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Aspects of how Burkholderia escape the host's intrinsic immune response to replicate in the cell cytosol remain enigmatic. Here, we show that Burkholderia has evolved two mechanisms to block the activity of Ring finger protein 213 (RNF213)-mediated non-canonical ubiquitylation of bacterial lipopolysaccharide (LPS), thereby preventing the initiation of antibacterial autophagy. First, Burkholderia's polysaccharide capsule blocks RNF213 association with bacteria and second, the Burkholderia deubiquitylase (DUB), TssM, directly reverses the activity of RNF213 through a previously unrecognized esterase activity. Structural analysis provides insight into the molecular basis of TssM esterase activity, allowing it to be uncoupled from its isopeptidase function. Furthermore, a putative TssM homolog also displays esterase activity and removes ubiquitin from LPS, establishing this as a virulence mechanism. Of note, we also find that additional immune-evasion mechanisms exist, revealing that overcoming this arm of the host's immune response is critical to the pathogen.
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Proteínas Bacterianas , Burkholderia , Lipopolisacáridos , Ubiquitinación , Lipopolisacáridos/metabolismo , Humanos , Burkholderia/inmunología , Proteínas Bacterianas/metabolismo , Esterasas/metabolismo , Evasión Inmune , Ubiquitina-Proteína Ligasas/metabolismo , Interacciones Huésped-Patógeno/inmunología , Autofagia , VirulenciaRESUMEN
OBJECTIVE: Quantification of the epileptogenic zone network (EZN) most frequently implies analysis of seizure onset. However, important information can also be obtained from the postictal period, characterized by prominent changes in the EZN. We used permutation entropy (PE), a measure of signal complexity, to analyze the peri-ictal stereoelectroencephalography (SEEG) signal changes with emphasis on the postictal state. We sought to determine the best PE-derived parameter (PEDP) for identifying the EZN. METHODS: Several PEDPs were computed retrospectively on SEEG-recorded seizures of 86 patients operated on for drug-resistant epilepsy: mean baseline preictal entropy, minimum ictal entropy, maximum postictal entropy, the ratio between the maximum postictal and the minimum ictal entropy, and the ratio between the maximum postictal and the baseline preictal entropy. The performance of each biomarker was assessed by comparing the identified epileptogenic contacts or brain regions against the EZN defined by clinical analysis incorporating the Epileptogenicity Index and the connectivity epileptogenicity index methods (EZNc), using the receiver-operating characteristic and precision-recall. RESULTS: The ratio between the maximum postictal and the minimum ictal entropy (defined as the Permutation Entropy Index [PEI]) proved to be the best-performing PEDP to identify the EZNC . It demonstrated the highest area under the curve (AUC) and F1 score at the contact level (AUC 0.72; F1 0.39) and at the region level (AUC 0.78; F1 0.47). PEI values gradually decreased between the EZN, the propagation network, and the non-involved regions. PEI showed higher performance in patients with slow seizure-onset patterns than in those with fast seizure-onset patterns. The percentage of resected epileptogenic regions defined by PEI was significantly correlated with surgical outcome. SIGNIFICANCE: PEI is a promising tool to improve the delineation of the EZN. PEI combines ease and robustness in a routine clinical setting with high sensitivity for seizures without fast activity at seizure onset.
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Encéfalo , Electroencefalografía , Humanos , Electroencefalografía/métodos , Estudios Retrospectivos , Entropía , Encéfalo/diagnóstico por imagen , ConvulsionesRESUMEN
Magnetoencephalography based on superconducting quantum interference devices (SQUIDs) has been shown to improve the diagnosis and surgical treatment decision for presurgical evaluation of drug-resistant epilepsy. Still, its use remains limited because of several constraints such as cost, fixed helmet size, and the obligation of immobility. A new generation of sensors, optically pumped magnetometers (OPMs), could overcome these limitations. In this study, we validate the ability of helium-based OPM (4He-OPM) sensors to record epileptic brain activity thanks to simultaneous recordings with intracerebral EEG [stereotactic EEG (SEEG)]. We recorded simultaneous SQUIDs-SEEG and 4He-OPM-SEEG signals in one patient during two sessions. We show that epileptic activities on intracerebral EEG can be recorded by OPMs with a better signal-to noise ratio than classical SQUIDs. The OPM sensors open new venues for the widespread application of magnetoencephalography in the management of epilepsy and other neurologic diseases and fundamental neuroscience.
