Familial mesial temporal lobe epilepsy phenotype is associated with novel LGI1 variants: A report of two families.

OBJECTIVE: To expand the clinical phenotype and mutation spectrum of familial mesial temporal lobe epilepsy (FMTLE) and provide a new perspective for exploring the pathological mechanisms of epilepsy caused by leucine-rich glioma inactivated 1 (LGI1) variants. METHODS: We reported clinical data from two families with FMTLE and screened patients for variants in the LGI1 gene using Whole-exome sequencing and Sanger sequencing. The clinical features of FMTLE were analysed. The pathogenicity of the causative loci was assessed according to the American College of Medical Genetics and Genomics guidelines, and potential pathogenic mechanisms were predicted through multiple bioinformatics and molecular dynamics software. RESULTS: We identified two novel LGI1 truncating variants within two large families with FMTLE: LGI1 (c.1174C>T, p.Q392X) and LGI1 (c.703C>T, p.Q235X). Compared to previous reports, we found that focal to bilateral tonic-clonic seizures are a common type of seizure in FMTLE. The clinical phenotypes of patients with FMTLE caused by LGI1 variants were relatively mild, and all patients responded well to valproic acid. Bioinformatics analyses and molecular dynamics simulations showed that protein structure and interactions were considerably weakened or damaged as a result of both variants. CONCLUSION: This study presents the first report identifying LGI1 as a potential novel pathogenic gene within FMTLE families, thereby broadening the mutation spectrum associated with FMTLE. The findings of this study offer novel insights and avenues for understanding the intricate molecular mechanisms underlying LGI1 variants and their correlations with patient phenotypes. This study proposes the possibility of familial focal epilepsy syndromes overlapping.

Prognostic factors underlying the development of drug-resistant epilepsy in patients with autoimmune encephalitis: a retrospective cohort study.

OBJECTIVE: The aim of our study was to analyze the characteristics of patients with autoimmune encephalitis (AE) to identify prognostic factors associated with the development of drug-resistant epilepsy (DRE). METHODS: In this retrospective observational cohort study, we enrolled adult patients with AE between January 2016 and December 2022. The patients were categorized into two groups based on the presence or absence of DRE at the last follow-up. The predictors of the development of DRE were investigated using logistic regression analysis. RESULTS: Among 121 AE patients, 75.2% (n = 91) experienced acute symptomatic seizures, and 29.8% (n = 36) developed DRE at the last follow-up. On multivariate regression analysis, the factors associated with DRE were antibody negativity (OR 3.628, 95% CI 1.092-12.050, p = 0.035), focal seizure (OR 6.431, 95% CI 1.838-22.508, p = 0.004), refractory status epilepticus (OR 8.802, 95% CI 2.445-31.689, p = 0.001), interictal epileptiform discharges on EEG (OR 6.773, 95% CI 2.206-20.790, p = 0.001), and T2/FLAIR hyperintensity in the limbic system (OR 3.286, 95% CI 1.060-10.183, p = 0.039). CONCLUSIONS: In this study, the risk of developing DRE was mainly observed among AE patients who were negative for antibodies or had focal seizures, refractory status epilepticus, interictal epileptiform discharges on EEG, and T2/FLAIR hyperintensity in the limbic system.

Did the modern Yellow River form at the Mid-Pleistocene transition?

The incision of the Sanmen Gorge marks the birth of the modern Yellow River, but its timing varies from the late Miocene-early Pliocene to the late Pleistocene (∼0.15 Ma), and the suggested forcing mechanisms vary from the uplift of the Tibetan Plateau to global climate change. Here, we report sedimentologic, geochronologic, and provenance data from a drill core near the Sanmen Gorge, the last gorge along the main course of the Yellow River. Our results indicate that typical river channel deposits, with detritus from the Ordos Block in the upstream regions, started to accumulate in the Sanmen Gorge at ∼1.25 Ma. When integrated with river terrace evidence from the upstream and downstream regions, the results provide robust evidence that the final integration of the modern Yellow River occurred at ∼1.25 Ma, consistent with the beginning of the Mid-Pleistocene transition (MPT). We propose that the accelerated lowering of eustatic sea level during the MPT may play as important a role as tectonism in driving the birth and evolution of the modern Yellow River.

