Apolipoprotein E ε4 Polymorphism as a Risk Factor for Ischemic Stroke: A Systematic Review and Meta-Analysis.

INTRODUCTION: Rising studies indicate that the apolipoprotein E (APOE) gene is related to the susceptibility of ischemic stroke (IS). However, certain consensus is limited by the lack of a large sample size of researches. This meta-analysis was performed to explore the potential association between the APOE gene and IS. METHODS: To identify relevant case control studies in English publications by October 2020, we searched PubMed, Embase, Web of Science, and the Cochrane Library. Pooled odds ratios (ORs) with fixed- or random-effect models and corresponding 95% confidence intervals (CIs) were calculated to analyze potential associations. RESULTS: A total of 55 researches from 32 countries containing 12207 IS cases and 27742 controls were included. The association between APOE gene ε4 mutation and IS was confirmed (ε4 vs. ε3 allele: pooled OR = 1.374, 95% CI, 1.214-1.556; ε2/ε4 vs. ε3/ε3: pooled OR = 1.233, 95% CI, 1.056-1.440; ε3/ε4 vs. ε3/ε3: pooled OR = 1.340, 95% CI, 1.165-1.542; ε4/ε4 vs. ε3/ε3: pooled OR = 1.833, 95% CI, 1.542-2.179; and APOE ε4 carriers vs. non-ε4 carriers: pooled OR = 1.377; 95% CI, 1.203-1.576). Interestingly, APOE ε4 mutation showed a dose-response correlation with IS risk (ε4/ε4 vs. ε2/ε4: pooled OR = 1.625; 95% CI, 1.281-2.060; ε4/ε4 vs. ε3/ε4: pooled OR = 1.301; 95% CI, 1.077-1.571). Similar conclusions were drawn in the small artery disease (SAD) subtype, but not in large artery atherosclerosis (LAA) or in cardioaortic embolism (CE), by subgroup analysis. CONCLUSIONS: These observations reveal that specific APOE ε4 mutation was significantly associated with the risk of IS in a dose-dependent manner, while APOE ε4 mutation was related to SAD subtype onset without a cumulative effect.

AR-12 Has a Bactericidal Activity and a Synergistic Effect with Gentamicin against Group A Streptococcus.

Streptococcus pyogenes (group A Streptococcus (GAS) is an important human pathogen that can cause severe invasive infection, such as necrotizing fasciitis and streptococcal toxic shock syndrome. The mortality rate of streptococcal toxic shock syndrome ranges from 20% to 50% in spite of antibiotics administration. AR-12, a pyrazole derivative, has been reported to inhibit the infection of viruses, intracellular bacteria, and fungi. In this report, we evaluated the bactericidal activities and mechanisms of AR-12 on GAS infection. Our in vitro results showed that AR-12 dose-dependently reduced the GAS growth, and 2.5 µg/mL of AR-12 significantly killed GAS within 2 h. AR-12 caused a remarkable reduction in nucleic acid and protein content of GAS. The expression of heat shock protein DnaK and streptococcal exotoxins was also inhibited by AR-12. Surveys of the GAS architecture by scanning electron microscopy revealed that AR-12-treated GAS displayed incomplete septa and micro-spherical structures protruding out of cell walls. Moreover, the combination of AR-12 and gentamicin had a synergistic antibacterial activity against GAS replication for both in vitro and in vivo infection. Taken together, these novel findings obtained in this study may provide a new therapeutic strategy for invasive GAS infection.

Remote Limb Ischemic Postconditioning Protects Against Ischemic Stroke by Promoting Regulatory T Cells Thriving.

