Profile of Chinese Cluster Headache Register Individual Study (CHRIS): Clinical characteristics, diagnosis and treatment status data of 816 patients in China.

BACKGROUND: The clinical profile of cluster headache may differ among different regions of the world, warranting interest in the data obtained from the initial Chinese Cluster Headache Register Individual Study (CHRIS) for better understanding. METHODS: We conducted a multicenter, prospective, longitudinal cohort study on cluster headache across all 31 provinces of China, aiming to gather clinical characteristics, treatment approaches, imaging, electrophysiological and biological samples. RESULTS: In total 816 patients were enrolled with a male-to-female ratio of 4.33:1. The mean age at consultation was 34.98 ± 9.91 years, and 24.89 ± 9.77 years at onset. Only 2.33% were diagnosed with chronic cluster headache, and 6.99% had a family history of the condition. The most common bout was one to two times per year (45.96%), lasting two weeks to one month (44.00%), and occurring frequently in spring (76.23%) and winter (73.04%). Of these, 68.50% experienced one to two attacks per day, with the majority lasting one to two hours (45.59%). The most common time for attacks was between 9 am and 12 pm (75.86%), followed by 1 am and 3 am (43.48%). Lacrimation (78.80%) was the most predominant autonomic symptom reported. Furthermore, 39.22% of patients experienced a delay of 10 years or more in receiving a correct diagnosis. Only 35.67% and 24.26% of patients received common acute and preventive treatments, respectively. CONCLUSION: Due to differences in ethnicity, genetics and lifestyle conditions, CHRIS has provided valuable baseline data from China. By establishing a dynamic cohort with comprehensive multidimensional data, it aims to advance the management system for cluster headache in China.

MiR196a-5p in extracellular vesicles released from human nasopharyngeal carcinoma enhance the phagocytosis and secretion of microglia by targeting ROCK1.

The microenvironment of the brain has become increasingly recognized as an essential regulator in metastatic and primary brain tumors. Recent studies demonstrate that circulating tumor-derived exosomes are critical for the brain tumor microenvironment. Nasopharyngeal carcinoma (NPC), a malignant tumor of the head and neck, often invades the skull base but infrequently extends to brain parenchyma. Neurobiological communication between microglia and tumor-derived extracellular vesicles (EVs) has been extensively studied, but how NPC cells regulate the immune microenvironment in the brain remains unknown. Here, we report that NPC derived EVs lead to increased microglial phagocytosis and proliferation, and heightened levels of IL-6, IL-8, CXCL1 and TGF-ß1. Analysis of microRNAs in EVs reveal that miR196a-5p is the major effector microRNA. Moreover, we demonstrate an enrichment of miR196a-5p in the plasmatic EVs of NPC patients. Further investigation demonstrated that miR196a-5p was transferred to microglia and regulated microglial structure and functions by downregulating the expression of ROCK1. Therefore, these data indicate that NPC-derived EVs are potent modulators of microglial functions in brain microenvironment. Regardless of brain colonization, EVs-mediated functional changes in microglia may be a universal phenomenon that results in the alteration of the tumor host's microenvironment in the brain.

Acute Treatment with Nicotinamide Riboside Chloride Reduces Hippocampal Damage and Preserves the Cognitive Function of Mice with Ischemic Injury.

Nicotinamide adenine dinucleotide (NAD) is a critical cosubstrate for enzymes involved in supplying energy to the brain. Nicotinamide riboside (NR), an NAD+ precursor, emerges as a neuroprotective factor after chronic brain insults. However, researchers have not determined whether it improves cognition after acute ischemia. In the present study, mice with middle cerebral artery occlusion were treated with NR chloride (NRC, 300 mg/kg, IP., 20 min after reperfusion). The results of the Morris water maze test revealed better recovery of learning and memory function in the NRC-treated group. Acute NRC treatment decreased hippocampal infarct volume, reduced neuronal loss and apoptosis in the hippocampus. Western blot and high-performance liquid chromatography assays of hippocampal tissues revealed that the activation of Sirtin-1 and adenosine 5' monophosphate-activated protein kinase was increased, the NAD content was elevated, and the production of adenosine triphosphate was strengthened by NRC. Collectively, acute NRC treatment increased the energy supply, reduced the neuronal loss and apoptosis, protected the hippocampus and ultimately promoted the recovery of cognitive function after brain ischemia.