Development and Validation of a Deep Learning Model for Predicting Treatment Response in Patients With Newly Diagnosed Epilepsy.

Importance: Selection of antiseizure medications (ASMs) for epilepsy remains largely a trial-and-error approach. Under this approach, many patients have to endure sequential trials of ineffective treatments until the "right drugs" are prescribed. Objective: To develop and validate a deep learning model using readily available clinical information to predict treatment success with the first ASM for individual patients. Design, Setting, and Participants: This cohort study developed and validated a prognostic model. Patients were treated between 1982 and 2020. All patients were followed up for a minimum of 1 year or until failure of the first ASM. A total of 2404 adults with epilepsy newly treated at specialist clinics in Scotland, Malaysia, Australia, and China between 1982 and 2020 were considered for inclusion, of whom 606 (25.2%) were excluded from the final cohort because of missing information in 1 or more variables. Exposures: One of 7 antiseizure medications. Main Outcomes and Measures: With the use of the transformer model architecture on 16 clinical factors and ASM information, this cohort study first pooled all cohorts for model training and testing. The model was trained again using the largest cohort and externally validated on the other 4 cohorts. The area under the receiver operating characteristic curve (AUROC), weighted balanced accuracy, sensitivity, and specificity of the model were all assessed for predicting treatment success based on the optimal probability cutoff. Treatment success was defined as complete seizure freedom for the first year of treatment while taking the first ASM. Performance of the transformer model was compared with other machine learning models. Results: The final pooled cohort included 1798 adults (54.5% female; median age, 34 years [IQR, 24-50 years]). The transformer model that was trained using the pooled cohort had an AUROC of 0.65 (95% CI, 0.63-0.67) and a weighted balanced accuracy of 0.62 (95% CI, 0.60-0.64) on the test set. The model that was trained using the largest cohort only had AUROCs ranging from 0.52 to 0.60 and a weighted balanced accuracy ranging from 0.51 to 0.62 in the external validation cohorts. Number of pretreatment seizures, presence of psychiatric disorders, electroencephalography, and brain imaging findings were the most important clinical variables for predicted outcomes in both models. The transformer model that was developed using the pooled cohort outperformed 2 of the 5 other models tested in terms of AUROC. Conclusions and Relevance: In this cohort study, a deep learning model showed the feasibility of personalized prediction of response to ASMs based on clinical information. With improvement of performance, such as by incorporating genetic and imaging data, this model may potentially assist clinicians in selecting the right drug at the first trial.

Genetic Polymorphisms in Enzymes Involved in One-Carbon Metabolism and Anti-epileptic Drug Monotherapy on Homocysteine Metabolism in Patients With Epilepsy.

Aims: To investigate the effects of single nucleotide polymorphisms (SNPs) in genes of one-carbon metabolism (OCM) related enzymes and anti-epileptic drug (AED) monotherapy on homocysteine (Hcy) metabolism in patients with epilepsy, and to further explore specific SNPs that may increase patients' susceptibility to the effects of AEDs on the Hcy imbalance. Method: This case-control study analyzed 279 patients with epilepsy, including patients receiving monotherapy with valproate (VPA) (n = 53), oxcarbazepine (OXC) (n = 71), lamotrigine (LTG) (n = 55), or levetiracetam (LEV) (n = 35) and patients who had not taken any AEDs (controls, n = 65) for at least 6 months. Serum levels of vitamin B12 (vit B12), folate (FA) and Hcy were measured, and 23 SNPs in 13 genes of OCM-related enzymes were genotyped in all patients. Results: Methylenetetrahydrofolate reductase (MTHFR) rs1801133 was associated with elevated serum Hcy levels in patients with epilepsy (P < 0.001), and patients presenting the TT genotype exhibited higher serum Hcy levels than patients with the CC (P < 0.001) or CT (P < 0.001) genotype. A subsequent multiple linear regression analysis showed that AED monotherapy with VPA (vs. control: P = 0.023) or OXC (vs. control: P = 0.041), and genotypes of MTHFR rs1801133 TT (vs. CC: P < 0.001; vs. CT: P < 0.001), transcobalamin 2 (TCN2) rs1801198 CC (vs. GC: P = 0.039) and folate receptor 1 (FOLR1) rs2071010 AA (vs. GA: P = 0.031) were independent risk factors for higher Hcy levels. In the subgroup analysis of patients taking OXC, we found that patients with genotypes of MTHFR rs1801133 TT (vs. CC: P = 0.001; vs. CT: P < 0.001) and TCN2 rs1801198 CC (vs. GC: P = 0.021; vs. GG: P = 0.018) exhibited higher serum Hcy levels. Conclusions: VPA, OXC, and genotypes of MTHFR rs1801133 TT, TCN2 rs1801198 CC, and FOLR1 rs2071010 AA are all independent risk factors for elevated Hcy levels in patients with epilepsy. Moreover, genotypes of MTHFR rs1801133 TT and TCN2 rs1801198 CC may increase patients' susceptibility to the effect of OXC on disrupting Hcy homeostasis.