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Epilepsia , Helio , Humanos , Animales , Magnetoencefalografía , Epilepsia/diagnóstico , Electroencefalografía , Decapodiformes , EncéfaloRESUMEN
Pathogenic bacteria have evolved diverse mechanisms to counteract cell-autonomous immunity, which otherwise guards both immune and non-immune cells from the onset of an infection1,2. The versatile immunity protein Ring finger protein 213 (RNF213)3-6 mediates the non-canonical ester-linked ubiquitylation of lipopolysaccharide (LPS), marking bacteria that sporadically enter the cytosol for destruction by antibacterial autophagy4. However, whether cytosol-adapted pathogens are ubiquitylated on their LPS and whether they escape RNF213-mediated immunity, remains unknown. Here we show that Burkholderia deubiquitylase (DUB), TssM7-9, is a potent esterase that directly reverses the ubiquitylation of LPS. Without TssM, cytosolic Burkholderia became coated in polyubiquitin and autophagy receptors in an RNF213-dependent fashion. Whereas the expression of TssM was sufficient to enable the replication of the non-cytosol adapted pathogen Salmonella, we demonstrate that Burkholderia has evolved a multi-layered defence system to proliferate in the host cell cytosol, including a block in antibacterial autophagy10-12. Structural analysis provided insight into the molecular basis of TssM esterase activity, allowing it to be uncoupled from isopeptidase function. TssM homologs conserved in another Gram-negative pathogen also reversed non-canonical LPS ubiquitylation, establishing esterase activity as a bacterial virulence mechanism to subvert host cell-autonomous immunity.
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OBJECTIVE: We studied the rate dynamics of interictal events occurring over fast-ultradian time scales, as commonly examined in clinics to guide surgical planning in epilepsy. METHODS: Stereo-electroencephalography (SEEG) traces of 35 patients with good surgical outcome (Engel I) were analyzed. For this we developed a general data mining method aimed at clustering the plethora of transient waveform shapes including interictal epileptiform discharges (IEDs) and assessed the temporal fluctuations in the capability of mapping the epileptogenic zone (EZ) of each type of event. RESULTS: We found that the fast-ultradian dynamics of the IED rate may effectively impair the precision of EZ identification, and appear to occur spontaneously, that is, not triggered by or exclusively associated with a particular cognitive task, wakefulness, sleep, seizure occurrence, post-ictal state, or antiepileptic drug withdrawal. Propagation of IEDs from the EZ to the propagation zone (PZ) could explain the observed fast-ultradian fluctuations in a reduced fraction of the analyzed patients, suggesting that other factors like the excitability of the epileptogenic tissue could play a more relevant role. A novel link was found between the fast-ultradian dynamics of the overall rate of polymorphic events and the rate of specific IEDs subtypes. We exploited this feature to estimate in each patient the 5 min interictal epoch for near-optimal EZ and resected-zone (RZ) localization. This approach produces at the population level a better EZ/RZ classification when compared to both (1) the whole time series available in each patient (p = .084 for EZ, p < .001 for RZ, Wilcoxon signed-rank test) and (2) 5 min epochs sampled randomly from the interictal recordings of each patient (p < .05 for EZ, p < .001 for RZ, 105 random samplings). SIGNIFICANCE: Our results highlight the relevance of the fast-ultradian IED dynamics in mapping the EZ, and show how this dynamics can be estimated prospectively to inform surgical planning in epilepsy.
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Epilepsia Refractaria , Epilepsias Parciales , Epilepsia , Humanos , Epilepsia Refractaria/cirugía , Convulsiones , Epilepsia/cirugía , Electroencefalografía/métodos , Epilepsias Parciales/cirugíaRESUMEN
Magnetoencephalography (MEG) is a powerful tool for estimating brain connectivity with both good spatial and temporal resolution. It is particularly helpful in epilepsy to characterize non-invasively the epileptic networks. However, using MEG to map brain networks requires solving a difficult inverse problem that introduces uncertainty in the activity localization and connectivity measures. Our goal here was to compare independent component analysis (ICA) followed by dipole source localization and the linearly constrained minimum-variance beamformer (LCMV-BF) for characterizing regions with interictal epileptic activity and their dynamic connectivity. After a simulation study, we compared ICA and LCMV-BF results with intracerebral EEG (stereotaxic EEG, SEEG) recorded simultaneously in 8 epileptic patients, which provide a unique 'ground truth' to which non-invasive results can be confronted. We compared the signal time courses extracted applying ICA and LCMV-BF on MEG data to that of SEEG, both for the actual signals and the dynamic connectivity computed using cross-correlation (evolution of links in time). With our simulations, we illustrated the different effect of the temporal and spatial correlation among sources on the two methods. While ICA was more affected by the temporal correlation but robust against spatial configurations, LCMV-BF showed opposite behavior. Moreover, ICA seems more suited to retrieve the simulated networks. In case of real patient data, good MEG/SEEG correlation and good localization were obtained in 6 out of 8 patients. In 4 of them ICA had the best performance (higher correlation, lower localization distance). In terms of dynamic connectivity, the evolution in time of the cross-correlation links could be retrieved in 5 patients out of 6, however, with more variable results in terms of correlation and distance. In two patients LCMV-BF had better results than ICA. In one patient the two methods showed equally good outcomes, and in the remaining two patients ICA performed best. In conclusion, our results obtained by exploiting simultaneous MEG/SEEG recordings suggest that ICA and LCMV-BF have complementary qualities for retrieving the dynamics of interictal sources and their network interactions.