Abnormalities of retinal structure and microvasculature are associated with cerebral white matter hyperintensities.

BACKGROUND AND PURPOSE: Whilst retinal microvasculature represents cerebral small vessels, the retinal nerve fiber layer is the extended white matter of the brain. The aim was to investigate the correlation between changes in retina and white matter hyperintensities (WMHs). METHODS: Sixty-four candidates with WMHs received an optical coherence tomography angiography examination. WMHs were divided into mild or moderate/severe groups according to the Fazekas score. After imaging the superficial capillary plexus (SCP) and deep capillary plexus (DCP), the microvascular density parameters (vascular perfusion density [VPD], vascular length density [VLD] and fovea avascular zone area) and morphological parameters (vessel diameter index [VDI], fractal dimension [FD] and vessel tortuosity) were identified. A software algorithm measured the thickness of the peripapillary retina nerve fiber layer (PRNFL). RESULTS: Thirty-two were classified as having mild WMHs and 32 were moderate/severe. The median (interquartile range) ages of the two groups were 58 (54-64) and 61 (57-67) years, respectively. A decrease of FD, VPD and VLD in either SCP or DCP appeared with an increased risk of moderate/severe WMHs. Although changes of capillary plexus were not associated with paraventricular WMHs, decreased FD, VPD, VLD and fovea avascular zone area in either SCP or DCP were associated with an increased risk of moderate/severe deep WMHs (DWMHs). Participants with moderate/severe WMHs demonstrated reduced PRNFL thickness, particularly in the DWMHs, compared with mild WMHs. CONCLUSIONS: Abnormalities of retinal microvascular density, morphological parameters and PRNFL thickness are correlated with the incidence of moderate/severe WMHs, particularly the DWMHs, suggesting that arteriosclerosis and hypoperfusion are the causes of DWMHs.

Triglyceride glucose index influences platelet reactivity in acute ischemic stroke patients.

AIM: Insulin resistance was reported to increase the risk of ischemic stroke, which can be assessed by the triglyceride glucose (TyG) index. However, it remains unclear whether the TyG index influences the platelet reactivity during the treatment of ischemic patients. METHODS: Ischemic stroke patients receiving dual antiplatelet therapy (DAPT) within 48 h onset were consecutively included. The TyG index was calculated as ln (fasting triglyceride [mg/dL] × fasting glucose [mg/dL]/2). The top quartile of TyG index was defined as insulin resistance. The platelet reactivity was assessed by thromboelastography. The platelet inhibition rate induced by arachidonic acid (AA) or adenosine diphosphate (ADP) was used to confirm the high residual on-treatment platelet reactivity (HRPR) to aspirin or clopidogrel, respectively. The association between TyG index and platelet reactivity was assessed by Kruskal-Wallis test. The independent risk factors of HRPR were determined by multivariate logistic regression analysis. RESULTS: A total of 1002 patients were included and divided into 4 groups by quartiles of the TyG index (< 2.02; 2.02-2.27; 2.27-2.52; ≥2.52). The findings demonstrated that the maximum intensity of the clot increased, but the AA-induced platelet inhibition rate decreased, depending on the TyG index quartiles. No significant difference was found in the ADP-induced platelet inhibition rate among groups. The prevalence of aspirin HRPR increased depending on the TyG index quartile. Unlike the non-insulin resistance group, the insulin resistance group was independently associated with aspirin HRPR (OR = 1.689, 95% CI 1.14 to 2.51, P = 0.009). CONCLUSIONS: In acute ischemic stroke patients taking DAPT, the elevation of the TyG index is associated with enhanced platelet reactivity and higher prevalence of aspirin HRPR. Insulin resistance assessed by the TyG index could be an independent risk factor for aspirin HRPR.