Downregulation of hyperpolarization-activated cyclic nucleotide-gated channels (HCN) in the hippocampus of patients with medial temporal lobe epilepsy and hippocampal sclerosis (MTLE-HS).

Changes in the expression of HCN ion channels leading to changes in Ih function and neuronal excitability are considered to be possible mechanisms involved in epileptogenesis in kinds of human epilepsy. In previous animal studies of febrile seizures and temporal lobe epilepsy, changes in the expression of HCN1 and HCN2 channels at different time points and in different parts of the brain were not consistent, suggesting that transcriptional disorders involving HCNs play a crucial role in the epileptogenic process. Therefore, we aimed to assess the transcriptional regulation of HCN channels in Medial temporal lobe epilepsy with hippocampal sclerosis (MTLE-HS) patients. This study included eight nonhippocampal sclerosis patients and 40 MTLE-HS patients. The mRNA expression of HCN channels was evaluated by qRT-PCR, while the protein expression was quantitatively analyzed by Western blotting. The subcellular localization of HCN channels in the hippocampus was explored by immunofluorescence. We demonstrated that the mRNA and protein expression of HCN1 and HCN2 are downregulated in controls compared to that in MTLE-HS patients. In the hippocampal CA1/CA4 subregion and GCL, in addition to a large decrease in neurons, the expression of HCN1 and HCN2 on neuronal cell membranes was also downregulated in MTLE-HS patients. These findings suggest that the expression of HCN channels are downregulated in MTLE-HS, which indicates that the decline in HCN channels in the hippocampus during chronic epilepsy in MTLE-HS patients leads to the downregulation of Ih current density and function, thereby reducing the inhibitory effect and increasing neuronal excitability and eventually causing disturbances in the electrical activity of neurons.

Associations between seizures and MRI in patients with anti-NMDAR encephalitis.

OBJECTIVES: Seizures are a prominent feature of anti-N-methyl-d-aspartate receptor (anti-NMDAR) encephalitis. Nearly half of brain magnetic resonance image (MRI) results are abnormal. The aim of our study was to evaluate the associations between seizures and brain MRI results in patients with anti-NMDAR encephalitis. METHODS: Patients with anti-NMDAR encephalitis were enrolled between January 2015 and December 2018. The patients included were divided into normal and abnormal MRI groups. Seizure outcomes and modified Rankin Scale scores at the 1-year follow-up were assessed. Seizure characteristics and outcomes were compared between groups. RESULTS: Of 35 patients with anti-NMDAR encephalitis, 28 patients (80%) had reported seizures in the acute phase. Patients with abnormal MRI findings more frequently had focal seizures than patients with normal MRI findings (72.7% vs 17.6%, P < .01). The incidence of patients treated with 2 or more antiepileptic drugs was higher in the normal MRI group than in the abnormal MRI group (100% vs 45.4%, P < .01). The onset-immunotherapy time was shorter in the abnormal MRI group than in the normal MRI group (P < .05). There were no statistically significant differences in seizure outcomes between the normal and abnormal MRI groups (P > .05). CONCLUSIONS: Focal seizures were most common in patients with abnormal MRI lesions. In the acute stage of the disease, the abnormal MRI group was more likely than the normal MRI group to achieve seizure control. Abnormal MRI findings did not affect the overall good prognosis of patients with anti-NMDAR encephalitis with seizures.

