RESUMO
The nucleus accumbens (NAc) is the key area of the reward circuit, but its heterogeneity has been poorly studied. Using single-cell RNA sequencing, we revealed a subcluster of GABAergic neurons characterized by cell division cycle 20 (Cdc20) mRNA expression in the NAc of adult rats. We studied the coexpression of Cdc20 and Gad1 mRNA in the NAc neurons of adult rats and assessed Cdc20 protein expression in the NAc during rat development. Moreover, we microinjected AAV2/9-hSyn-Cdc20 with or without the dual-AAV system into the bilateral NAc for sparse labeling to observe changes in the synaptic morphology of mature neurons and assessed rat behaviors in open field and elevated plus maze tests. Furthermore, we performed the experiments with a Cdc20 inhibitor, Cdc20 over-expression AAV vector, and Cdc20 conditional knockout primary striatal neurons to understand the ubiquitination-dependent degradation of fragile X mental retardation protein (FMRP) in vitro and in vivo. We confirmed the mRNA expression of Cdc20 in the NAc GABAergic neurons of adult rats, and its protein level was decreased significantly 3 weeks post-birth. Up-regulated Cdc20 expression in the bilateral NAc decreased the dendritic spine density in mature neurons and induced anxiety-like behavior in rats. Cdc20-APC triggered FMRP degradation through K48-linked polyubiquitination in Neuro-2a cells and primary striatal neurons and down-regulated FMRP expression in the NAc of adult rats. These data revealed that up-regulation of Cdc20 in the bilateral NAc reduced dendritic spine density and led to anxiety-like behaviors, possibly by enhancing FMRP degradation via K48-linked polyubiquitination.
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Proteínas Cdc20 , Espinhas Dendríticas , Proteína do X Frágil da Deficiência Intelectual , Animais , Proteínas Cdc20/genética , Ciclo Celular , Espinhas Dendríticas/metabolismo , Proteína do X Frágil da Deficiência Intelectual/genética , Proteína do X Frágil da Deficiência Intelectual/metabolismo , Neurônios/metabolismo , Núcleo Accumbens/metabolismo , RNA Mensageiro/metabolismo , Ratos , Ubiquitinação , Regulação para CimaRESUMO
BACKGROUND AND OBJECTIVE: The imbalanced hemostatic equilibrium caused by brain tissue or vessel damage underlies the pathophysiology of traumatic brain injury (TBI)-induced coagulopathy, and cranial computed tomography (CT) is the gold standard for evaluating brain injury. The present study aimed to explore the correlation between quantitative cranial CT parameters and coagulopathy after TBI. METHODS: We retrospectively collected the medical records of TBI patients with extracranial abbreviated injury scale (AIS) scores <3 who were admitted to our institution. The quantitative cranial CT parameters of patients with and without coagulopathy were compared, and univariate correlation analysis between CT parameters and coagulation subtest values and platelet counts was performed. The predictors for each subtest of coagulation function were probed by multivariate regression. RESULTS: TBI patients with coagulopathy had a larger intracerebral haematoma/contusion (ICH/C) volume (p < 0.001), a higher incidence of compressed basal cisterns (p = 0.015), a higher Graeb score (p < 0.001) and subarachnoid haematoma (Fisher's scaling score) (p = 0.019) than those without coagulopathy. IH/C volume was identified as an independent risk factor for predicting coagulopathy. ICH/C volume showed a significantly positive correlation with APTT (Pearson's correlation = 0.333, p < 0.001), while a significant negative correlation with PLT (Pearson's correlation = - 0.312, p < 0.001). CONCLUSION: ICH/C volume was a main quantitative cranial CT parameter for predicting coagulopathy, suggesting that parenchymal brain damage and vessel injury were closely associated with coagulopathy after TBI.
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Transtornos da Coagulação Sanguínea , Lesões Encefálicas Traumáticas , Lesões Encefálicas , Transtornos da Coagulação Sanguínea/complicações , Transtornos da Coagulação Sanguínea/etiologia , Lesões Encefálicas Traumáticas/complicações , Lesões Encefálicas Traumáticas/diagnóstico por imagem , Hematoma , Humanos , Estudos Retrospectivos , Tomografia Computadorizada por Raios XRESUMO
ABSTRACT: Abnormal muscular response (AMR) has been widely used in the intraoperative monitoring of microvascular decompression due to its advantages for the identification of responsible arteries and the evaluation of adequate decompression. Here the authors report a 48-year-old man with an unusual AMR during microvascular decompression under endoscope assistance. The morphology and number of AMRs were influenced by different stimulation and recording sites. Abnormal muscular response disappeared and hemifacial spasm was completely relieved without facial paralysis postoperatively.
