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Hemispheric epilepsy is quite frequent in children, compared with adults, and encompasses pathological substrates as diverse as hemimegalencephaly, Rasmussen encephalitis, Sturge-Weber syndrome, and porencephaly, among others. These patients most often become pharmacoresistant and thus require surgical management. Although anatomical hemispherectomy is a possibility, the technique that is favored by most epilepsy surgery centers worldwide is functional hemispherotomy, which results in equivalent outcomes with fewer postoperative complications. Therefore, it is essential that pediatric epilepsy neurosurgeons become familiar with these techniques. The present video describes in detail all surgical aspects of the perisylvian hemispherotomy.
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We investigated the participation of the nucleus of the tractus solitarius (NTS) in tonicâclonic seizures and postictal antinociception control mediated by NMDA receptors, the role of NTS GABAergic interneurons and noradrenergic pathways from the locus coeruleus (LC) in these phenomena. The NTS-lateral nucleus reticularis paragigantocellularis (lPGi)-LC pathway was studied by evaluating neural tract tracer deposits in the lPGi. NMDA and GABAergic receptors agonists and antagonists were microinjected into the NTS, followed by pharmacologically induced seizures. The effects of LC neurotoxic lesions caused by DSP-4, followed by NTS-NMDA receptor activation, on both tonicâclonic seizures and postictal antinociception were also investigated. The NTS is connected to lPGi neurons that send outputs to the LC. Glutamatergic vesicles were found on dendrites and perikarya of GABAergic interneurons in the NTS. Both tonicâclonic seizures and postictal antinociception are partially dependent on glutamatergic-mediated neurotransmission in the NTS of seizing rats in addition to the integrity of the noradrenergic system since NMDA receptor blockade in the NTS and intrathecal administration of DSP-4 decrease the postictal antinociception. The GABAA receptor activation in the NTS decreases both seizure severity and postictal antinociception. These findings suggest that glutamatergic inputs to NTS-GABAergic interneurons, in addition to ascending and descending noradrenergic pathways from the LC, are critical for the control of both seizures and postictal antinociception.
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Benzilaminas , Locus Cerúleo , Receptores de N-Metil-D-Aspartato , Ratos , Animais , Locus Cerúleo/fisiologia , Receptores de N-Metil-D-Aspartato/metabolismo , Bulbo/metabolismo , Núcleo Solitário/metabolismo , Norepinefrina/metabolismo , Convulsões/metabolismoRESUMO
INTRODUCTION: Studies addressing the methylation pattern in adamantinomatous craniopharyngioma (ACP) are lacking. OBJECTIVE: To identify methylation signatures in ACPs regarding clinical presentation and outcome. METHODS: Clinical and pathology data were collected from 35 patients with ACP (54% male; 18.1 years [2-68]). CTNNB1 mutations and methylation profile (MethylationEPIC/Array-Illumina) were analyzed in tumoral DNA. Unsupervised machine learning analysis of this comprehensive methylome sample was achieved using hierarchical clustering and multidimensional scaling. Statistical associations between clusters and clinical features were achieved using the Fisher test and global biological process interpretations were aided by Gene Ontology enrichment analyses. RESULTS: Two clusters were revealed consistently by all unsupervised methods (ACP-1: n = 18; ACP-2: n = 17) with strong bootstrap statistical support. ACP-2 was enriched by CTNNB1 mutations (100% vs 56%, P = .0006), hypomethylated in CpG island, non-CpG Island sites, and globally (P < .001), and associated with greater tumor size (24.1 vs 9.5 cm3, P = .04). Enrichment analysis highlighted pathways on signaling transduction, transmembrane receptor, development of anatomical structures, cell adhesion, cytoskeleton organization, and cytokine binding, and cell type-specific biological processes as regulation of oligodendrocytes, keratinocyte, and epithelial cells differentiation. CONCLUSION: Two clusters of patients with ACP were consistently revealed by unsupervised machine learning methods, with one of them significantly hypomethylated, enriched by CTNNB1 mutated ACPs, and associated with increased tumor size. Enrichment analysis reinforced pathways involved in tumor proliferation and in cell-specific tumoral microenvironment.