LncRNA ILF3-AS1 mediated the occurrence of epilepsy through suppressing hippocampal miR-212 expression.

Increased expression of some matrix metalloproteinases (MMPs) is closely associated with epilepsy. However, factors that promote their expression have not been clarified. Long noncoding RNAs (lncRNAs) play crucial roles in the development of human diseases, including various cancers, but its potential function in temporal lobe epilepsy (TLE) has remained unexplored. In this study, we showed that hippocampal and serum ILF3-AS1 levels are higher in TLE patients than in matched controls. Interleukin (IL)-1ß and tumor necrosis factor (TNF)-α induced ILF3-AS1 expression in astrocytes, while ectopic expression of ILF3-AS1 enhanced IL-6 and TNF-α expression. Ectopic ILF3-AS1 in astrocytes also increased expression of MMP2, MMP3, MMP9 and MMP14, but suppressed expression of miR-212. Consistent with that finding, miR-212 levels were lower in the hippocampus and serum of TLE patients than their controls. This suggests that ILF3-AS1 promotes expression of inflammatory cytokines and MMPs by targeting miR-212 and that ILF3-AS1 plays a crucial role in the development of TLE.

A rapid and simple HPLC-MS/MS method for the simultaneous quantification of valproic acid and its five metabolites in human plasma and application to study pharmacokinetic interaction in Chinese epilepsy patients.

Valproic acid(VPA) is a classic drug that used to treat epilepsy in monotherapy or combination with other anticonvulsant drugs such as lamotrigine (LTG). Although it was reported that VPA could increase lamotrigine trough concentration in clinical practice, there was no report about the effect of LTG on the trough concentration of VPA and its main metabolites, such as 4-ene-VPA, 3-OH-VPA, 4-OH-VPA, 3-keto-VPA, 2-PGA which are related to the therapeutic and toxic effects of VPA. In this study, a simple and rapid method for the simultaneous determination of VPA and its five metabolites in human plasma using HPLC-MS/MS was developed for the first time. Benzoic acid was used as an internal standard (IS). Separation was performed on a Hypersil GOLD C18 column by isocratic elution using acetonitrile: 10mM ammonium acetate solution (90:10, v/v) as mobile phase at a flow rate of 0.3mL/min. A triple quadrupole mass spectrometer operating in the negative ion-switching, electron spray ionization mode with selection reaction monitoring (SRM) was employed to determine transitions of m/z 143.183→143.183, 157.033→113.165, 173.017→129.074, 159.058→101.082, 140.870→140. 870, 159.049→123.076, 121.035→77.136 for VPA, 2-PGA, 3-keto-VPA, 3-OH-VPA, 4-ene-VPA, 4-OH-VPA and IS, respectively. The method also afforded satisfactory results in terms of sensitivity, specificity, precision (intra- and inter-batch), accuracy, recovery, matrix effect and stability. This method was successfully applied to evaluate the effect of LTG on the trough concentration of VPA, 2-PGA, 3-keto-VPA, 3-OH-VPA, 4-ene-VPA, 4-OH-VPA in Chinese epilepsy patients. The result showed that there was no significant difference in the concentration of VPA and its five metabolites between patients in VPA monotherapy and patients in therapy combining VPA with LTG.

Associations between genetic variation in one-carbon metabolism and leukocyte DNA methylation in valproate-treated patients with epilepsy.

