In vivo three-dimensional brain imaging with chemiluminescence probes in Alzheimer's disease models.

Optical three-dimensional (3D) molecular imaging is highly desirable for providing precise distribution of the target-of-interest in disease models. However, such 3D imaging is still far from wide applications in biomedical research; 3D brain optical molecular imaging, in particular, has rarely been reported. In this report, we designed chemiluminescence probes with high quantum yields, relatively long emission wavelengths, and high signal-to-noise ratios to fulfill the requirements for 3D brain imaging in vivo. With assistance from density-function theory (DFT) computation, we designed ADLumin-Xs by locking up the rotation of the double bond via fusing the furan ring to the phenyl ring. Our results showed that ADLumin-5 had a high quantum yield of chemiluminescence and could bind to amyloid beta (Aß). Remarkably, ADLumin-5's radiance intensity in brain areas could reach 4 × 107 photon/s/cm2/sr, which is probably 100-fold higher than most chemiluminescence probes for in vivo imaging. Because of its strong emission, we demonstrated that ADLumin-5 could be used for in vivo 3D brain imaging in transgenic mouse models of Alzheimer's disease.

Cardiac involvement in muscular dystrophies: Role of myocardial perfusion imaging.

Technetium-99m-methoxy isobutyl isonitrile (99mTc-MIBI) myocardial perfusion imaging (MPI) is a functional imaging method with relatively poor specificity but high sensitivity. We present 48-year-old man with cardiac involvement due to muscular dystrophies (MD). Myocardial perfusion imaging rest images revealed regional myocardial perfusion decrease in multiple walls, enlarged heart and decreased left ventricular systolic function. The lesion location of MPI was consistent with that seen on CMR. Our case showed MPI was useful for detection and evaluation of the MD patient with cardiac involvement. In addition, imaging findings in combination with clinical history and other data are important. The case highlight is thevalue of MPI in myocardiopathy.

Triglyceride-glucose index, symptomatic intracranial artery stenosis and recurrence risk in minor stroke patients with hypertension.

BACKGROUND: The triglyceride-glucose (TyG) index, a simple measure of insulin resistance, is associated with intracranial atherosclerosis (ICAS) and stroke. In hypertensive populations, this association may be pronounced. The aim was to investigate the relationship between TyG and symptomatic intracranial atherosclerosis (sICAS) and recurrence risk in ischemic stroke patients with hypertension. METHODS: This prospective, multicenter cohort study included patients with acute minor ischemic stroke with a preadmission diagnosis of hypertension from September 2019 to November 2021 with a 3-month follow-up. The presence of sICAS was determined by a combination of clinical manifestations, the location of the infarction, and the corresponding artery with moderate-to-severe stenosis. ICAS burden was determined by the degree and number of ICAS occurrences. Fasting blood glucose (FBG) and triglyceride (TG) were measured to calculate TyG. The main outcome was ischemic stroke recurrence during the 90-day follow-up. Multivariate regression models were used to explore the association of TyG, sICAS, and ICAS burden with stroke recurrence. RESULTS: There were 1281 patients with a mean age of 61.6 ± 11.6 years; 70.1% were male, and 26.4% were diagnosed with sICAS. There were 117 patients who experienced stroke recurrence during follow-up. Patients were categorized according to quartiles of TyG. After adjusting for confounders, the risk of sICAS was greater (OR 1.59, 95% CI 1.04-2.43, p = 0.033) and the risk of stroke recurrence was significantly higher (HR 2.02, 95% CI 1.07-3.84, p = 0.025) in the fourth TyG quartile than in the first quartile. The restricted cubic spline (RCS) plot revealed a linear relationship between TyG and sICAS, and the threshold value for TyG was 8.4. Patients were then dichotomized into low and high TyG groups by the threshold. Patients with high TyG combined with sICAS had a higher risk of recurrence (HR 2.54, 95% CI 1.39-4.65) than patients with low TyG without sICAS. An interaction effect on stroke recurrence between TyG and sICAS was found (p = 0.043). CONCLUSION: TyG is a significant risk factor for sICAS in hypertensive patients, and there is a synergistic effect of sICAS and higher TyG on ischemic stroke recurrence. TRIAL REGISTRATION NUMBER: The study was registered on 16 August 2019 at https://www.chictr.org.cn/showprojen.aspx?proj=41160 (No. ChiCTR1900025214).

