Ticagrelor versus Clopidogrel in CYP2C19 Loss-of-Function Carriers with Stroke or TIA.

BACKGROUND: Comparisons between ticagrelor and clopidogrel for the secondary prevention of stroke in CYP2C19 loss-of-function carriers have not been extensively performed. METHODS: We conducted a randomized, double-blind, placebo-controlled trial at 202 centers in China involving patients with a minor ischemic stroke or transient ischemic attack (TIA) who carried CYP2C19 loss-of-function alleles. Patients were assigned within 24 hours after symptom onset, in a 1:1 ratio, to receive ticagrelor (180 mg on day 1 followed by 90 mg twice daily on days 2 through 90) and placebo clopidogrel or to receive clopidogrel (300 mg on day 1 followed by 75 mg once daily on days 2 through 90) and placebo ticagrelor; both groups received aspirin for 21 days. The primary efficacy outcome was new stroke, and the primary safety outcome was severe or moderate bleeding, both within 90 days. RESULTS: A total of 11,255 patients were screened and 6412 patients were enrolled, with 3205 assigned to the ticagrelor group and 3207 to the clopidogrel group. The median age of the patients was 64.8 years, and 33.8% were women; 98.0% belonged to the Han Chinese ethnic group. Stroke occurred within 90 days in 191 patients (6.0%) in the ticagrelor group and 243 patients (7.6%) in the clopidogrel group (hazard ratio, 0.77; 95% confidence interval, 0.64 to 0.94; P = 0.008). Secondary outcomes were generally in the same direction as the primary outcome. Severe or moderate bleeding occurred in 9 patients (0.3%) in the ticagrelor group and in 11 patients (0.3%) in the clopidogrel group; any bleeding occurred in 170 patients (5.3%) and 80 patients (2.5%), respectively. CONCLUSIONS: Among Chinese patients with minor ischemic stroke or TIA who were carriers of CYP2C19 loss-of-function alleles, the risk of stroke at 90 days was modestly lower with ticagrelor than with clopidogrel. The risk of severe or moderate bleeding did not differ between the two treatment groups, but ticagrelor was associated with more total bleeding events than clopidogrel. (Funded by the Ministry of Science and Technology of the People's Republic of China and others; CHANCE-2 ClinicalTrials.gov number, NCT04078737.).

Epigenetic transcripts of LINC01311 and hsa-miR-146a-5p regulate neural development in a cellular model of Alzheimer's disease.

Emerging evidence has shown that Long noncoding RNAs (LncRNAs) are aberrantly expressed and functionally involved in the development of neurodegenerative disorders. In this work, we investigated the regulatory effects of lncRNA of LINC01311 and its competing endogenous RNA target of hsa-miR-146a-5p in a cellular model of Alzheimer's disease (AD). SH-SY5Y cells were treated with synthetic Βeta-Amyloid Peptide (1-42) (AB1-42) in vitro to induce AD-like neural injuries. Expressions of LINC01311 and hsa-miR-146a-5p were monitored by qRT-PCR. LINC01311 was upregulated and hsa-miR-146a-5p downregulated to examine their functional regulations on AB1-42-induced apoptosis, proliferation slowdown, autophagy, and amyloid precursor protein (APP) accumulations. Hsa-miR-146a-5p was also overexpressed in LINC01311-upregulated SH-SY5Y cells to examine their correlated regulations on AB1-42-induced neural injuries. LINC01311 was downregulated whereas hsa-miR-146a-5p upregulated in AB1-42 treated SH-SY5Y cells. LINC01311 upregulation and hsa-miR-146a-5p downregulation protected AB1-42-induced apoptosis, proliferation slowdown, autophagy, and APP accumulations in SH-SY5Y cells. Hsa-miR-146a-5p overexpression reversed the protection of LINC01311 on AB1-42-induced neural injuries. Our work demonstrated that the epigenetic axis of LINC01311/hsa-miR-146a-5p was involved in the functional regulation of human-lineage neurons in a cellular model of AD, thus suggesting a clinical potential of exploring epigenetic network for treating AD patients.

The association of metabolic syndrome components and diabetes mellitus: evidence from China National Stroke Screening and Prevention Project.