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Espasmo Hemifacial , Cirurgia de Descompressão Microvascular , Endoscópios , Músculos Faciais/cirurgia , Nervo Facial/cirurgia , Espasmo Hemifacial/cirurgia , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos , Resultado do TratamentoRESUMO
Secretory carrier membrane proteins (SCAMPs) play an important role in exocytosis in animals, but the precise function of SCAMPs in human disease is unknown. In this study, we identified a homozygous mutation, SCAMP5 R91W, in a Chinese consanguineous family with pediatric epilepsy and juvenile Parkinson's disease. Scamp5 R91W mutant knock-in mice showed typical early-onset epilepsy similar to that in humans. Single-neuron electrophysiological recordings showed that the R91W mutation significantly increased the frequency of miniature excitatory postsynaptic currents (mEPSCs) at a resting state and also increased the amplitude of evoked EPSCs. The R91W mutation affected the interaction between SCAMP5 and synaptotagmin 1 and may affect the function of the SNARE complex, the machinery required for vesicular trafficking and neurotransmitter release. Our work shows that dysfunction of SCAMP5 shifted the excitation/inhibition balance of the neuronal network in the brain, and the deficiency of SCAMP5 leads to pediatric epilepsy.
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Potenciais de Ação , Encéfalo , Epilepsia , Proteínas de Membrana , Mutação de Sentido Incorreto , Rede Nervosa , Neurotransmissores/metabolismo , Potenciais Sinápticos , Animais , Encéfalo/metabolismo , Encéfalo/patologia , Epilepsia/genética , Epilepsia/metabolismo , Epilepsia/patologia , Técnicas de Introdução de Genes , Células HEK293 , Humanos , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Transgênicos , Rede Nervosa/metabolismo , Rede Nervosa/patologiaRESUMO
It has been suggested that the trigemino-thalamic and trigemino-parabrachial projection neurons in the medullary dorsal horn (MDH) are highly implicated in the sensory-discriminative and emotional/affective aspects of orofacial pain, respectively. In previous studies, some neurons were reported to send projections to both the thalamus and parabrachial nucleus by way of collaterals in the MDH. However, little is known about the chemoarchitecture of this group of neurons. Thus, in the present study, we determined whether the neurokinin-1 (NK-1) receptor, which is crucial for primary orofacial pain signaling, was expressed in MDH neurons co-innervating the thalamus and parabrachial nucleus. Vesicular glutamate transporter 2 (VGLUT2) mRNA, a biomarker for the subgroup of glutamatergic neurons closely related to pain sensation, was assessed in trigemino-parabrachial projection neurons in the MDH. After stereotactic injection of fluorogold (FG) and cholera toxin subunit B (CTB) into the ventral posteromedial thalamic nucleus (VPM) and parabrachial nucleus (PBN), respectively, triple labeling with fluorescence dyes for FG, CTB and NK-1 receptor (NK-1R) revealed that approximately 76 % of the total FG/CTB dually labeled neurons were detected as NK-1R-immunopositive, and more than 94 % of the triple-labeled neurons were distributed in lamina I. In addition, by FG retrograde tract-tracing combined with fluorescence in situ hybridization (FISH) for VGLUT2 mRNA, 54, 48 and 70 % of FG-labeled neurons in laminae I, II and III, respectively, of the MDH co-expressed FG and VGLUT2 mRNA. Thus, most of the MDH neurons co-innervating the thalamus and PBN were glutamatergic. Most MDH neurons providing the collateral axons to both the thalamus and parabrachial nucleus in rats were NK-1R-immunopositive and expressed VGLUT2 mRNA. NK-1R and VGLUT2 in MDH neurons may be involved in both sensory-discriminative and emotional/affective aspects of orofacial pain processing.
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Axônios/química , Bulbo/química , Núcleos Parabraquiais/química , Células do Corno Posterior/química , Receptores da Neurocinina-1/análise , Tálamo/química , Animais , Axônios/metabolismo , Masculino , Bulbo/metabolismo , Núcleos Parabraquiais/metabolismo , Células do Corno Posterior/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores da Neurocinina-1/metabolismo , Tálamo/metabolismoRESUMO
BACKGROUND: Symptomatic intracranial hemorrhage (ICH) may lead to permanent neurological disability of patients and has impeded the extensive clinical application of deep brain stimulation (DBS). The present study was conducted to discuss the incidence, prevention, and treatment of symptomatic ICH after DBS surgery. METHODS: From January 2009 to December 2014, 396 patients underwent DBS with a total of 691 implanted leads. In all, 10 patients had symptomatic ICH. We analyzed these cases' clinical characteristics, including comorbid diagnoses and coagulation profile. We described the onset of ICH, imaging features, clinical manifestations, treatment, neurological impairment, and outcome of DBS. RESULTS: Of the 10 patients with symptomatic ICH, 2 had hypertension. Three cases of ICH occurred within 12 h of the procedure; four cases within 24 h. Five experienced grand mal seizures concurrently with hemorrhage. Unilateral frontal lobe hemorrhage occurred in all cases. In seven cases, hematomas occurred around the electrodes. Some hematomas were not well-circumscribed and had perihematomal edema. Conservative therapy was administered to 8 patients, and 2 patients underwent craniotomy and hematoma evacuation. All electrodes were successfully preserved. Neurological dysfunction in all patients gradually improved. Nine patients ultimately experienced effective symptom relief of Parkinson's disease with DBS. CONCLUSIONS: Symptomatic ICH should be identified as soon as possible after implantation surgery and treated effectively to limit neurological deficit and preserve DBS leads.
