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PURPOSE: Anti-gamma-aminobutyric acid B receptor (GABABR) encephalitis is an uncommon form of autoimmune encephalitis associated with a poor prognosis and a high fatality rate. We aim to find diagnostic markers for anti- GABABR encephalitis as well as the effects of immune cell infiltration on this pathology. METHODS: For quantitative proteomic analysis, isobaric tags for relative and absolute quantitation were used in conjunction with LC-MS/MS analysis. To conduct functional correlation analyses, differentially expressed proteins (DEPs) were identified. Following that, we used bioinformatics analysis to screen for and determine the diagnostic signatures of anti- GABABR encephalitis. ROC curves were used to evaluate the diagnostic values. To assess the inflammatory status of anti- GABABR encephalitis, we used cell-type identification by estimating relative subsets of the RNA transcript (CIBERSORT) and explored the link between diagnostic markers and infiltrating immune cells. RESULTS: Overall, 108 robust DEPs (47 upregulated and 61 downregulated) were identified, of which 11 were immune related. The most impressively enriched pathways were complemented and coagulation cascades, actin cytoskeleton regulation, and cholesterol metabolism; GSEA revealed that the enriched pathways were considerably differentially connected to immune modulation. Eleven immune-related DEPs were chosen for further investigation. We developed a novel diagnostic model based on CSF1R and AZGP1 serum levels using ROC analysis (area under the ROC curve = 1). M1 macrophages and activated natural killer cells are likely to play a role in course of anti- GABABR encephalitis. CONCLUSION: We identified CSF1R and AZGP1 are possible anti-GABABR encephalitis diagnostic indicators, and immune cell infiltration may have a significant impact on the development and occurrence of anti- GABABR encephalitis.
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Encefalitis , Ácido gamma-Aminobutírico , Humanos , Autoanticuerpos , Cromatografía Liquida , Proteómica , Receptores de GABA-B , Espectrometría de Masas en TándemRESUMEN
Background: The pathophysiological processes linked to an acute ischemic stroke (IS) can be reflected in the circulating metabolome. Amino acids (AAs) have been demonstrated to be one of the most significant metabolites that can undergo significant alteration after a stroke. Methods: We sought to identify the potential biomarkers for the early detection of IS using an extensive targeted technique for reliable quantification of 27 different AAs based on ultra-performance liquid chromatography tandem mass spectrometry (UPLC-MS/MS). A cohort with 216 participants was enrolled, including 70 mild to moderate ischemic stroke patients (National Institutes of Health Stroke Scale < 15, MB group), 76 stroke mimics (MM group) and 70 healthy controls (NC group). Results: It was found that upon comparing MB and MM to control patients, AAs shifts were detected via partial least squares discrimination analysis (PLS-DA) and pathway analysis. Interestingly, MB and MM exhibited similar AAs pattern. Moreover, ornithine, asparagine, valine, citrulline, and cysteine were identified for inclusion in a biomarker panel for early-stage stroke detection based upon an AUC of 0.968 (95% CI 0.924-0.998). Levels of ornithine were positively associated with infract volume, 3 months mRS score, and National Institutes of Health Stroke Scale (NIHSS) score in MB. In addition, a metabolites biomarker panel, including ornithine, taurine, phenylalanine, citrulline, cysteine, yielded an AUC of 0.99 (95% CI 0.966-1) which can be employed to effectively discriminate MM patients from control. Conclusion: Overall, alternations in serum AAs are characteristic metabolic features of MB and MM. AAs could serve as promising biomarkers for the early diagnosis of MB patients since mild to moderate IS patients were enrolled in the study. The metabolism of AAs can be considered as a key indicator for both the prevention and treatment of IS.
