Dl-3-n-Butylphthalide Alleviates Secondary Brain Damage and Improves Working Memory After Stroke in Cynomolgus Monkeys.

BACKGROUND: Remote secondary neurodegeneration is associated with poststroke cognitive impairment (PSCI). Dl-3-n-butylphthalide (NBP) improves PSCI clinically. However, whether it ameliorates PSCI by alleviating secondary neurodegeneration remains uncertain. Nonhuman primates provide more relevant models than rodents for human stroke and PSCI. This study investigated the effects of NBP on PSCI and secondary neurodegeneration in cynomolgus monkeys after permanent left middle cerebral artery occlusion (MCAO). METHODS: Thirteen adult male cynomolgus monkeys were randomly assigned to sham (n=4), MCAO+placebo (n=5), and MCAO+NBP groups (n=4). The MCAO+placebo and MCAO+NBP groups received saline and NBP injections intravenously, respectively, starting at 6-hour postsurgery for 2 weeks, followed by soybean oil and NBP orally, respectively, for 10 weeks after MCAO. Infarct size was assessed at week 4 by magnetic resonance imaging. Working memory and executive function were evaluated dynamically using the delayed response task and object retrieval detour task, respectively. Neuron loss, glia proliferation, and neuroinflammation in the ipsilateral dorsal lateral prefrontal cortex, thalamus, and hippocampus were analyzed by immunostaining 12 weeks after MCAO. RESULTS: Infarcts were located in the left middle cerebral artery region, apart from the ipsilateral dorsal lateral prefrontal cortex, thalamus, or hippocampus, with no significant difference between the MCAO+placebo and MCAO+NBP group. Higher success in delayed response task was achieved at weeks 4, 8, and 12 after NBP compared with placebo treatments (P<0.05), but not in the object retrieval detour task (all P>0.05). More neurons and less microglia, astrocytes, CD68-positive microglia, tumor necrosis factor-α, and inducible NO synthase were observed in the ipsilateral dorsal lateral prefrontal cortex and thalamus after 12 weeks of NBP treatment (P<0.05), but not in the hippocampus (P>0.05). CONCLUSIONS: Our findings indicate that NBP improves working memory by alleviating remote secondary neurodegeneration and neuroinflammation in the ipsilateral dorsal lateral prefrontal cortex and thalamus after MCAO in cynomolgus monkeys.

Glucose-6-phosphate dehydrogenase deficiency and intracranial atherosclerotic stenosis in stroke patients.

BACKGROUND AND PURPOSE: Intracranial atherosclerotic stenosis (ICAS) is a major cause of stroke in Asian countries. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, a hereditary enzyme defect prevalent in Asian countries, has been associated with atherosclerotic cardiovascular disease and worse poststroke outcomes. However, the impact of G6PD deficiency on ICAS remains unclear. We aimed to compare the risk of ICAS in stroke patients with and without G6PD deficiency in a Chinese cohort. METHODS: We prospectively and consecutively recruited stroke patients from four centers in China. All patients received intracranial artery assessment by magnetic resonance/computed tomography angiography or digital subtraction angiography, as well as G6PD enzyme evaluation. The prevalence, burden, and characteristics of ICAS were compared between patients with and without G6PD deficiency using multivariate regression analysis. RESULTS: Among 1593 patients, 116 (63.7%) of 182 patients with G6PD deficiency and 714 (50.6%) of 1411 patients with normal G6PD levels were identified as ICAS. Age, hypertension, diabetes, and G6PD deficiency were independent predictors of ICAS. Among patients with ICAS, G6PD-deficient individuals were more likely to have multiple (≥2 segments) intracranial stenosis (odds ratio [OR] = 1.87, 95% confidence interval [CI] = 1.25-2.81, p = 0.002). G6PD deficiency increased the risk of ICAS in patients who were male (OR = 1.82, 95% CI = 1.24-2.66, p = 0.002), aged ≥70 years (OR = 2.40, 95% CI = 1.33-4.31, p = 0.004), or hypertensive (OR = 1.88, 95% CI = 1.28-2.77, p = 0.001). CONCLUSIONS: Stroke patients with G6PD deficiency have a higher prevalence and ICAS burden than those with normal G6PD, particularly those who are male, older, and hypertensive.