BACKGROUND: Valproate (VPA) as a first-line antiepileptic drug is useful for the most types of epileptic seizure treatment. Previous studies observed that VPA influenced one-carbon metabolism (OCM), consequently, DNA methylation. However, other individual genetic variations, as well as VPA, modify DNA methylation. OBJECTIVE: In this study, we investigated associations between genetic variations in OCM and leukocyte DNA methylation in VPA-treated patients with epilepsy. METHODS: This was a cross-sectional study of 101 epileptic patients who underwent VPA monotherapy and 68 healthy controls. All subjects were measured OCM-related nutrients (folate, homocysteine and vitamin B12), and DNA methylation of specific regions were analyzed. Furthermore, we examined the associations between genetic variations in OCM and DNA methylation levels in epileptic patients. RESULTS: VPA-treated patients with epilepsy exhibited both higher serum homocysteine and vitaminB12 levels and lower folate levels relative to controls (P = 0.018, P = 0.003, P < 0.001 respectively), the methylation level of the MTHFR amplicon was significantly lower in the VPA group compared with those in the controls (P = 0.043). VPA-treated epileptic patients carrying the T-allele of methylenetetrahydrofolate reductase (MTHFR) c.677C>T showed higher serum Hcy levels than those observed in the 677CC group (P < 0.01). Epileptic patients who carried G-allele of methionine synthase (MTR) c.2756A>G showed significantly lower MTHFR amplicon methylation levels compared to carriers of the wild-type MTR 2756AA genotype (P = 0.028). CONCLUSION: Our study provided evidence that the MTR c.2756A>G polymorphism is associated with MTHFR amplicon hypomethylation in VPA-treated patients with epilepsy.

Association between mossy fiber sprouting and expression of semaphorin-3f protein in dentate gyrus of hippocampus in lithium-pilocarpine-induced status epilepticus mouse model.

OBJECTIVES: Mossy fiber sprouting is involved in the pathogenesis of mesial temporal lobe epilepsy. But the exact mechanism of formation of mossy fiber sprouting is still unclear. Semaphorin-3f protein could inhibit the growth of neuron axons. The aim of this research is to evaluate the association between semaphorin-3f expression and mossy fiber sprouting. METHODS: We established pilocarpine-induced status epilepticus (PISE) models firstly. Then, mossy fiber sprouting in the hippocampus of PISE models was examined by Timm staining. Expression of semaphorin-3f was evaluated by western blot analysis and immunohistochemical examination. Expression of semaphorin-3f protein in different subregions of hippocampus and its relationship with mossy fiber sprouting were studied. RESULTS: We found that in PISE group, mossy fiber sprouting appeared in dentate gyrus (DG) region. It started to develop in the latent phase of PISE group and increased significantly in the chronic phase. Expression of semaphorin-3f protein in DG region started to decrease in the latent phase, and stayed at low level in the chronic phase. No such change was found in the other groups. CONCLUSIONS: These results indicate that the decrease in semaphorin-3f expression in DG region was in parallel to the change of mossy fiber sprouting in PISE models, suggesting that mossy fiber sprouting is closely associated with reduced expression of semaphorin-3f in this model.

Pluronic P85-coated poly(butylcyanoacrylate) nanoparticles overcome phenytoin resistance in P-glycoprotein overexpressing rats with lithium-pilocarpine-induced chronic temporal lobe epilepsy.

P-glycoprotein (Pgp) overexpression in the blood brain barrier (BBB) is hypothesized to lower brain drug concentrations and thus inhibit anticonvulsant effects in drug-resistant epilepsy. Recently, the poly(butylcyanoacrylate) (PBCA) nanoparticle system was shown to overcome the obstacle of the BBB to deliver drugs into the brain. To determine whether pluronic P85-coated phenytoin poly(butylcyanoacrylate) nanoparticles (P85-PHT-PBCA-NPs) target PHT to the brain, PHT-resistant rats overexpressing Pgp in the BBB were screened by response to PHT treatment after chronic temporal lobe epilepsy induced by lithium-pilocarpine, followed by direct verification of PHT transport via measurement of brain PHT concentrations using microdialysis. Thereafter, the PHT-resistant rats were divided into three groups, which were treated with PHT, PHT + tariquidar (TQD), or P85-PHT-PBCA-NPs. PHT + TQD and P85-PHT-PBCA-NPs showed anticonvulsant activity in the PHT-resistant rats and increased the ratio of the area under the curve of the PHT concentrations in the brain/plasma in comparison with that observed in animals subjected to PHT treatment. However, the ratios of the PHT concentrations in the liver/plasma and kidney/plasma following P85-PHT-PBCA-NPs treatment were much lower than those measured following PHT + TQD treatment. Thus, Pgp overexpression decreases therapeutic drug concentrations in the brains of subjects with drug-resistant epilepsy and P85-PHT-PBCA-NPs could increase these drug concentrations.