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BACKGROUND: We sought to explore the effects of sodium valproate combined with lamotrigine on quality of life and serum inflammatory factors in patients with poststroke secondary epilepsy. METHODS: A total of 145 patients with post-stroke secondary epilepsy admitted to our hospital from January 2017 to June 2018 were collected: 76 treated with sodium valproate combined with lamotrigine (study group) and 69 patients treated with sodium valproate alone (control group). The levels of serum high-mobility group protein B1, matrix metalloproteinase 9, and interleukin 6 were detected before and after treatment, and the therapeutic efficacy and adverse reactions were compared between the 2 groups. RESULTS: The total effective rate of the study group was higher than that of the control group. Both groups decreased in epileptiform discharges or in the number of involved leads after treatment, with the results of the study group being lower than those of the control group. The quality of life scores in both groups was increased after treatment, albeit the scores of the study group were higher than those of the control group. In terms of the levels of serum inflammatory factors, the 2 groups were reduced after treatment; the levels of the study group were lower than those of the control group. Regarding the incidence of adverse reactions, no significant difference was seen between the 2 groups. CONCLUSIONS: Sodium valproate combined with lamotrigine has better clinical efficacy and higher safety in the treatment of poststroke secondary epilepsy and is able to reduce the expression levels of serum inflammatory factors.
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Anticonvulsivantes/uso terapéutico , Encéfalo/efectos de los fármacos , Epilepsia/tratamiento farmacológico , Mediadores de Inflamación/sangre , Lamotrigina/uso terapéutico , Calidad de Vida , Accidente Cerebrovascular/complicaciones , Ácido Valproico/uso terapéutico , Anciano , Anticonvulsivantes/efectos adversos , Biomarcadores/sangre , Encéfalo/fisiopatología , Estudios de Casos y Controles , Regulación hacia Abajo , Quimioterapia Combinada , Epilepsia/sangre , Epilepsia/etiología , Epilepsia/fisiopatología , Femenino , Proteína HMGB1/sangre , Humanos , Interleucina-6/sangre , Lamotrigina/efectos adversos , Masculino , Metaloproteinasa 9 de la Matriz/sangre , Persona de Mediana Edad , Accidente Cerebrovascular/sangre , Accidente Cerebrovascular/fisiopatología , Factores de Tiempo , Resultado del Tratamiento , Ácido Valproico/efectos adversosRESUMEN
Anti-leucine-rich glioma inactivated-1 (anti-LGI1) encephalitis is a subgroup of autoimmune encephalitis. We herein report the case of a 60-year-old man who presented with typical symptoms, including short-term memory loss, mental abnormalities, hyponatremia and seizures characterized by faciobrachial dystonic seizures and who was diagnosed with anti-LGI1 encephalitis. At the same time, he was diagnosed with essential thrombocythemia. A significant improvement was obtained by treatment with corticosteroid, immunoglobulin, mycophenolate mofetil, and hydroxyurea. Autoimmune diseases are associated with a significantly increased risk of developing myeloproliferative neoplasms, which may explain the coexistence of anti-LGI1 encephalitis and essential thrombocythema in this patient; however, but more cases and studies are needed to determine whether there is any correlation between these conditions.