Cerebral Embolism as a Result of Facial Filler Injections: A Literature Review.

BACKGROUND: With the growth in the popularity of facial filler injections, increased numbers of severe adverse events, such as cerebral embolism, have been reported. OBJECTIVES: The aim of this article was to summarize the clinical manifestations and proposed mechanisms of filler-induced cerebral embolism (FICE). METHODS: A literature review was performed with the search keywords "filler injection," "hyaluronic acid," "fat graft," "cerebral infarction," "cerebral embolism," "stroke," "cerebrovascular infarction," "disorders of consciousness," and "hemiplegia." RESULTS: Among the 43 cases of FICE enrolled from 35 articles, 37 patients were female, and 6 were male. Twenty-nine of these patients had received fat grafting, and 12 hyaluronic acid injection. Most FICE patients had been injected in the glabella, followed by the temporal, forehead, and nasal areas. Among 30 patients injected under local anesthesia, 43.33% presented with neurologic symptoms during the procedure. The main symptoms were consciousness disorders and hemiplegia. Most of the embolization sites were in the middle cerebral artery, followed by frontal lobe infarction and anterior cerebral artery infarction. Three patients developed cerebral hemorrhage after embolism. Twenty-six patients presented with newly acquired vision loss. The management for FICE cases included embolectomy, thrombolysis, decompressive craniectomy, antiplatelet/anticoagulant therapy, and symptomatic and nutritional treatment. Nearly half of the patients recovered or exhibited improved neurologic manifestations but not visual loss. Five patients died. CONCLUSIONS: FICE is a severe complication following facial filler injection. Careful prevention, timely identification, and treatment are crucial to decreasing the morbidity and mortality of FICE.

Structural Damage Identification Based on Integrated Utilization of Inverse Finite Element Method and Pseudo-Excitation Approach.

The attempt to integrate the applications of conventional structural deformation reconstruction strategies and vibration-based damage identification methods is made in this study, where, more specifically, the inverse finite element method (iFEM) and pseudo-excitation approach (PE) are combined for the first time, to give rise to a novel structural health monitoring (SHM) framework showing various advantages, particularly in aspects of enhanced adaptability and robustness. As the key component of the method, the inverse finite element method (iFEM) enables precise reconstruction of vibration displacements based on measured dynamic strains, which, as compared to displacement measurement, is much more adaptable to existing on-board SHM systems in engineering practice. The PE, on the other hand, is applied subsequently, relying on the reconstructed displacements for the identification of structural damage. Delamination zones in a carbon fibre reinforced plastic (CFRP) laminate are identified using the developed method. As demonstrated by the damage detection results, the iFEM-PE method possesses apparently improved accuracy and significantly enhanced noise immunity compared to the original PE approach depending on displacement measurement. Extensive parametric study is conducted to discuss the influence of a variety of factors on the effectiveness and accuracy of damage identification, including the influence of damage size and position, measurement density, sensor layout, vibration frequency and noise level. It is found that different factors are highly correlated and thus should be considered comprehensively to achieve optimal detection results. The application of the iFEM-PE method is extended to better adapt to the structural operational state, where multiple groups of vibration responses within a wide frequency band are used. Hybrid data fusion is applied to process the damage index (DI) constructed based on the multiple responses, leading to detection results capable of indicating delamination positions precisely.

Alternative complement pathway is activated in the brains of scrapie-infected rodents.

Activation of complement system in central nervous system (CNS) of the patients suffering from prion diseases or animal models infected with prion agents experimentally is reported repeatedly, but which pathways are involved in the complement system during prion infection is not well documented. Here, we evaluated the level of complement factor B (CFB), which is the key factor that triggers alterative pathway (AP) of complement in the brain tissues of scrapie-infected mice with various methodologies. We found that the levels of mRNA and protein of CFB significantly increased in the brain tissues of scrapie-infected mice. Morphologically, the increased CFB-specific signal overlapped with the elevated C3 signal in brain sections of scrapie-infected mice, meanwhile overlapped with damaged neurons and activated microglia, but not with the proliferative astrocytes. Additionally, the level of complement factor P (CFP), the key positive regulator of AP, also increased remarkably in the brain tissues of infected mice. The transcriptional levels of CD55 and CD46, two negative regulators of AP, decreased without significance in brain tissues of scrapie-infected mice at the terminal stage. However, the mRNA and protein levels of CFH, another negative regulator of AP, increased. Through the dynamic analyses of the expressions of CFB, CFP, and CFH in brain sections of 139A-infected mice, which were collected at different time-points during incubation period, illustrated time-dependent increase levels of each factor during the incubation period of scrapie infection. Taken together, our data here demonstrate that the AP of complement cascade is activated in the CNS microenvironment during prion infection.

