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1.
BMC Neurol ; 23(1): 7, 2023 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-36609211

RESUMO

BACKGROUND: Cytokine levels have been measured in acute encephalopathy (AE) to determine its pathology or as a diagnostic biomarker to distinguish it from febrile seizures (FS); however, the dynamics of cytokine level changes have not yet been fully captured in these two neurological manifestations. Thus, we aimed to explore the time course of serum cytokine level changes within 72 h after onset in AE and FS. METHODS: We retrospectively measured cytokine level in residual serum samples at multiple timepoints in seven children whose final diagnoses were AE or FS. RESULTS: The levels of 13 cytokines appeared to increase immediately after onset and peaked within 12-24 h after onset: interleukin (IL)-1ß, IL-4 IL-5, IL-6, IL-8, IL-10, IL-17, eotaxin, fibroblast growth factor, granulocyte colony-stimulating factor, interferon gamma, interferon-inducible protein-10, and macrophage chemoattractant protein-1. There were no dynamic changes in the levels of three cytokines (IL-1 receptor agonist, macrophage inflammatory protein-1α, and platelet-derived growth factor-bb) 72 h after onset. Levels of some cytokines decreased to around control levels within 48 h after onset: IL-1ß, IL-4, IL-5, IL-17, fibroblast growth factor, and interferon gamma. The levels of most cytokines appeared to be higher in AE, especially in hemorrhagic shock encephalopathy syndrome, than in FS. CONCLUSIONS: Cytokine levels in both AE and FS change dynamically, such as the levels of several cytokines increased within a few hours after onset and decreased at 12-24 h after onset. Therefore, it will be desirable to make clinical decisions regarding the administration of anti-inflammatory therapy in 24 h after onset in AE.


Assuntos
Encefalopatias , Convulsões Febris , Criança , Humanos , Citocinas , Interleucina-17 , Interferon gama , Interleucina-4 , Estudos Retrospectivos , Interleucina-5
2.
Nat Commun ; 14(1): 105, 2023 Jan 06.
Artigo em Inglês | MEDLINE | ID: mdl-36609405

RESUMO

Myelination processes are closely related to higher brain functions such as learning and memory. While their longitudinal observation has been crucial to understanding myelin-related physiology and various brain disorders, skull opening or thinning has been required to secure clear optical access. Here we present a high-speed reflection matrix microscope using a light source with a wavelength of 1.3 µm to reduce tissue scattering and aberration. Furthermore, we develop a computational conjugate adaptive optics algorithm designed for the recorded reflection matrix to optimally compensate for the skull aberrations. These developments allow us to realize label-free longitudinal imaging of cortical myelin through an intact mouse skull. The myelination processes of the same mice were observed from 3 to 10 postnatal weeks to the depth of cortical layer 4 with a spatial resolution of 0.79 µm. Our system will expedite the investigations on the role of myelination in learning, memory, and brain disorders.


Assuntos
Encefalopatias , Microscopia , Camundongos , Animais , Bainha de Mielina , Encéfalo/diagnóstico por imagem , Encéfalo/fisiologia , Crânio/fisiologia
3.
Diagn Pathol ; 18(1): 1, 2023 Jan 04.
Artigo em Inglês | MEDLINE | ID: mdl-36597112

RESUMO

BACKGROUND: Hyperammonemic encephalopathy (HE) is a rare and life-threatening complication of multiple myeloma, with underlying mechanisms that are not fully understood. In contrast to previously reported cases, most of which have been associated with IgG or IgA isotypes, we describe a patient with HE as the presenting symptom of non-producer multiple myeloma (NPMM). CASE PRESENTATION: A 60-year-old man developed lethargy that progressed into coma. He was found to have an elevated ammonia level, despite normal hepatic function. He was diagnosed with HE secondary to NPMM, demonstrating 80% plasma cells without light chain expression in the bone marrow and absence of a monoclonal protein in the serum or urine, including by matrix-assisted laser desorption ionization time-of-flight mass-spectrometry (MASS-FIX). Myeloma-directed therapy with daratumumab, bortezomib, cyclophosphamide and dexamethasone successfully reversed his HE. At clinical relapse, he received salvage chemotherapy followed by venetoclax therapy, leading to a short period of neurological recovery. CONCLUSIONS: This case demonstrates that HE can occur in a patient with NPMM and challenges the mechanism suggested by limited prior studies; i.e., that excess ammonia in multiple myeloma arises from degradation of M-proteins. We postulate that the neoplastic plasma cells in NPMM have amplified amino acid metabolism, despite lacking detectable intracellular or secreted immunoglobulins.