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Encefalitis/complicaciones , Glioma/complicaciones , Enfermedad de Hashimoto/complicaciones , Encefalitis Límbica/complicaciones , Trombocitemia Esencial/complicaciones , Corticoesteroides/uso terapéutico , Autoanticuerpos/inmunología , Encefalitis/tratamiento farmacológico , Enfermedad de Hashimoto/tratamiento farmacológico , Humanos , Hiponatremia/etiología , Péptidos y Proteínas de Señalización Intracelular/antagonistas & inhibidores , Leucina , Encefalitis Límbica/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Convulsiones/etiología , Trombocitemia Esencial/tratamiento farmacológicoRESUMEN
BACKGROUND: Neuromyelitis optica spectrum disorder (NMOSD) can coexist with anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis. Patients with overlapping Aquaporin 4 immunoglobulin G (AQP4-IgG)-seropositive NMOSD and anti-NMDAR encephalitis with positive NMDAR antibodies in the cerebrospinal fluid (CSF) are rare but should not be ignored. METHODS: A unique case of NMOSD coexisting with anti-NMDAR encephalitis is presented. Case reports of AQP4-IgG-seropositive NMOSD overlapping with anti-NMDAR encephalitis with positive NMDAR antibodies in the CSF were reviewed. RESULTS: A 61-year-old female presented with headache, blurred vision, dysuria, limb weakness, coma, respiratory failure, and hypotension. Brain magnetic resonance imaging (MRI) showed abnormal signals in the left temporal lobe, white matter around the bilateral ventricles, midbrain, medulla oblongata, cervical, and upper thoracic medulla. AQP4-IgG antibodies were positive in the serum and CSF. NMDAR antibodies were positive in the CSF. The patient's condition was stable following intravenous gamma globulin, corticosteroids, immunosuppressants, and symptomatic support treatments. Only a single met the criteria of NMOSD simultaneously coexisting with anti-NMDAR encephalitis in addition to our own case. CONCLUSIONS: This case provides further evidence for the occurrence of NMOSD with AQP4-IgG-seropositive overlapping anti-NMDAR encephalitis in a Chinese patient. The mechanisms underlying the occurrence of double positive antibodies remains elusive. When NMOSD patients show unusual symptoms (abnormal behavior, prominent psychiatric manifestations, cognitive dysfunction, autonomic dysfunction), or atypical supratentorial lesions, the coexistence of anti-NMDAR encephalitis should be considered.
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Encefalitis Antirreceptor N-Metil-D-Aspartato/complicaciones , Acuaporina 4/inmunología , Neuromielitis Óptica/complicaciones , Encefalitis Antirreceptor N-Metil-D-Aspartato/tratamiento farmacológico , Encefalitis Antirreceptor N-Metil-D-Aspartato/inmunología , Autoanticuerpos/sangre , Femenino , Glucocorticoides/uso terapéutico , Humanos , Inmunoglobulina G/sangre , Inmunoglobulinas Intravenosas/uso terapéutico , Persona de Mediana Edad , Neuromielitis Óptica/tratamiento farmacológico , Neuromielitis Óptica/inmunología , Resultado del TratamientoRESUMEN
MicroRNAs (miRNAs) function as potential novel biomarkers for disease detection due to their marked stability in the blood and the characteristics of their expression profile in several diseases. In the present study, microarraybased serum miRNA profiling was performed on serum obtained from three patients with epilepsy at diagnosis and from three healthy individuals as controls. This was followed by reverse transcriptionquantitative polymerase chain reaction analysis in a separate cohort of 35 health volunteers and 90 patients with epilepsy. The correlations between miRNAs and clinical parameters were analyzed. The array results showed that 15 miRNAs were overexpressed and 10 miRNAs were underexpressed (>2fold) in the patients with epilepsy. In addition, four miRNAs, including miR30a, miR378, miR106b and miR15a were found to be overexpressed in the serum of patients at seizure onset, compared with postseizure. When the patients were at seizure onset, the expression of miR30a was positively associated with seizure frequency. No significant differences were found between miR30a and gender, age or number of years following diagnosis. The expression levels of miR378, miR106b and mir15a were not associated with the clinical parameters in the patients with seizures. Calcium/calmodulindependent protein kinase type IV was a target of miR30a, and its expression was increased following seizure and was negatively correlated with miR30a in the patients with epilepsy. The present study provided the first evidence, to the best of our knowledge, that the expression levels of miR378, miR30a, miR106b and miR15a were enhanced in epileptic patients with seizures. miR-30a may be useful for prognostic prediction in epilepsy.