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Epilepsia , Magnetoencefalografía , Humanos , Magnetoencefalografía/métodos , Encéfalo , Electroencefalografía/métodos , Mapeo Encefálico/métodosRESUMEN
OBJECTIVE: This study was undertaken to characterize clinical expression and intracerebral electroencephalographic (EEG) correlates of emotional expression during prefrontal epileptic seizures. METHODS: We performed a descriptive analysis of seizure semiology in patients explored with stereo-EEG (SEEG) for pharmacoresistant prefrontal epilepsy, using a semiquantitative score for seizure-related emotional behavior. Two independent observers scored occurrence and intensity of objective emotional features (face/body movements/vocalization/overall appearance), testing interobserver reliability. Intracerebral electrophysiological changes were documented. Cluster analysis and principal component analysis (PCA) compared behavioral signs with neural SEEG correlates. For each patient, the clinical and anatomoelectrophysiological scores were established, based on a prototypical emotional seizure. RESULTS: Forty-two patients (469 seizures) were included. Interobserver correlation for emotional signs was satisfactory (kappa = 0.6-0.8). Prevalence of any subjective and/or objective ictal emotional phenomena was 79% (33/42); objective emotional signs occurred in 27 of 42 subjects (64%). Negatively valenced emotional semiology (ictal feeling of fear, defensive and/or aggressive behaviors) was much more prevalent than positively valenced, prosocial behaviors. Cluster analysis and PCA identified 4 groups with different occurrence of emotional signs and cerebral correlates. Two main clusters of negatively valenced behavior were identified: "active threat response," associated with seizure organizations involving posterior orbitofrontal cortex, anterior cingulate, and dorsolateral and/or ventrolateral prefrontal cortex; and "passive fear," associated with amygdala, other mesial temporal structures, and posterior orbitofrontal cortex. INTERPRETATION: Emotional behaviors, especially fear/threat response, are common in prefrontal seizures, reflecting the role of the prefrontal cortex in emotional control. Different cortical seizure localizations were associated with "passive fear" and "active threat response" seizure behaviors at the group level. ANN NEUROL 2022;92:1052-1065.
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Epilepsias Parciales , Epilepsia , Humanos , Reproducibilidad de los Resultados , Convulsiones/diagnóstico , ElectroencefalografíaRESUMEN
BACKGROUND: Patients with non-ST-segment elevation acute coronary syndromes (NSTE-ACS) are at high residual risk for long-term cardiovascular (CV) mortality. Cathepsin S (CTSS) is a lysosomal cysteine protease with elastolytic and collagenolytic activity that has been involved in atherosclerotic plaque rupture. OBJECTIVES: The purpose of this study was to determine the following: 1) the prognostic value of circulating CTSS measured at patient admission for long-term mortality in NSTE-ACS; and 2) its additive value over the GRACE (Global Registry of Acute Coronary Events) risk score. METHODS: This was a single-center cohort study, consecutively recruiting patients with adjudicated NSTE-ACS (n = 1,112) from the emergency department of an academic hospital. CTSS was measured in serum using enzyme-linked immunosorbent assay. All-cause mortality at 8 years was the primary endpoint. CV death was the secondary endpoint. RESULTS: In total, 367 (33.0%) deaths were recorded. CTSS was associated with increased risk of all-cause mortality (HR for highest vs lowest quarter of CTSS: 1.89; 95% CI: 1.34-2.66; P < 0.001) and CV death (HR: 2.58; 95% CI: 1.15-5.77; P = 0.021) after adjusting for traditional CV risk factors, high-sensitivity C-reactive protein, left ventricular ejection fraction, high-sensitivity troponin-T, revascularization and index diagnosis (unstable angina/ non-ST-segment elevation myocardial infarction). When CTSS was added to the GRACE score, it conferred significant discrimination and reclassification value for all-cause mortality (Delta Harrell's C: 0.03; 95% CI: 0.012-0.047; P = 0.001; and net reclassification improvement = 0.202; P = 0.003) and CV death (AUC: 0.056; 95% CI: 0.017-0.095; P = 0.005; and net reclassification improvement = 0.390; P = 0.001) even after additionally considering high-sensitivity troponin-T and left ventricular ejection fraction. CONCLUSIONS: Circulating CTSS is a predictor of long-term mortality and improves risk stratification of patients with NSTE-ACS over the GRACE score.