Assuntos
Encefalopatias , Mieloma Múltiplo , Masculino , Humanos , Pessoa de Meia-Idade , Mieloma Múltiplo/complicações , Mieloma Múltiplo/diagnóstico , Amônia/uso terapêutico , Recidiva Local de Neoplasia , Bortezomib/uso terapêutico
4.
Rev. esp. anestesiol. reanim ; 70(1): 51-55, Ene. 2023. ilus
Artigo em Espanhol | IBECS | ID: ibc-214184

RESUMO

El síndrome de encefalopatía posterior reversible es un trastorno neurológico agudo caracterizado por una sintomatología variable e imágenes radiológicas características de edema vasogénico parietooccipital. Está asociado a condiciones clínicas como hipertensión arterial, infección/sepsis o fármacos citotóxicos/inmunosupresores, entre otros. Se caracteriza fisiopatológicamente por daño endotelial con rotura de la barrera hematoencefálica, hipoperfusión cerebral y edema vasogénico. Presentamos 2 casos de pacientes críticos COVID-19 que ingresaron por neumonía con necesidad de ventilación mecánica y que tras retirar la sedación desarrollaron clínica neurológica aguda y reversible consistente en epilepsia y encefalopatía, asociada a lesiones subcorticales hiperintensas en la resonancia magnética cerebral compatibles con síndrome de encefalopatía posterior reversible. El coronavirus SARS-CoV-2 activaría una respuesta inflamatoria que produciría daño en el endotelio cerebral. Este último podría ser desencadenado por la liberación de citocinas, así como por una lesión viral directa, dado que el endotelio expresa receptores ACE2. Esto podría explicar la posible asociación entre el síndrome de encefalopatía posterior reversible y la COVID-19.(AU)


Posterior reversible encephalopathy syndrome is an acute neurological disorder characterized by variable symptoms and radiological images characteristic of vasogenic parietal-occipital edema. It is associated with clinical conditions such as high blood pressure, infection/sepsis, or cytotoxic/immunosuppressive drugs, among others. It is characterized pathophysiologically by endothelial damage with breakdown of blood-brain barrier, cerebral hypoperfusion, and vasogenic edema. The cases are presented on 2 critical COVID-19 patients who were admitted to pneumonia requiring mechanical ventilation and who, after removing sedation, developed acute and reversible neurological symptoms consisting of epilepsy and encephalopathy, associated with hyperintense subcortical lesions on brain magnetic resonance imaging compatible with posterior reversible encephalopathy syndrome. SARS-CoV-2 coronavirus would activate an inflammatory response that would damage brain endothelium. It could be triggered by cytokine release, as well as by direct viral injury, given that endothelium expresses ACE2 receptors. It could explain the possible association between posterior reversible encephalopathy syndrome and COVID-19.(AU)


Assuntos
Humanos , Masculino , Idoso , Encefalopatias , Infecções por Coronavirus , Epilepsia , Pacientes Internados , Exame Físico , Leucoencefalopatia Multifocal Progressiva , Doenças do Sistema Nervoso
5.
Signal Transduct Target Ther ; 8(1): 39, 2023 Jan 17.
Artigo em Inglês | MEDLINE | ID: mdl-36650130

RESUMO

Nucleic acid drugs have the advantages of rich target selection, simple in design, good and enduring effect. They have been demonstrated to have irreplaceable superiority in brain disease treatment, while vectors are a decisive factor in therapeutic efficacy. Strict physiological barriers, such as degradation and clearance in circulation, blood-brain barrier, cellular uptake, endosome/lysosome barriers, release, obstruct the delivery of nucleic acid drugs to the brain by the vectors. Nucleic acid drugs against a single target are inefficient in treating brain diseases of complex pathogenesis. Differences between individual patients lead to severe uncertainties in brain disease treatment with nucleic acid drugs. In this Review, we briefly summarize the classification of nucleic acid drugs. Next, we discuss physiological barriers during drug delivery and universal coping strategies and introduce the application methods of these universal strategies to nucleic acid drug vectors. Subsequently, we explore nucleic acid drug-based multidrug regimens for the combination treatment of brain diseases and the construction of the corresponding vectors. In the following, we address the feasibility of patient stratification and personalized therapy through diagnostic information from medical imaging and the manner of introducing contrast agents into vectors. Finally, we take a perspective on the future feasibility and remaining challenges of vector-based integrated diagnosis and gene therapy for brain diseases.