An α-glucan isolated from root of Isatis Indigotica, its structure and adjuvant activity.

The root of Isatis indigotica is a traditional Chinese herbal medicine. An α-glucan (IIP-A-1) was firstly isolated from the roots. In this study we elucidated the chemical structure of IIP-A-1 and determined its adjuvant activity by co-immunizing mice with H1N1 influenza virus split and recombinant hepatitis B surface antigen (HBsAg), respectively. The polysaccharide was pretreated with periodate oxidation, Smith degradation and methylation in order to analyze its structure using GC, HPGPC, FT-IR, NMR and GC-MS. The adjuvant effect was evaluated by determining the antibody titers of serum against H1N1 influenza and HBsAg using ELISA. The proliferation and TNF-α secretion of macrophages administrated with different dose of IIP-A-1 were measured in vitro. The results of this study revealed that IIP-A-1 was an α-glucan with the molecular weight of 3,600 Da. The backbone was α-(1 → 4)-D-glucan with (1 → 6) branch chain. The α-glucan could significantly enhance the immune response of mice immunized with H1N1 influenza or HBsAg in vivo and exert good dose-dependent effects on the proliferation and the TNF-α secretion of macrophages in vitro. These results supported that IIP-A-1 was expected to be an efficacious adjuvant candidate for prophylactic and therapeutic vaccines.

Continual naringin treatment benefits the recovery of traumatic brain injury in rats through reducing oxidative and inflammatory alterations.

Naringin is neuroprotective in ischemia and other disease models. However, the effects of naringin are unknown after traumatic brain injury (TBI). The present study explored the role of naringin for neuroprotection in TBI rats. TBI was performed with the weight drop technique, and naringin was given orally at a dose of 100 mg/kg/day. The neurological scores, tissue edema, and oxidative stress/inflammation parameters [malondialdehyde (MDA), superoxide dismutase, nitric oxide, inducible nitric oxide synthase (iNOS), as well as interleukin-1ß (IL-1ß)] were measured. Compared to sham controls, TBI rats displayed obvious sensorimotor dysfunction, significant brain edema, and elevated oxidative and inflammatory molecules. Although a 7-day pre-treatment of naringin was unable to reverse these pathological changes, a 14-day continual treatment (7 days before and 7 days after the TBI) attenuated the increases in MDA and nitric oxide; enhanced the activation of superoxide dismutase; depressed the over-activation of iNOS; down-regulated the over-expression of IL-1ß; and reduced the cortex edema. Additionally, the TBI-induced behavioral dysfunction was reduced. These results suggest that naringin treatment can attenuate cellular and histopathological alterations and improve the sensorimotor dysfunction of TBI rats, which may be partly due to the attenuation of oxidative and inflammatory damages.

Association of life's essential 8 with risk of recurrent cardiovascular events among patients with coronary heart disease.