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Craniofaringioma , Metilação de DNA , Epigênese Genética , Neoplasias Hipofisárias , beta Catenina , Humanos , Craniofaringioma/genética , Craniofaringioma/patologia , Masculino , Feminino , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/patologia , Adolescente , Adulto , Criança , Pessoa de Meia-Idade , Adulto Jovem , beta Catenina/genética , beta Catenina/metabolismo , Pré-Escolar , Idoso , Mutação , Ilhas de CpG/genética , Regulação Neoplásica da Expressão GênicaRESUMO
PURPOSE: Hydrocephalus is a brain disease prevalent in the pediatric population that presents complex pathophysiology and multiple etiologies. The best treatment is still ventricular shunting. Mechanical obstruction is the most frequent complication, but the resulting pathological effects are still unknown. OBJECTIVE: Evaluation and comparison of clinical, histopathological, and immunohistochemical aspects in the acute phase of experimental hydrocephalus induced by kaolin, after treatment with adapted shunt, and after shunt obstruction and posterior disobstruction. METHODS: Wistar rats aged 7 days were used and divided into 4 groups: control group without kaolin injection (n = 6), untreated hydrocephalic group (n = 5), hydrocephalic group treated with ventriculosubcutaneous shunt (DVSC) (n = 7), and hydrocephalic group treated with shunt, posteriorly obstructed and disobstructed (n = 5). The animals were submitted to memory and spatial learning evaluation through the Morris water maze test. The rats were sacrificed at 28 days of age and histological analysis of the brains was performed with luxol fast blue, in addition to immunohistochemical analysis in order to evaluate reactive astrocytosis, inflammation, neuronal labeling, and apoptotic activity. RESULTS: The group with shunt obstruction had worse performance in memory tests. Reactive astrocytosis was more evident in this group, as was the inflammatory response. CONCLUSIONS: Obstruction of the shunt results in impaired performance of behavioral tests and causes irreversible histopathological changes when compared to findings in the group with treated hydrocephalus, even after unblocking the system. The developed model is feasible and efficient in simulating the clinical context of shunt dysfunction.
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Hidrocefalia , Caulim , Criança , Humanos , Ratos , Animais , Ratos Wistar , Gliose/patologia , Hidrocefalia/cirurgia , Encéfalo/patologiaRESUMO
The present article describes pathophysiological and clinical aspects of congenital malformations of the cerebral tissue (cortex and white matter) that cause epilepsy and very frequently require surgical treatment. A particular emphasis is given to focal cortical dysplasias, the most common pathology among these epilepsy-related malformations. Specific radiological and surgical features are also highlighted, so a thorough overview of cortical dysplasias is provided.
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Epilepsia , Displasia Cortical Focal , Malformações do Desenvolvimento Cortical , Humanos , Malformações do Desenvolvimento Cortical/complicações , Epilepsia/etiologia , Córtex Cerebral/diagnóstico por imagem , Imageamento por Ressonância Magnética/efeitos adversosRESUMO
Neuropathic pain (NP) represents a complex disorder with sensory, cognitive, and emotional symptoms. The medial prefrontal cortex (mPFC) takes critical regulatory roles and may change functionally and morphologically during chronic NP. There needs to be a complete understanding of the neurophysiological and psychopharmacological bases of the NP phenomenon. This study aimed to investigate the participation of the infralimbic division (IFL) of the mPFC in chronic NP, as well as the role of the N-methyl-D-aspartic acid receptor (NMDAr) in the elaboration of chronic NP. Male Wistar rats were submitted to the von Frey and acetone tests to assess mechanical and cold allodynia after 21 days of chronic constriction injury (CCI) of the sciatic nerve or Sham-procedure ("false operated"). Electrical neurostimulation of the IFL/mPFC was performed by low-frequency stimuli (20 µA, 100 Hz) applied for 15 s by deep brain stimulation (DBS) device 21 days after CCI. Either cobalt chloride (CoCl2 at 1.0 mM/200 nL), NMDAr agonist (at 0.25, 1.0, and 2.0 nmol/200 nL) or physiological saline (200 nL) was administered into the IFL/mPFC. CoCl2 administration in the IFL cortex did not alter either mechanical or cold allodynia. DBS stimulation of the IFL cortex decreased mechanical allodynia in CCI rats. Chemical stimulation of the IFL cortex by an NMDA agonist (at 2.0 nmol) decreased mechanical allodynia. NMDA at any dose (0.25, 1.0, and 2.0 nmol) reduced the flicking/licking duration in the cold test. These findings suggest that the IFL/mPFC and the NMDAr of the neocortex are involved in attenuating chronic NP in rats.