BACKGROUND: The metabolic syndrome (MetS) is related with cardiovascular disease. However, its relationship with diabetes mellitus (DM) has not been examined in Chinese population with a larger sample. We aimed to assess the relationship between metabolic syndrome (MetS) and its components, and DM, and to determine the best one from the available definitions of Mets when assessing the risk of DM. METHODS: This was a cross-sectional survey in a nationally representative sample of 109,551 Chinese adults aged ≥40 years in 2014-15. MetS was defined according to three criteria including the updated International Diabetes Federation (IDF) criterion, the National Cholesterol Education Program Third Adult Treatment Panel (NCEP ATP III) criterion and American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) criterion. Logistic regression models were used to estimate the odds of DM. RESULTS: MetS as defined by three criteria including IDF, NCEP ATP III,and AHA/NHLBI all increased the prevalence of DM, and the adjusted ORs with 95% CI was more higher using NCEP ATP III (3.65, 3.52-3.79) than IDF (2.50, 2.41-2.60) and AHA/NHLBI (3.03, 2.92-3.24). The odds of DM was highest in hyperglycemia with cut-off glucose≥6.1 mmol/L (14.55, 13.97-15.16), and other components were also associated significantly with DM. There was heterogeneity for OR of DM associated with various trait combinations. CONCLUSIONS: The NCEP ATPIII MetS definition may be more suitable for assessment of DM risk in Chinese population. Hyperglycemia, as previous study reported, are important risk factors of DM. Besides, other traits of Mets are also significantly associated with DM and should therefore be of greater concern.

Effects of Hyperbaric Oxygen Therapy on Inflammasome Signaling after Traumatic Brain Injury.

OBJECTIVE: Neuroinflammation plays an important role in secondary tissue damage after traumatic brain injury (TBI). Recently, the inflammasome-mediated inflammatory pathway has been observed in the inflammatory response of TBI. In this study, we investigated the influence of hyperbaric oxygen therapy (HBOT) on inflammasome activation after TBI. METHODS: The experimental mice were randomly divided into 4 groups as follows: sham-operated normobaric air (21% O2 at one absolute atmosphere), HBOT only, TBI + normobaric air and TBI + HBOT. Following the evaluation of motor deficits and brain edema, the expression of inflammasome components and effectors was measured by qRT-PCR and Western blotting. Moreover, alterations in IL-1ß, IL-18 and high-mobility group box 1 (HMGB1) were calculated by enzyme-linked immunosorbent assay at each time point after injury. RESULTS: HBOT improved motor score and reduced brain edema. Furthermore, it suppressed protein expression of inflammasome components and reduced the levels of IL-1ß and IL-18, accompanied by the reduction of HMGB1 in brain tissues and serum. CONCLUSION: These results suggest that HBOT may alleviate the inflammatory response after TBI by inhibiting the activation of inflammasome signaling.

SCG5 and MITF may be novel markers of copper metabolism immunorelevance in Alzheimer's disease.

The slow-developing neurological disorder Alzheimer's disease (AD) has no recognized etiology. A bioinformatics investigation verified copper metabolism indicators for AD development. GEO contributed AD-related datasets GSE1297 and GSE5281. Differential expression analysis and WGCNA confirmed biomarker candidate genes. Each immune cell type in AD and control samples was scored using single sample gene set enrichment analysis. Receiver Operating Characteristic (ROC) analysis, short Time-series Expression Miner (STEM) grouping, and expression analysis between control and AD samples discovered copper metabolism indicators that impacted AD progression. We test clinical samples and cellular function to ensure study correctness. Biomarker-targeting miRNAs and lncRNAs were predicted by starBase. Trust website anticipated biomarker-targeting transcription factors. In the end, Cytoscape constructed the TF/miRNA-mRNA and lncRNA-miRNA networks. The DGIdb database predicted biomarker-targeted drugs. We identified 57 differentially expressed copper metabolism-related genes (DE-CMRGs). Next, fourteen copper metabolism indicators impacting AD progression were identified: CCK, ATP6V1E1, SYT1, LDHA, PAM, HPRT1, SCG5, ATP6V1D, GOT1, NFKBIA, SPHK1, MITF, BRCA1, and CD38. A TF/miRNA-mRNA regulation network was then established with two miRNAs (hsa-miR-34a-5p and 34c-5p), six TFs (NFKB1, RELA, MYC, HIF1A, JUN, and SP1), and four biomarkers. The DGIdb database contained 171 drugs targeting ten copper metabolism-relevant biomarkers (BRCA1, MITF, NFKBIA, CD38, CCK2, HPRT1, SPHK1, LDHA, SCG5, and SYT1). Copper metabolism biomarkers CCK, ATP6V1E1, SYT1, LDHA, PAM, HPRT1, SCG5, ATP6V1D, GOT1, NFKBIA, SPHK1, MITF, BRCA1, and CD38 alter AD progression, laying the groundwork for disease pathophysiology and novel AD diagnostic and treatment.