AIMS: To examine the association of Life's Essential 8 (LE8) with the risk of recurrent cardiovascular events among patients with CHD. METHODS: This prospective cohort study included 11,997 patients with CHD from the UK Biobank. The LE8 score was generated using five lifestyle factors (diet, body mass index, physical activity, smoking, and sleep) and three biological factors (blood lipids, blood glucose, and blood pressure). LE8 score ranged from 0 to 100 and was categorized into quartiles. Cox proportional hazards regression models were applied to estimate the hazard ratio (HR) and 95% CI (confidence interval). RESULTS: During a median follow up of 12.5 years, we documented 3366 recurrent cardiovascular events, 1068 myocardial infarction, 1829 heart failure events, 703 strokes, and 934 cardiovascular deaths. The multivariable-adjusted HR (95% CI) for the highest versus the lowest quartile of LE8 score was 0.57 (0.50, 0.65) for recurrent cardiovascular events, 0.66 (0.52, 0.83) for myocardial infarction, 0.54 (0.45, 0.67) for heart failure, 0.50 (0.36, 0.68) for stroke, and 0.46 (0.37, 0.56) for cardiovascular death. Furthermore, the population attributable fraction of the lowest to the highest quartile of LE8 score were ranged from 16.2% to 32.5% for the various cardiovascular outcomes. In addition, biomarkers including renal function and inflammation collectively explained 47.6%-87.7% of the associations between the lifestyle factors and recurrent cardiovascular events. CONCLUSIONS: Better cardiovascular health as measured by LE8 was associated with significantly lower risk of recurrent cardiovascular events among patients with CHD. Clinicians should prioritize educating patients with CHD on the importance of optimal cardiovascular health for secondary prevention. In addition, our findings indicated significant mediation effect of biomarkers involving of glycemic control, renal function, liver function, lipid profile, and systemic inflammation on the associations between overall lifestyle factors and recurrent cardiovascular events.

Thrombolysis increases the risk of persistent headache attributed to ischemic stroke: A prospective observational study.

BACKGROUND AND OBJECTIVE: Persistent headache attributed to ischemic stroke (PHPIS) is increasingly acknowledged and was added to the 2018 ICHD-3. Intravenous thrombolysis (IVT) is a common treatment for acute ischemic stroke. It remains unknown whether this treatment influences the occurrence of a persistent poststroke headache. We aimed to describe the incidence and clinical characteristics of persistent headaches occurring after acute ischemic stroke in patients with or without IVT and explore the risk factors. METHODS: A prospective observational study was performed between the 234 individuals who received IVT and 226 individuals without IVT in 5 stroke units from Wuhan, China. Subjects were followed for 6 months after stroke via a structured questionnaire. RESULTS: Age, gender, vascular risk factors, and infarct location/ circulation distribution did not differ between the groups, although IVT group had higher initial NIHSS scores. At the end of the follow-up, 12.0% (55/460) of subjects reported persistent headaches after ischemic stroke. The prevalence of persistent headache was significantly higher in the IVT group than non-IVT group (15.4% vs. 8.4%, p = .021). Patients with younger age (p = .033; OR 0.97; 95% CI 0.939-0.997), female sex (p = .007; OR 2.40; 95% CI 1.269-4.520), posterior circulation infarct (p = .024; OR 2.19; 95% CI 1.110-4.311), and IVT (p = .005; OR 2.51; 95% CI 1.313-4.782) were more likely to develop persistent headache after ischemic stroke. CONCLUSION: The potential influence of IVT should be considered when assessing persistent poststroke headache. Future studies will investigate the underlying mechanisms.

[Efficient method for analyzing absorbed ingredients of traditional Chinese medicine genitana macrophyllae radix].

In present study, a method for analyzing the absorbed ingredients of traditional Chinese medicine QinJiao has been developed. A rat everted gut sac (EGS) model has been established, and the transporting capacity of gut sacs was identified by histological examinations. The ingredients including loganic acid, sweroside, gentiopicroside, and swertiamarian in serosal solution absorbed by active transport of rat everted ileum and jejunum from Qinjiao extraction were determined using an HPLC method. Histological integrality of the gut sacs remains perfect and the active transport activity of them is normal within 45 min of the experiment. The HPLC method employed in this study presents high specificity and good correlation. The relative standard deviation of precision of this method is less than 5.5%. Extraction recovery of samples is more than 90%. And stability of the samples in room temperature is perfect. Eight ingredients of Qinjiao absorbed in serosal solution are identified. Furthermore, concentration of Qinjiao extraction significantly affects accumulated absorption and absorption coefficient of the ingredients. However, there is no significant impact on the accumulated absorption and absorption coefficient by diverse of everted gut sections. From above, the EGS techniques might be an efficient method, which can be employed for investigation of absorbed ingredients of Traditional Chinese Medicines.

