS; OR=1.27; 95% CI, 1.19-1.36; P=4.7x10-12). Independent of baseline stroke severity, lower mtDNA-CN was associated with increased odds of greater 1-month disability (ordinal mRS; OR=1.16; 95% CI, 1.08-1.24; P=4.4x10-5), poor functional outcome status (mRS 3-6 vs. 0-2; OR=1.21; 95% CI, 1.08-1.34; P=6.9x10-4), and mortality (OR=1.35; 95% CI, 1.14-1.59; P=3.9x10-4). Subgroup analyses demonstrated consistent effects across stroke type, sex, age, country income level, and education level. In addition, mtDNA-CN significantly improved reclassification of poor functional outcome status (Net Reclassification Index (NRI)=0.16; 95% CI, 0.08-0.23; P=3.6x10-5) and mortality (NRI=0.31; 95% CI, 0.19-0.43; P=1.7x10-7) beyond known prognosticators. Using independent datasets, Mendelian Randomization revealed that a 1 SD decrease in genetically determined mtDNA-CN was associated with increased odds of greater 3-month disability quantified by ordinal mRS (OR=2.35; 95% CI, 1.13-4.90; P=0.02) and poor functional outcome status (OR=2.68; 95% CI, 1.05-6.86; P=0.04).Conclusions:Buffy coat mtDNA-CN is a novel and robust marker of post-stroke prognosis that may also be a causal determinant of post-stroke outcomes.Classification of Evidence:This study provides class II evidence that low buffy coat mtDNA-CN (>1-standard deviation) was associated with worse baseline severity and 1-month outcomes in patients with ischemic or hemorrhagic stroke.

Are the Items of the Starkstein Apathy Scale Fit for the Purpose of Measuring Apathy Post-stroke?

Importance: Given the importance of apathy for stroke, we felt it was time to scrutinize the psychometric properties of the commonly used Starkstein Apathy Scale (SAS) for this purpose.Objectives: The objectives were to: (i) estimate the extent to which the SAS items fit a hierarchical continuum of the Rasch Model; and (ii) estimate the strength of the relationships between the Rasch analyzed SAS and converging constructs related to stroke outcomes.Methods: Data was from a clinical trial of a community-based intervention targeting participation. A total of 857 SAS questionnaires were completed by 238 people with stroke from up to 5 time points. SAS has 14 items, rated on a 4-point scale with higher values indicating more apathy. Psychometric properties were tested using Rasch partial-credit model, correlation, and regression. Items were rescored so higher scores are interpreted as lower apathy levels.Results: Rasch analysis indicated that the response options were disordered for 8/14 items, pointing to unreliability in the interpretation of the response options; they were consequently reduced from 4 to 3. Only 9/14 items fit the Rasch model and therefore suitable for creating a total score. The new rSAS was deemed unidimensional (residual correlations: < 0.3), reasonably reliable (person separation index: 0.74), with item-locations uniform across time, age, sex, and education. However, 30% of scores were > 2 SD above the standardized mean but only 2/9 items covered this range (construct mistargeting). Apathy (rSAS/SAS) was correlated weakly with anxiety/depression and uncorrelated with physical capacity. Regression showed that the effect of apathy on participation and health perception was similar for rSAS/SAS versions: R2 participation measures ranged from 0.11 to 0.29; R2 for health perception was ∼0.25. When placed on the same scale (0–42), rSAS value was 6.5 units lower than SAS value with minimal floor/ceiling effects. Estimated change over time was identical (0.12 units/month) which was not substantial (1.44 units/year) but greater than expected assuming no change (t: 3.6 and 2.4).Conclusion: The retained items of the rSAS targeted domains of behaviors more than beliefs and results support the rSAS as a robust measure of apathy in people with chronic stroke.

Optimising the Photothrombotic Model of Stroke in the C57BI/6 and FVB/N Strains of Mouse

The photothrombotic stroke model relies on the interaction between photosensitive-dye and light for clot formation. Interestingly, the relationship between the length of light exposure and stroke-outcome has never been examined. This model has yet to be established in the FVB/N strain, even though stroke-outcomes are strain-specific. Therefore, this study aimed to examine the effect of different lengths of light exposure in two strains of mice on photothrombotic stroke. Male FVB/N and C57Bl/6 mice were subjected to stroke using 15, 18, or 20-mins light exposure. Mice underwent functional testing for up to 7 days. Infarct volume was assessed with thionin staining, and cellular responses to injury analysed via immunofluorescence. Blood brain barrier (BBB) breakdown was assessed using Evans blue dye. Increasing light exposure from 15 to 20-minutes increased infarct volume but not functional deficit. Interestingly, there were strain-specific differences in functional outcomes, with FVB/N mice having less deficit on the hanging wire test than C57BI/6 after 15-minutes of light exposure. The opposite was seen in the adhesive removal test. There was no difference in number of neurons, astrocytes, microglia, macrophages, and T cells between the strains, despite FVB/N mice demonstrating greater BBB breakdown and an enlarged spleen post-stroke. Increasing light exposure systematically increases infarct volume but does not worsen functional outcomes. FVB/N and C57Bl/6 mice exhibit subtle differences in functional outcomes post stroke, which highlights the need to choose tests which are appropriate for the mouse strain being used.

PROGNOSTIC MEANING OF SERUM NSE AS THE FACTOR OF BAD OUTCOME IN SECONDARY BRAIN DAMAGE

This research is dedicated to the study of brain neuronspecific markers and indicators of brain damage outcome. Purpose of the study: To examine the prognostic role of serum NSE as the predictor of unfavorable outcome in traumatic and vascular brain damages. Methods: Prospective cohort study with 219 patients. Blood serum neuronspecific markers (NSE,S100B),acid-base state, blood gas were derived during the period of observation: upon enrolment, on the 3-rd, 5-th and 7-th days spent in the hospital in the intensive care unit. Results: The most significant risk factor of unfavorable outcome is the marker NSE with the cut point 12,5 ng|ml. The results of the analysis indicate the presence of a statistically significant direct relationship between NSE> 12.5 ng / ml and LDH, compared to other variables, 3.7 times more often; with an increase in blood lactate more than 4,1 mmol/l almost 3,8 times; with GCS 13 points below by 1,7 times; S100≥0,2 by 2,8 times; with an increase of PCO2 <38,5 it was documented more than 3 times often. The measure of certainty the resulting model by the pseudo R2 Nagelkerke criterion-250.6; logLikelihood - 154.04 which corresponds to the excellent predictive ability of the mathematical model. The best predictive value of the model is a cut-off point of 88.89%, AuROC-0.809; Se-51.59%; Sp-95.06%; NPV-55.80%; PPV-94.20%. This model can be used to predict the outcome in patients with acute cerebral pathology. Keywords: strokes, brain traumatic damages, neuronspecific markers, diagnostic and prognostic criterias, stroke outcomes.