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Epilepsia/genética , Regulación de la Expresión Génica , MicroARNs/genética , Convulsiones/genética , Adulto , Biomarcadores , Análisis por Conglomerados , Epilepsia/sangre , Epilepsia/diagnóstico , Femenino , Perfilación de la Expresión Génica , Humanos , Masculino , MicroARNs/sangre , Persona de Mediana Edad , Interferencia de ARN , ARN Mensajero/genética , Convulsiones/sangre , Convulsiones/diagnóstico , Adulto JovenRESUMEN
MicroRNA (miRNA or miR) expression profiles are altered in tissues under hypoxic-ischemic conditions. The expression of miR140 is downregulated >2-fold following hypoxic-ischemic brain damage, however, its role in angiogenesis subsequent to cerebral ischemia is not fully understood. The present study aimed to investigate the role of miR-140-5p in angiogenesis and the molecular mechanism mediated by vascular endothelial growth factor A (VEGFA) in an in vitro model for brain ischemia. A rat middle cerebral artery occlusion (MCAO) model was constructed, and the results from reverse transcription-quantitative polymerase chain reaction and western blot analysis demonstrated that the expression levels of miR-1405p were significantly decreased, while the expression levels of VEGFA were significantly increased between 12 and 48 h in the rat cerebral following MCAO. Furthermore, human umbilical vein endothelial cells (HUVECs) were exposed to low oxygen conditions and it was demonstrated that hypoxia downregulated miR-140-5p and upregulated VEGFA expression levels. The miR-140-5p mimic was transfected into the normoxic and hypoxic HUVECs and 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide, Transwell migration and tube formation assays were performed. The results indicated that miR1405p inhibited angiogenesis by decreasing cell proliferation, migration and tube formation. Additionally, in human embryonic kidney 293 cells, results from the luciferase reporter assay revealed that miR1405p directly targeted the 3' untranslated region of VEGFA and that miR1405p regulated the protein expression of VEGFA. To further analyze this effect, a VEGFApEGFPC1 plasmid was transfected into the normoxic and hypoxic HUVECs, and it was revealed that the inhibitory effect of miR1405p on angiogenesis was attenuated by the overexpression of VEGFA. In conclusion, to the best of our knowledge, the present study is the first to suggest that miR1405p exerts an inhibitory effect on angiogenesis in an in vitro model of ischemia, and this effect is achieved partially by targeting VEGFA. The present study provided a novel biomarker for the treatment of cerebral ischemia.
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Isquemia Encefálica/metabolismo , MicroARNs/biosíntesis , Neovascularización Fisiológica , Accidente Cerebrovascular/metabolismo , Factor A de Crecimiento Endotelial Vascular/biosíntesis , Animales , Isquemia Encefálica/genética , Isquemia Encefálica/patología , Isquemia Encefálica/fisiopatología , Hipoxia de la Célula/genética , Células HEK293 , Humanos , Masculino , MicroARNs/genética , Ratas , Ratas Sprague-Dawley , Accidente Cerebrovascular/genética , Accidente Cerebrovascular/patología , Accidente Cerebrovascular/fisiopatología , Factor A de Crecimiento Endotelial Vascular/genéticaRESUMEN
Our previous study on proteomic analysis has shown that clusterin (CLU) is significantly decreased in the cerebrospinal fluid (CSF) of patients with epilepsy. Therefore, the present study aimed to confirm CLU concentration reduction in the CSF of patients with drug-resistant epilepsy and drug-responsive epilepsy. Fifty-two patients with epilepsy (23 drug resistance and 29 drug effectivity) and 20 control individuals were recruited. The concentrations of CSF and serum CLU were detected. Moreover, alteration of CLU was detected in the rat hippocampus over time after pilocarpine-induced status epilepticus (SE). Our results showed that human CSF-CLU levels were decreased in patients with both drug-resistant epilepsy and drug-responsive epilepsy compared to controls, and concentration of CSF-CLU was obviously lower in drug-resistant epilepsy than in drug-responsive epilepsy. In the pilocarpine-induced seizure rats, expression of neuronal CLU was gradually decreased in a time-dependent manner from acute phase to chronic phase after the onset of SE. In conclusion, CLU level is decreased in the CSF of human epilepsy and the similar alteration is confirmed in a rat model with epilepsy. Therefore, CLU might contribute to the development of epilepsy and be a potential CSF biomarker for resistant epilepsy.