Dual Versus Mono Antiplatelet Therapy in Patients with Acute Mild-to-Moderate Stroke: A Multicentre Perspective Cohort Study.

BACKGROUND AND PURPOSE: The purpose of this study was to evaluate the association between different antiplatelet therapy regimens and the functional outcomes and bleeding complications among mild-to-moderate ischaemic stroke patients based on real-world data. METHODS: We used data from the SEACOAST trial (Safety and efficacy of aspirin-clopidogrel in acute noncardiogenic minor ischaemic stroke) to analyse the data of patients with mild-to-moderate stroke within 72 h after onset who were treated with aspirin or clopidogrel alone or a combination of clopidogrel and aspirin from September 2019 to November 2021. Propensity score matching (PSM) was used to balance the differences between groups. We performed an analysis to evaluate the association of different antiplatelet regimens and 90-day disability, which was defined as a modified Rankin Scale score ≥2, as well as disability ascribed to index or recurrent stroke by the local investigator. In terms of safety, we then compared the bleeding events between the two groups. RESULTS: A total of 2822 mild-to-moderate ischaemic stroke patients were treated with either clopidogrel plus aspirin (n = 1726, 61.2%) or aspirin/clopidogrel (n = 1096, 38.8%). Of 1726 patients in the dual antiplatelet group, 1350 (78.5%) received less than or equal to 30 days of combined therapy. At 90 days, 433 (15.3%) patients were disabled. Patients who received combined therapy had a lower overall disability rate (13.7% versus 17.9%; OR 0.78 (0.6-1.01); P = 0.064). However, investigators found that index stroke was the reason for significantly fewer patients in the dual antiplatelet group having disability (8.4% versus 12%; OR, 0.72 (0.52-0.98); P = 0.038). There was no statistically significant difference in the incidence of moderate to severe bleeding complications between the dual and mono antiplatelet drug regimens (0.4% versus 0.2%; HR 1.5 (0.25, 8.98); P = 0.657). CONCLUSION: Aspirin plus clopidogrel was associated with a reduction in the incidence of disability attributed to index stroke. There was no statistically significant difference in the incidence of moderate to severe bleeding complications between the two antiplatelet drug regimens. TRIAL REGISTRATION NUMBER: ChiCTR1900025214.

Sleep disorder, Mediterranean diet, and all-cause and cause-specific mortality: a prospective cohort study.

BACKGROUND: There is a bidirectional effect between sleep disorders and Mediterranean diet (MED), but the joint effect of MED and sleep disorders on mortality is unclear. The aim of this study was to investigate whether there is a synergistic effect of adherence to MED and sleep disorders on all-cause and cause-specific mortality. METHODS: The study included 23,212 individuals in the National Health and Nutrition Examination Survey (NHANES) from 2005 to 2014. A 9-point evaluation score, alternative Mediterranean diet (aMED) index was used to assess adherence to MED. Sleep disorder and hours of sleep were assessed by structured questionnaires. Cox regression models were used to assess the relationship between sleep disorders, aMED and all-cause mortality, cause-specific mortality (cardiovascular-related death, cancer-related death). The interaction effect of sleep disorders with aMED on mortality was further assessed. RESULTS: Results showed that participants with lower aMED and presence of sleep disorders had significantly higher risk of all-cause mortality and cardiovascular-related mortality (HR, 2.16, 95% CI, 1.49-3.13, P < 0.0001; HR, 2.68, 95% CI, 1.58-4.54, P = 0.0003). A significant interaction effect was found between aMED and sleep disorders on cardiovascular mortality (p for interaction = 0.033). No significant interaction existed between aMED and sleep disorders on all-cause mortality (p for interaction = 0.184) and cancer-related mortality (p for interaction = 0.955). CONCLUSIONS: Poorer adherence to MED and sleep disorders synergistically increased long-term all-cause mortality and cardiovascular mortality in NHANES population.