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Hiperalgesia , Neuralgia , Ratos , Masculino , Animais , N-Metilaspartato/farmacologia , Medição da Dor , Ratos Wistar , Neuralgia/terapia , Receptores de N-Metil-D-Aspartato/metabolismo , Córtex Pré-Frontal/metabolismoRESUMO
OBJECTIVE: Rasmussen Encephalitis (RE) is a rare inflammatory neurodegenerative disease associated with refractory seizures, hemiparesis, and cognitive deterioration, due to lateralized cortical atrophy. Hemispheric surgery (hemispherotomy) is the mainstay of treatment, but its unavoidable motor deficits and lack of long-term data regarding seizure outcomes can make patients and families apprehensive to undergo this procedure. The present study aimed at analyzing the results of surgical treatment for RE from a motor and epilepsy standpoint, and mitigate such concerns. METHODS: Clinical and operative data were retrospectively collected from medical records of pharmacoresistant patients treated with functional hemispherectomy at a tertiary reference center for epilepsy surgery, during a 24-year period (1996-2020). Variables such as age of epilepsy onset, seizure semiology, seizure frequency, immunomodulatory therapy, age at surgery, duration of epilepsy, surgical procedures and complications, number of medications used preoperatively and postoperatively were described and statistically analyzed. RESULTS: Forty-three (43) patients were included in this study. Mean age of epilepsy onset was 6.14 years, the average interval between epilepsy onset and hemispherotomy was 2.21 years. and the mean age at surgery was 8.28 years. Thirty patients (69.7%) were Engel I at their last follow-up, of whom 23 (56.4%) were Engel Ia, within a mean follow-up of 11.3 years. Duration of epilepsy, seizure frequency, and age at surgery, among others, did not correlate with seizure outcome, except the use of immunotherapy which led to worse outcomes (p < .05). Also, after surgery, motor functionality was significantly recovered (i.e., most patients returned to their previous status) with time. SIGNIFICANCE: This study tackled some issues regarding the surgical treatment of this disease, particularly showing that hemispherotomy is safe and leads to potentially recoverable disability of motor functions while providing high rates of effective and long-lasting seizure control; therefore, early surgical indication should be warranted once medical refractoriness has been established.
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Encefalite , Epilepsia , Hemisferectomia , Doenças Neurodegenerativas , Criança , Humanos , Resultado do Tratamento , Estudos Retrospectivos , Doenças Neurodegenerativas/complicações , Convulsões/cirurgia , Convulsões/complicações , Hemisferectomia/efeitos adversos , Encefalite/complicaçõesRESUMO
Groups (Grp) 3 and 4 are aggressive molecular subgroups of medulloblastoma (MB), with high rates of leptomeningeal dissemination. To date, there is still a paucity of biomarkers for these subtypes of MBs. In this study, we investigated the clinical significance and biological functions of Musashi-1 (MSI1) in Grp3 and Grp4-MBs. First, we assessed the expression profile of MSI1 in 59 primary MB samples (15-WNT, 18-SHH, 9-Grp3, and 17-Grp4 subgroups) by qRT-PCR. MSI1 mRNA expression levels were also validated in an additional public dataset of MBs (GSE85217). The ROC curve was used to validate the diagnostic standards of MSI1 expression. Next, the potential correlated cell-cycle genes were measured by RNA-Seq. Cell cycle, cell viability, and apoptosis were evaluated in a Grp3/Grp4 MB cell line after knockdown of MSI1 and cisplatin treatment. We identified an overexpression of MSI1 with a high accuracy to discriminate Grp3/Grp4-MBs from non-Grp3/Grp4-MBs. We identified that MSI1 knockdown not only triggered transcriptional changes in the cell-cycle pathway, but also affected G2/M phase in vitro, supporting the role of knockdown of MSI1 in cell-cycle arrest. Finally, MSI1 knockdown decreased cell viability and sensitized D283-Med cells to cisplatin treatment by enhancing cell apoptosis. Based on these findings, we suggest that MSI1 modulates cell-cycle progression and may play a role as biomarker for Grp3/Grp4-MBs. In addition, MSI1 knockdown combined with cisplatin may offer a potential strategy to be further explored in Grp3/Grp4-MBs.
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OBJECTIVE: To explore pituitary tumors by methylome and transcriptome signatures in a heterogeneous ethnic population. METHODS: In this retrospective cross-sectional study, clinicopathological features, methylome, and transcriptome were evaluated in pituitary tumors from 77 patients (61% women, age 12-72 years) followed due to functioning (FPT: GH-secreting n = 18, ACTH-secreting n = 14) and nonfunctioning pituitary tumors (NFPT, n = 45) at Ribeirao Preto Medical School, University of São Paulo. RESULTS: Unsupervised hierarchical clustering analysis (UHCA) of methylome (n = 77) and transcriptome (n = 65 out of 77) revealed 3 clusters each: one enriched by FPT, one by NFPT, and a third by ACTH-secreting and NFPT. Comparison between each omics-derived clusters identified 3568 and 5994 differentially methylated and expressed genes, respectively, which were associated with each other, with tumor clinical presentation, and with 2017 and 2022 WHO classifications. UHCA considering 11 transcripts related to pituitary development/differentiation also supported 3 clusters: POU1F1-driven somatotroph, TBX19-driven corticotroph, and NR5A1-driven gonadotroph adenomas, with rare exceptions (NR5A1 expressed in few GH-secreting and corticotroph silent adenomas; POU1F1 in few ACTH-secreting adenomas; and TBX19 in few NFPTs). CONCLUSION: This large heterogenic ethnic Brazilian cohort confirms that integrated methylome and transcriptome signatures classify FPT and NFPT, which are associated with clinical presentation and tumor invasiveness. Moreover, the cluster NFPT/ACTH-secreting adenomas raises interest regarding tumor heterogeneity, supporting the challenge raised by the 2017 and 2022 WHO definition regarding the discrepancy, in rare cases, between clinical presentation and pituitary lineage markers. Finally, making our data publicly available enables further studies to validate genes/pathways involved in pituitary tumor pathogenesis and prognosis.