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Síndrome Coronario Agudo , Catepsinas , Infarto del Miocardio sin Elevación del ST , Síndrome Coronario Agudo/diagnóstico , Catepsinas/sangre , Estudios de Cohortes , Humanos , Infarto del Miocardio sin Elevación del ST/diagnóstico , Pronóstico , Medición de Riesgo , Volumen Sistólico , Troponina T , Función Ventricular IzquierdaRESUMEN
BACKGROUND: The noncoding antisense transcript for ß-secretase-1 (BACE1-AS) is a long noncoding RNA with a pivotal role in the regulation of amyloid-ß (Aß). We aimed to explore the clinical value of BACE1-AS expression in atherosclerotic cardiovascular disease (ASCVD). METHODS: Expression of BACE1-AS and its target, ß-secretase 1 (BACE1) mRNA, was measured in peripheral blood mononuclear cells derived from 434 individuals (259 without established ASCVD [non-CVD], 90 with stable coronary artery disease [CAD], and 85 with acute coronary syndrome). Intima-media thickness and atheromatous plaques evaluated by ultrasonography, as well as arterial wave reflections and pulse wave velocity, were measured as markers of subclinical ASCVD. Patients were followed for a median of 52 months for major adverse cardiovascular events (MACE). RESULTS: In the cross-sectional arm, BACE1-AS expression correlated with BACE1 expression (r = 0.396, p < 0.001) and marginally with Aß1-40 levels in plasma (r = 0.141, p = 0.008). Higher BACE1-AS was associated with higher estimated CVD risk assessed by HeartScore for non-CVD subjects and by European Society of Cardiology clinical criteria for the total population (p < 0.05 for both). BACE1-AS was associated with higher prevalence of CAD (odds ratio [OR] = 1.85, 95% confidence interval [CI]: 1.37-2.5), multivessel CAD (OR = 1.36, 95% CI: 1.06-1.75), and with higher number of diseased vascular beds (OR = 1.31, 95% CI: 1.07-1.61, for multiple diseased vascular beds) after multivariable adjustment for traditional cardiovascular risk factors. In the prospective arm, BACE1-AS was an independent predictor of MACE in high cardiovascular risk patients (adjusted hazard ratio = 1.86 per ascending tertile, 95% CI: 1.011-3.43, p = 0.046). CONCLUSION: BACE1-AS is associated with the incidence and severity of ASCVD.
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Envejecimiento , Aterosclerosis , Enfermedades Cardiovasculares , ARN Largo no Codificante , Humanos , Secretasas de la Proteína Precursora del Amiloide/genética , Secretasas de la Proteína Precursora del Amiloide/metabolismo , Ácido Aspártico Endopeptidasas/genética , Ácido Aspártico Endopeptidasas/metabolismo , Aterosclerosis/genética , Enfermedades Cardiovasculares/genética , Grosor Intima-Media Carotídeo , Estudios Transversales , Leucocitos Mononucleares/metabolismo , Estudios Prospectivos , Análisis de la Onda del Pulso , ARN sin Sentido , ARN Largo no Codificante/genéticaRESUMEN
OBJECTIVE: Adenosine deaminase acting on RNA-1 (ADAR1) enzyme is a type I interferon (IFN)-stimulated gene (ISG) catalyzing the deamination of adenosine-to-inosine, a process called A-to-I RNA editing. A-to-I RNA editing takes place mainly in Alu elements comprising a primate-specific level of post-transcriptional gene regulation. Whether RNA editing is involved in type I IFN responses in systemic sclerosis (SSc) patients remains unknown. METHODS: ISG expression was quantified in skin biopsies and peripheral blood mononuclear cells derived from SSc patients and healthy subjects. A-to-I RNA editing was examined in the ADAR1-target cathepsin S (CTSS) by an RNA editing assay. The effect of ADAR1 on interferon-α/ß-induced CTSS expression was assessed in human endothelial cells in vitro. RESULTS: Increased expression levels of the RNA editor ADAR1, and specifically the long ADAR1p150 isoform, and its target CTSS are strongly associated with type I IFN signature in skin biopsies and peripheral blood derived from SSc patients. Notably, IFN-α/ß-treated human endothelial cells show 8-10-fold increased ADAR1p150 and 23-35-fold increased CTSS expression, while silencing of ADAR1 reduces CTSS expression by 60-70%. In SSc patients, increased RNA editing rate of individual adenosines located in CTSS 3' UTR Alu elements is associated with higher CTSS expression (r = 0.36-0.6, P < 0.05 for all). Similar findings were obtained in subjects with activated type I IFN responses including SLE patients or healthy subjects after influenza vaccination. CONCLUSION: ADAR1p150-mediated A-to-I RNA editing is critically involved in type I IFN responses highlighting the importance of post-transcriptional regulation of proinflammatory gene expression in systemic autoimmunity, including SSc.