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Clusterina/líquido cefalorraquídeo , Resistencia a Medicamentos , Epilepsia/metabolismo , Adolescente , Adulto , Animales , Anticonvulsivantes/farmacología , Biomarcadores/sangre , Biomarcadores/líquido cefalorraquídeo , Biomarcadores/metabolismo , Estudios de Casos y Controles , Clusterina/sangre , Clusterina/metabolismo , Epilepsia/diagnóstico , Epilepsia/tratamiento farmacológico , Femenino , Hipocampo/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Ratas , Ratas Sprague-DawleyRESUMEN
Methyl CpG binding protein-2 (MeCP2) is a multifunctional nuclear protein, and regulates dendritic morphology, synaptic transmission, spontaneous neurotransmission, and short-term synaptic plasticity in the central nervous system. This study was designed to investigate the expression of MeCP2 mRNA and protein in intractable temporal lobe epilepsy (TLE) patients and an experimental animal model. MeCP2 expression was detected in 35 temporal neocortex tissue samples from patients with intractable TLE and 14 histologically normal temporal lobe tissue samples from trauma patients without epilepsy by reverse transcription-polymerase chain reaction (RT-PCR), immunohistochemistry and double-label immunofluorescence. In addition, the timing of MeCP2 expression was evaluated in the hippocampus and adjacent cortex of lithium chloride/pilocarpine-induced TLE rats and uninduced controls. MeCP2 was found to be expressed mainly in the nuclei of neurons, and not expressed in astrocytes. MeCP2 expression was significantly higher in the TLE patients and rats than in the control groups. Following seizures in the rat model, MeCP2 expression gradually increased in the hippocampus and adjacent cortex during the acute period (days 1 and 2) and the latent period (days 7 and 14), but decreased during the chronic period (days 30 and 60). Up-regulated expression of MeCP2 in intractable TLE patients and experimental animals suggested that MeCP2 may be involved in the pathogenesis of TLE.
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Epilepsia del Lóbulo Temporal/metabolismo , Proteína 2 de Unión a Metil-CpG/biosíntesis , Actinas/biosíntesis , Actinas/genética , Adolescente , Adulto , Animales , Corteza Cerebral/efectos de los fármacos , Corteza Cerebral/metabolismo , Niño , Preescolar , Electroencefalografía , Femenino , Técnica del Anticuerpo Fluorescente , Hipocampo/efectos de los fármacos , Hipocampo/metabolismo , Humanos , Inmunohistoquímica , Excitación Neurológica , Masculino , Persona de Mediana Edad , Plasticidad Neuronal/efectos de los fármacos , Neuronas/efectos de los fármacos , Neuronas/metabolismo , ARN/biosíntesis , ARN/aislamiento & purificación , Ratas , Ratas Sprague-Dawley , Reacción en Cadena en Tiempo Real de la Polimerasa , Tomografía Computarizada por Rayos X , Regulación hacia Arriba , Adulto JovenRESUMEN
Intractable epilepsy (IE) patients have synaptic dysfunction. However, the exact mechanism of synaptic function needs further elucidation. The aim of this study was to use immunohistochemistry, immunofluorescence, and Western blotting to investigate the expression of the Liprin-α1 protein, one of the synapse-associated proteins, in human IE brain tissues and experimental rats and to discuss the possible role of Liprin-α1 in IE. We selected 30 temporal neocortical tissue samples from patients with intractable temporal lobe epilepsy (TLE) and 10 histologically normal temporal lobes from controls. Fifty-six Sprague-Dawley rats were divided randomly into seven groups; one control group and six groups with epilepsy induced by lithium-pilocarpine administration. Temporal lobe tissues were taken from controls and from rats at 1, 3, 7, 14, 30, and 60 days postseizure. Liprin-α1 was mainly expressed in neurons of human controls and TLE patients and was significantly higher in TLE patients than in controls. Liprin-α1 was also expressed in neurons of control and experimental rats and it was significantly higher in experimental rats than in the control group. The expression of Liprin-α1 in animals in the experimental group gradually increased from Days 1 to 30 postseizure induction and reached a stable level when spontaneous recurrent seizures (SRS) appeared. These results suggest that an increased expression of Liprin-α1 in the brain may be associated with human IE.