Differences in Gray Matter Volume in Cerebral Small Vessel Disease Patients with and without Sleep Disturbance.

Recently, there has been increased interest in the relationship between cerebral small vessel disease (CSVD) and circadian rhythm disruption, particularly sleep disturbance. However, the neural mechanism of sleep disturbance in CSVD patients remains poorly understood. The purpose of this study is to explore the gray matter alterations in CSVD patients with and without sleep disturbance. 59 patients with CSVD and 40 healthy controls (HC) were recruited for the present study. Sleep quality was assessed using the Pittsburgh Sleep Quality Index (PSQI) questionnaire. CSVD patients were categorized into either the good sleepers group (CSVD-GS, n = 23) or the poor sleepers group (CSVD-PS, n = 36) based on PSQI score. Voxel-based morphometry (VBM) analysis was used to assess differences in gray matter volume (GMV) between groups. Multivariate regression analyses were performed to investigate the relationships between sleep quality, GMV, and white matter hyperintensities (WMH). We observed GMV differences between the three groups in the bilateral caudate, right thalamus, bilateral calcarine cortex, left precentral gyrus, right orbitofrontal cortex, left cingulate gyrus, and right sub-gyral temporal lobe. Additionally, the CSVD-PS group exhibited decreased GMV in the bilateral calcarine cortex yet increased GMV in the right caudate compared to the CSVD-GS group. In fully adjusted models, GMV of the right caudate and bilateral calcarine cortex was associated with sleep quality in CSVD patients. The present study revealed structural brain alterations in CSVD patients with sleep disturbance. These findings may provide novel insights into the neural mechanisms of sleep disturbance in CSVD.

Current Knowledge about Headaches Attributed to Ischemic Stroke: Changes from Structure to Function.

Headaches are common after ischemic stroke (IS). Unlike primary headaches, headaches attributed to IS have specific clinical features. This review describes the epidemiology, clinical characteristics, risk factors, and influence of IS headaches. Previous reports were summarized to show the correlations between headaches and structural lesions in the cerebral cortex, subcortical white matter, deep gray matter nuclei, brainstem, and cerebellum. However, the substantial heterogeneity of IS, subjective evaluations of headaches, and inadequate cohort studies make it difficult to explore the pathophysiology of headaches attributed to IS. In our recommendation, favorable imaging techniques, such as magnetic resonance imaging and positron emission tomography, may provide new insights into mechanical studies of IS headaches from structure to function. It may also be helpful to extend the research field by targeting several shared signal transducers between headaches and IS. These markers might be neuropeptides, vasoactive substances, ion channels, or electrophysiologic changes.

Effect of PCSK9 inhibition in combination with statin therapy on intracranial atherosclerotic stenosis: A high-resolution MRI study.

Introduction: Intracranial atherosclerotic stenosis (ICAS) is a common cause of stroke worldwide. Evolocumab, a proprotein convertase subtilisin/kexin type-9 inhibitor (PCSK9i), effectively lowers low-density lipoprotein (LDL) and produces favorable changes in coronary atherosclerosis. This study aimed to determine the effects of PCSK9i on intracranial plaques in moderate-intensity statin-treated individuals with ICAS. Methods: This prospective, observational study monitored the imaging and clinical outcomes of individuals with ICAS who were consecutively treated with moderate-intensity statins with or without PCSK9i. Individuals underwent monthly visits and repeat high-resolution MRI (HR-MRI) at week 12. The primary outcome was a change in HR-MRI after 12 weeks of treatment and the secondary outcome was major vascular events during follow-up. Results: Forty-nine individuals were studied (PCSK9i group: 26 individuals with 28 abnormal vascular regions; statin group: 23 with 27 regions). The PCSK9i group showed a significant reduction in the normalized wall index (0.83 vs. 0.86, p = 0.028) and stenosis degree (65.5 vs. 74.2%, p = 0.01). Similarly, a greater percentage of individuals with a good response to the efficacy of treatment were treated in the PCSK9i group than that in the statin group (75 vs. 44.4%, p = 0.021). The incidence of major vascular events was overall similar between the groups. The treatment options (OR = 8.441, p = 0.01) and prior diabetes (OR = 0.061, p = 0.001) were significantly associated with the efficacy of treatment. Discussion: Statin and PCSK9i combination treatment stabilized intracranial atherosclerotic plaques more often compared to statins alone, as documented by HR-MRI. Further study is warranted to determine if combination treatment improves clinical outcomes in ICAS.