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Interferón Tipo I , Esclerodermia Sistémica , Adenosina/genética , Adenosina Desaminasa/genética , Adenosina Desaminasa/metabolismo , Animales , Células Endoteliales/metabolismo , Humanos , Inosina/genética , Interferón Tipo I/metabolismo , Leucocitos Mononucleares/metabolismo , ARN , Edición de ARN , Proteínas de Unión al ARN/genética , Esclerodermia Sistémica/genética , Esclerodermia Sistémica/metabolismoRESUMEN
Long non-coding RNAs (lncRNAs) have emerged as critical regulators in human disease including atherosclerosis. However, the mechanisms involved in the post-transcriptional regulation of the expression of disease-associated lncRNAs are not fully understood. Gene expression studies revealed that Nuclear Paraspeckle Assembly Transcript 1 (NEAT1) lncRNA expression was increased by >2-fold in peripheral blood mononuclear cells (PBMCs) derived from patients with coronary artery disease (CAD) or in carotid artery atherosclerotic plaques. We observed a linear association between NEAT1 lncRNA expression and prevalence of CAD which was independent of age, sex, cardiovascular traditional risk factors and renal function. NEAT1 expression was induced by TNF-α, while silencing of NEAT1 profoundly attenuated the TNF-α-induced vascular endothelial cell pro-inflammatory response as defined by the expression of CXCL8, CCL2, VCAM1 and ICAM1. Overexpression of the RNA editing enzyme adenosine deaminase acting on RNA-1 (ADAR1), but not of its editing-deficient mutant, upregulated NEAT1 levels. Conversely, silencing of ADAR1 suppressed the basal levels and the TNF-α-induced increase of NEAT1. NEAT1 lncRNA expression was strongly associated with ADAR1 in CAD and peripheral arterial vascular disease. RNA editing mapping studies revealed the presence of several inosines in close proximity to AU-rich elements within the AluSx3+/AluJo- double-stranded RNA complex. Silencing of the stabilizing RNA-binding protein AUF1 reduced NEAT1 levels while silencing of ADAR1 profoundly affected the binding capacity of AUF1 to NEAT1. Together, our findings propose a mechanism by which ADAR1-catalyzed A-to-I RNA editing controls NEAT1 lncRNA stability in ASCVD.
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Adenosina/metabolismo , Elementos Alu/genética , Aterosclerosis/sangre , Enfermedad de la Arteria Coronaria/sangre , Inosina/metabolismo , Placa Aterosclerótica/sangre , Edición de ARN/genética , Estabilidad del ARN/genética , ARN Largo no Codificante/metabolismo , Transducción de Señal/genética , Adenosina Desaminasa/genética , Adenosina Desaminasa/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Aterosclerosis/genética , Sitios de Unión , Células Cultivadas , Estudios de Cohortes , Enfermedad de la Arteria Coronaria/genética , Femenino , Silenciador del Gen , Ribonucleoproteína Nuclear Heterogénea D0/genética , Ribonucleoproteína Nuclear Heterogénea D0/metabolismo , Células Endoteliales de la Vena Umbilical Humana , Humanos , Leucocitos Mononucleares/metabolismo , Masculino , Persona de Mediana Edad , Placa Aterosclerótica/genética , ARN Largo no Codificante/genética , Proteínas de Unión al ARN/genética , Proteínas de Unión al ARN/metabolismo , TransfecciónRESUMEN
BACKGROUND AND AIMS: Preclinical data suggest that the ageing-induced miR-34a regulates vascular senescence. Herein we sought to assess whether the miR-34 family members miR-34a, miR-34b and miR-34c are involved in human arterial disease. METHODS: Expression levels of miR-34a/b/c were quantified by TaqMan assay in peripheral blood mononuclear cells (PBMCs) derived from a consecutive cohort of 221 subjects who underwent cardiovascular risk assessment and thorough vascular examination for aortic stiffness and extent of arterial atherosclerosis. RESULTS: High miR-34a was independently associated with the presence of CAD [OR (95%C.I.): 3.87 (1.56-9.56); p = 0.003] and high miR-34c with the number of diseased arterial beds [OR (95%C.I.): 1.88 (1.034-3.41); p = 0.038], while concurrent high expression of miR-34-a/c or all three miR-34a/b/c was associated with aortic stiffening (miR-34a/c: p = 0.022; miR-34a/b/c: p = 0.041) and with the extent of atherosclerosis [OR (95%C.I.) for number of coronary arteries [miR-34a/c: 3.29 (1.085-9.95); miR-34a/b/c: 6.06 (1.74-21.2)] and number of diseased arterial beds [miR-34a/c: 3.51 (1.45-8.52); miR-34a/b/c: 2.89 (1.05-7.92)] after controlling for possible confounders (p < 0.05 for all). Mechanistically, the increased levels of miR-34a or miR-34c were inversely associated with expression of SIRT1 or JAG1, NOTCH2, CTNNB1 and ATF1, respectively. The association of miR-34a/c or miR-34a/b/c with CAD was mainly mediated through SIRT1 and to a lesser extent through JAG1 as revealed by generalized structural equation modeling. Leukocyte-specific ablation of miR-34a/b/c ameliorates atherosclerotic plaque development and increases Sirt1 and Jag1 expression in an atherosclerosis mouse model confirming the human findings. CONCLUSIONS: The present study reveals the clinical significance of the additive role of miR-34a/b/c in vascular ageing and atherosclerotic vascular disease.