Assuntos
Encefalopatias , Ácidos Nucleicos , Humanos , Preparações Farmacêuticas , Ácidos Nucleicos/genética , Ácidos Nucleicos/uso terapêutico , Terapia Genética , Encefalopatias/diagnóstico , Encefalopatias/tratamento farmacológico , Encefalopatias/genética , Sistemas de Liberação de Medicamentos/métodos
6.
Int J Mol Sci ; 24(2)2023 Jan 10.
Artigo em Inglês | MEDLINE | ID: mdl-36674898

RESUMO

Exposure to the toxin thioacetamide (TAA) causes acute hepatic encephalopathy (HE), changes in the functioning of systemic organs, and an imbalance in a number of energy metabolites. The deferred effects after acute HE development are poorly understood. The study considers the balance of the tricarboxylic acid (TCA) cycle metabolites in the blood plasma, liver, kidneys, and brain tissues of rats in the post-rehabilitation period. The samples of the control (n = 3) and TAA-induced groups of rats (n = 13) were collected six days after the administration of a single intraperitoneal TAA injection at doses of 200, 400, and 600 mg/kg. Despite the complete physiological recovery of rats by this date, a residual imbalance of metabolites in all the vital organs was noted. The results obtained showed a trend of stabilizing processes in the main organs of the animals and permit the use of these data both for prognostic purposes and the choice of potential therapeutic agents.


Assuntos
Encefalopatias , Encefalopatia Hepática , Falência Hepática Aguda , Ratos , Animais , Encefalopatia Hepática/induzido quimicamente , Tioacetamida/toxicidade , Ácidos Tricarboxílicos/metabolismo , Fígado/metabolismo , Falência Hepática Aguda/induzido quimicamente , Encefalopatias/metabolismo
7.
Cochrane Database Syst Rev ; 1: CD013808, 2023 01 10.
Artigo em Inglês | MEDLINE | ID: mdl-36625680