Th17/Treg cells regulated by interleukin 6 in the pathogenesis of chronic rhinosinusitis with nasal polyps.

PURPOSE: To be investigated whether Th17/Treg cells regulated by Interleukin-6 in the pathogenesis of chronic rhinosinusitis with nasal polyps. METHODS: The distributions of Th17 and Treg cells in peripheral blood mononuclear cells (PBMCs) and tissues got from 46 CRSwNP patients and 14 controls were evaluated. Th17 and Treg cells and cells-related cytokines in serum were assessed in means of cytometric bead array (CBA) multiplex assays and enzyme-linked immunosorbent assays (ELISAs). Spleen cells were isolated from spleen of 20 normal BALB/c mice (male), isolated and purified with CD4 antibody immunomagnetic bead kit. CD4+ cells were divided into three groups, including TGF-ß1, TGF-ß1+ IL-6 and control (PBS). Treg and Th17 cells and cells related cytokines were detected by flow cytometry (FCM) after collecting spleen cells. The level of IL-10 and IL-17 in supernatant was measured by ELISA. RESULTS: Th17/Treg ratio and the level of IL-6 in both ECRSwNP (P < 0.05) and non-ECRSwNP (P < 0.05) were significantly increased when compared with control group, these were consistent with the previous findings. Experiments in vitro suggested that the level of Th17 cells in IL-6+ TGF-ß1 group was significantly increased than TGF-ß1 group and control group (P < 0.05). The ratio of cells expressed RoRγt in IL-6+ TGF-ß1 group was much higher than TGF-ß1 group (P < 0.05). CONCLUSION: IL-6 might regulate the function of Th17 and Treg cells and the Th17/Treg ratio and have a role in the pathogenesis of CRSwNP.

Lumbar Artery Injury during Transforaminal Percutaneous Endoscopic Lumbar Discectomy: Successful Treatment by Emergent Transcatheter Arterial Embolization.

Injury to the lumbar artery during percutaneous endoscopic lumbar discectomy (PELD) is a very severe complication and only rarely reported. We present a 64-year-old patient with an injury to the right third lumbar artery during PELD which was successfully treated with intraoperative angiography and coil embolization. To our knowledge, this is the first report of the use of intraoperative angiography and coil embolization to treat a lumbar artery that had been lacerated during PELD.

Synthesis and Characterization of a New Carbon-11 Labeled Positron Emission Tomography Radiotracer for Orexin 2 Receptors Neuroimaging.

Purpose: Orexin receptors (OXRs) play a crucial role in modulating various physiological and neuropsychiatric functions within the central nervous system (CNS). Despite their significance, the precise role of OXRs in the brain remains elusive. Positron emission tomography (PET) imaging is instrumental in unraveling CNS functions, and the development of specific PET tracers for OXRs is a current research focus. Methods: The study investigated MDK-5220, an OX2R-selective agonist with promising binding properties (EC50 on OX2R: 0.023 µM, Ki on hOX2R: 0.14 µM). Synthesized and characterized as an OX2R PET probe, [11C]MDK-5220 was evaluated for its potential as a tracer. Biodistribution studies in mice were conducted to assess OX2R binding selectivity, with particular attention to its interaction with P-glycoprotein (P-gp) on the blood-brain barrier. Results: [11C]MDK-5220 exhibited promising attributes as an OX2R PET probe, demonstrating robust OX2R binding selectivity in biodistribution studies. However, an observed interaction with P-gp impacted its brain uptake. Despite this limitation, [11C]MDK-5220 presents itself as a potential candidate for further development. Discussion: The study provides insights into the functionality of the OX system and the potential of [11C]MDK-5220 as an OX2R PET probe. The observed interaction with P-gp highlights a consideration for future modifications to enhance brain uptake. The findings pave the way for innovative tracer development and propel ongoing research on OX systems, contributing to a deeper understanding of their role in the CNS. Conclusion: [11C]MDK-5220 emerges as a promising OX2R PET probe, despite challenges related to P-gp interaction. This study lays the foundation for further exploration and development of PET probes targeting OXRs, opening avenues for advancing our understanding of OX system functionality within the brain.