Elevated Plasma Oligomeric Amyloid ß-42 Is Associated with Cognitive Impairments in Cerebral Small Vessel Disease.

Due to the heterogeneity of amyloid ß-42 (Aß42) species, the potential correlation between plasma oligomeric Aß42 (oAß42) and cognitive impairments in cerebral small vessel disease (CSVD) remains unclear. Herein, a sandwich ELISA for the specific detection of Aß42 oligomers (oAß42) and total Aß42 (tAß42) was developed based on sequence- and conformation-specific antibody pairs for the evaluation of plasma samples from a Chinese CSVD community cohort. After age and gender matching, 3-Tesla magnetic resonance imaging and multidimensional cognitive assessment were conducted in 134 CSVD patients and equal controls. The results showed that plasma tAß42 and oAß42 levels were significantly elevated in CSVD patients. By regression analysis, these elevations were correlated with the presence of CSVD and its imaging markers (i.e., white matter hyperintensities). Plasma Aß42 tests further strengthened the predictive power of vascular risk factors for the presence of CSVD. Relative to tAß42, oAß42 showed a closer correlation with memory domains evaluated by neuropsychological tests. In conclusion, this sensitive ELISA protocol facilitated the detection of plasma Aß42; Aß42, especially its oligomeric form, can serve as a biosensor for the presence of CSVD and associated cognitive impairments represented by memory domains.

Type A personality, sleep quality, and cerebral small vessel disease: investigating the mediating role of sleep in a community-based study.

Purpose: Type A behavior pattern (TABP) is a personality type characterized by rapid speech, impatience, competition, and hostility. Asymptomatic cerebral small vessel disease (CSVD) is often endemic in older adults. Individuals with TABP commonly experience suboptimal sleep quality, and a correlation exists between sleep disturbances and CSVD. We investigated the relationship between TABP and CSVD markers and further explored the mediating role of sleep quality in the relationship between TABP and CSVD. Methods: A cross-sectional survey included 764 community-dwelling adults aged 55-85 years. The TABP Scale and the Pittsburgh Sleep Quality Index (PSQI) were used to assess personality and sleep quality, respectively. Linear and logistic regression analyses were used to examine relationships between variables of interest. In addition, mediation analyses with bootstrapping were used to test whether sleep quality mediated the relationship between TABP and CSVD. Results: Of the 764 participants [median age 65 (61-69) years, 59.9% female], the population with type A personality accounted for 44.8%. After adjusting for covariates, TABP scores (p = 0.03) and PSQI scores (p < 0.001) were significantly correlated with CSVD. In addition, sleep quality partially mediated the association between type A behavior and CSVD, and the mediating effect was 10.67%. Conclusion: This study showed that type A behavior was a risk factor for CSVD among older community-dwelling adults and that sleep quality mediated the relationship between type A behavior and CSVD. Changing type A behavior may help improve sleep quality, which may in turn reduce the prevalence of CSVD.

NAD+ precursor nutritional supplements sensitize the brain to future ischemic events.