Effects of antiepileptic drug monotherapy on one-carbon metabolism and DNA methylation in patients with epilepsy.

PURPOSE: The aim of this study was to compare the serum levels of one-carbon metabolism (OCM) nutrients (e.g., folate, homocysteine and vitamin B12) and peripheral blood DNA methylation in epileptic patients under treatment with antiepileptic drugs (AEDs) and in healthy controls. METHODS: In this cross-sectional study, 60 patients with epilepsy who were receiving valproate (VPA) (n = 30) or lamotrigine (LTG) (n = 30) monotherapy were enrolled. Thirty age and sex matched healthy subjects served as the controls. Serum concentrations of OCM nutrients and peripheral blood DNA methylation status were measured. RESULTS: Compared to the control group, the VPA group had higher serum levels of homocysteine (p<0.05). No difference in homocysteine concentration was observed in the LTG group. Patients receiving VPA or LTG had significantly lower serum folate levels in comparison with controls (p<0.001). The level of methylation of long interspersed nucleotide element-1 (LINE-1) in peripheral blood was not significantly different between the AED monotherapy group and healthy controls. A difference in the methylation levels of methylenetetrahydrofolate reductase (MTHFR) amplicon was observed between AED-treated patients with epilepsy and controls (p<0.01). A positive correlation between serum folate levels and peripheral blood MTHFR amplicon methylation status was also observed (r = 0.25, p = 0.023). CONCLUSION: Our findings suggest that the effects of AED monotherapy on OCM may induce specific regions of DNA hypomethylation.

Association of LEPR and ANKK1 Gene Polymorphisms with Weight Gain in Epilepsy Patients Receiving Valproic Acid.

BACKGROUND: Weight gain is the most frequent adverse effect of valproic acid (VPA) treatment, resulting in poor compliance and many endocrine disturbances. Similarities in the weight change of monozygotic twins receiving VPA strongly suggests that genetic factors are involved in this effect. However, few studies have been conducted to identify the relevant genetic polymorphisms. Additionally, the causal relationship between the VPA concentration and weight gain has been controversial. Thus, we investigated the effects of single nucleotide polymorphisms (SNPs) in several appetite stimulation and energy homeostasis genes and the steady state plasma concentrations (Css) of VPA on the occurrence of weight gain in patients. METHODS: A total of 212 epilepsy patients receiving VPA were enrolled. Nineteen SNPs in 11 genes were detected using the Sequenom MassArray iPlex platform, and VPA Css was determined by high-performance liquid chromatography (HPLC). RESULTS: After 6 months of treatment, 20.28% of patients were found to gain a significant amount of weight (weight gained ≥7%). Three SNPs in the leptin receptor (LEPR), ankyrin repeat kinase domain containing 1 (ANKK1), and α catalytic subunit of adenosine monophosphate-activated protein kinase (AMPK) showed significant associations with VPA-induced weight gain (p < 0.001, p = 0.017 and p = 0.020, respectively). After Bonferroni correction for multiple tests, the genotypic association of LEPR rs1137101, the allelic association of LEPR rs1137101, and ANKK1 rs1800497 with weight gain remained significant. However, the VPA Css in patents who gained weight were not significantly different from those who did not gain weight (p = 0.121). CONCLUSIONS: LEPR and ANKK1 genetic polymorphisms may have value in predicting VPA-induced weight gain.

Increased homocysteine levels in valproate-treated patients with epilepsy: a meta-analysis.