Colchicine in patients with acute ischaemic stroke or transient ischaemic attack (CHANCE-3): multicentre, double blind, randomised, placebo controlled trial.

OBJECTIVES: To assess the efficacy and safety of colchicine versus placebo on reducing the risk of subsequent stroke after high risk non-cardioembolic ischaemic stroke or transient ischaemic attack within the first three months of symptom onset (CHANCE-3). DESIGN: Multicentre, double blind, randomised, placebo controlled trial. SETTING: 244 hospitals in China between 11 August 2022 and 13 April 2023. PARTICIPANTS: 8343 patients aged 40 years of age or older with a minor-to-moderate ischaemic stroke or transient ischaemic attack and a high sensitivity C-reactive protein ≥2 mg/L were enrolled. INTERVENTIONS: Patients were randomly assigned 1:1 within 24 h of symptom onset to receive colchicine (0.5 mg twice daily on days 1-3, followed by 0.5 mg daily thereafter) or placebo for 90 days. MAIN OUTCOME MEASURES: The primary efficacy outcome was any new stroke within 90 days after randomisation. The primary safety outcome was any serious adverse event during the treatment period. All efficacy and safety analyses were by intention to treat. RESULTS: 4176 patients were assigned to the colchicine group and 4167 were assigned to the placebo group. Stroke occurred within 90 days in 264 patients (6.3%) in the colchicine group and 270 patients (6.5%) in the placebo group (hazard ratio 0.98 (95% confidence interval 0.83 to 1.16); P=0.79). Any serious adverse event was observed in 91 (2.2%) patients in the colchicine group and 88 (2.1%) in the placebo group (P=0.83). CONCLUSIONS: The study did not provide evidence that low-dose colchicine could reduce the risk of subsequent stroke within 90 days as compared with placebo among patients with acute non-cardioembolic minor-to-moderate ischaemic stroke or transient ischaemic attack and a high sensitivity C-reactive protein ≥2 mg/L. TRIAL REGISTRATION: ClinicalTrials.gov, NCT05439356.

Development of a novel immune infiltration-related diagnostic model for Alzheimer's disease using bioinformatic strategies.

Background: The pathogenesis of Alzheimer's disease (AD) is complex and multi-factorial. Increasing evidence has shown the important role of immune infiltration in AD. Thus the current study was designed to identify immune infiltration-related genes and to explore their diagnostic value in AD. Methods: The expression data of AD patients were downloaded from the GEO database. The limma R package identified differentially expressed genes (DEGs) between AD and controls. The CIBERSORT algorithm identified differentially infiltrated immune cells (DIICs) between AD and controls. DIIC-correlated DEGs were obtained by Pearson correlation analysis. WGCNA was employed to identify DIIC-related modules. Next, LASSO, RFE, and RF machine learning methods were applied to screen robust DIIC-related gene signatures in AD, followed by the construction and validation of a diagnostic nomogram. Detection of the expression of related genes in the peripheral blood of Alzheimer's disease and healthy volunteers by RT-PCR. In addition, the CTD database predicted chemicals targeting DIIC-related gene signatures in the treatment of AD. Results: NK cells, M0 macrophages, activated myeloid dendritic cells, resting mast cells, CD8+ T cells, resting memory CD4+ T cells, gamma delta T cells, and M2 macrophages were differentially infiltrated between AD and controls. Pearson analysis identified a total of 277 DIIC-correlated DEGs between AD and controls. Thereafter, 177 DIIC-related genes were further obtained by WGCNA analysis. By LASSO, RFE and RF algorithms, CMTM2, DDIT4, LDHB, NDUFA1, NDUFB2, NDUFS5, RPL17, RPL21, RPL26 and NDUFAF2 were identified as robust gene signature in AD. The results of RT-PCR detection of peripheral blood samples from Alzheimer's disease and healthy volunteers showed that the expression trend of ten genes screened was consistent with the detection results; among them, the expression levels of CMTM2, DDIT4, LDHB, NDUFS5, and RPL21 are significantly different among groups. Thus, a diagnostic nomogram based on a DIIC-related signature was constructed and validated. Moreover, candidate chemicals targeting those biomarkers in the treatment of AD, such as 4-hydroxy-2-nonenal, rosiglitazone, and resveratrol, were identified in the CTD database. Conclusion: For the first time, we identified 10 immune infiltration-related biomarkers in AD, which may be helpful for the diagnosis of AD and provide guidance in the treatment of AD.