Nicotinamide adenine dinucleotide (NAD+) is a redox cofactor critical for oxidative phosphorylation. Nicotinamide (NAM) and nicotinamide riboside (NR) are NAD+ precursors widely used as nutritional supplements to augment oxidative phosphorylation. Indeed, NAD+ precursors have been reported to improve outcomes in ischemic stroke when administered as a rescue therapy after stroke onset. However, we have also reported that enhanced reliance on oxidative phosphorylation before ischemia onset might worsen outcomes. To address the paradox, we examined how NAD+ precursors modulate the outcome of middle cerebral artery occlusion in mice, when administered either 20 minutes after reperfusion or daily for three days before ischemia onset. A single post-ischemic dose of NAM or NR indeed improved tissue and neurologic outcomes examined at 72 hours. In contrast, pre-ischemic treatment for three days enlarged the infarcts and worsened neurological deficits. As a possible explanation for the diametric outcomes, a single dose of NAM or NR augmented tissue AMPK, PGC1α, SIRT1, and ATP in both naïve and ischemic brains, while the multiple-dose paradigm failed to do so. Our data suggest that NAD+ precursor supplements may sensitize the brain to subsequent ischemic events, despite their neuroprotective effect when administered after ischemia onset.

Regulatory T cells promote functional recovery after spinal cord injury by alleviating microglia inflammation via STAT3 inhibition.

BACKGROUND: Immediately after spinal trauma, immune cells, and proinflammatory cytokines infiltrate the spinal cord and disrupt the focal microenvironment, which impedes axon regeneration and functional recovery. Previous studies have reported that regulatory T cells (Tregs) enter the central nervous system and exert immunosuppressive effects on microglia during multiple sclerosis and stroke. However, whether and how Tregs interact with microglia and modulate injured microenvironments after spinal cord injury (SCI) remains unknown. METHOD: Regulatory T cells spatiotemporal characteristics were analyzed in a mouse contusion SCI model. Microglia activation status was evaluated by immunostaining and RNA sequencing. Cytokine production in injured spinal cord was examined using Luminex. The role of STAT3 in Treg-microglia crosstalk was investigated in a transwell system with isolated Tregs and primary microglia. RESULTS: Regulatory T cells infiltration of the spinal cord peaked on day 7 after SCI. Treg depletion promoted microglia switch to a proinflammatory phenotype. Inflammation-related genes, such as ApoD, as well as downstream cytokines IL-6 and TNF-α were upregulated in microglia in Treg-depleted mice. STAT3 inhibition was involved in Treg-microglia crosstalk, and STAT3 chemical blockade improved function recovery in Treg-depleted mice. CONCLUSION: Our results suggest that Tregs promote functional recovery after SCI by alleviating microglia inflammatory reaction via STAT3.

Inhibition of EGFR/MAPK signaling reduces microglial inflammatory response and the associated secondary damage in rats after spinal cord injury.

BACKGROUND: Emerging evidence indicates that reactive microglia-initiated inflammatory responses are responsible for secondary damage after primary traumatic spinal cord injury (SCI); epidermal growth factor receptor (EGFR) signaling may be involved in cell activation. In this report, we investigate the influence of EGFR signaling inhibition on microglia activation, proinflammatory cytokine production, and the neuronal microenvironment after SCI. METHODS: Lipopolysaccharide-treated primary microglia/BV2 line cells and SCI rats were used as model systems. Both C225 and AG1478 were used to inhibit EGFR signaling activation. Cell activation and EGFR phosphorylation were observed after fluorescent staining and western blot. Production of interleukin-1 beta (IL-1 ß) and tumor necrosis factor alpha (TNF α) was tested by reverse transcription PCR and ELISA. Western blot was performed to semi-quantify the expression of EGFR/phospho-EGFR, and phosphorylation of Erk, JNK and p38 mitogen-activated protein kinases (MAPK). Wet-dry weight was compared to show tissue edema. Finally, axonal tracing and functional scoring were performed to show recovery of rats. RESULTS: EGFR phosphorylation was found to parallel microglia activation, while EGFR blockade inhibited activation-associated cell morphological changes and production of IL-1 ß and TNF α. EGFR blockade significantly downregulated the elevated MAPK activation after cell activation; selective MAPK inhibitors depressed production of cytokines to a certain degree, suggesting that MAPK mediates the depression of microglia activation brought about by EGFR inhibitors. Subsequently, seven-day continual infusion of C225 or AG1478 in rats: reduced the expression of phospho-EGFR, phosphorylation of Erk and p38 MAPK, and production of IL-1 ß and TNF α; lessened neuroinflammation-associated secondary damage, like microglia/astrocyte activation, tissue edema and glial scar/cavity formation; and enhanced axonal outgrowth and functional recovery. CONCLUSIONS: These findings indicate that inhibition of EGFR/MAPK suppresses microglia activation and associated cytokine production; reduces neuroinflammation-associated secondary damage, thus provides neuroprotection to SCI rats, suggesting that EGFR may be a therapeutic target, and C225 and AG1478 have potential for use in SCI treatment.