RESUMO

BACKGROUND: Continuous fetal heart rate monitoring by cardiotocography (CTG) is used in labour for women with complicated pregnancies. Fetal heart rate abnormalities are common and may result in the decision to expedite delivery by caesarean section. Fetal scalp stimulation (FSS) is a second-line test of fetal well-being that may provide reassurance that the labour can continue. OBJECTIVES: To evaluate methods of FSS as second-line tests of intrapartum fetal well-being in cases of non-reassuring CTG. FSS and CTG were compared to CTG alone, and to CTG with fetal blood sampling (FBS). SEARCH METHODS: We searched Cochrane Pregnancy and Childbirth's Trials Register (which includes trials from CENTRAL, MEDLINE, Embase, CINAHL, the WHO ICTRP and conference proceedings), ClinicalTrials.gov (18 October 2022), and reference lists of retrieved studies. SELECTION CRITERIA: Eligible studies were randomised controlled trials (RCTs) that compared any form of FSS to assess fetal well-being in labour. Quasi-RCTs, cluster-RCTs and studies published in abstract form were also eligible for inclusion, but none were identified. DATA COLLECTION AND ANALYSIS: Two review authors independently assessed studies for inclusion and risk of bias, extracted data and checked them for accuracy. We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS: Two trials, involving 377 women, met the inclusion criteria for this review. Both trials were conducted in hospital settings and included women with singleton, term (37+0 weeks or more) pregnancies, a cephalic presentation, and abnormal CTG. Follow-up was until hospital discharge after the birth. A pilot trial of 50 women in a high-income country (Ireland) compared CTG and digital fetal scalp stimulation (dFSS) with CTG and fetal blood sampling (FBS). A single-centre trial of 327 women in a lower middle-income country (India) compared CTG and manual fetal stimulation (abdominal or vaginal scalp stimulation) with CTG alone. The two included studies were at moderate or unclear risk of bias. Both trials provided clear information on allocation concealment but it was not possible to blind participants or health professionals in relation to the intervention. Although objective outcome measures were reported, outcome assessment was not blinded or blinding was unclear. dFSS and CTG versus FBS and CTG There were no perinatal deaths and data were not reported for neurodevelopmental disability at >/= 12 months. The risk of caesarean section (CS) may be lower with dFSS compared to FBS (risk ratio (RR) 0.38, 95% confidence interval (CI) 0.16 to 0.92; 1 pilot trial, 50 women; very low-certainty evidence) but the evidence is very uncertain. There were no cases of neonatal encephalopathy reported. The evidence was also very uncertain between dFSS and FBS for assisted vaginal birth (RR 1.44, 95% CI 0.76 to 2.75; very low-certainty evidence) and for the spontaneous vaginal birth rate (RR 2.33, 95% CI 0.68 to 8.01, very low-certainty evidence). Maternal acceptability of the procedures was not reported. FSS and CTG versus CTG alone Manual stimulation of the fetus was performed either abdominally (92/164) or vaginally (72/164). There were no perinatal deaths and data were not reported for neurodevelopmental disability at >/= 12 months. There may be little differences in the risk of CS on comparing manual fetal stimulation and CTG with CTG alone (RR 0.83, 95% CI 0.59 to 1.18; 1 trial, 327 women; very low-certainty evidence), but again the evidence was very uncertain. There were no cases of neonatal encephalopathy reported. There may be no differences in the risk of assisted vaginal birth (RR 1.43, 95% CI 0.78 to 2.60; very low-certainty evidence) or in the rates of spontaneous vaginal birth (RR 1.01, 95% CI 0.85 to 1.21, very low-certainty evidence), but again the evidence is very uncertain. Maternal acceptability of abdominal stimulation/FSS was not reported although 13 women withdrew consent after randomisation due to concerns about fetal well-being. AUTHORS' CONCLUSIONS: There is very low-certainty evidence available which makes it unclear whether stimulating the fetal scalp is a safe and effective way to confirm fetal well-being in labour. Evidence was downgraded based on limitations in study design and imprecision. Further high-quality studies of adequate sample size are required to evaluate this research question. In order to be generalisable, these trials should be conducted in different settings, including broad clinical criteria at both preterm and term gestational ages, and standardising the method of stimulation. There is an ongoing study (FIRSST) that will be incorporated into this review in a subsequent update.


Assuntos
Encefalopatias , Trabalho de Parto , Morte Perinatal , Recém-Nascido , Feminino , Gravidez , Humanos , Couro Cabeludo , Parto , Feto
9.
Brain Dev ; 45(2): 102-109, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36503814

RESUMO

AIM: To identify prognostic factors for severe neurological sequelae and epileptic seizures in children with human herpes virus (HHV) 6/7-associated acute encephalopathy (AE). METHODS: We retrospectively studied pediatric cases of HHV6/7-associated AE between April 2011 and March 2021. Neurological sequelae were assessed using the Pediatric Cerebral Performance Category scale (PCPC) and the presence of epileptic seizures 1 year after onset. We investigated the prognostic factors between the non-severe sequelae group (PCPC scores ≤ 2) and severe sequelae group (PCPC scores ≥ 3) in patients without severe neurological complications before onset. RESULTS: Forty patients, ranging from 4 to 95 months old, were included. AE with biphasic seizures and late reduced diffusion were the most common types of encephalopathy (n = 28). Among the 36 patients evaluated neurological sequelae, 17, nine, eight, and two were categorized as PCPC 1, 2, 3 and 4, respectively. Epileptic seizures were observed in nine patients. In the severe sequelae group, significantly more cases with coma in the acute phase and thalamic lesions on MRI and higher serum aspartate aminotransferase, alanine aminotransferase (ALT), and lactate dehydrogenase levels were observed. Multivariate analysis showed a significant between-group difference in the rate of coma (p = 0.0405). Patients with epileptic seizures had a higher rate of coma and thalamic lesions and higher serum ALT and urinary beta 2-microglobulin levels, but there was no significant difference in the multivariate analysis. CONCLUSIONS: In HHV6/7-associated AE, coma was a significant prognostic factor for severe neurological sequelae.