Efficacy and Safety of Panax notoginseng Saponins in the Treatment of Adults With Ischemic Stroke in China: A Randomized Clinical Trial.

Importance: Preclinical and clinical studies have suggested the neuroprotective effect of Panax notoginseng saponins (Xuesaitong soft capsules). However, robust evidence in patients with ischemic stroke is lacking. Objective: To assess the efficacy and safety of Xuesaitong soft capsules in patients with ischemic stroke. Design, Setting, and Participants: This multicenter, double-blind, placebo-controlled randomized clinical trial was conducted at 67 tertiary health centers in China from July 1, 2018, to June 30, 2020. Included patients were aged 18 to 75 years with a diagnosis of ischemic stroke and a National Institutes of Health Stroke Scale score between 4 and 15. Interventions: Eligible patients were randomly assigned within 14 days after symptom onset to receive either treatment with Xuesaitong soft capsules (120 mg orally twice daily) or placebo (120 mg orally twice daily) for 3 months. Main Outcomes and Measures: The primary outcome was functional independence at 3 months, defined as a modified Rankin Scale score of 0 to 2. Results: Among 3072 eligible patients with ischemic stroke who were randomized, 2966 (96.5%) were included in the modified intention-to-treat cohort (median [IQR] age, 62 [55-68] years; 1982 male [66.8%]). The number of patients who achieved functional independence at 3 months was 1328 (89.3%) in the Xuesaitong group and 1218 (82.4%) in the control group (odds ratio, 1.95; 95% CI, 1.56-2.44; P < .001). In the safety cohort, serious adverse events occurred in 15 of 1488 patients (1.0%) in the Xuesaitong group and 16 of 1482 (1.1%) in the control group (P = .85). Conclusions and Relevance: In this randomized clinical trial, Xuesaitong soft capsules significantly increased the likelihood of functional independence at 3 months in patients with ischemic stroke, indicating that this may be a safe and effective alternative therapy to improve prognosis in this population. Trial Registration: Chinese Clinical Trial Registry Identifier: ChiCTR1800016363.

Prognostic Value of Blood Pressure Variability for Patients With Acute or Subacute Intracerebral Hemorrhage: A Meta-Analysis of Prospective Studies.

The results on the role of systolic blood pressure (SBP) variability in the functional outcome for patients with intracerebral hemorrhage (ICH) have been inconsistent. Hence, this meta-analysis of prospective studies was conducted to assess the association between SBP variability and poor outcomes in patients with acute or subacute ICH. PubMed, Embase, and the Cochrane Library were electronically searched for eligible studies from their inception to July 2020. The role of SBP variability assessed using standard deviation (SD), coefficient of variation (CV), successive variation (SV), average real variability (ARV), and residual standard deviation (RSD) in the risk of poor functional outcomes were assessed using odds ratio (OR) with 95% confidence interval (CI) through the random-effects model. Seven prospective studies involving 5,201 patients with ICH were selected for the final meta-analysis. Increased SBP variability was associated with an increased risk of poor functional outcomes, regardless of its assessment using SD (OR: 1.38; 95% CI: 1.14-1.68; P = 0.001), CV (OR: 1.98; 95% CI: 1.13-3.47; P = 0.017), SV (OR: 1.30; 95% CI: 1.08-1.58; P = 0.006), ARV (OR: 1.13; 95% CI: 1.03-1.24; P = 0.010), or RSD (OR: 1.22; 95% CI: 1.00-1.50; P = 0.049). Moreover, the role of SBP variability in the risk of poor functional outcomes for patients with ICH was affected by country, study design, mean age, stroke type, outcome definition, and study quality. This study indicated that SBP variability was a predictor of poor outcomes for patients with ICH.