OBJECTIVE: To determine whether valproate (VPA) monotherapy influences homocysteine metabolism in patients with epilepsy. DESIGN: Systematic review and meta-analysis. DATA SOURCES: We searched all articles in English through PubMed, Web of Science and EMBASE published up to August 2013 concerning the homocysteine levels in VPA monotherapeutic patients with epilepsy. PARTICIPANTS: VPA-treated patients with epilepsy (n=266) and matched healthy controls (n=489). OUTCOME MEASURES: Heterogeneity between studies was assessed using I(2) statistics. Pooled standardised mean difference (SMD) and 95% CIs were calculated using a random effect model. RESULTS: A total of eight eligible studies were enrolled in our meta-analysis. We compared the plasma levels of homocysteine in VPA-treated patients with epilepsy and healthy controls. There was significant heterogeneity in the estimates according to the I(2) test (I(2)=65.6%, p=0.005). Plasma homocysteine levels in VPA-treated patients with epilepsy were significantly higher than in healthy controls under a random effect model. (SMD, 0.62; 95% CI 0.32 to 0.92). Further subgroup analyses suggested that no significant differences were present when grouped by ethnicity and age, but the risk of heterogeneity in the West Asian group (I(2)=47.4%, p=0.107) was diminished when compared with that of the overall group (I(2)=65.6%, p=0.005). CONCLUSIONS: Our meta-analysis indicates that VPA monotherapy is associated with the increase in plasma homocysteine levels in patients with epilepsy. Whether this association is influenced by ethnicity needs further research.

Impacts and interactions of PDGFRB, MMP-3, TIMP-2, and RNF213 polymorphisms on the risk of Moyamoya disease in Han Chinese human subjects.

Polymorphisms of PDGFRB, MMP-3, TIMP-2, RNF213, TGFB1, Raptor and eNOS genes have been associated with Moyamoya disease (MMD) separately in studies, but their interactions on MMD have never been evaluated in one study. This study enrolled 96 MMD patients and 96 controls to evaluate the contributions and interactions of these polymorphisms on MMD in Chinese Hans. After genotyping, five polymorphisms loci were deemed suitable for analysis, rs3828610 in PDGFRB, rs3025058 in MMP-3, rs8179090 in TIMP-2, rs112735431 and rs148731719 in RNF213. Interactions of different loci on MMD were evaluated by multifactor dimensionality reduction (MDR) method. Significantly higher frequencies of A allele and G/A genotype of rs112735431 in RNF213 were observed in MMD patients compared with controls (P=0.011; P=0.018, respectively). In the dominant model, G/A genotype of rs112735431 was associated with increased risk of MMD (P=0.018). A higher frequency of G allele and G/G genotype of rs148731719 in RNF213 gene in patient than control group (P<0.001; P<0.01, respectively) was also detected. No significant association between MMD and other three loci (P>0.05) was detected. MDR analysis failed to detect any significant interaction among these five loci in the occurrence of MMD (P>0.05), but the combination of three loci (rs112735431 in RNF213, rs3828610 in PDGFRB, rs3025058 in MMP-3) could have the maximum testing accuracy (57.29%) and cross-validation consistency (10/10). The results indicated that RNF213 rs112735431 and rs148731719 may exert a significant influence on MMD occurrence. Compared with this overwhelming effect, the influences of PDGFRB, MMP-3, and TIMP-2 on MMD may be unremarkable in Chinese Hans. There may be no prominent interaction among these five gene polymorphisms on the occurrence of MMD.

Distal hyperintense vessels on FLAIR: a prognostic indicator of acute ischemic stroke.

