Anti-osteopontin therapy leads to improved edema and infarct size in a murine model of ischemic stroke.

Ischemic stroke is a serious neurological disorder that is associated with dysregulation of the neurovascular unit (NVU) and impairment of the blood-brain barrier (BBB). Paradoxically, reperfusion therapies can aggravate NVU and BBB dysfunction, leading to deleterious consequences in addition to the obvious benefits. Using the recently established EPAM-ia method, we identified osteopontin as a target dysregulated in multiple NVU cell types and demonstrated that osteopontin targeting in the early acute phase post-transient middle cerebral artery occlusion (tMCAO) evolves protective effects. Here, we assessed the time course of osteopontin and CD44 receptor expression in NVU cells and examined cerebroprotective effects of osteopontin targeting in early and late acute phases of ischemic stroke. Expression analysis of osteopontin and CD44 receptor post-tMCAO indicated increased levels of both, from early to late acute phases, which was supported by their co-localization in NVU cells. Combined osteopontin targeting in early and late acute phases with anti-osteopontin antibody resulted in further improvement in BBB recovery and edema reduction compared to targeting only in the early acute phase comprising the reperfusion window. Combined targeting led to reduced infarct volumes, which was not observed for the single early acute phase targeting. The effects of the therapeutic antibody were confirmed both in vitro and in vivo in reducing osteopontin and CD44 expression. Osteopontin targeting at the NVU in early and late acute phases of ischemic stroke improves edema and infarct size in mice, suggesting anti-osteopontin therapy as promising adjunctive treatment to reperfusion therapy.

Profiling the neurovascular unit unveils detrimental effects of osteopontin on the blood-brain barrier in acute ischemic stroke.

Blood-brain barrier (BBB) dysfunction, characterized by degradation of BBB junctional proteins and increased permeability, is a crucial pathophysiological feature of acute ischemic stroke. Dysregulation of multiple neurovascular unit (NVU) cell types is involved in BBB breakdown in ischemic stroke that may be further aggravated by reperfusion therapy. Therefore, therapeutic co-targeting of dysregulated NVU cell types in acute ischemic stroke constitutes a promising strategy to preserve BBB function and improve clinical outcome. However, methods for simultaneous isolation of multiple NVU cell types from the same diseased central nervous system (CNS) tissue, crucial for the identification of therapeutic targets in dysregulated NVU cells, are lacking. Here, we present the EPAM-ia method, that facilitates simultaneous isolation and analysis of the major NVU cell types (endothelial cells, pericytes, astrocytes and microglia) for the identification of therapeutic targets in dysregulated NVU cells to improve the BBB function. Applying this method, we obtained a high yield of pure NVU cells from murine ischemic brain tissue, and generated a valuable NVU transcriptome database ( https://bioinformatics.mpi-bn.mpg.de/SGD_Stroke ). Dissection of the NVU transcriptome revealed Spp1, encoding for osteopontin, to be highly upregulated in all NVU cells 24 h after ischemic stroke. Upregulation of osteopontin was confirmed in stroke patients by immunostaining, which was comparable with that in mice. Therapeutic targeting by subcutaneous injection of an anti-osteopontin antibody post-ischemic stroke in mice resulted in neutralization of osteopontin expression in the NVU cell types investigated. Apart from attenuated glial activation, osteopontin neutralization was associated with BBB preservation along with decreased brain edema and reduced risk for hemorrhagic transformation, resulting in improved neurological outcome and survival. This was supported by BBB-impairing effects of osteopontin in vitro. The clinical significance of these findings is that anti-osteopontin antibody therapy might augment current approved reperfusion therapies in acute ischemic stroke by minimizing deleterious effects of ischemia-induced BBB disruption.

Data-Driven Risk Classification of Concussion Rates: A Systematic Review and Meta-Analysis.