Late-onset aspirin-related hemolysis and subsequent subdural hemorrhage in patient with glucose-6-phosphate dehydrogenase deficiency.

Key Clinical Message: Aspirin-related hemolysis in G6PD deficiency could be late-onset during long-term administration. Hemolytic anemia could continue for a relatively long time in elder patient with G6PD deficiency, which might be related to other adverse events. Abstract: Aspirin-related hemolysis in G6PD-deficient individuals was generally reported among patients who received high-dose supplements within several days after ingestion. The safety of long-term and low-dose (50-325 mg/day) aspirin in patients coexist G6PD deficiency and cardiovascular disease is neglected in clinical practice. In this case, we observed a late-onset hemolysis and subsequent fatal subdural hemorrhage in one G6PD-deficient individual who had received long-term and low-dose aspirin. An 83-year-old male was diagnosed with acute ischemic stroke and treated with 100 mg/day aspirin at the emergency room. After admission, the patient was diagnosed with severe G6PD deficiency based on enzyme activity, but no hemolysis occurred within 10-day aspirin therapy in the hospital. Hence, 100 mg/day aspirin was continued on discharge. Two months later, the patient presented acute hemolysis manifested as fatigue, dark urine, and moderate jaundice. Although hemolysis was self-limit in a few days, hemoglobin decline continued for 20 days until a fatal subdural hemorrhage occurred. Our study indicated aspirin-related hemolysis could be late-onset in G6PD-deficient individual even receiving low-dose treatment and is probably linked to subsequent major bleeding events.

Efficacy and safety of agomelatine versus SSRIs/SNRIs for post-stroke depression: a systematic review and meta-analysis of randomized controlled trials.

Agomelatine is effective in the treatment of depression, but its effect for post-stroke depression (PSD) remains unclear. This study was conducted to compare the efficacy and safety of agomelatine versus SSRIs/SNRIs in treating PSD. We systematically searched Embase, PubMed, Cochrane Library, WanFang Data, China National Knowledge Infrastructure, and Cqvip databases for double-blind randomized controlled studies comparing the efficacy and safety of agomelatine versus SSRIs/SNRIs for PSD until December 2022. The primary efficacy endpoint was the Hamilton Depression Rating Scale (HAMD) score, and the primary safety endpoint was the incidence of overall adverse reactions. Nine studies comprising 857 patients with PSD were included. After 6-12 weeks of treatment, the HAMD score ( P  = 0.16) and the overall response rates ( P  = 0.20) in the agomelatine group were comparable to that in the SSRIs/SNRIs group. Participants treated with agomelatine achieved higher Barthel Index scores compared with the SSRIs/SNRIs group ( P  = 0.02). There was a significantly lower incidence of overall adverse reactions ( P  = 0.008) and neurological adverse reactions ( P  < 0.0001) in the agomelatine group. The efficacy of agomelatine for treating PSD is probably comparable to that of SSRIs/SNRIs, and it may improve stroke outcomes with better safety.

Certification of stroke centers at primary hospitals and the improvement of thrombolysis n South China during 2020-2022.

INTRODUCTION: IVT use declined globally in 2020 due to the Corona Virus Disease 2019 (COVID-19) pandemic, but it increased in South China. This study was conducted to evaluate the association of establishing Stroke Prevention Centers (SPCs) at primary hospitals with IVT increase in South China. MATERIALS AND METHODS: We conducted a longitudinal observational study across 336 hospitals in 114 areas in South China during 2020-2022. Data regarding certified stroke centers, IVT volumes, and IVT rates were collected. Correlations between IVT rates and the number or density of stroke centers were accessed. IVT use was compared among areas with different levels of stroke centers or on different certification process. RESULTS: During 2020-2022, there were 83, 125, and 152 stroke centers, with 26, 65, and 92 SPCs, respectively. IVT therapies were 12,795, 17,266, and 20,411, representing a 29.8% increase/year (all p < 0.001). IVT rates increased from 7.2% in 2020 to 8.8% and 10.4% in 2021 and 2022, demonstrating a 22.2% increase/year (all p < 0.001). IVT rates correlated with the number and density of SPCs (all p < 0.05). IVT rates were higher in areas equipped with SPCs than in those without stroke centers (all p < 0.05). IVT rates consistently increased during the SPC certification process from 1 year before through the certification and subsequent maintenance (both p < 0.05). DISCUSSION AND CONCLUSION: Well-organised SPCs and IVT therapy demonstrated substantial increase during the 3-year period. Certification of SPCs at primary hospitals is associated with improved IVT therapy in South China even with city lockdown during COVID-19 pandemic.