Assuntos
Encefalopatias , Epilepsia , Herpesvirus Humano 6 , Humanos , Criança , Lactente , Pré-Escolar , Coma , Prognóstico , Estudos Retrospectivos , Encefalopatias/patologia , Convulsões/etiologia , Epilepsia/complicações , Progressão da Doença
12.
Glia ; 71(1): 103-126, 2023 01.
Artigo em Inglês | MEDLINE | ID: mdl-35353392

RESUMO

The discovery of cannabinoid receptors as the primary molecular targets of psychotropic cannabinoid Δ9 -tetrahydrocannabinol (Δ9 -THC) in late 1980s paved the way for investigations on the effects of cannabis-based therapeutics in brain pathology. Ever since, a wealth of results obtained from studies on human tissue samples and animal models have highlighted a promising therapeutic potential of cannabinoids and endocannabinoids in a variety of neurological disorders. However, clinical success has been limited and major questions concerning endocannabinoid signaling need to be satisfactorily addressed, particularly with regard to their role as modulators of glial cells in neurodegenerative diseases. Indeed, recent studies have brought into the limelight diverse, often unexpected functions of astrocytes, oligodendrocytes, and microglia in brain injury and disease, thus providing scientific basis for targeting glial cells to treat brain disorders. This Review summarizes the current knowledge on the molecular and cellular hallmarks of endocannabinoid signaling in glial cells and its clinical relevance in neurodegenerative and chronic inflammatory disorders.


Assuntos
Encefalopatias , Canabinoides , Animais , Humanos , Endocanabinoides , Canabinoides/farmacologia , Receptores de Canabinoides/fisiologia , Dronabinol , Microglia
13.
Neurotoxicology ; 94: 217-222, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36481359

RESUMO

Increasing evidence reveals that delayed encephalopathy after acute carbon monoxide poisoning (DEACMP) results from the combined effects of environmental and genetic factors. The main pathological feature of DEACMP was generalized demyelination of cerebral white matter. Myelin basic protein (MBP) levels in cerebrospinal fluid (CSF) and serum samples from DEACMP patients were elevated. This study investigated the association of MBP single nucleotide polymorphisms(SNPs) (rs470555, rs470724, rs4890785, rs595997, rs76452994, and rs921336) with DEACMP. We genotyped 416 DEACMP patients and 785 age, educational level, and sex-matched ACMP patients for rs470555, rs470724, rs4890785, rs595997, rs76452994, and rs921336 SNPs using the Agena MassArray. There were no significant differences in the allele frequency distribution, four genetic models, and genotype distributions between the DEACMP and ACMP groups for rs470555, rs470724, rs4890785, and rs595997. However, significant differences were observed for rs76452994 and rs921336. This study revealed that the MBP polymorphisms, rs470555, rs470724, rs4890785, and rs595997, were not associated with DEACMP. Based on the codominant, dominant, and overdominant genetic inheritability patterns, the MBP rs76452994 and rs921366 polymorphisms were associated with DEACMP. Furthermore, the G allele of rs76452994 and T allele of rs921336 could lead to higher DEACMP risk.


Assuntos
Encefalopatias , Intoxicação por Monóxido de Carbono , Humanos , Encefalopatias/complicações , Intoxicação por Monóxido de Carbono/complicações , Intoxicação por Monóxido de Carbono/genética , Genótipo , Polimorfismo de Nucleotídeo Único
14.
Epilepsy Res ; 189: 107068, 2023 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-36549242

RESUMO

Collaboration is essential to the conduct of basic, applied and clinical research and its translation into the technologies and treatments urgently needed to improve the lives of people living with brain diseases and the health professionals who care for them. EPICLUSTER was formed in 2019 by the European Brain Research Area (EBRA) to support the coordination of epilepsy research in Europe. A key objective was to provide a platform to discuss shared research priorities by bringing together scientists and clinicians with multiple stakeholders including patient organisations and industry and the networks and infrastructures that provide healthcare and support research. Additional objectives were to facilitate access and sharing of data and biosamples, working together to ensure epilepsy is a priority for research funding, and embedding a culture of public and patient involvement (PPI) among epilepsy researchers. In this meeting report, we summarise the shared research priorities discussed by the leadership of EPICLUSTER at the recent final meeting. We also briefly review the discussion on patient and industry priorities, guidance on starting PPI for epilepsy researchers, and the sustainability of funding and infrastructures needed to ensure a comprehensive stakeholder-embedded community for epilepsy research.