Development and Characterization of a Novel Carbon-11 Labeled Positron Emission Tomography Radiotracer for Neuroimaging of Sirtuin 1 with Benzoxazine-Based Compounds.

Introduction: Sirtuins (SIRTs) comprise a group of histone deacetylase enzymes crucial for regulating metabolic pathways and contributing significantly to various disease mechanisms. Sirtuin 1 (SIRT1), among the seven known mammalian homologs, is extensively investigated and understood, playing a key role in neurodegenerative disorders and cancer. This study focuses on potential as a therapeutic target for conditions such as Parkinson's disease (PD), Huntington's disease (HD), and Alzheimer's disease (AD). Methods: Utilizing positron emission tomography (PET) as a noninvasive molecular imaging modality, we aimed to expedite the validation of a promising sirtuin 1 inhibitor for clinical trials. However, the absence of a validated sirtuin 1 PET radiotracer impedes clinical translation. We present the development of [11C]1, and 11C-labeled benzoxazine-based derivative, as a lead imaging probe. The radiosynthesis of [11C]1 resulted in a radiochemical yield of 31 ± 4%. Results: Baseline studies demonstrated that [11C]1 exhibited excellent blood-brain barrier (BBB) penetration capability, with uniform accumulation throughout various brain regions. Self-blocking studies revealed that introducing an unlabeled compound 1, effectively blocking sirtuin 1, led to a substantial reduction in whole-brain uptake, emphasizing the in vivo specificity of [11C]1 for sirtuin 1. Discussion: The development of [11C]1 provides a valuable tool for noninvasive imaging investigations in rodent models with aberrant sirtuin 1 expression. This novel radiotracer holds promise for advancing our understanding of sirtuin 1's role in disease mechanisms and may facilitate the validation of sirtuin 1 inhibitors in clinical trials.

Molecular Imaging of Alzheimer's Disease-Related Sigma-1 Receptor in the Brain via a Novel Ru-Mediated Aromatic 18F-deoxyfluorination Probe.

Sigma-1 receptor (σ1R) is an intracellular protein implicated in a spectrum of neurodegenerative conditions, notably Alzheimer's disease (AD). Positron emission tomography (PET) imaging of brain σ1R could provide a powerful tool for better understanding the underlying pathomechanism of σ1R in AD. In this study, we successfully developed a 18F-labeled σ1R radiotracer [18F]CNY-05 via an innovative ruthenium (Ru)-mediated 18F-deoxyfluorination method. [18F]CNY-05 exhibited preferable brain uptake, high specific binding, and slightly reversible pharmacokinetics within the PET scanning time window. PET imaging of [18F]CNY-05 in nonhuman primates (NHP) indicated brain permeability, metabolic stability, and safety. Moreover, autoradiography and PET studies of [18F]CNY-05 in the AD mouse model found a significantly decreased brain uptake compared to that in wild-type mice. Collectively, we have provided a novel 18F-radiolabeled σ1R PET probe, which enables visualizing brain σ1R in health and neurological diseases.

Minor stroke patients with mild-moderate diastolic blood pressure derive greater benefit from dual antiplatelet therapy.