Risk Factors and Prognostic Implications of New-Onset Paroxysmal Atrial Fibrillation in Patients Hospitalized with Intracerebral Hemorrhage.

Objective: We aimed to assess the prevalence and risk factors of new-onset paroxysmal atrial fibrillation (PAF) in patients hospitalized with ICH and determine whether the new-onset PAF had influenced functional outcomes. Methods: We analyzed a database of all consecutive patients with ICH from October 2013 to May 2022. Univariate and multivariable regression analyses were performed to identify risk factors for new-onset PAF in patients with ICH. Multivariate models were also constructed to assess whether the new-onset PAF was an independent predictor of poor functional outcome, as measured using the modified Rankin scale. Results: This study included 650 patients with ICH, among whom 24 patients had new-onset PAF. In the multivariable model, older age (OR per 10-y increase, 2.26 [95% CI, 1.52-3.35]; P<0.001), hematoma volume (OR per 10-mL increase, 1.80 [95% CI, 1.26-2.57]; P=0.001), and heart failure (OR, 21.77 [95% CI, 5.52-85.91]; P<0.001) were independent risk factors for new-onset PAF. In a sensitivity analysis restricted to 428 patients with N-terminal pro-B-type natriuretic peptide (NT-proBNP), older age, larger hematoma volume, heart failure, and increased NT-proBNP were associated with new-onset PAF. After adjusting for baseline variables, new-onset PAF was an independent predictor of poor functional outcome (OR, 10.35 [95% CI, 1.08-98.80]; P=0.042). Conclusion: Older age, larger hematoma volume, and heart failure were independent risk factors for new-onset PAF after ICH. Increased NT-proBNP is correlated with higher risks for new-onset PAF when their information is available at admission. Furthermore, new-onset PAF is a significant predictor of poor functional outcome.

Network Pharmacology Prediction and Experimental Verification for Anti-Ferroptosis of Edaravone After Experimental Intracerebral Hemorrhage.

Neuronal ferroptosis plays an important role in secondary brain injuries after intracerebral hemorrhage (ICH). Edaravone (Eda) is a promising free radical scavenger that inhibits ferroptosis in neurological diseases. However, its protective effects and underlying mechanisms in ameliorating post-ICH ferroptosis remain unclear. We employed a network pharmacology approach to determine the core targets of Eda against ICH. Forty-two rats were subjected to successful striatal autologous whole blood injection (n=28) or sham operation (n=14). The 28 blood-injected rats were randomly assigned to either the Eda or vehicle group (n=14) for immediate administration and then for 3 consecutive days. Hemin-induced HT22 cells were used for in vitro studies. The effects of Eda in ICH on ferroptosis and the MEK/ERK pathway were investigated in vivo and in vitro. Network pharmacology-based analysis revealed that candidate targets of Eda-treated ICH might be related to ferroptosis; among which prostaglandin G/H synthase 2 (PTGS2) was a ferroptosis marker. In vivo experiments showed that Eda alleviated sensorimotor deficits and decreased PTGS2 expression (all p<0.05) after ICH. Eda rescued neuron pathological changes after ICH (increased NeuN+ cells and decreased FJC+ cells, all p<0.01). In vitro experiments showed that Eda reduced intracellular reactive oxygen species and reversed mitochondria damage. Eda repressed ferroptosis by decreasing malondialdehyde and iron deposition and by influencing ferroptosis-related protein expression (all p<0.05) in ICH rats and hemin-induced HT22 cells. Mechanically, Eda significantly suppressed phosphorylated-MEK and phosphorylated-ERK1/2 expression. These results indicate that Eda has protective effects on ICH injury through ferroptosis and MEK/ERK pathway suppression.