Assuntos
Encefalopatias , Epilepsia , Médicos , Humanos , Epilepsia/terapia , Europa (Continente) , Encéfalo
15.
Pediatr Neurol ; 139: 59-64, 2023 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-36527993

RESUMO

Progressive encephalopathy with brain atrophy and thin corpus callosum (PEBAT) is a severe and rare progressive neurodegenerative disease (OMIM 617913). This condition has been described in individuals with pathogenic variants affecting tubulin-specific chaperone protein D (TBCD), which is responsible for proper folding and assembly of tubulin subunits. Here we describe two unrelated infants from Central America presenting with worsening neuromuscular weakness, respiratory failure, polyneuropathy, and neuroimaging findings of severe cerebral volume loss with thin corpus callosum. These individuals harbored the same homozygous variant of uncertain significance in the TBCD gene on whole exome sequencing (WES). Predicted protein modeling of this variant confirmed disruption of the protein helix at the surface of TBCD. The goal of this report is to emphasize the importance of rapid WES, careful interpretation of uncertain variants, prognostication, and family counseling especially when faced with a neurodegenerative clinical course.


Assuntos
Encefalopatias , Doenças Neurodegenerativas , Lactente , Humanos , Tubulina (Proteína)/genética , Tubulina (Proteína)/metabolismo , Proteínas Associadas aos Microtúbulos/genética , Doenças Neurodegenerativas/complicações , Doenças Neurodegenerativas/diagnóstico por imagem , Doenças Neurodegenerativas/genética , Encefalopatias/patologia
16.
J Exp Med ; 220(2)2023 Feb 06.
Artigo em Inglês | MEDLINE | ID: mdl-36441145

RESUMO

Upregulation of Notch signaling is associated with brain arteriovenous malformation (bAVM), a disease that lacks pharmacological treatments. Tetracycline (tet)-regulatable endothelial expression of constitutively active Notch4 (Notch4*tetEC) from birth induced bAVMs in 100% of mice by P16. To test whether targeting downstream signaling, while sustaining the causal Notch4*tetEC expression, induces AVM normalization, we deleted Rbpj, a mediator of Notch signaling, in endothelium from P16, by combining tet-repressible Notch4*tetEC with tamoxifen-inducible Rbpj deletion. Established pathologies, including AV connection diameter, AV shunting, vessel tortuosity, intracerebral hemorrhage, tissue hypoxia, life expectancy, and arterial marker expression were improved, compared with Notch4*tetEC mice without Rbpj deletion. Similarly, Rbpj deletion from P21 induced advanced bAVM regression. After complete AVM normalization induced by repression of Notch4*tetEC, virtually no bAVM relapsed, despite Notch4*tetEC re-expression in adults. Thus, inhibition of endothelial Rbpj halted Notch4*tetEC bAVM progression, normalized bAVM abnormalities, and restored microcirculation, providing proof of concept for targeting a downstream mediator to treat AVM pathologies despite a sustained causal molecular lesion.


Assuntos
Malformações Arteriovenosas , Encefalopatias , Malformações do Sistema Nervoso , Animais , Camundongos , Antibacterianos , Malformações Arteriovenosas/genética , Encéfalo , Endotélio , Proteína de Ligação a Sequências Sinal de Recombinação J de Imunoglobina/genética , Tetraciclina , Receptor Notch4/metabolismo
17.
Hum Mol Genet ; 31(6): 901-913, 2022 03 21.
Artigo em Inglês | MEDLINE | ID: mdl-34617111