Effect of second-generation antiepileptic drugs on diplopia: a meta-analysis of placebo-controlled studies.

Different antiepileptic drugs (AEDs) may cause similar adverse effects, one of which is diplopia. However, the AEDs causing diplopia and the dose-response effect of each drug remains uncertain. In this study, we compared several second-generation AEDs to find out whether they would contribute to the risk of diplopia and their effect-causing dose. A meta-analysis was performed on 19 studies in agreement with our inclusion criteria. The results showed that eight commonly used second-generation AEDs (gabapentin, levetiracetam, oxcarbazepine, lamotrigine, pregabalin, topiramate, vigabatrin and zonisamide) could cause diplopia. The reported odds ratios (ORs) ranged from 1.406 to 7.996. Ranking risks from the highest to the lowest ORs of the eight AEDs of any dose resulted in the following order: use of oxcarbazepine (7.996), levetiracetam (7.472), lamotrigine (5.258), vigabatrin (3.562), pregabalin (3.048), topiramate (2.660), gabapentin (1.966), zonisamide (1.406). Taking into account the ORs above, we can conclude that second-generation AEDs of any dose may cause diplopia. However, the levetiracetam-caused diplopia needs to be further studied according to the data (OR, 7.472; 95% confidence interval, 0.375-148.772). These findings ask for better concerns about patients' quality of life when giving antiepileptic treatments.

Thromboelastography predicts dual antiplatelet therapy-related hemorrhage in patients with acute ischemic stroke.

BACKGROUND: Stratification of the risk of hemorrhage in patients with acute ischemic stroke following dual antiplatelet therapy (DAPT) is challenging. It remains unclear whether thromboelastography (TEG) can be used to predict DAPT-related hemorrhagic events. OBJECTIVE: The present study aims to discover predictors for hemorrhage events after DAPT based on parameters such as TEG. METHODS: A total of 859 patients with acute ischemic stroke who received DAPT were recruited consecutively. Demographic, clinical, and neuroimaging characteristics were evaluated at baseline; TEG parameters were obtained 7 days later after DAPT. Hemorrhagic events were monitored about 1 month after the stroke. RESULTS: Of the patients, 61 (7.1%) had hemorrhagic events. Patients in the hemorrhage group had a lower adenosine diphosphate (ADP)-induced platelet-fibrin clot maximum amplitude and a higher ADP inhibition rate (ADP%) than those in the non-hemorrhage group (p<0.05). ADP% was confirmed as an independent predictor of hemorrhagic events with an optimal cut-off point of 83.3% (area under the curve (AUC) = 0.665, 95% CI 0.573 to 0.767, p<0.01). We constructed a logistic model based on D-dimer, National Institutes of Health Stroke Scale scores, and ADP% to predict hemorrhagic events in patients with acute ischemic stroke during DAPT (AUC=0.720, 95% CI 0.625 to 0.858, p<0.01), with a sensitivity of 72.1% and a specificity of 76.5%. CONCLUSIONS: Monitoring changes of TEG parameters helps to guide personalized DAPT for patients with ischemic stroke. A 30-82.3% range of ADP% is recommended for DAPT treatment.