Background Remote limb ischemic postconditioning (RLIPoC) has been demonstrated to protect against ischemic stroke. However, the underlying mechanisms of RLIPoC mediating cross-organ protection remain to be fully elucidated. Methods and Results Ischemic stroke was induced by middle cerebral artery occlusion for 60 minutes. RLIPoC was performed with 3 cycles of 10-minute ischemia followed by 10-minute reperfusion of the bilateral femoral arteries immediately after middle cerebral artery reperfusion. The percentage of regulatory T cells (Tregs) in the spleen, blood, and brain was detected using flow cytometry, and the number of Tregs in the ischemic hemisphere was counted using transgenic mice with an enhanced green fluorescent protein-tagged Foxp3. Furthermore, the metabolic status was monitored dynamically using a multispectral optical imaging system. The Tregs were conditionally depleted in the depletion of Treg transgenic mice after the injection of the diphtheria toxin. The inflammatory response and neuronal apoptosis were investigated using immunofluorescent staining. Infarct volume and neurological deficits were evaluated using magnetic resonance imaging and the modified neurological severity score, respectively. The results showed that RLIPoC substantially reduced infarct volume, improved neurological function, and significantly increased Tregs in the spleen, blood, and ischemic hemisphere after middle cerebral artery occlusion. RLIPoC was followed by subsequent alteration in metabolites, such as flavin adenine dinucleotide and nicotinamide adenine dinucleotide hydrate, both in RLIPoC-conducted local tissues and circulating blood. Furthermore, nicotinamide adenine dinucleotide hydrate can mimic RLIPoC in increasing Tregs. Conversely, the depletion of Tregs using depletion of Treg mice compromised the neuroprotective effects conferred by RLIPoC. Conclusions RLIPoC protects against ischemic brain injury, at least in part by activating and maintaining the Tregs through the nicotinamide adenine dinucleotide/nicotinamide adenine dinucleotide hydrate pathway.

IL-33/ST2 Axis Plays a Protective Effect in Streptococcus pyogenes Infection through Strengthening of the Innate Immunity.

Group A Streptococcus (GAS) causes invasive human diseases with the cytokine storm. Interleukin-33 (IL-33)/suppression of tumorigenicity 2 (ST2) axis is known to drive TH2 response, while its effect on GAS infection is unclear. We used an air pouch model to examine the effect of the IL-33/ST2 axis on GAS-induced necrotizing fasciitis. GAS infection induced IL-33 expression in wild-type (WT) C57BL/6 mice, whereas the IL-33- and ST2-knockout mice had higher mortality rates, more severe skin lesions and higher bacterial loads in the air pouches than those of WT mice after infection. Surveys of infiltrating cells in the air pouch of GAS-infected mice at the early stage found that the number and cell viability of infiltrating cells in both gene knockout mice were lower than those of WT mice. The predominant effector cells in GAS-infected air pouches were neutrophils. Absence of the IL-33/ST2 axis enhanced the expression of inflammatory cytokines, but not TH1 or TH2 cytokines, in the air pouch after infection. Using in vitro assays, we found that the IL-33/ST2 axis not only enhanced neutrophil migration but also strengthened the bactericidal activity of both sera and neutrophils. These results suggest that the IL-33/ST2 axis provided the protective effect on GAS infection through enhancing the innate immunity.

Regulatory T cells protect against brain damage by alleviating inflammatory response in neuromyelitis optica spectrum disorder.