RESUMO

Synaptic inhibition is essential for shaping the dynamics of neuronal networks, and aberrant inhibition is linked to epilepsy. Gephyrin (Geph) is the principal scaffolding protein at inhibitory synapses and is essential for postsynaptic clustering of glycine (GlyRs) and GABA type A receptors. Consequently, gephyrin is crucial for maintaining the relationship between excitation and inhibition in normal brain function and mutations in the gephyrin gene (GPHN) are associated with neurodevelopmental disorders and epilepsy. We identified bi-allelic variants in the GPHN gene, namely the missense mutation c.1264G > A and splice acceptor variant c.1315-2A > G, in a patient with developmental and epileptic encephalopathy. We demonstrate that the splice acceptor variant leads to nonsense-mediated mRNA decay. Furthermore, the missense variant (D422N) alters gephyrin structure, as examined by analytical size exclusion chromatography and circular dichroism-spectroscopy, thus leading to reduced receptor clustering and sensitivity towards calpain-mediated cleavage. In addition, both alterations contribute to an observed reduction of inhibitory signal transmission in neurons, which likely contributes to the pathological encephalopathy.


Assuntos
Encefalopatias , Epilepsia , Encefalopatias/metabolismo , Proteínas de Transporte/metabolismo , Epilepsia/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Receptores de GABA-A/metabolismo , Sinapses/metabolismo
18.
Rev Neurosci ; 33(5): 467-490, 2022 07 26.
Artigo em Inglês | MEDLINE | ID: mdl-34551223

RESUMO

Imaging in the second near-infrared II (NIR-II) window, a kind of biomedical imaging technology with characteristics of high sensitivity, high resolution, and real-time imaging, is commonly used in the diagnosis of brain diseases. Compared with the conventional visible light (400-750 nm) and NIR-I (750-900 nm) imaging, the NIR-II has a longer wavelength of 1000-1700 nm. Notably, the superiorities of NIR-II can minimize the light scattering and autofluorescence of biological tissue with the depth of brain tissue penetration up to 7.4 mm. Herein, we summarized the main principles of NIR-II in animal models of traumatic brain injury, cerebrovascular visualization, brain tumor, inflammation, and stroke. Simultaneously, we encapsulated the in vivo process of NIR-II probes and their in vivo and in vitro toxic effects. We further dissected its limitations and following optimization measures.


Assuntos
Encefalopatias , Imagem Óptica , Animais , Encéfalo/diagnóstico por imagem , Humanos , Imagem Óptica/métodos
19.
Zhongguo Zhong Yao Za Zhi ; 47(22): 5965-5977, 2022 Nov.
Artigo em Chinês | MEDLINE | ID: mdl-36471922

RESUMO

The blood-brain barrier(BBB), a protective barrier between brain tissues and brain capillaries, can prevent drugs from entering the brain tissues to exert the effect, which greatly increases the difficulty in treating brain diseases. The drug delivery system across the BBB can allow efficient drug delivery across the BBB by virtue of carriers and formulations, thereby enhancing the therapeutic effect of drugs on brain tissue diseases. Liposomes and micelles have been extensively studied with advances in the targeted therapy across the BBB for the brain due to their unique structures and drug delivery advantages. This study summarized the research status of liposome and micelle drug delivery systems across the BBB based on the literature in recent years and analyzed their application advantages and mechanism in terms of trans-BBB capability, targeting, and safety. Moreover, the problems and possible countermeasures in the research on trans-BBB liposomes and micelles were discussed according to the current clinical translation, which may provide refe-rences and ideas for the development of trans-BBB targeted nano-drugs.


Assuntos
Barreira Hematoencefálica , Encefalopatias , Humanos , Lipossomos , Micelas , Sistemas de Liberação de Medicamentos , Transporte Biológico , Encéfalo
20.
Cell Stem Cell ; 29(12): 1617-1618, 2022 Dec 01.
Artigo em Inglês | MEDLINE | ID: mdl-36459963

RESUMO

Human cortical organoids transplanted into the somatosensory cortex of rats integrate into the host neural circuits, receive inputs from host cells, and can produce behavioral responses. In a publication in Nature, Revah et al.1 highlight the potential of this platform for modeling circuit defects associated with neurodevelopmental disorders.


Assuntos
Encefalopatias , Transtornos do Neurodesenvolvimento , Humanos , Animais , Ratos , Organoides
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