BACKGROUND: Hyperintense vessels (HVs) on fluid-attenuated inversion recovery (FLAIR) are frequently observed in acute ischemic stroke (AIS). The presence of HVs represents altered blood flow from collaterals distal to arterial occlusion or stenosis. This study aimed to evaluate the prognostic value of HVs in AIS. METHODS: Fifty-four consecutive patients with acute middle cerebral artery occlusion were enrolled in the study. The location and extent of the HVs was determined by FLAIR. Clinical data were obtained and compared between patients with different grades of HVs. Additionally, the relationship between distal HVs and leptomeningeal collaterals (LMCs) was assessed using angiography. RESULTS: HVs were observed in 41 (75.9%) of the 54 patients enrolled. The initial NIHSS score was lower (p<0.001) and the infarction volume was smaller (p<0.001) in patients with distal HVs. Adjusting of other factors, regression analysis revealed that distal HVs are an independent predictor of a favorable outcome at 90 days (p=0.006; OR 0.049; 95% CI 0.006-0.420). Furthermore, the presence of distal HVs was correlated with the presence of LMCs. CONCLUSION: Distal HVs may be a marker for LMCs and act as a predictor of a favorable clinical outcome for patients with AIS.

Stereotactic aspiration plus subsequent thrombolysis for moderate thalamic hemorrhage.

OBJECTIVE: This study aimed to evaluate the efficacy and safety of stereotactic aspiration combined with subsequent thrombolysis in treating moderate thalamic hemorrhage (TH). METHODS: A total of 105 patients with TH were nonrandomly assigned to the conservative treatment group (n = 60) or to the aspiration group (n = 45). Patients in the aspiration group were treated with stereotactic aspiration plus subsequent thrombolysis for removal for their hematomas. RESULTS: The 30-day mortality in the conservative group was significantly higher than that in the aspiration group (28.3% (17/60) vs. 11.2% (5/45), P = 0.032). The rank of the 30-day Glasgow outcome scale in the conservative group was significantly lower than that in the aspiration group (P = 0.041), and the mean 30-day National Institutes of Health Stroke Scale score of the survivors in the conservative group was significantly higher than that in the aspiration group (16.5 ± 4. 2 vs. 14.2 ± 3.9, P = 0.012). There were a greater reduction in TH volume in the aspiration group than in the conservative group from day 1 to day 3 (-0.24% and 39.28%, respectively, P < 0.0001) and from day 1 to day 7 (26.58% and 63.26%, respectively, P < 0.0001). The rank of 90-day Glasgow outcome scale was significantly lower in the conservative group than that in the aspiration group (P = 0.015). Eighteen of 60 patients (30.0%) had a favorable outcome in the conservative group, whereas 23 of 45 patients (51.1%) had a favorable outcome in the aspiration group, and this difference was significant (P = 0.028). The 90-day cumulative mortality rate in the conservative group was significantly higher than that in the aspiration group (33.3% (20/60)) vs. 15.6% (7/45), P = 0.039). CONCLUSIONS: Stereotactic aspiration plus subsequent thrombolysis is effective and safe for moderate TH.

Neuroprotective effect of ginsenoside Rb1 on glutamate-induced neurotoxicity: with emphasis on autophagy.

Ginsenoside Rb1 has been demonstrated with neuroprotective effects, but the mechanisms remain unclear. This study aimed to probe the effects and mechanisms of ginsenoside Rb1 on activation of autophagy in glutamate-injured neurons. Ginsenoside Rb1 of exponential concentrations (1.2, 12, 120 microM) or autophagy inhibitor 3-methyladenine (5mM) was added to culture medium for cortical neurons after being treated with glutamate. Cell viability was measured by MTT assay. Autophagosomes formation was observed with transmission electron microscope. Autophagy marked protein LC3 was detected with immunofluorescence and visualized under laser confocal microscopy. Changes of autophagy related protein Beclin-1 were measured with Western blot. We found that ginsenoside Rb1 protected cortical neurons from glutamate-induced cell injury. Autophagy was activated after glutamate treatment, with both autophagosomes and punctate LC3 increased significantly compared with control. Beclin-1 was elevated in glutamate-treated cells. Formation of autophagosome and punctate LC3 was attenuated by ginsenoside Rb1. The level of Beclin-1 in ginsenoside Rb1 treated cells was simultaneously decreased compared with glutamate-treated cells. These results suggested that inhibition of autophagy could be responsible for neuroprotective effects of ginsenoside Rb1 in glutamate-induced injury. Down-regulation of Beclin-1 may play an important role in this process.