BACKGROUND AND PURPOSE: Neuromyelitis optica spectrum disorder (NMOSD) is mainly an anti-aquaporin 4 (anti-AQP4) autoantibodies-mediated idiopathic inflammatory demyelinating disease of the central nervous system. Systemic and local inflammatory responses play a key role in the pathophysiology of NMOSD. However, the role of the crucial immunomodulators CD4+CD25+ forkhead box P3+ (Foxp3) regulatory T cells (Tregs) has not been investigated in NMOSD. METHODS: Twenty-five patients with anti-AQP4-postive NMOSD undergoing an attack and 21 healthy controls (HCs) were enrolled. Frequencies of T cell subsets and Tregs in the peripheral blood were assessed by flow cytometry. Additionally, a model of NMOSD using purified immunoglobulin G from anti-AQP4-antibodies-positive patients with NMOSD and human complement injected into brain of female adult C57BL/6J mice was established. Infiltrated Tregs into NMOSD mouse brain lesions were analyzed by flow cytometry, histological sections, and real-time quantitative Polymerase Chain Reaction. Astrocyte loss, demyelination, and inflammatory response were also evaluated in our NMOSD mouse model. Finally, we examined the effects of both depletion and adoptive transfer of Tregs. RESULTS: The percentage of Tregs, especially naïve Tregs, among total T cells in peripheral blood was significantly decreased in NMOSD patients at acute stage when compared to HCs. Within our animal model, the number and proportion of Tregs among CD4+ T cells were increased in the lesion of mice with NMOSD. Depletion of Tregs profoundly enhanced astrocyte loss and demyelination in these mice, while adoptive transfer of Tregs attenuated brain damage. Mechanistically, the absence of Tregs induced more macrophage infiltration, microglial activation, and T cells invasion, and modulated macrophages/microglia toward a classical activation phenotype, releasing more chemokines and pro-inflammatory cytokines. In contrast, Tregs transfer ameliorated immune cell infiltration in NMOSD mice, including macrophages, neutrophils, and T cells, and skewed macrophages and microglia towards an alternative activation phenotype, thereby decreasing the level of chemokines and pro-inflammatory cytokines. CONCLUSION: Tregs may be key immunomodulators ameliorating brain damage via dampening inflammatory response after NMOSD.

Dynamic Changes in AQP4-IgG Level and Immunological Markers During Protein-A Immunoadsorption Therapy for NMOSD: A Case Report and Literature Review.

The changes in the serum levels of aquaporin-4-IgG (AQP4-IgG), immunoglobulins, and inflammatory mediators in neuromyelitis optica spectrum disorder (NMOSD) cases treated with immunoadsorption have been rarely described in detail. Here we report a 29-year-old steroid-resistant NMOSD female with a severe disability (bilateral blindness and paraplegia) who received protein-A immunoadsorption as a rescue treatment. During the total 5 sessions, the circulating level of AQP4-IgG, immunoglobulins, and complement proteins (C3 and C4) showed a rapid and sawtooth-like decrease, and the serum AQP4-IgG titer declined from 1:320 to below the detectable limit at the end of the 3rd procedure. Of all the antibodies, IgG had the biggest removal rate (>96.1%), followed by IgM (>66.7%) and IgA (53%), while complement C3 and C4 also dropped by 73% and 65%, respectively. The reduced pro-inflammatory cytokines (interleukin-8 and tumor necrosis factor-α) and marked increased lymphocyte (T and B cell) counts were also observed. The improvement of symptoms initiated after the last session, with a low AQP4-IgG titer (1:32) persisting thereafter. Accordingly, protein-A immunoadsorption treatment could be one of the potential rescue therapies for steroid-resistant NMOSD patients with a severe disability.

Effects of Exercise on Sleep Quality and Insomnia in Adults: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Study Objectives: We conducted a meta-analysis to assess the effects of different regular exercise (lasting at least 2 months on a regular basis) on self-reported and physiological sleep quality in adults. Varied exercise interventions contained traditional physical exercise (e.g., walking, cycling) and mind-body exercise characterized by gentle exercise with coordination of the body (e.g., yoga). Methods: Procedures followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. Systematical searches were conducted in three electronic databases (PubMed, Embase, and Web of Science) for relevant research that involved adult participants without pathological diseases receiving exercise intervention. The search strategy was based on the population, intervention, comparison, and outcome study design (PICOS) framework. The self-reported outcomes included varied rating scales of Pittsburgh Sleep Quality Index (PSQI), Insomnia Severity Index (ISI), and Epworth Sleepiness Scale (ESS). Subgroup meta-analyses of PSQI scores were conducted based on type of exercise, duration of intervention, and participants' age and gender. The physiological outcomes were measured by Actigraph. All meta-analyses were performed in a fixed or random statistic model using Revman software. Results: Twenty-two randomized controlled trials were included in the analysis. The overall analysis on subjective outcomes suggests that exercise interventions significantly improved sleep quality in adults compared with control interventions with lower PSQI (MD -2.19; 95% CI -2.96 to -1.41), ISI (MD -1.52; 95% CI -2.63 to -0.41), and ESS (MD -2.55; 95% CI -3.32 to -1.78) scores. Subgroup analyses of PSQI scores showed both physical and mind-body exercise interventions resulted in improvements of subjective sleep to the same extent. Interestingly, short-term interventions (≤3 months) had a significantly greater reduction in sleep disturbance vs. long-term interventions (>3 months). Regarding physiological sleep, few significant effects were found in various sleep parameters except the increased sleep efficiency in the exercise group vs. control group. Conclusions: Results of this systematic review suggest that regular physical as well as mind-body exercise primarily improved subjective sleep quality rather than physiological sleep quality in adults. Specifically, self-reported sleep quality, insomnia severity, and daytime sleepiness could be improved or ameliorated with treatment of exercise, respectively, evaluated by PSQI, ISI, and ESS sleep rating scales.