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Envejecimiento , Aterosclerosis , MicroARNs , Humanos , Proteína Jagged-1 , Leucocitos Mononucleares , Sirtuina 1RESUMEN
OBJECTIVE: To determine the involvement of subcortical regions in human epilepsy by analyzing direct recordings from these regions during epileptic seizures using stereo-EEG (SEEG). METHODS: We studied the SEEG recordings of a large series of patients (74 patients, 157 seizures) with an electrode sampling the thalamus and in some cases also the basal ganglia (caudate nucleus, 22 patients; and putamen, 4 patients). We applied visual analysis and signal quantification methods (Epileptogenicity Index [EI]) to their ictal recordings and compared electrophysiologic with clinical data. RESULTS: We found that in 86% of patients, thalamus was involved during seizures (visual analysis) and 20% showed high values of epileptogenicity (EI >0.3). Basal ganglia may also disclose high values of epileptogenicity (9% in caudate nucleus) but to a lesser degree than thalamus (p < 0.01). We observed different seizure onset patterns including low voltage high frequency activities. We found high values of thalamic epileptogenicity in different epilepsy localizations, including opercular and motor epilepsies. We found no difference between epilepsy etiologies (cryptogenic vs malformation of cortical development, p = 0.77). Thalamic epileptogenicity was correlated with the extension of epileptogenic networks (p = 0.02, ρ 0.32). We found a significant effect (p < 0.05) of thalamic epileptogenicity regarding the postsurgical outcome (higher thalamic EI corresponding to higher probability of surgical failure). CONCLUSIONS: Thalamic involvement during seizures is common in different seizure types. The degree of thalamic epileptogenicity is a possible marker of the epileptogenic network extension and of postsurgical prognosis.
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Ganglios Basales/fisiopatología , Electroencefalografía/métodos , Epilepsias Parciales/fisiopatología , Técnicas Estereotáxicas , Tálamo/fisiopatología , Grabación en Video/métodos , Adolescente , Adulto , Ganglios Basales/diagnóstico por imagen , Niño , Preescolar , Epilepsias Parciales/diagnóstico por imagen , Femenino , Humanos , Masculino , Tálamo/diagnóstico por imagen , Adulto JovenRESUMEN
PURPOSE: Frontal seizures are organized according to anatomo-functional subdivisions of the frontal lobe. Prefrontal seizures have been the subject of few detailed studies to date. The objective of this study was to identify subcategories of prefrontal seizures based on seizure onset quantification and to look for semiological differences. METHODS: Consecutive patients who underwent stereoelectroencephalography (SEEG) for drug-resistant prefrontal epilepsy between 2000 and 2018 were included. The different prefrontal regions investigated in our patients were dorsolateral prefrontal cortex (DLPFC), ventrolateral prefrontal cortex (VLPFC), dorsomedial prefrontal cortex (DMPFC), ventromedial prefrontal cortex (VMPFC), and orbitofrontal cortex (OFC). The seizure onset zone (SOZ) was determined from one or two seizures in each patient, using the epileptogenicity index (EI) method. The presence or absence of 16 clinical ictal manifestations was analyzed. Classification of prefrontal networks was performed using the k-means automatic classification method. RESULTS: A total of 51 seizures from 31 patients were analyzed. The optimal clustering was 4 subgroups of prefrontal seizures: a "pure DLPF" group, a "pure VMPF" group, a "pure OFC" group, and a "global prefrontal" group. The first 3 groups showed a mean EI considered epileptogenic (>0.4) only in one predominant structure, while the fourth group showed a high mean EI in almost all prefrontal structures. The median number of epileptogenic structures per seizure (prefrontal or extrafrontal) was 5 for the "global prefrontal" group and 2 for the other groups. We found that the most common signs were altered consciousness, automatisms/stereotypies, integrated gestural motor behavior, and hyperkinetic motor behavior. We found no significant difference in the distribution of ictal signs between the different groups. CONCLUSION: Our study showed that although most prefrontal seizures manifest as a network of several anatomically distinct structures, we were able to determine a sublobar organization of prefrontal seizure onset with four groups.