Population-Average Brain Templates and Application to Automated Voxel-Wise Analysis Pipelines for Cynomolgus Macaque.

The growing number of neuroimaging studies of cynomolgus macaques require extending existing templates to facilitate species-specific application of voxel-wise neuroimaging methodologies. This study aimed to create population-averaged structural magnetic resonance imaging (MRI) and diffusion tensor imaging (DTI) templates for the cynomolgus macaques and apply the templates in fully automated voxel-wise analyses. We presented the development of symmetric and asymmetric MRI and DTI templates from a sample of 63 young male cynomolgus monkeys with the use of optimized template creation approaches. We also generated the associated average tissue probability maps and Diffeomorphic Anatomical Registration using Exponentiated Lie Algebra templates for use with the Statistical Parametric Mapping (SPM), as well as the average fractional anisotropy/skeleton targets for incorporation into tract-based spatial statistics (TBSS) framework. Both asymmetric and symmetric templates in a standardized coordinate space demonstrated low bias and high contrast. Fully automated processing using SPM was accomplished for all native MRI datasets and demonstrated outstanding performance regarding skull-stripping, segmentation, and normalization when using the MRI templates. Automated normalization to the DTI template was excellently achieved for all native DTI images using the TBSS pipeline. The cynomolgus MRI and DTI templates are anticipated to provide a common platform for precise single-subject data analysis and facilitate comparison of neuroimaging findings in cynomolgus monkeys across studies and sites. It is also hoped that the procedures of template creation and fully-automated voxel-wise frameworks will provide a straightforward avenue for investigating brain function, development, and neuro-psychopathological disorders in non-human primate models.

Impact of stroke center certification on rt-PA thrombolysis after acute ischemic stroke in South China from 2015 to 2020.

BACKGROUND AND PURPOSE: In China, stroke center certification was launched in 2015, but little is known about its impact on intravenous thrombolysis. This study aimed to evaluate the effects of stroke center certification on the use of intravenous thrombolysis during a five-year period in South China. METHODS: We retrospectively collected data regarding the use of recombinant tissue plasminogen activator (rt-PA) in 21 cities of Guangdong from 2015 to 2020. The annual thrombolysis rate was defined as the number of patients who underwent intravenous rt-PA therapy divided by the number of those who had acute ischemic stroke within the same year. The density of stroke centers was calculated as the number of stroke centers divided by the corresponding residents. Spearman's correlation analysis was used to determine the correlations between the annual thrombolysis rates and the number/density of stroke centers. Paired t-test was used to compare differences in growth in annual thrombolysis rates before and after having stroke centers. RESULTS: From 2015 to 2020, the annual rt-PA thrombolysis rates of Guangdong increased from 1.4% to 7.2%, which was accompanied by an increase in the number of stroke centers from 0 to 82 and density of stroke centers from 0.00 to 0.71 per million population. The average annual rt-PA use in stroke centers was higher than that in non-stroke centers from 2016 to 2020 (all P < 0.05). There was a positive correlation of annual thrombolysis rates with the number of stroke centers (r = 1.00, P = 0.0028) and with the density of stroke centers in the 21 cities from 2018 to 2020 (all P < 0.05). The growth in annual thrombolysis rates significantly accelerated at the city-level after having stroke centers (1.55%/y vs. 0.77%/y, P < 0.001). CONCLUSIONS: Stroke center certification may partially drive the increased use of rt-PA thrombolysis. Stroke center certification should be continually promoted to facilitate access to intravenous thrombolysis for patients with acute ischemic stroke.

Association between aspirin-induced hemoglobin decline and outcome after acute ischemic stroke in G6PD-deficient patients.