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Estimulação Encefálica Profunda/efeitos adversos , Hemorragias Intracranianas/etiologia , Hemorragias Intracranianas/terapia , Procedimentos Neurocirúrgicos/efeitos adversos , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/terapia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Edema Encefálico/etiologia , Edema Encefálico/prevenção & controle , Edema Encefálico/terapia , Criança , Comorbidade , Craniotomia , Drenagem , Eletrodos Implantados/efeitos adversos , Feminino , Lobo Frontal , Humanos , Hemorragia Intracraniana Hipertensiva/etiologia , Hemorragia Intracraniana Hipertensiva/prevenção & controle , Hemorragia Intracraniana Hipertensiva/terapia , Hemorragias Intracranianas/prevenção & controle , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Exame Neurológico , Doença de Parkinson/cirurgia , Complicações Pós-Operatórias/prevenção & controle , Adulto JovemRESUMO
BACKGROUND: The nucleus accumbens (NAcc) has been proven to be associated with drug and food craving. NAcc ablative neurosurgery has been suggested to modulate the balance of the brain reward system and thus alleviate drug dependence in patients. It has been hypothesized that it would also alleviate food craving in patients as well as altering their nutritional status. AIMS: This study aimed to estimate the effect of NAcc neurosurgery on drug craving and nutritional status in patients with drug dependence at 5 years postoperatively. METHODS: The study included 100 patients with NAcc surgery and 92 patients without surgery. Body mass index (BMI) and body fat percentage (BF%) were examined to assess nutritional status, and questionnaires were administered to assess drug craving. RESULTS: Compared with the nonsurgery group and the relapse patients from the surgery group, the nonrelapse patients from the surgery group had higher BMI and BF% but lower drug craving. There were no significant differences between the nonsurgery group and the relapse patients in BMI, but the relapse patients had higher drug craving than the nonsurgery group. CONCLUSIONS: Long-term follow-up suggested that NAcc ablative neurosurgery would alleviate drug craving and yield a better nutritional status if individuals sustained abstinence. It would increase drug craving but would not ruin the nutritional status of patients even when individuals relapsed postoperatively.
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Fissura , Procedimentos Neurocirúrgicos/métodos , Núcleo Accumbens/cirurgia , Transtornos Relacionados ao Uso de Opioides/cirurgia , Adulto , Feminino , Humanos , Masculino , Estado Nutricional , Transtornos Relacionados ao Uso de Opioides/psicologia , Período Pós-Operatório , Resultado do TratamentoRESUMO
BACKGROUND: Watertight duraplasty is essential for surgical management of traumatic anterior skull base (ASB) dural defect but challenging in the deep and narrow operative corridor. Here, the authors report a trans-defect underlay watertight duraplasty (TDUWD) technique for traumatic ASB dural defect. METHODS: TDUWD was performed by inserting a free pericranium graft under the dural defect. The diameter of the pericranium graft was larger than the dural defect. The pericranium graft was sutured to the dural defect watertightly in an "inside-to-outside" direction, with the needle not penetrating the inner layer of pericranium graft. The pedicled pericranium flap was used as a second layer of reconstruction. The characteristics, complications, and outcomes of patients who received TDUWD are reported. RESULTS: A total of 29 patients received TDUWD. Immediate postoperative cessation of cerebrospinal fluid (CSF) leak occurred in 28 patients. One patient recovered after lumber drainage. No patient needed a second operation or reported delayed recurrence of CSF leak. No complication related to the surgical technique was observed. CONCLUSIONS: Use of TDUWD for traumatic ASB dural defect results in an immediate, 1-stage, and definitive correction of CSF leak and seems to be simple, safe, and reliable for large and deeply located dural defects.