BACKGROUND: Concussion is a growing public health concern and generating concussion prevention programs depends on identifying high-risk sports and characteristics. Identifying the roles of sport, sex, and participation level (e.g., high school versus collegiate athletics) in concussion risk would facilitate more informed decision-making regarding sports participation and generate better targeted prevention strategies. OBJECTIVES: The current study's objectives were to: (1) determine the magnitude and hierarchy of sports-related concussion (SRC) risk across an array of events and (2) evaluate the modifying roles of sex, participation level, and session type on SRC rates. METHODS: A literature search was conducted on PubMed, searching concussion studies published between 2001 and December 2019. Inclusion criteria for studies required: (1) concussion occurred during sport, (2) that the SRC was clinically diagnosed, and (3) athlete exposures and concussions could be extracted or estimated. A study was excluded if it: (1) was not an original research article, (2) was not written in English language, (3) was an animal study, (4) did not have enough data to calculate SRC rates, (5) included professional or youth sample, and/or (6) contained data collected prior to 2001. The meta-analysis and meta-regression analyses were fit using a random effects model. RESULTS: Search results returned 2695 unique research articles, with 83 studies included in analyses. Sport, sex, participation level, and session type all significantly influenced SRC rates. Overall, rugby had the highest concussion rate and was classified as the highest risk sport (28.25 concussions per 10,000 athlete exposures). Overall, females had a higher concussion rate than males. Only lacrosse demonstrated a higher concussion rate for males compared to females. Collegiate athletes had higher concussion rates than high school athletes. Games were associated with 2.01 more concussions per 10,000 AEs than practices. CONCLUSIONS: This meta-analysis demonstrated rugby has the highest concussion risk, followed by American Football, ice hockey, and wrestling. Concussion risk was influenced by sport, sex, participation, and session. Identifying the factors and environments that influence concussion risk can facilitate risk reduction and prevention strategies.

Concussion recovery time among high school and collegiate athletes: a systematic review and meta-analysis.

BACKGROUND: Concussion diagnosis and management is made through the clinical exam using assessment tools that include self-report symptomatology, postural control, and cognitive evaluations. The specific timing of concussion resolution varies between individuals. However, despite a lack of research in concussion recovery, it is widely accepted that the majority of young adults will recover in 7-10 days, with youth athletes taking longer. OBJECTIVES: The purpose of this review is to directly compare the recovery duration among high school and collegiate athletes on symptom reports and cognitive assessments following concussion. DATA SOURCES: Data were collected from a literature search comprising high school or college athletes only. This included studies (n = 6) that reported symptom or cognitive performance recovery to the exact day. RESULTS: High school athletes self-reported symptom recovery at 15 days compared with 6 days in collegiate athletes. Both college and high school athletes showed cognitive recovery at similar rates of 5 and 7 days. LIMITATIONS: This review only included articles that were directly related to concussed high school or college athletes. Additionally, athletes in the high school and college setting typically receive a battery of neurocognitive tests that may not be as sensitive or as comprehensive as a full neuropsychological exam. CONCLUSION: The review finds that neurocognitive recovery rates are similar among high school and college athletes, while symptom reporting shows longer recovery time points in high school than in college. IMPLICATIONS OF KEY FINDINGS: An individualized and stepwise concussion management plan is important for proper concussion recovery regardless of age.

Effect of caffeine on leg muscle pain during cycling exercise among females.

PURPOSE: This double-blind, within-subjects experiment examined the effects of ingesting two doses of caffeine on perceptions of leg muscle pain during moderate-intensity cycling exercise among females. METHODS: Low-caffeine-consuming college-aged females (N = 11) ingested one of two doses of caffeine (5 or 10 mg x kg(-1) body weight) or a placebo and 1 h later completed 30 min of cycling on an ergometer at approximately 60% VO2peak. The conditions were completed in a counterbalanced order. Perceptions of leg muscle pain as well as power output, heart rate, systolic blood pressure, and oxygen consumption (VO2) were recorded during exercise. RESULTS: Caffeine had a significant effect on leg muscle pain ratings [F (2,20) = 10.63, P = 0.001, n2 = 0.52]. The mean pain intensity scores during exercise after ingesting 10 mg x kg(-1) body weight caffeine, 5 mg x kg(-1) body weight caffeine, and placebo were 1.6 +/- 1.1, 1.3 +/- 0.7, and 2.4 +/- 1.1, respectively. CONCLUSION: The results support that caffeine ingestion has a large effect on reducing leg muscle pain during exercise among females, but this effect does not appear to be dose-dependent between 5 and 10 mg.kg body weight caffeine.