AIMS: The risk of hemoglobin decline induced by low-dose aspirin in glucose-6-phosphate dehydrogenase (G6PD) deficiency remains unknown, and its influence on stroke outcome remains to be investigated. This study aimed to evaluate the effect of G6PD deficiency on hemoglobin level during aspirin treatment and its association with outcome after acute ischemic stroke. METHODS: In total, 279 patients (40 G6PD-deficient and 239 G6PD-normal) with acute ischemic stroke treated with aspirin 100 mg/day from a cohort study were examined. The primary safety endpoint was a hemoglobin decline ≥25 g/L or 25% from baseline within 14 days after aspirin treatment. Poor outcomes were defined as a modified Rankin Scale score ≥2 at 3 months. The χ2 test was used to compare stroke outcomes, and multivariate logistic regression analyses were performed to analyze the association between hemoglobin level and outcomes. RESULTS: The G6PD-deficient group had lower baseline hemoglobin and tended to develop comorbid pulmonary infection more frequently (p < 0.05). The proportion of patients with hemoglobin decline ≥25 g/L or 25% from baseline (15.0% vs. 3.3%; p = 0.006) and anemia (30.0% vs. 14.6%; p = 0.016) after aspirin treatment was higher in the G6PD-deficient group, which was accompanied by a more significant bilirubin increase. The rate of poor functional outcomes at 3 months after acute ischemic stroke was higher in the G6PD-deficient group (Risk ratio = 1.31 [95% confidence interval (CI) = 1.10-1.56]; p = 0.017). Confounder-adjusted analysis showed that lower hemoglobin levels (odds ratio = 0.98 [95% CI = 0.96-0.99]; adjusted p = 0.009) increased the risk of poor functional outcomes. CONCLUSION: Hemoglobin decrease with bilirubin increase after aspirin treatment in patients with G6PD deficiency suggests hemolysis, which may influence stroke prognosis. The risk of hemoglobin decline should be carefully monitored in G6PD-deficient patients with ischemic stroke taking aspirin.

Aspirin Therapy in Cardiovascular Disease with Glucose-6-Phosphate Dehydrogenase Deficiency, Safe or Not?

Glucose-6-phosphate dehydrogenase (G6PD) deficiency is the most common human enzyme defect, which may present as acute hemolysis, neonatal jaundice, or chronic hemolysis. Ingestion of fava beans, as well as infection and certain drugs, are the most typical causes of acute hemolysis in people with G6PD deficiency. Aspirin, the cornerstone in current therapies for the prevention of cardiovascular disease (CVD), is occasionally reported to induce acute hemolysis in G6PD-deficient individuals. G6PD deficiency is typically asymptomatic and many CVD patients with this enzyme defect start to take long-term aspirin therapy without G6PD activity examination; however, no consensus on the safety of aspirin in this population has been reached. A few studies have reported on this issue and produced contradictory results. In this review, we discuss the possible mechanisms of aspirin-induced hemolysis, and summarize clinical evidence regarding the safety of aspirin in subjects with G6PD deficiency.

Safety and efficacy of low-dose aspirin in ischemic stroke patients with different G6PD conditions.

BACKGROUND AND PURPOSE: Aspirin is the first recommended antiplatelet agent to prevention secondary stroke, but its safety and efficacy in stroke patients with glucose-6-phosphate dehydrogenase deficiency remain unclear. We sought to evaluate its safety and efficacy in ischemic stroke patients with and without glucose-6-phosphate dehydrogenase deficiency. METHODS: Patients with ischemic stroke receiving aspirin (100 mg/day) for three months were recruited for a multicenter, prospective, cohort study. Blood glucose-6-phosphate dehydrogenase activity was examined after stroke. Safety outcomes including acute hemolysis, moderate-to-severe bleeding, and death (vascular, all-cause), and efficacy outcome indicated as stroke recurrence were evaluated at three months. Risk factors associated with moderate-to-severe bleeding and all-cause death were determined using multivariate or Cox regression analysis. RESULTS: Among the included 1121 patients, 81 of 130 glucose-6-phosphate dehydrogenase deficient and 576 of 991 glucose-6-phosphate dehydrogenase normal patients received aspirin for three months. Acute hemolysis was observed in one of the glucose-6-phosphate dehydrogenase deficient and in none of the glucose-6-phosphate dehydrogenase normal patients (p = 0.876). The rates of moderate-to-severe bleeding were 2.5% and 0.3% (p = 0.045), and the percentages of all-cause death were 6.2% and 1.4% (p = 0.008) in the glucose-6-phosphate dehydrogenase deficient and glucose-6-phosphate dehydrogenase normal patients. Stroke recurrence rate was similar in the two groups (2.5% vs. 1.7%; p = 0.608). Glucose-6-phosphate dehydrogenase deficiency was significantly associated with increased risk of moderate-to-severe bleeding (adjust p = 0.048) and all-cause death during aspirin use (adjust p = 0.008). CONCLUSIONS: Long-term low-dose aspirin therapy might relate to worse safety outcomes in patients with glucose-6-phosphate dehydrogenase deficiency and large clinical trials are needed to further confirm these findings.