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Epilepsia del Lóbulo Frontal , Análisis por Conglomerados , Electroencefalografía , Epilepsia del Lóbulo Frontal/diagnóstico por imagen , Epilepsia del Lóbulo Frontal/cirugía , Humanos , Convulsiones/diagnóstico , Convulsiones/cirugía , Técnicas EstereotáxicasRESUMEN
OBJECTIVE: Hyperkinetic epileptic seizures (HKS) are difficult to characterize and localize according to semiologic features. We propose a multicriteria scale to help visual analysis and report results of cerebral localization. METHODS: We assessed seizures from 37 patients with HKS, explored with stereoelectroencephalography during presurgical evaluation. We used a multicriteria scale (hyperkinetic seizure scale [HSS]) with 10 semiologic features, scored independently by two neurologists. The item scores were used to group seizures using the k-means method. Semiologic features were correlated with the seizure onset zone (SOZ) localization (temporal, prefrontal dorsolateral, prefrontal ventromesial, parietal, insular). RESULTS: Fifty-five seizures were analyzed, and each item of the HSS was compared between the two examiners with good interrater agreement (85.3%). Dystonia, integrated behavior, and bilateral or unilateral hyperkinetic movements were statistically significant according to localization. Three clusters were identified according to the HSS and correlated with different patterns of anatomic localization of SOZ. Cluster 1 was characterized clinically by asymmetric hyperkinetic movements associated with marked dystonia and vocalization. It mainly included parietal seizures. Cluster 2 was characterized by bilateral and symmetrical stereotyped hyperkinetic movements without dystonia. It represented half of temporal seizures and one-third of prefrontal seizures (dorsolateral). Cluster 3 was characterized by seizures with strong emotionality and vocalization with bilateral and symmetrical hyperkinetic movements and integrated behavior. It involved half of temporal seizures and a majority of prefrontal (ventromesial) seizures. SIGNIFICANCE: We propose a first attempt to quantify clinical patterns of HKS. The HSS may help to predict SOZ localization according to three main groups of hyperkinetic seizures.
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Encéfalo/fisiopatología , Hipercinesia/diagnóstico , Convulsiones/diagnóstico , Adolescente , Adulto , Encéfalo/diagnóstico por imagen , Niño , Electroencefalografía , Femenino , Humanos , Hipercinesia/diagnóstico por imagen , Hipercinesia/fisiopatología , Imagen por Resonancia Magnética , Masculino , Persona de Mediana Edad , Neuroimagen , Convulsiones/diagnóstico por imagen , Convulsiones/fisiopatología , Índice de Severidad de la Enfermedad , Adulto JovenRESUMEN
OBJECTIVE Post-stroke epilepsy (PSE) represents a rare etiology in patients undergoing pre-surgical evaluation for epilepsy. Refractory PSE has been traditionally surgically treated with hemispherotomy. The aim of this study was to define the electrophysiological features of epileptogenic zone (EZ) using stereoelectroencephalography (SEEG) recordings in patients with refractory PSE. METHODS We analyzed ictal SEEG recordings from 21 consecutive patients. Epileptogenicity was quantified using the "epileptogenicity index" (EI) method in distant and perilesional cortical structures. We identified different seizure onset patterns (SOP) through a visual and time-frequency analysis. RESULTS We found that 81% of patients showed a complex organization of EZ, involving remote and perilesional structures. EZ involved a significantly (pâ¯<â¯0.01) higher number of distant regions displaying a high epileptogenicity (EIâ¯≥â¯0.3). Low voltage fast activity (LFA) and high amplitude slow activity (HAS) patterns were observed respectively in 85.7% and 14.3% of patients. Surgery was proposed in 12/21 patients. Good surgical outcome (Engel Class I or II) was observed for all patients who underwent tailored functional disconnection based on SEEG results. Shorter epilepsy duration to surgery was found in the seizure-free group. SIGNIFICANCE Refractory PSE may present a complex organization of EZ. SEEG recordings are warranted to guide tailored hemispherectomy.