Not only systolic blood pressure (SBP) but also diastolic blood pressure (DBP) increases the risk of recurrence in the short- or long-term outcomes of stroke. The interaction between DBP and antiplatelet treatment for China stroke patients is unclear. This multicenter, observational cohort study included 2976 minor ischemic stroke patients. Patients accepted single antiplatelet therapy (SAPT) or dual antiplatelet therapy (DAPT) after arrival, and baseline DBP levels were trichotomized into <90 mmHg, 90-110 mmHg and ≥110 mmHg. We explore the interaction effect between antiplatelet therapy and DBP on 90-days composite vascular events. A total of 257 (8.6%) patients reached a composite vascular event during follow-up. The interaction term between DBP levels and treatment group (SAPT vs. DAPT) was significant (P for interaction = 0.013). DAPT's adjusted HR for composite events in patients with DBP between 90 and 110 mmHg was 0.56 (95% confidence interval, 0.36 0.88; P = 0.011) and DBP ≥ 110 mmHg was 4.35 (95% confidence interval, 1.11-19.94; P = 0.046). The association between treatment and DBP was still consistent after propensity score matching of the baseline characteristics. The interaction term of DBP × treatment was not significant for the safety outcomes of severe bleeding (P for interaction = 0.301) or hemorrhage stroke (P for interaction = 0.831). In this cohort study based on the real world, patients with a DBP between 90 and 110 mmHg received a greater benefit from 90 days of DAPT than those with lower and higher baseline DBP. REGISTRATION: ( https://www.chictr.org.cn ; Unique identifier: ChiCTR1900025214).

Development of a New Positron Emission Tomography Imaging Radioligand Targeting RIPK1 in the Brain and Characterization in Alzheimer's Disease.

Targeting receptor-interacting protein kinase 1 (RIPK1) has emerged as a promising therapeutic stratagem for neurodegenerative disorders, particularly Alzheimer's disease (AD). A positron emission tomography (PET) probe enabling brain RIPK1 imaging can provide a powerful tool to unveil the neuropathology associated with RIPK1. Herein, the development of a new PET radioligand, [11C]CNY-10 is reported, which may enable brain RIPK1 imaging. [11C]CNY-10 is radiosynthesized with a high radiochemical yield (41.8%) and molar activity (305 GBq/µmol). [11C]CNY-10 is characterized by PET imaging in rodents and a non-human primate, demonstrating good brain penetration, binding specificity, and a suitable clearance kinetic profile. It is performed autoradiography of [11C]CNY-10 in human AD and healthy control postmortem brain tissues, which shows strong radiosignal in AD brains higher than healthy controls. Subsequently, it is conducted further characterization of RIPK1 in AD using [11C]CNY-10-based PET studies in combination with immunohistochemistry leveraging the 5xFAD mouse model. It is found that AD mice revealed RIPK1 brain signal significantly higher than WT control mice and that RIPK1 is closely related to amyloid plaques in the brain. The studies enable further translational studies of [11C]CNY-10 for AD and potentially other RIPK1-related human studies.

Comparison of Aspirin and P2Y12 Inhibitors for Secondary Prevention of Ischaemic Stroke: A Systematic Review and Meta-analysis.