Glucose-6-phosphate dehydrogenase deficiency and stroke outcomes.

OBJECTIVE: To assess the risk of glucose-6-phosphate dehydrogenase (G6PD) on stroke prognosis, we compared outcomes between patients with stroke with and without G6PD deficiency. METHODS: The study recruited 1,251 patients with acute ischemic stroke. Patients were individually categorized into G6PD-deficiency and non-G6PD-deficiency groups according to G6PD activity upon admission. The primary endpoint was poor outcome at 3 months defined by a modified Rankin Scale (mRS) score ≥2 (including disability and death). Secondary outcomes included the overall mRS score at 3 months and in-hospital death and all death within 3 months. Logistic regression and Cox models, adjusted for potential confounders, were fitted to estimate the association of G6PD deficiency with the outcomes. RESULTS: Among 1,251 patients, 150 (12.0%) were G6PD-deficient. Patients with G6PD deficiency had higher proportions of large-artery atherosclerosis (odds ratio [OR] 1.53, 95% confidence interval [CI] 1.09-2.17) and stroke history (OR 1.93, 95% CI 1.26-2.90) compared to the non-G6PD-deficient group. The 2 groups differed significantly in the overall mRS score distribution (adjusted common OR 1.57, 95% CI 1.14-2.17). Patients with G6PD deficiency had higher rates of poor outcome at 3 months (adjusted OR 1.73, 95% CI 1.08-2.76; adjusted absolute risk increase 13.0%, 95% CI 2.4%-23.6%). The hazard ratio of in-hospital death for patients with G6PD-deficiency was 1.46 (95% CI 1.37-1.84). CONCLUSIONS: G6PD deficiency is associated with the risk of poor outcome at 3 months after ischemic stroke and may increase the risk of in-hospital death. These findings suggest the rationality of G6PD screening in patients with stroke.

Persistence of Gut Microbiota Dysbiosis and Chronic Systemic Inflammation After Cerebral Infarction in Cynomolgus Monkeys.

Background: The bidirectional interaction between the gut and brain after stroke through the immune-mediated pathway has been studied. However, the long-term effects of gut microbiota and systemic immune homeostasis after cerebral ischemia remain unclear. We examined long-term changes in the gut microbiota and systemic inflammatory cytokines after cerebral infarction in cynomolgus monkeys. Methods: Twelve monkeys underwent successful distal M1 segment of the left middle cerebral artery occlusion (MCAO) and were randomly and equally assigned to the MCAO-1.5 m, MCAO-6 m, and MCAO-12 m groups, which were sacrificed 1.5, 6, and 12 months after cerebral infarction induction, respectively. Four monkeys that underwent a sham operation were sacrificed 12 months later. The gut microbiota and short-chain fatty acids (SCFAs) were analyzed by 16S rDNA sequencing and gas chromatography mass spectrometry, respectively. Histological examinations of the transverse colon were performed. Plasma D-lactate, zonulin, lipopolysaccharide (LPS), tumor necrosis factor (TNF-α), interferon (IFN)-γ, and interleukin (IL)-6 were detected by immunoassay kits. Results: The levels of the Bacteroidetes phylum and Prevotella genus were significantly increased, while the Firmicutes phylum as well as the Faecalibacterium, Oscillospira, and Lactobacillus genera were decreased after cerebral infarction. Gut-originating SCFAs were significantly decreased 6 and 12 months after cerebral infarction (P < 0.05). We observed intestinal mucosal damage, evaluated by Chiu's score. Plasma D-lactate, zonulin, LPS, TNF-α, IFN-γ, and IL-6 were significantly increased after cerebral infarction (P < 0.05). Additionally, the increases in plasma LPS, TNF-α, IFN-γ, and IL-6 after cerebral infarction coincided with overgrowth of the Bacteroidetes phylum (P < 0.001). Conclusion: Cerebral infarction induces persistent host gut microbiota dysbiosis, intestinal mucosal damage, and chronic systemic inflammation in cynomolgus monkeys.