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Vazamento de Líquido Cefalorraquidiano , Dura-Máter , Procedimentos de Cirurgia Plástica , Base do Crânio , Humanos , Dura-Máter/cirurgia , Dura-Máter/lesões , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Base do Crânio/cirurgia , Base do Crânio/lesões , Procedimentos de Cirurgia Plástica/métodos , Vazamento de Líquido Cefalorraquidiano/cirurgia , Vazamento de Líquido Cefalorraquidiano/etiologia , Adulto Jovem , Idoso , Adolescente , Retalhos Cirúrgicos , Procedimentos Neurocirúrgicos/métodos , Resultado do TratamentoRESUMO
Neuroinflammation after traumatic brain injury (TBI) exhibits a strong correlation with neurological impairment, which is a crucial target for improving the prognosis of TBI patients. The involvement of CXCL5/CXCR2 signaling in the regulation of neuroinflammation in brain injury models has been documented. Therefore, the effects of CXCL5 on post-TBI neuroinflammation and its potential mechanisms need to be explored. Following TBI, C57BL/6 mice were administered intraperitoneal injections of a CXCL5 neutralizing antibody (Nab-CXCL5) (5â mg/kg, 2 times/day). Subsequently, the effects on neuroinflammation, nerve injury, and neurological function were assessed. Nab-CXCL5 significantly reduced the release of inflammatory factors, inhibited the formation of inflammatory microglia and astrocytes, and reduced the infiltration of peripheral immune cells in TBI mice. Additionally, this intervention led to a reduction in neuronal impairment and facilitated the restoration of sensorimotor abilities, as well as improvements in learning and memory functions. Peripheral administration of the Nab-CXCL5 to TBI mice could suppress neuroinflammation, reduce neurological damage, and improve neurological function. Our data suggest that neutralizing antibodies against CXCL5 (Nab-CXCL5) may be a promising agent for treating TBI.
Assuntos
Lesões Encefálicas Traumáticas , Quimiocina CXCL5 , Doenças Neuroinflamatórias , Animais , Masculino , Camundongos , Anticorpos Neutralizantes/farmacologia , Lesões Encefálicas Traumáticas/imunologia , Lesões Encefálicas Traumáticas/tratamento farmacológico , Quimiocina CXCL5/metabolismo , Camundongos Endogâmicos C57BL , Microglia/efeitos dos fármacos , Microglia/metabolismo , Doenças Neuroinflamatórias/tratamento farmacológico , Recuperação de Função Fisiológica/efeitos dos fármacosRESUMO
Neuroadaptive changes in the hippocampus underlie addictive-like behaviors in humans or animals chronically exposed to cocaine. miR-181a, which is widely expressed in the hippocampus, acts as a regulator for synaptic plasticity, while its role in drug reinstatement is unclear. In this study, we found that miR-181a regulates the reinstatement of cocaine conditioned place preference(CPP), and altered miR-181a expression changes the complexity of hippocampal neurons and the density and morphology of dendritic spines. By using a luciferase gene reporter, we found that miR-181a targets PRKAA1, an upstream molecule in the mTOR pathway. High miR-181a expression reduced the expression of the PRKAA1 mRNA and promoted mTOR activity and the reinstatement of cocaine CPP. These results indicate that miR-181a is involved in neuronal structural plasticity induced by reinstatement of cocaine CPP, possibly through the activation of the mTOR signaling pathway. This study provides new microRNA targets and a theoretical foundation for the prevention of cocaine-induced reinstatement.
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Cocaína , Hipocampo , MicroRNAs , Serina-Treonina Quinases TOR , MicroRNAs/metabolismo , Animais , Hipocampo/metabolismo , Hipocampo/efeitos dos fármacos , Cocaína/farmacologia , Masculino , Serina-Treonina Quinases TOR/metabolismo , Plasticidade Neuronal/efeitos dos fármacos , Plasticidade Neuronal/fisiologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/fisiologia , Proteínas Quinases Ativadas por AMP/metabolismo , Neurônios/efeitos dos fármacos , Neurônios/metabolismo , Espinhas Dendríticas/efeitos dos fármacos , Espinhas Dendríticas/metabolismo , Inibidores da Captação de Dopamina/farmacologia , Transtornos Relacionados ao Uso de Cocaína/metabolismo , Camundongos , Ratos , Ratos Sprague-DawleyRESUMO
The nucleus accumbens (NAc) and the anterior limb of internal capsule (ALIC) are effective targets for treating addiction using deep brain stimulation (DBS). However, there have been no reports on the electrophysiological characteristics of addiction nuclei at the single-cell level in humans. This study aimed to investigate the electrical activity characteristics of neurons in the NAc and ALIC using microelectrode recording (MER) during DBS surgery in patients with addiction, and six patients with addiction were included (five with heroin addiction and one with alcohol addiction). The microelectrode recording trajectories were reconstructed and recording sites at different depths were determined by merging the pre- and post-operative images in the FrameLink system. The results showed that among the 256 neurons, 204 (80 %) were burst neurons. NAc neurons accounted for the majority (57 %), and the mean firing rate (MFR) was the highest (1.94 Hz). ALIC neurons accounted for the least (14 %), and MFR was the lowest (0.44 Hz). MFR increased after entering the NAc and decreased after entering the ALIC. In the patients with addiction treated using DBS, the single-cell level electrophysiological characteristics of the different nuclei were found to be distinct along the surgical trajectory.
