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.
Structural and functional brain abnormalities in schizophrenia (SZ) have been widely reported. However, a few studies have investigated both structural and functional characteristics in SZ patients at different stages to understand the neuropathology of SZ.In this study, we recruited 44 first-episode drug-naive SZ (FESZ) patients, 44 medicated chronic SZ (CSZ) patients, and 56 normal controls (NCs) and acquired their structural and resting-state functional magnetic resonance imaging (MRI). We then made group comparisons on structural and functional characteristics, including regional gray matter volume (GMV), regional homogeneity, amplitude of low-frequency fluctuation, and degree centrality. A linear support vector machine (SVM) combined with a recursive feature elimination (RFE) algorithm was implemented to discriminate three groups.Our results indicated that the regional GMV was significantly decreased in patients compared with that in NCs; CSZ patients have more diffused GMV decreases primarily involved in the frontal and temporal lobes when compared with FESZ patients. Both FESZ and CSZ patients showed significant functional alterations compared with NCs; when compared with FESZ patients, CSZ patients showed significant reductions in functional characteristics in several brain regions associated with auditory, visual processing, and sensorimotor functions. Moreover, a linear SVM combined with a RFE algorithm was implemented to discriminate three groups. The accuracies of the three classifiers were 79.80%, 83.16%, and 81.71%, respectively. The performance of classifiers in this study with multimodal MRI was better than that of previous discriminative analyses of SZ patients with single-modal MRI.Our findings bring new insights into the understanding of the neuropathology of SZ and contribute to stage-specific biomarkers in diagnosis and interventions of SZ.
Background The effect of penicillin therapy on clinical outcomes vary among patients with general paresis ( GP ). We sought to explore biomarkers that might serve as predictors of clinical outcomes in GP and identify patients requiring early intervention. Methods Thirty‐five inpatients with GP were recruited. Each GP patient underwent comprehensive neuropsychological, neuroimaging and laboratory assessments before receiving penicillin therapy, and returned for follow‐up evaluations after 6 months. The visual rating of medial temporal lobe atrophy ( MTA ) and the Fazekas scale was used to analyze the neuroimaging abnormalities. Results MTA scores were correlated with the pre‐treatment cognitive scores and change in Mini Mental State Examination scores. GP patients with a Clinical Dementia Rating Scale ( CDR ) ≤1 or MTA scores ≤2 achieved significant improvement in neuropsychological test scores, as compared with patients with CDR >1 or MTA scores >2. Fazekas scale scores correlated with the pre‐treatment attention scores. Significant improvements in cognitive test scores were observed in GP patients with normalization of serum rapid plasma regain ( RPR ) titers, but not those without normalization of RPR titers. Conclusions Severe MTA may serve as a predictor of poor cognitive outcome and an indicator of severe cognitive impairment in GP patients. Thus, early interventions for improving cognitive function may be considered for GP patients with severe MTA . White matter hyperintensities may associated with attention impairment. Serum RPR titer may serve as a sensitive indicator of therapeutic effect in GP .
P-glycoprotein (Pgp) overexpressed in blood brain barrier (BBB) is hypothesized to lower brain drug concentrations and thus inhibit anticonvulsant effects in drug-resistant epilepsy. Pluronic P85 (P85) was proved to enhance the delivery of drugs into the brain by inhibition of Pgp. To determine whether the surfactant P85 [versus Pgp inhibitor tariquidar (TQD)] enhance phenytoin (PHT) into the brain in drug-resistant rats with chronic mesial temporal lobe epilepsy (MTLE) induced by lithium-pilocarpine, in brain of which Pgp were overexpressed, then direct verification of PHT transport via measurement of PHT concentration in brain using microdialysis. The drug-resistant model rats were randomly divided into three groups, which were treated with PHT, 1%P85+PHT, or PHT+TQD, respectively. 1%P85+PHT treatment displayed a lower ratio of the area under the curve (AUC) of the PHT concentration in the brain/plasma even than that of the PHT treatment in model rats (p < 0.05), while PHT+TQD showed the highest ratio of the AUC of all treatments. However, the ratio of the PHT concentration in the liver/plasma was similar in three model groups (p > 0.05). For the ratio of the kidney/plasma, PHT+TQD treatment model group had the highest ratio of the other treatments in model rats. Thus, P85 oppositely decreased PHT concentration in brain in drug-resistant model rats with Pgp overexpressed MTLE while TQD could increase PHT distribution in brain.
Objective To determine whether valproic acid (VPA) monotherapy influences homocysteine metabolism in patients with epilepsy. Methods Articles in English concerning the homocysteine levels in VPA monotherapeutic patients with epilepsy and published from January 1990 to August 2013 were searched through PubMed, Web of Science and EMBASE. Observational case-control studies that evaluated homocysteine levels in subjects with epilepsy compared to controls were selected. Any study lacking information regarding specific effect of VPA on homocysteine in patients with epilepsy was rejected. Definitely, non-controlled design studies, reviews, and animal or in vitro studies were also excluded. Two reviewers independently evaluated the quality of included articles and extracted the data using Newcastle-Ottawa Scale. A Meta-analysis was conducted by using Stata 12.0 software. Results A total of 8 eligible studies were enrolled in this Meta-analysis. VPA treated patients with epilepsy (N = 266) and matched healthy controls (N = 489) were included. All included studies reached a total quality score of 6 or higher. Results of the Meta-analysis showed that plasma homocysteine levels in VPA treated patients with epilepsy was significantly higher than healthy controls under a random effect model [standardized mean difference ( SMD ) = 0.620, 95% CI: 0.320-0.920; P = 0.000]. There was significant heterogeneity in the estimates according to I 2 test ( I 2 = 65.600% , P = 0.005). Further subgroup analysis suggested that no significant difference was present when grouped by ethnicity and age, but the risk of heterogeneity in West-Asian group ( I 2 = 47.400%, P = 0.107) was diminished when compared with overall groups ( I 2 = 65.600%, P = 0.005). Sensitivity analysis was also conducted to evaluate the stability of Meta?analysis. When any single study was deleted, the corresponding pooled SMD was not substantially altered. Conclusions VPA monotherapy is associated with the increase of plasma homocysteine levels in patients with epilepsy, and whether this association is influenced by ethnicity needs further research. doi: 10.3969/j.issn.1672-6731.2014.12.006
Abstract Changes in the expression of HCN ion channels leading to changes in I h 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 I h current density and function, thereby reducing the inhibitory effect and increasing neuronal excitability and eventually causing disturbances in the electrical activity of neurons.
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