Postural sway in patients with early Parkinson's disease performing cognitive tasks while standing.

OBJECTIVES: We investigated postural sway in patients with early Parkinson's disease (PD) to test the hypothesis that the postural control system was affected already at an early stage of PD. Moreover, we identified cases of dysfunction of stereopsis in PD patients. METHODS: We examined 23 patients with early PD and 23 healthy, sex- and age-matched control subjects. Postural sway was measured with an accelerometer at the center of mass at the lower spine. Subjects were asked to stand quietly for 30 s under two usual conditions (eyes open and eyes closed) and two dual tasks conditions (eyes open with dual task, eyes closed with dual task). Stereopsis was assessed using the Titmus fly test. RESULTS: In the usual conditions, no differences were found between the control group and PD group. With increasing task difficulty, PD patients showed an increase of RMS values of sway acceleration, compared to control subjects. These differences reached significance during cognitive task performance. PD patients showed larger JERK values with increasing difficulty of the sway task which also reached significance during cognitive task performance. Relative to controls, PD patients showed decreased stereopsis function. But, there were no statistically significant correlations between log seconds of arc of the Titmus test and JERK, even during cognitive task performance. CONCLUSION: Our results indicate that patients with early PD have subtle signs of postural instability when their attention is diverted or reduced. In addition, deficits of stereopsis may be common in early PD patients. St Abbreviations: ACC: Accelerometers; ANOVA: Analysis of variance; AP: Antero-posterior; COP: Center of pressure; EC: Eyes closed; ECDT: eyes closed with dual task; EO: Eyes open; EODT: Eyes open with dual task; GDS: Geriatric depression scale; JERK: Jerkiness of sway; ML: Medio-lateral; MMSE: Mini mental state examination; MoCA: Montreal cognitive assessment; PD: Parkinson's disease; PDAbS: PD Patients with abnormal stereopsis; PDNrS: PD Patients with normal stereopsis; PIGD: Postural instability and gait disorder; RMS: Root mean square; UPDRS: Unified Parkinson's disease rating scale.

Disrupted pursuit compensation during self-motion perception in early Alzheimer's disease.

Our perception of the world is remarkably stable despite of distorted retinal input due to frequent eye movements. It is considered that the brain uses corollary discharge, efference copies of signals sent from motor to visual regions, to compensate for distortions and stabilize visual perception. In this study, we tested whether patients with Alzheimer's disease (AD) have impaired corollary discharge functions as evidenced by reduced compensation during the perception of optic flow that mimics self-motion in the environment. We asked a group of early-stage AD patients and age-matched healthy controls to indicate the perceived direction of self-motion based on optic flow while tracking a moving target with smooth pursuit eye movement, or keeping eye fixation at a stationary target. We first replicated the previous findings that healthy participants were able to compensate for distorted optic flow in the presence of eye movements, as indicated by similar performance of self-motion perception between pursuit and fixation conditions. In stark contrast, AD patients showed impaired self-motion perception when the optic flow was distorted by eye movements. Our results suggest that early-stage AD pathology is associated with disrupted eye movement compensation during self-motion perception.

Upregulation of microRNA-206 induces apoptosis of vascular smooth muscle cells and decreases risk of atherosclerosis through modulating FOXP1.