Assuntos
Estimulação Encefálica Profunda , Cápsula Interna , Microeletrodos , Neurônios , Núcleo Accumbens , Núcleo Accumbens/fisiologia , Núcleo Accumbens/fisiopatologia , Humanos , Masculino , Estimulação Encefálica Profunda/métodos , Adulto , Cápsula Interna/fisiologia , Cápsula Interna/fisiopatologia , Neurônios/fisiologia , Pessoa de Meia-Idade , Feminino , Potenciais de Ação/fisiologia , Alcoolismo/fisiopatologia , Dependência de Heroína/fisiopatologiaRESUMO
Pivotal roles of extracellular vesicles (EVs) in the pathogenesis of central nervous system (CNS) disorders including acute brain injury are increasingly acknowledged. Through the analysis of EVs packaged miRNAs in plasma samples from patients with intracerebral hemorrhage (ICH), it is discovered that the level of EVs packaged miR-143-3p (EVs-miR-143-3p) correlates closely with perihematomal edema and neurological outcomes. Further study reveals that, upon ICH, EVs-miR-143-3p is robustly secreted by astrocytes and can shuttle into brain microvascular endothelial cells (BMECs). Heightened levels of miR-143-3p in BMECs induce the up-regulated expression of cell adhesion molecules (CAMs) that bind to circulating neutrophils and facilitate their transendothelial cell migration (TEM) into brain. Mechanism-wise, miR-143-3p directly targets ATP6V1A, resulting in impaired lysosomal hydrolysis ability and reduced autophagic degradation of CAMs. Importantly, a VCAM-1-targeting EVs system to selectively deliver miR-143-3p inhibitor to pathological BMECs is created, which shows satisfactory therapeutic effects in both ICH and traumatic brain injury (TBI) mouse models. In conclusion, the study highlights the causal role of EVs-miR-143-3p in BMECs' dysfunction in acute brain injury and demonstrates a proof of concept that engineered EVs can be devised as a potentially applicable nucleotide drug delivery system for the treatment of CNS disorders.
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Lesões Encefálicas , Vesículas Extracelulares , MicroRNAs , Humanos , Animais , Camundongos , Células Endoteliais , Migração Transendotelial e Transepitelial , Astrócitos , Neutrófilos , Movimento CelularRESUMO
Persistent neuroinflammation and progressive neuronal loss are defining features of acute brain injury including traumatic brain injury (TBI) and cerebral stroke. Microglia, the most abundant type of brain-resident immune cells, continuously surveil the environment and play a central role in shaping the inflammatory state of the central nervous system (CNS). In the study, we discovered that the protein expression of METTL3 (a m6A methyltransferase) was upregulated in inflammatory microglia independent of increased Mettl3 gene transcription following TBI in both human and mouse subjects. Subsequently, we identified TRIP12, a HECT-domain E3 ubiquitin ligase, as a negative regulator of METTL3 protein expression by facilitating METTL3 K48-linked polyubiquitination. Importantly, selective ablation of Mettl3 inhibited microglial pathogenic activities, diminished neutrophil infiltration, rescued neuronal loss and facilitated functional recovery post-TBI. Using MeRIP-seq and CUT&Tag sequencing, we identified that METTL3 promoted the expression of Basic Leucine Zipper Transcriptional Factor ATF-Like (BATF), which in turn directly bound to a cohort of characteristic inflammatory cytokines and chemokine genes. Enhanced activities of BATF in microglia elicited TNF-dependent neurotoxicity and can also promote neutrophil recruitment through releasing CXCL2. Pharmacological inhibition of METTL3 using a BBB-penetrating drug-loaded nano-system showed satisfactory therapeutic effects in both TBI and stroke mouse models. Collectively, our findings identified METTL3-m6A-BATF axis as a potential therapeutic target for terminating detrimental neuroinflammation and progressive neuronal loss following acute brain injury. METTL3 protein is significantly up-regulated in inflammatory microglia due to the decreased proteasomal degradation mediated by TRIP12 and ERK-USP5 pathways. METTL3 stabilized BATF mRNA stability and promoted BATF expression through the m6A-IGF2BP2-dependent mechanism. Elevated expression of BATF elicits a pro-inflammatory gene program in microglia, and aggravates neuroinflammatory response including local immune responses and peripheral immune cell infiltration. Genetic deletion or pharmaceutically targeting METTL3-BATF axis suppressed microglial pro-inflammatory activities and promoted neurological recovery following TBI and stroke.