BACKGROUND: P2Y12 inhibitors have been widely used as an alternative to aspirin in clinical practice for secondary stroke prevention. We aimed to compare the efficiency and safety of P2Y12 inhibitors and aspirin for stroke prevention in patients with previous stroke or transient ischaemic attack (TIA). METHODS: PubMed, Embase, and Cochrane Central Register of Controlled Trials were searched. All randomized trials that compared P2Y12 inhibitors with aspirin among patients with stroke were included. The primary efficacy outcomes of our meta-analysis included stroke, vascular events, and all-cause death. The primary safety outcome was minor or major bleeding events. RESULTS: The search identified 4 randomized clinical trials comparing P2Y12 inhibitors with aspirin for secondary stroke prevention that collectively enrolled 24508 patients (12253 received P2Y12 inhibitor and 12255 received aspirin). Pooled results from the random-effects model showed that there were no significant differences in the risk of any stroke (OR 0.90 (0.78-1.04); I²=56.9%), vascular event (OR 0.91 (0.74-1.13); I²=78.3%), all-cause death (OR 0.98 (0.83-1.17); I²=0%), or minor or major bleeding (OR 1.13 (0.70-1.82); I²=79%) among patients who received a P2Y12 inhibitor or aspirin. P2Y12 inhibitors were associated with a significantly lower risk of recurrent ischaemic stroke (OR 0.84 (0.73- 0.96); I²=25%) than aspirin. CONCLUSION: This meta-analysis suggests that P2Y12 inhibitors are more effective than aspirin in preventing recurrent ischaemic stroke among ischaemic stroke patients despite the absence of any effect on a new ischaemic or haemorrhagic stroke, a new clinical vascular event, all-cause death, and major or minor bleeding events.

Circulating Th17/Treg as a promising biomarker for patients with rheumatoid arthritis in indicating comorbidity with atherosclerotic cardiovascular disease.

BACKGROUND: Immune and inflammatory responses have a pivotal role in the pathogenesis of rheumatoid arthritis (RA) and atherosclerotic cardiovascular disease (ASCVD). This study aims to explore the change of peripheral lymphocytes, especially the absolute and relative changes in peripheral T cells in RA patients with and without ASCVD. HYPOTHESIS: The changes in the lymphocyte subsets were assessed to provide a novel insight in diagnosing and preventing ASCVD in patients with RA. METHODS: A propensity score matching system (1:1) was conducted to perform a matched case-control study with 169 pairs RA-ASCVD and RA participants. Univariate and multivariate analyses were performed to determine the association between peripheral lymphocytes and RA-ASCVD. RESULT: Multivariate logistic regression analysis demonstrated that Th17 cell absolute, Th17 cell Ratio, Th17/Treg were associated with a significantly higher risk of ASCVD after model adjustment. Then we focused on Th17/Treg, multivariate logistic analyses in tri-sectional Th17/Treg groups showed that the odds of ASCVD is gradually increasing with Th17/Treg rank's rising after model adjustment. Finally, the restricted cubic spline of Th17/Treg and odds ratio of RA-ASCVD was conducted. Interestingly, we found a critical point of Th17/Treg (critical point = 0.2399). Th17/Treg shows a protective role in the odds of ASCVD when Th17/Treg < 0.2399. With smaller Th17/Treg, the protective efficiency is more obvious when Th17/Treg < 0.2399. CONCLUSIONS: Our study suggested that increasing absolute and percentage of Th17 cells in the peripheral blood of patients with RA was associated with the development of ASCVD. And Th17/Treg may be a promising biomarker for patients with RA in indicating comorbidity with ASCVD.

Mediterranean diet lowers all-cause and cardiovascular mortality for patients with metabolic syndrome.

A Mediterranean-style diet (MED) can promote people lengthen the span of life and avoid atherosclerotic cardiovascular disease (ASCVD) in primary prevention. Metabolic syndrome (MetS) can significantly reduce life expectancy and increase the risk of ASCVD. However, few studies have focused on the role of the Mediterranean diet in patients with MetS. Participants in the National Health and Nutrition Examination Survey (NHANES) with MetS (N = 8301) from 2007 to 2018 were examined. A 9-point evaluation scorewas used to measure the degree of adherence to the MED diet. In order to compare the various levels of adherence to the MED diet and the effects of the specific MED diet components on all-cause and cardiovascular mortality, Cox regression models were utilized. Among the 8301 participants with MetS, about 13.0% (1080 of 8301) died after a median follow-up of 6.3 years. In this study, participants with MetS with adherence to high-quality and moderate-quality Mediterranean diet were significantly associated with lower all-cause mortality as well as cardiovascular mortality during the follow-up period. Futhermore, in joint analysis of the Mediterranean diet and sedentary behavior or depression, we found that high-quality or moderate-quality Mediterranean diet could attenuate, even reverse the adverse effects of sedentary behavior and depression on all-cause and cardiovascular mortality in participants with MetS. Among the components of the MED diet, greater intakes of vegetables, legumes, nuts and high MUFA/SFA ratio were significantly associated with lower all-cause mortality and greater vegetables intake was significantly associated with lower cardiovascular mortality, while more red/processed meat intake was significantly associated with higher cardiovascular mortality in participants with MetS.