Decrease of RyR2 in the prion infected cell line and in the brains of the scrapie infected mice models and the patients of human prion diseases.

The levels of ryanodine receptors (RyRs) are usually increased in the brains of human Alzheimer disease (AD) and AD animal models. To evaluate the underlying alteration of brain RyRs in prion disease, scrapie infected cell line SMB-S15 and its infected mice were tested. RyR2 specific Western blots revealed markedly decreased RyR2 levels both in the cells and in the brains of infected mice. Assays of the brain samples of other scrapie (agents 139A and ME7) infected mice collected at different time-points during incubation period showed time-dependent decreases of RyR2. Immunofluorescent assays (IFA) verified that the expression of RyR2 locates predominantly in cytoplasm of SMB cells and overlapped with the neurons in the brain slices of mice. Furthermore, significant down-regulation of RyR2 was also detected in the postmortem cortical brains of the patients of various types of human prion diseases, including sporadic Creutzfeldt-Jakob disease (sCJD), fatal familial insomnia (FFI) and G114V-genetic CJD. Our data here propose the evidences of remarkably decreased brain RyR2 at terminal stages of both human prion diseases and prion infected rodent models. It also highlights that the therapeutic strategy with antagonist of RyRs in AD may not be suitable for prion disease.

Encephalitis with reversible splenial and deep cerebral white matter lesions associated with Epstein-Barr virus infection in adults.

BACKGROUND: Approximately 200 cases of mild encephalitis with reversible splenial (MERS) and deep cerebral white matter lesions have been reported since MERS was first defined in 2004. MERS occurs more frequently in children; in adults, only ~60 cases have been reported. Until now, only four cases of MERS in adults have been associated with Epstein-Barr virus (EBV). CASE PRESENTATION: We report three adult cases of MERS associated with EBV infection in China. For all three patients, cranial magnetic resonance imaging (MRI) indicated solitary reversible splenial and/or perilateral ventricle white matter lesions with reduced diffusion. In the present report, all patients were adults presenting with high fever, headache, apathy, and confusion, as well as significant signs of meningeal inflammation. These symptoms peaked 10-14 days after disease onset, with serious hyponatremia (112-129 mmol/L), an elevated cerebrospinal fluid white blood cell count (80-380/mm3), and significantly increased protein levels (1,010-1,650 mg/dL). Cranial MRI indicated abnormal signal intensity in the splenium of corpus callosum and symmetrically reversible lesions scattered in the thalamus and deep cerebral white matter. The clinical symptoms tended to improve after ~10-14 days of antiviral treatment. However, these patients recovered more slowly than patients with viral meningitis. CONCLUSION: MERS associated with EBV infection in adults occurs less frequently but with more severe symptoms than in children. EBV infection should be considered for patients with MERS symptoms. MERS has a good prognosis.

Increases of Galectin-1 and its S-nitrosylated form in the Brain Tissues of Scrapie-Infected Rodent Models and Human Prion Diseases.

Galectin-1 (Gal-1) shows neuroprotective activity in brain ischemia, spinal cord injury, and autoimmune neuroinflammation. To evaluate the Gal-1 situation in the brains of prion disease, the brain levels of Gal-1 in several scrapie-infected experimental rodent models were tested by Western blot, including agents 263K-infected hamsters, 139A-, ME7-, and S15-infected mice. Remarkable increases of brain Gal-1 were observed in all tested scrapie-infected rodents at the terminal stage. The brain levels of Gal-1 showed time-dependent increases along with the prolonging of incubation times. Immunohistochemical assays illustrated much stronger stainings in the brain sections of scrapie-infected rodents. Quantitative RT-PCR of Gal-1 gene demonstrated increased transcription in the brains of scrapie-infected mice. Gal-1 was colocalized with GFAP- and NeuN-positive cells, but not with Iba-1-positive cells in immunofluorescent test. Increases of Gal-1 were also detected in the several postmortem cortex regions of human prion diseases. Moreover, the S-nitrosylated forms of Gal-1 in the brains of scrapie-infected rodents were significantly higher than those of normal ones. Our finding here demonstrates markedly increased brain Gal-1 and S-nitrosylated Gal-1 both in scrapie-infected rodents and human prion diseases.