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OBJECTIVE: Patients with moderate traumatic brain injury (TBI) are under the threat of intracranial hypertension (IHT). However, it is unclear which moderate TBI patient will develop IHT and should receive intracranial pressure (ICP)-lowering treatment or invasive ICP monitoring after admission. The purpose of the present study was to develop and validate a prediction model that estimates the risk of IHT in moderate TBI patients. METHODS: Baseline data collected on admission of 296 moderate TBI patients with Glasgow Coma Scale (GCS) score of 9-11 was collected and analyzed. Multi-variable logistic regression modeling with backward stepwise elimination was used to develop a prediction model for IHT. The discrimination efficacy, calibration efficacy, and clinical utility of the prediction model were evaluated. Finally, the prediction model was validated in a separate cohort of 122 patients from 3 hospitals. RESULTS: Four independent prognostic factors for IHT were identified: GCS score, Marshall head computed tomography score, injury severity score and location of contusion. The C-statistic of the prediction model in internal validation was 84.30% (95% confidence interval [CI]: 0.794-0.892). The area under the curve for the prediction model in external validation was 82.80% (95% CI: 0.747â¼0.909). CONCLUSIONS: A prediction model based on baseline parameters was found to be highly sensitive in distinguishing moderate TBI patients with GCS score of 9-11 who would suffer IHT. The high discriminative ability of the prediction model supports its use in identifying moderate TBI patients with GCS score of 9-11 who need ICP-lowering therapy or invasive ICP monitoring.
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Mitochondrial dysfunction and oxidative stress are important mechanisms for secondary injury after traumatic brain injury (TBI), which result in progressive pathophysiological exacerbation. Although the Fibronectin type III domain-containing 5 (FNDC5) was reported to repress oxidative stress by retaining mitochondrial biogenesis and dynamics, its possible role in the secondary injury after TBI remain obscure. In present study, we observed that the level of serum irisin (the cleavage product of FNDC5) significantly correlated with the neurological outcomes of TBI patients. Knockout of FNDC5 increased the lesion volume and exacerbated apoptosis and neurological deficits after TBI in mice, while FNDC5 overexpression yielded a neuroprotective effect. Moreover, FNDC5 deficiency disrupted mitochondrial dynamics and function. Activation of Sirtuin 3 (SIRT3) alleviated FNDC5 deficiency-induced disruption of mitochondrial dynamics and bioenergetics. In neuron-specific SIRT3 knockout mice, FNDC5 failed to attenuate TBI-induced mitochondrial damage and brain injuries. Mechanically, FNDC5 deficiency led to reduced SIRT3 expression via enhanced ubiquitin degradation of transcription factor Nuclear factor erythroid 2-related factor 2 (NRF2), which contributed to the hyperacetylation and inactivation of key regulatory proteins of mitochondrial dynamics and function, including OPA1 and SOD2. Finally, engineered RVG29-conjugated nanoparticles were generated to selectively and efficiently deliver irisin to the brain of mice, which yielded a satisfactory curative effect against TBI. In conclusion, FNDC5/irisin exerts a protective role against acute brain injury by promoting SIRT3-dependent mitochondrial quality control and thus represents a potential target for neuroprotection after TBI.