A case-control study of risk factors for survival after laparotomy in patients with pancreatic trauma.

BACKGROUND: Pancreatic trauma results in significant morbidity and mortality. However, few studies have investigated the postoperative prognostic factors in patients with pancreatic trauma. MATERIAL AND METHODS: A retrospective study was conducted on consecutive patients with pancreatic trauma who underwent surgery in a national referral trauma center. Clinical data were retrieved from the electronic medical system. Univariate and binary logistic regression analyses were performed to identify the perioperative clinical parameters that may predict the factors of mortality of the patients. RESULTS: A total of 150 patients underwent laparotomy due to pancreatic trauma during the study period. 128(85.4%) patients survived and 22 (14.6%) patients died due to pancreatic injury (10 patients died of recurrent intra-abdominal active hemorrhage and 12 died of multiple organ failure). Univariate analysis showed that age, hemodynamic status, and injury severe score (ISS) as well as postoperative serum levels of C-reactive protein (CRP), procalcitonin, albumin, creatinine and the volume of intraoperative blood transfusion remained strongly predictive of mortality (P < 0.05). Binary logistic regression analysis showed that the independent risk factors for prognosis after pancreatic trauma were age (P = 0.010), preoperative hemodynamic instability (P = 0.015), postoperative CRP ≥154 mg/L (P = 0.014), and postoperative serum creatinine ≥177 µmol/L (P = 0.027). CONCLUSIONS: In this single-center retrospective study, we demonstrated that preoperative hemodynamic instability, severe postoperative inflammation (CRP ≥154 mg/L) and acute renal failure (creatinine ≥177 µmol/L) were associated with a significant risk of mortality after pancreatic trauma.

The circadian rhythms regulated by Cx43-signaling in the pathogenesis of Neuromyelitis Optica.

Introduction: Neuromyelitis Optica (NMO) is an inflammatory demyelinating disease of the central nervous system (CNS). NMO manifests as selective and severe attacks on axons and myelin of the optic nerve and spinal cord, resulting in necrotic cavities. The circadian rhythms are well demonstrated to profoundly impact cellular function, behavior, and disease. This study is aimed to explore the role and molecular basis of circadian rhythms in NMO. Methods: We used an Aquaporin 4(AQP4) IgG-induced NMO cell model in isolated astrocytes. The expression of Cx43 and Bmal1 were detected by real-time PCR and Western Blot. TAT-Gap19 and DQP-1105 were used to inhibit Cx43 and glutamate receptor respectively. The knockdown of Bmal1 were performed with the shRNA containing adenovirus. The levels of glutamate, anterior visual pathway (AVP), and vasoactive intestinal peptide (VIP) were quantified by ELISA kits. Results: We found that Bmal1 and Clock, two essential components of the circadian clock, were significantly decreased in NMO astrocytes, which were reversed by Cx43 activation (linoleic acid) or glutamate. Moreover, the expression levels of Bmal1 and Clock were also decreased by Cx43 blockade (TAT-Gap19) or glutamate receptor inhibition (DQP-1105). Furthermore, adenovirus-mediated Bmal1 knockdown by shRNA (Ad-sh-Bmal1) dramatically decreased the levels of glutamate, AVP, and VIP from neurons, and significantly down-regulated the protein level of Cx43 in NMO astrocytes with Cx43 activation (linoleic acid) or glutamate treatment. However, Bmal1 knockdown did not alter these levels in normal astrocytes with Cx43 blockade (TAT-Gap19) or glutamate receptor inhibition (DQP-1105). Discussion: Collectively, these results suggest that Cx43-glutamate signaling would be a critical upstream regulator that contributes to the NMO-induced rhythmic damage in SCN astrocytes.