Forkhead box protein subfamily P (FOXP) 1 has an important role in the control of gene transcription and is also reported to function as a tumor suppressor. The aim of the present study was to explore the regulatory mechanisms of atherosclerosis by investigating the function of microRNA-206 (miR-206) and the regulatory association between miR-206 and its potential target gene, FOXP1, in vascular smooth muscle cells (VSMCs). Bioinformatics tools were utilized to identify FOXP1 as a target of miR-206. Luciferase reporter analysis was used to confirm this relationship and to identify the miR-206 binding site in the FOXP1 3'-untranslated region. It was demonstrated that the relative survival rate of VSMCs was suppressed by miR-206 compared with scramble controls. Furthermore, reduced expression of miR-206 in atherosclerosis tissue samples was observed, and the mRNA and protein expression levels of FOXP1 were upregulated in atherosclerosis tissue samples, both compared with the controls, indicating a negative correlation between miR-206 and FOXP1. Additionally, when treated with miR-206 mimics, the relative survival rate of VSMCs was notably reduced, which was rescued by overexpression of FOXP1. These findings increased the understanding of the regulatory role of miR-206 in atherosclerosis in VSMCs via targeting the FOXP1 gene; therefore, intervention with miR-206 as a therapeutic technique may be a strategy for atherosclerosis treatment in the future.

Impaired Center-Surround Suppression in Patients with Alzheimer's Disease.

Alzheimer's disease (AD) is often associated with declined visual processing abilities. Here we tested whether the functions of center-surround suppression- a hallmark property in the visual system- are altered by AD. To this end, we recruited three groups of participants (AD, elderly, and young) in a motion direction discrimination task, in which we measured the temporal duration threshold of a  drifting Gabor with varying stimulus sizes. We first replicated the phenomena of center-surround suppression that the required duration for discriminating a high contrast grating decreases with increasing stimulus size. We then showed that the magnitudes of suppression varied among the three groups. There was progressive reduction of suppression in the elderly and AD groups compared with the young group. Interestingly, we found that the levels of suppression can predict the severity of dementia in the AD group. Our results suggest that AD is associated with impaired center-surround functions in the visual motion processing pathway.

Contribution of Pro-inflammatory Cytokine Signaling within Midbrain Periaqueductal Gray to Pain Sensitivity in Parkinson's Disease via GABAergic Pathway.

BACKGROUND/AIMS: Hypersensitive pain response is often observed in patients with Parkinson's disease (PD); however, the mechanisms responsible for hyperalgesia are not well understood. Chronic neuroinflammation is one of the hallmarks of PD pathophysiology. Since the midbrain periaqueductal gray (PAG) is an important component of the descending inhibitory pathway controlling on central pain transmission, we examined the role for pro-inflammatory cytokines (PICs) system of PAG in regulating exaggerated pain evoked by PD. METHODS: We used a rat model of PD to perform the experimental protocols. PD was induced by microinjection of 6-hydroxydopamine to lesion the left medial forebrain bundle. Pain responses to mechanical and thermal stimulation were first examined in control rats and PD rats. Then, ELISA and Western Blot analysis were used to determine PIC levels and their receptors expression. RESULTS: Protein expression of IL-1ß, IL-6, and TNF-α receptors (namely, IL-1R, IL-6R, and TNFR subtype TNFR1) in the plasma membrane PAG of PD rats was upregulated, whereas the total expression of PIC receptors was not significantly altered. The ratio of membrane protein and total protein (IL-1R, IL-6R, and TNFR1) was 1.48 ± 0.15, 1.59 ± 0.18, and 1.67 ± 0.16 in PAG of PD rats (P < 0.05 vs. their respective controls). This was accompanied with increases of PICs of PAG and decreases of GABA (623 ± 21 ng/mg in control rats and 418 ± 18 ng/mg in PD rats; P < 0.05 vs. control rats) and withdrawal thresholds to mechanical and thermal stimuli. Our data further showed that the concentrations of GABA and withdrawal thresholds were largely restored by blocking those PIC receptors in PAG of PD rats. Stimulation of GABA receptors in PAG of PD rats also blunted a decrease in withdrawal thresholds. CONCLUSION: Our data suggest that upregulation of the membrane PIC receptor in the PAG of PD rats is likely to impair the descending inhibitory pathways in regulating pain transmission and thereby plays a role in the development of hypersensitive pain response in PD.