Assuntos
Apoptose , Lesões Encefálicas Traumáticas , Fibronectinas , Camundongos Knockout , Mitocôndrias , Neurônios , Estresse Oxidativo , Sirtuína 3 , Animais , Lesões Encefálicas Traumáticas/metabolismo , Lesões Encefálicas Traumáticas/patologia , Lesões Encefálicas Traumáticas/genética , Sirtuína 3/metabolismo , Sirtuína 3/genética , Fibronectinas/metabolismo , Mitocôndrias/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Camundongos , Humanos , Masculino , Camundongos Endogâmicos C57BL , Fator 2 Relacionado a NF-E2/metabolismo , Dinâmica MitocondrialRESUMO
Background: Studies have been inconclusive on the risk for hemorrhage in patients with a history of aspirin use who underwent emergency external ventricular drainage (EVD)/intracranial pressure (ICP) probe placement. The aim of this study was to explore hemorrhage-related risk factors in order to reduce the risk for hemorrhage in these patients. Methods: Between July 2014 and July 2020, patients were retrospectively divided into EVD/ICP-related hemorrhage and non-hemorrhage groups. The collected data included age, gender, major diagnosis, medical history, imaging examinations, conventional coagulation test data, thromboelastography with platelet mapping (TEG-PM), surgical procedures and discharge conditions. Results: In total 94 patients, 21 in the hemorrhage group (15 males, 6 females) and 73 in the non-hemorrhage group (52 males, 21 females) were included. The majority of hemorrhages were recorded in EVD patients (19/21; 90.5%). Platelet AA pathway inhibition rate of ≥75% (sensitivity: 79.45% specificity: 52.38%) (P = 0.014) and SBP ≥125 mmHg (P = 0.006) were significantly related to hemorrhage. When the platelet AA pathway inhibition rate was ≥75% and the during-procedure SBP was ≥125 mmHg, the hemorrhage rate was significantly higher (83.3%) than with SBP <125 mmHg (6.7%) (P < 0.001). When the inhibition rate was <75%, there were no significant differences in the hemorrhage rates between the during-procedure SBP ≥125 mmHg group (17.2%) and the SBP <125 mmHg group (13.2%) (P > 0.05). Multivariate logistic regression analysis revealed that a platelet AA pathway inhibition rate ≥75% (OR = 5.183, 95% CI: 1.683-15.960) and during-procedure SBP ≥125 mmHg (OR = 4.609, 95% CI: 1.466-14.484) were independent risk factors for EVD/ICP-related hemorrhage. Conclusion: Patients with long-term aspirin therapy, a platelet AA pathway inhibition rate ≥75% and during-procedure SBP ≥125 mmHg had a significantly higher risk of hemorrhage, which could be reduced by adjusting the SBP to <125 mmHg.
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OBJECTIVE: To investigate the long-term outcome and changes of the personality and psychopathological profile of opiate addicts after bilateral stereotactic nucleus accumbens (NAc) ablative surgery. METHODS: 60 patients were followed up for 5 years and abstinent status and adverse events were evaluated. NAc lesion volumes and locations were obtained by postoperative MRI scans. The Chinese version of the Eysenck Personality Questionnaire (EPQ-RSC), the Symptom Checklist-90-Revised (SCL-90-R), the Beck Depression Inventory (BDI), the Yale-Brown Obsessive Compulsive Scale (Y-BOCS) and the World Health Organization's Quality of Life Questionnaire - Brief Version (WHOQOL-BREF) were administered to the patients before and 5 years after the stereotactic surgery. RESULTS: The total abstinence rate of all patients in their 5th postoperative year was 47.4%. The abstinent patients had a significantly larger lesion volume than the relapsed ones, but a larger lesion volume also increased the risk of adverse events. 5 years after surgery, the abstinent patients showed significant decreases on the Psychoticism (EPQ-P) and Neuroticism (EPQ-N) scores by EPQ-RSC, a significant decline on the Global Severity Index and the subscores in all 10 dimensions by SCL-90-R, significant decreases on the BDI and Y-BOCS scores, and significant improvements on the scores of all domains by WHOQOL-BREF, while for the relapsed patients, only the subscores of obsessive-compulsive by SCL-90-R and the Y-BOCS scores significantly decreased. Postoperative analysis revealed that the abstinent patients had a significantly better score than the relapsed ones by various instruments, and NAc lesion volumes and locations did not correlate with the outcome of any of these instruments. CONCLUSION: The bilateral ablation of NAc by stereotactic neurosurgery was a feasible method for alleviating psychological dependence on opiate drugs and preventing a relapse. Long-term follow-up suggested that surgery can improve the personality and psychopathological profile of opiate addicts with a trend towards normal levels, provided persistent abstinence can be maintained; relapse, on the other hand, may ruin this effect.