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Encéfalo/cirugía , Epilepsia Refractaria/cirugía , Hemisferectomía/métodos , Convulsiones/cirugía , Adolescente , Adulto , Encéfalo/fisiopatología , Epilepsia Refractaria/fisiopatología , Electroencefalografía , Femenino , Humanos , Masculino , Persona de Mediana Edad , Convulsiones/fisiopatología , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: Endothelial cells play important roles in tissue homeostasis and vascularization, a function that is impaired by aging. Here, we aim to decipher the role of the microenvironment underlying the impairment of endothelial cell functions by aging. APPROACH AND RESULTS: RNA sequencing of isolated cardiac endothelial cells derived from young and 18-month-old mouse hearts revealed that aging affects the endothelial expression of genes encoding extracellular matrix proteins, specifically the laminin ß1 (Lamb1) and laminin ß2 (Lamb2) chains. Whereas Lamb1 was upregulated, Lamb2 was decreased in endothelial cells in old mice compared with young controls. A similar change in expression patterns was observed after induction of acute myocardial infarction. Mimicking aging and injury conditions by plating endothelial cells on laminin ß1-containing laminin 411 matrix impaired endothelial cell adhesion, migration, and tube formation and augmented endothelial-to-mesenchymal transition and endothelial detachment compared with laminin 421, which contains the laminin ß2 chain. Because laminins can signal via integrin receptors, we determined the activation of ITGB1 (integrin ß1). Laminin 421 coating induced a higher activation of ITGB1 compared with laminin 411. siRNA-mediated silencing of ITGB1 reduced laminin ß2-dependent adhesion, suggesting that laminin ß2 more efficiently activates ITGB1. CONCLUSIONS: Mimicking age-related modulation of laminin ß1 versus ß2 chain expression changes the functional properties and phenotype of endothelial cells. The dysregulation of the extracellular matrix during vascular aging may contribute to age-associated impairment of organ function and fibrosis.
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Envejecimiento/metabolismo , Células Endoteliales/metabolismo , Laminina/metabolismo , Neovascularización Fisiológica , Factores de Edad , Envejecimiento/genética , Animales , Adhesión Celular , Movimiento Celular , Proliferación Celular , Separación Celular/métodos , Células Cultivadas , Microambiente Celular , Modelos Animales de Enfermedad , Células Endoteliales/patología , Matriz Extracelular/metabolismo , Regulación de la Expresión Génica , Células Endoteliales de la Vena Umbilical Humana/metabolismo , Humanos , Integrina beta1/metabolismo , Laminina/genética , Masculino , Ratones Endogámicos C57BL , Infarto del Miocardio/genética , Infarto del Miocardio/metabolismo , Infarto del Miocardio/patología , Fenotipo , Transducción de SeñalRESUMEN
BACKGROUND: Resective surgery established treatment for pharmacoresistant frontal lobe epilepsy (FLE), but seizure outcome and prognostic indicators are poorly characterized and vary between studies. OBJECTIVE: To study long-term seizure outcome and identify prognostic factors. METHODS: We retrospectively analyzed 42 FLE patients having undergone surgical resection, mostly preceded by invasive recordings with stereoelectroencephalography (SEEG). Postsurgical outcome up to 10-yr follow-up and prognostic indicators were analyzed using Kaplan-Meier analysis and multivariate and conditional inference procedures. RESULTS: At the time of last follow-up, 57.1% of patients were seizure-free. The estimated chance of seizure freedom was 67% (95% confidence interval [CI]: 54-83) at 6 mo, 59% (95% CI: 46-76) at 1 yr, 53% (95% CI: 40-71) at 2 yr, and 46% (95% CI: 32-66) at 5 yr. Most relapses (83%) occurred within the first 12 mo. Multivariate analysis showed that completeness of resection of the epileptogenic zone (EZ) as defined by SEEG was the main predictor of seizure outcome. According to conditional inference trees, in patients with complete resection of the EZ, focal cortical dysplasia as etiology and focal EZ were positive prognostic indicators. No difference in outcome was found in patients with positive vs negative magnetic resonance imaging. CONCLUSION: Surgical resection in drug-resistant FLE can be a successful therapeutic approach, even in the absence of neuroradiologically visible lesions. SEEG may be highly useful in both nonlesional and lesional FLE cases, because complete resection of the EZ as defined by SEEG is associated with better prognosis.