Microglia reprogram metabolic profiles for phenotype and function changes in central nervous system.

In response to various types of environmental and cellular stress, microglia rapidly activate and exhibit either pro- or anti-inflammatory phenotypes to maintain tissue homeostasis. Activation of microglia can result in changes in morphology, phagocytosis capacity, and secretion of cytokines. Furthermore, microglial activation also induces changes to cellular energy demand, which is dependent on the metabolism of various metabolic substrates including glucose, fatty acids, and amino acids. Accumulating evidence demonstrates metabolic reprogramming acts as a key driver of microglial immune response. For instance, microglia in pro-inflammatory states preferentially use glycolysis for energy production, whereas, cells in anti-inflammatory states are mainly powered by oxidative phosphorylation and fatty acid oxidation. In this review, we summarize recent findings regarding microglial metabolic pathways under physiological and pathological circumtances. We will then discuss how metabolic reprogramming can orchestrate microglial response to a variety of central nervous system pathologies. Finally, we highlight how manipulating metabolic pathways can reprogram microglia towards beneficial functions, and illustrate the therapeutic potential for inflammation-related neurological diseases.

P2X7 receptor activation aggravates NADPH oxidase 2-induced oxidative stress after intracerebral hemorrhage.

Oxidative stress is a crucial pathological process that contributes to secondary injury following intracerebral hemorrhage. P2X7 receptor (P2X7R), which is activated by the abnormal accumulation of extracellular ATP, plays an important role in the regulation of oxidative stress in the central nervous system, although the effects of activated P2X7R-associated oxidative stress after intracerebral hemorrhage remain unclear. Mouse models of intracerebral hemorrhage were established through the stereotactic injection of 0.075 U VII collagenase into the right basal ganglia. The results revealed that P2X7R expression peaked 24 hours after intracerebral hemorrhage, and P2X7R expressed primarily in neurons. The inhibition of P2X7R, using A438079 (100 mg/kg, intraperitoneal), reduced nicotinamide adenine dinucleotide phosphate oxidase 2 (NOX2) expression and malondialdehyde generation, increased superoxide dismutase and glutathione/oxidized glutathione levels, and alleviated neurological damage, brain edema, and apoptosis after intracellular hemorrhage. The P2X7R inhibitor A438079 (100 mg/kg, intraperitoneal injection) inhibited the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) and nuclear factor kappa-B (NF-κB) after intracerebral hemorrhage. Blocking ERK1/2 activation, using the ERK1/2 inhibitor U0126 (2 µg, intraventricular injection), reduced the level of NOX2-mediated oxidative stress induced by P2X7R activation after intracellular hemorrhage. Similarly, the inhibition of NF-κB, using the NF-κB inhibitor JSH-23 (3.5 µg, intraventricular), reduced the level of NOX2-mediated oxidative stress induced by P2X7R activation. Finally, GSK2795039 (100 mg/kg, intraperitoneal), a NOX2 antagonist, attenuated P2X7R-mediated oxidative stress, neurological damage, and brain edema after intracerebral hemorrhage. The results indicated that P2X7R activation aggravated NOX2-induced oxidative stress through the activation of the ERK1/2 and NF-κB pathways following intracerebral hemorrhage in mice. The present study was approved by the Ethics Committee of Huazhong University of Science and Technology, China (approval No. TJ-A20160805) on August 26, 2016.