Assuntos
Ablação por Cateter , Dependência de Heroína/cirurgia , Núcleo Accumbens/cirurgia , Personalidade , Psicocirurgia , Adulto , Ablação por Cateter/efeitos adversos , Feminino , Dependência de Heroína/complicações , Dependência de Heroína/fisiopatologia , Dependência de Heroína/psicologia , Humanos , Entrevista Psicológica , Imageamento por Ressonância Magnética , Masculino , Transtornos da Memória/etiologia , Morfina/urina , Transtornos Neuróticos/etiologia , Transtornos Neuróticos/psicologia , Núcleo Accumbens/patologia , Núcleo Accumbens/fisiopatologia , Transtornos do Olfato/etiologia , Inventário de Personalidade , Psicocirurgia/efeitos adversos , Transtornos Psicóticos/etiologia , Transtornos Psicóticos/psicologia , Qualidade de Vida , Recidiva , Índice de Gravidade de Doença , Fatores Socioeconômicos , Avaliação de Sintomas , Resultado do TratamentoRESUMO
OBJECTIVE: The alternative extension of the telomeres (ALT) mechanism is activated in lower grade glioma (LGG), but the role of the ALT mechanism has not been well discussed. The primary purpose was to demonstrate the significance of the ALT mechanism in prognosis estimation for LGG patients. METHOD: Gene expression and clinical data of LGG patients were collected from the Chinese Glioma Genome Atlas (CGGA) and the Cancer Genome Atlas (TCGA) cohort, respectively. ALT-related genes obtained from the TelNet database and potential prognostic genes related to ALT were selected by LASSO regression to calculate an ALT-related risk score. Multivariate Cox regression analysis was performed to construct a prognosis signature, and a nomogram was used to represent this signature. Possible pathways of the ALT-related risk score are explored by enrichment analysis. RESULT: The ALT-related risk score was calculated based on the LASSO regression coefficients of 22 genes and then divided into high-risk and low-risk groups according to the median. The ALT-related risk score is an independent predictor of LGG (HR and 95% CI in CGGA cohort: 5.70 (3.79, 8.58); in TCGA cohort: 1.96 (1.09, 3.54)). ROC analysis indicated that the model contained ALT-related risk score was superior to conventional clinical features (AUC: 0.818 vs 0.729) in CGGA cohorts. The results in the TCGA cohort also shown a powerful ability of ALT-related risk score (AUC: 0.766 vs 0.691). The predicted probability and actual probability of the nomogram are consistent. Enrichment analysis demonstrated that the ALT mechanism was involved in the cell cycle, DNA repair, immune processes, and others. CONCLUSION: ALT-related risk score based on the 22-gene is an important factor in predicting the prognosis of LGG patients.
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Objective: Traumatic brain injury (TBI) is a global social, economic, and health challenge that is associated with premature death and long-term disability. In the context of rapid development of urbanization, the analysis of TBI rate and mortality trend could provide abundant diagnosis and treatment suggestions, which helps to form future reference on public health strategies. Methods: In this study, as one of major neurosurgical centers in China, we focused on the regime shift of TBI based on 18-year consecutive clinical data and evaluated the epidemiological features. In our current study, a total of 11,068 TBI patients were reviewed. Results: The major cause of TBI was road traffic injuries (44.%), while the main type of injury was cerebral contusion (n = 4,974 [44.94%]). Regarding to temporal changes, a decreasing trend in TBI incidence for patients under 44 years old was observed, while an increasing trend for those aged over 45 years was indicated. Incidences of RTI and assaults decreased, while ground level fall presented increasing incidences. The total number of deaths was 933 (8.43%), with a decreasing trend in overall mortality since 2011. Age, cause of injury, GCS at admission, Injury Severity Score, shock state at admission, trauma-related diagnoses and treatments were significantly associated with mortality. A predictive nomogram model for poor prognosis was developed based on patient's GOS scores at discharge. Conclusions: The trends and characteristics of TBI patients changed with rapid development of urbanization in the past 18 years. Further larger studies are warranted to verify its clinical suggestions.
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OBJECTIVE: Spontaneous basal ganglia hemorrhage is a common type of intracerebral hemorrhage (ICH) with no definitive treatment. Minimally invasive endoscopic evacuation is a promising therapeutic approach for ICH. In this study the authors examined prognostic factors associated with long-term functional dependence (modified Rankin Scale [mRS] score ≥ 4) in patients who had undergone endoscopic evacuation of basal ganglia hemorrhage. METHODS: In total, 222 consecutive patients who underwent endoscopic evacuation between July 2019 and April 2022 at four neurosurgical centers were enrolled prospectively. Patients were dichotomized into functionally independent (mRS score ≤ 3) and functionally dependent (mRS score ≥ 4) groups. Hematoma and perihematomal edema (PHE) volumes were calculated using 3D Slicer software. Predictors of functional dependence were assessed using logistic regression models. RESULTS: Among the enrolled patients, the functional dependence rate was 45.50%. Factors independently associated with long-term functional dependence included female sex, older age (≥ 60 years), Glasgow Coma Scale score ≤ 8, larger preoperative hematoma volume (OR 1.02), and larger postoperative PHE volume (OR 1.03, 95% CI 1.01-1.05). A subsequent analysis evaluated the effect of stratified postoperative PHE volume on functional dependence. Specifically, patients with large (≥ 50 to < 75 ml) and extra-large (≥ 75 to 100 ml) postoperative PHE volumes had 4.61 (95% CI 0.99-21.53) and 6.75 (95% CI 1.20-37.85) times greater likelihood of long-term dependence, respectively, than patients with a small postoperative PHE volume (≥ 10 to < 25 ml). CONCLUSIONS: A large postoperative PHE volume is an independent risk factor for functional dependence among basal ganglia hemorrhage patients after endoscopic evacuation, especially with postoperative PHE volume ≥ 50 ml.