Dual versus mono antiplatelet therapy in mild-to-moderate stroke during hospitalization.

OBJECTIVE: Subsequent vascular events are common after acute ischemic stroke during hospitalization. This study aimed to analyze the effectiveness of combination therapy with clopidogrel and aspirin among mild-to-moderate ischemic stroke patients treated within 72 h on the basis of a high-intensity dose of statins. METHODS: In a retrospective and multicenter cohort study, acute (within 72 h of onset) mild-to-moderate stroke patients were divided into aspirin and clopidogrel-aspirin groups on the basis of a high-intensity dose of statin therapy. The primary outcome was compound vascular events during hospitalization. Cox's proportional hazards model was used to assess differences, with the study center as a random effect. RESULTS: Among the 506 patients meeting the eligibility criteria, all subjects received a high-intensity dose of statins, including 20 mg rosuvastatin or 40 mg atorvastatin while in the hospital. In an unadjusted analysis, compound vascular events occurred in 7.2% of patients in the clopidogrel-aspirin group compared with 13.7% of those in the aspirin group (p = 0.022). In a Cox proportional hazards regression analysis, clopidogrel-aspirin was associated with a lower risk of compound vascular events (hazard ratio [95% CI], 0.47 [0.25-0.87]; p = 0.017) and ischemic vascular events (p = 0.008). Moderate and severe hemorrhage occurred in four patients (1.07%) in the clopidogrel-aspirin group and three patients (2.30%) in the aspirin group (p = 0.626). INTERPRETATION: In this study based on high-intensity statin therapy, clopidogrel-aspirin reduced the risk of compound vascular events and did not increase the risk of hemorrhage during patients' hospitalization after mild-to-moderate ischemic stroke within 72 h.

Evaluation of the association between admission systolic blood pressure and the choice of initial antiplatelet therapy for minor ischemic stroke in real-world.

To evaluate whether admission systolic blood pressure (SBP) is associated with the choice of initial antiplatelet therapy for minor stroke. Eligible patients retrospectively gathered from 2010 to 2018. Finally, 1312 of 1494 patients were divided into three groups: aspirin monotherapy (AM, n = 538, 41.0%), dual antiplatelet therapy with aspirin and load-clopidogrel (clopidogrel loading dose of 300 mg on the first day, DAPT-ALC, n = 474, 35.6%), and dual antiplatelet therapy with aspirin and unload-clopidogrel (clopidogrel 75 mg daily with no loading dose, DAPT-AUC, n = 300, 22.9%). The mean ± SD age of final patients was 62.0 ± 12.7 years old; 903 (70.9%) participants were male. Patients in the DAPT-ALC group were more likely to be younger, to arrive earlier, and to have a lower proportion of intracerebral hemorrhage than those in the AM group. DAPT-AUC group patients were more like to have a history of acute myocardial infarction and less likely to have a history of ICH than the AM group (4.7% vs. 1.7% and .3% vs. 2.6%, p < .05). Overall, there was a likely "S-shaped" association between the selection of the DAPT-ALC or DAPT-AUC scheme and admission systolic blood pressure (P for nonlinearity = .012). Compared with the SBP < 140 mmHg group, the SBP ≥ 180 mmHg group was more likely to be given DAPT-AUC (OR = 2.92 [1.62-5.26], p < .001) than DAPT-ALC. Our findings support that admission SBP is associated with the choice of initial antiplatelet, especially when the SBP was greater than or equal to 180 mmHg.