FTY720 Modulates Microglia Toward Anti-inflammatory Phenotype by Suppressing Autophagy via STAT1 Pathway.

Since microglia-associated neuroinflammation plays a pivotal role in the progression of white matter diseases, modulating microglial activation has been suggested as a potential therapeutic strategy. Here, we investigated the anti-inflammatory effects of fingolimod (FTY720) on microglia and analyzed the crosstalk between microglia autophagy and neuroinflammation. Lipopolysaccharide (LPS)-induced primary cultured microglia model was established. Microglial phenotypes were assessed by Western blot, quantitative real-time polymerase chain reaction (RT-PCR) and flow cytometry. Autophagy was evaluated by immunofluorescence, MDC staining and Western blot. Rapamycin was used to investigate the role of autophagic process in regulating microglial phenotypes. The signaling markers were screened by RT-PCR and Western blot. FTY720 shifted microglial phenotype from pro-inflammatory state to anti-inflammatory state and inhibited microglial autophagy under lipopolysaccharide (LPS) treatment. Rapamycin reversed the effect of FTY720 on phenotype transformation of microglia. The results of mechanism studies have shown that FTY720 notably repressed LPS-induced STAT1 activity, which was reactivated by rapamycin. Our research suggested that FTY720 could significantly transform pro-inflammatory microglia into anti-inflammatory microglia by suppressing autophagy via STAT1.

Predictive Factors of Resistance to High-Dose Steroids Therapy in Acute Attacks of Neuromyelitis Optica Spectrum Disorder.

High-dose steroids, the first-line therapy for acute attacks in neuromyelitis optica spectrum disorder (NMOSD), were ineffective in a proportion of NMOSD attacks. This study aimed to explore possible predictors of high-dose steroid resistance. Demographics and disease characteristics of acute attacks were compared between those who responded to high-dose intravenous methylprednisolone (IVMP) and those resistant to IVMP. In total, 197 attacks in 160 patients were identified in our NMOSD registry. Compared with responders, attacks resistant to high-dose steroids tended to have a higher proportion of previous history of immunosuppressive use (25.5 vs. 15.5%, p = 0.080). Significantly higher levels of proteins in the cerebrospinal fluid (CSF) were found in non-responders than in responders [485.5 (388-656) vs. 387 (291.5-532) mg/L, p = 0.006]. More active lesions were found in the brain stem of non-responders (8 attacks in 55, 14.5%), especially in the pons (7.3%) and medulla (14.5%), as opposed to responders (7 patients in 142, 4.9%). Multivariable logistic regression showed that resistance to high-dose steroid treatment was associated with previous immunosuppressant use [odds ratio (OR), 2.31; 95% confidence interval (CI) 1.002-5.34, p = 0.049], CSF protein level above 450 mg/L (OR 3.42, 95% CI 1.72-6.82, p < 0.001), and active lesions in the brainstem (OR 3.80, 95% CI 1.17-12.32, p = 0.026). In conclusion, NMOSD patients with previous use of immunosuppressants, higher levels of CSF protein, and active lesions in the brainstem are more likely to respond poorly to high-dose IVMP alone during an acute attack.

Efficacy of plasma exchange in acute attacks of neuromyelitis optica spectrum disorders: A systematic review and meta-analysis.

BACKGROUND: Plasma exchange (PE) has usually to be considered as a rescue therapy when intravenous corticosteroids is insufficient in acute attacks of neuromyelitis optica spectrum disorders (NMOSD). The efficacy of PE has not been quantified. This system review and meta-analysis was aimed to evaluate the efficacy of PE therapy in acute attacks of NMOSD. METHODS: Studies evaluating the efficacy of PE in patients with NMOSD were identified from PubMed and Embase. Changes of Expanded Disability Status Scale (EDSS) score between before and after PE therapy, and the rate of response to PE, were defined as the main efficacy outcomes. Meta-regression was performed to identify the sources of heterogeneity. Subgroup meta-analysis were performed based on the interval of initiation PE after attack onset and AQP4-IgG serostatus of patients. RESULTS: Twenty-four studies containing 528 patients with NMOSD were included in this meta-analysis. As a rescue therapy when patients failed to respond to intravenous corticosteroids (PE rescue), PE treatment resulted in a reduction in the mean EDSS score by 1.69 (95% CI: 0.88-2.50), with a response rate of 75%(95%CI: 66%-83%). As a first-line therapy being used alone or simultaneously with intravenous corticosteroids (PE first-line), PE resulted in a reduction in the mean EDSS score by 2.34 (95% CI: 1.69-2.98), with a response rate of 71%(95%CI: 44%-93%). Overall, PE resulted in a reduction in the mean EDSS score by 1.83 (95% CI: 1.19-2.47), with a response rate of 74% (95%CI: 66%-82%). Subgroup analysis suggested that earlier PE initiation and AQP4-IgG seronegative patients seemed to be associated with a superior response to PE therapy. CONCLUSION: Plasma exchange, whether used as rescue or as first-line therapy, is an effective therapeutic method in patients during acute attacks of NMOSD.

D-dimer level is associated with the severity of COVID-19.

INTRODUCTION: Abnormal coagulation function has been demonstrated to be involved in the disease progression of COVID-19. However, the association between D-dimer levels and the severity of COVID-19 is not clear. The study was aimed to investigate the association between D-dimer levels and the severity of COVID-19 based on a cohort study and meta-analysis. MATERIALS AND METHODS: Demographic and clinical data of all confirmed cases with COVID-19 on admission to Tongji Hospital from January 27 to March 5, 2020, were collected and analyzed, and coagulation function parameters were described and compared between patients with severe infection and those with non-severe infection. Cohort studies reporting risk estimates for the D-dimer and severity of COVID-19 association were searched and included to perform a meta-analysis. RESULTS: In our cohort study, patients with severe disease were more likely to exhibit dysregulated coagulation function, and a significantly higher D-dimer level (median 1.8 µg/ml [interquartile range 0.9-4.6] vs 0.5 [0.3-1.1], p < 0.001) was found in severe cases than the mild ones, on admission. In the meta-analysis of 13 cohort studies (including the current study), patients with severe disease had an increase in mean D-dimer value by 0.91 (95% confidence interval, 0.51-1.31, p < 0.001) µg/ml compared to those with non-severe disease, and odds of severe infection was associated with D-dimer greater than 0.5 µg/ml (odds ratio = 5.78, 95% confidence interval, 2.16-15.44, p < 0.001) on admission. CONCLUSIONS: Patients with severe COVID-19 have a higher level of D-dimer than those with non-severe disease, and D-dimer greater than 0.5 µg/ml is associated with severe infection in patients with COVID-19.

Unilateral cerebral cortical encephalitis with epilepsy: a possible special phenotype of MOG antibody-associated disorders.

Myelin oligodendrocyte glycoprotein (MOG) antibody-related encephalomyelitis is an increasingly recognized entity with heterogeneity in phenotype. Among all clinical phenotypes, encephalitis restricted to cerebral cortex might be most easily ignored and under-estimated type. Here, we described two cases of cerebral cortical encephalitis with MOG seropositivity to facilitate the awareness of the manifestations of the disease. In case 1, the patient presented with headaches and fevers turned out to have elevated CSF cells and cerebral cortical FLAIR hyperintense lesions in brain MRI. He was treated as intracranial infection during his first and second admission and fully resolved when discharged. During the patient's third admission, the patient experienced a seizure, and we found cerebral cortical FLAIR hyperintensity again and MOG antibody was positive in the serum. Therefore, we considered the patient suffered from MOG antibody encephalitis. In case 2, the patient also had headache, fever, and experienced a seizure. MOG antibody was positive in the serum and brain MRI showed cortical hyperintense lesions. Both the patients were young man, response well to corticosteroids and recovered completely. The two cases suggested that encephalitis, especially benign recurrent unilateral cerebral cortical encephalitis with epilepsy, might be a special phenotype of MOG antibody-associated disorders.

Apolipoprotein E Gene Polymorphisms Are Risk Factors for Spontaneous Intracerebral Hemorrhage: A Systematic Review and Meta-analysis.

Intracerebral hemorrhage (ICH) is a serious clinical disease with high morbidity, whose pathogenesis might be related to apolipoprotein E (APOE) gene polymorphisms. To comprehensively evaluate the risk factors for ICH occurrence, we performed a meta-analysis. We searched online databases to identify eligible studies based on the relationship between APOE genetic polymorphisms and ICH occurrence risk. Specific and pooled odds ratios (ORs) were calculated and by assessing small study bias, we drew the relationship between APOE polymorphisms and ICH risk. We included 15 eligible studies in our study containing a total of 1642 ICH samples and 5545 normal controls. The comparison of ɛ4 and ɛ3 APOE genotypes revealed that specific and pooled ORs showed a significantly increased odds ratio in ICH patients with the ɛ4 genotype, indicating that ɛ4 gene is a risk factor for ICH occurrence, and the heterogeneity is acceptable. Similarly, it was found that the ɛ2 genotype also contributed to the incidence rate of ICH. However, after the subgroup analysis by ethnicity, this APOE genetic polymorphism acted as a harmful factor only in white populations, but did not show an effect in Asian populations. It was suggested that both ε2 and ε4 APOE alleles were risk factors for ICH in general. They were risk factors in white populations only, neither had a detectable effect in Asian populations after subgroup analysing by ethnicity.

Efficacy and safety of rituximab for relapsing-remitting multiple sclerosis: A systematic review and meta-analysis.

OBJECTIVE: To evaluate the efficacy and safety of rituximab for relapsing-remitting multiple sclerosis. RESULTS: Fifteen studies that collectively included 946 patients were selected for the meta-analysis. Rituximab therapy was associated with the mean annualized relapse rates decreasing by 0.80 (95% confidence interval, 0.45-1.15) and the mean Expanded Disability Status Scale score decreasing by 0.46 (95% confidence interval, 0.05-0.87). The likelihood of patients experiencing a relapse after starting rituximab therapy was only 15% (95% confidence interval, 7%-26%). Although mild-to-moderate adverse events occurred in 29.6% of the patients, there were no severe adverse events. CONCLUSIONS AND RELEVANCE: This systematic review and meta-analysis shows that rituximab is associated with reduced annualized relapse rates and disability levels in patients with relapsing-remitting multiple sclerosis. It is also well tolerated and is not associated with serious adverse events.

Effects of Prior Antiplatelet Therapy on the Prognosis of Primary Intracerebral Hemorrhage: A Meta-analysis.

BACKGROUND: Antiplatelet therapy (APT) was prevalently being used in the prevention of vascular disease, but the influence of prior APT on the prognosis of patients with intracerebral hemorrhage (ICH) remains controversial. This meta-analysis was to explore the effects of prior APT on the prognosis of patients with primary ICH. METHODS: PubMed and Embase were searched to identify the eligible studies. The studies comparing the mortality of ICH patients with or without prior APT were included. The quality of these studies was evaluated by the Newcastle-Ottawa quality assessment scale. The adjusted or unadjusted odds ratio (OR) for mortality between ICH patients with and without prior APT were pooled with 95% confidence interval (95% CI) as the effect of this meta-analysis. RESULTS: Twenty-two studies fulfilled the inclusion criteria and exhibited high qualities. The pooled OR was 1.37 (95% CI: 1.13-1.66, P = 0.001) for univariate analysis and 1.41 (95% CI: 1.05-1.90, P = 0.024) for multivariate analysis. The meta-regression indicated that for each 1-day increase in the time of assessment, the adjusted OR for the mortality of APT patients decreased by 0.0049 (95% CI: 0.0006-0.0091, P = 0.026) as compared to non-APT patients. CONCLUSION: Prior APT was associated with high mortality in patients with ICH that might be attributed primarily to its strong effect on early time.