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Adenoma Hipofisário Secretor de ACT , Adenoma , Neoplasias Hipofisárias , Humanos , Feminino , Criança , Adolescente , Adulto Jovem , Adulto , Pessoa de Meia-Idade , Idoso , Masculino , Neoplasias Hipofisárias/genética , Neoplasias Hipofisárias/patologia , Adenoma/genética , Adenoma/patologia , Epigenoma , Transcriptoma , Estudos Retrospectivos , Estudos Transversais , Adenoma Hipofisário Secretor de ACT/genética , Hormônio Adrenocorticotrópico/genéticaRESUMO
PURPOSE: We aimed to analyze the potential for postoperative (PO) medication suspension and reduction, emphasizing passive withdrawal. METHODS: Retrospective study of patients under 18 years old submitted to surgical treatment for pharmacoresistant epilepsy and classified as Engel I during the first year of PO follow-up. Therapeutic management was evaluated through discontinuation or reduction of medications, both in terms of the number of ASM prescribed and in daily maintenance dosages in mg/kg. RESULTS: ASM withdrawal started in the first year PO and occurred in 1.2% of cases, with a significant yearly reduction in the number of ASM during follow-up (p < 0.001). A comparison of the most commonly used ASM in daily mg/kg between the preoperative period (preop) and PO showed a reduction of ASM maintenance dosages during PO. Even though recurrence of seizures was observed 5 years after surgery, 125 patients (85%) were still classified as Engel I, albeit a higher number of ASM per patient was observed. Most patients showed no changes in cognitive and adaptive behavior evaluation between preop and PO, even in those who were able to reduce ASM. CONCLUSION: Significant reduction observed both in the number and daily maintenance dosages of ASM following each year of PO may be an indirect measure of the effectiveness of epilepsy surgery.
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Anticonvulsivantes , Epilepsia , Humanos , Criança , Adolescente , Estudos Retrospectivos , Anticonvulsivantes/uso terapêutico , Anticonvulsivantes/efeitos adversos , Resultado do Tratamento , Epilepsia/tratamento farmacológico , Epilepsia/cirurgia , Procedimentos NeurocirúrgicosRESUMO
Objectives: To evaluate how telomere length behaves in adamantinomtous craniopharyngioma (aCP) and if it contributes to the pathogenesis of aCPs with and without CTNNB1 mutations. Design: Retrospective cross-sectional study enrolling 42 aCP patients from 2 tertiary institutions. Methods: Clinicopathological features were retrieved from the patient's charts. Fresh frozen tumors were used for RNA and DNA analyses. Telomere length was evaluated by qPCR (T/S ratio). Somatic mutations in TERT promoter (TERTp) and CTNNB1 were detected by Sanger and/or whole-exome sequencing. We performed RNA-Seq to identify differentially expressed genes in aCPs presenting with shorter or longer telomere lengths. Results: Mutations in CTNNB1 were detected in 29 (69%) tumors. There was higher frequency of CTNNB1 mutations in aCPs from patients diagnosed under the age of 15 years (85% vs 15%; P = 0.04) and a trend to recurrent disease (76% vs 24%; P = 0.1). No mutation was detected in the TERTp region. The telomeres were shorter in CTNNB1-mutated aCPs (0.441, IQR: 0.297-0.597vs 0.607, IQR: 0.445-0.778; P = 0.04), but it was neither associated with clinicopathological features nor with recurrence. RNAseq identified a total of 387 differentially expressed genes, generating two clusters, being one enriched for short telomeres and CTNNB1-mutated aCPs. Conclusions: CTNNB1: mutations are more frequent in children and adolescents and appear to associate with progressive disease. CTNNB1-mutated aCPs have shorter telomeres, demonstrating a relationship between the Wnt/ß-catenin pathway and telomere biology in the pathogenesis of aCPs.
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Craniofaringioma , Telômero , beta Catenina , Adolescente , Criança , Craniofaringioma/genética , Estudos Transversais , Humanos , Mutação , Estudos Retrospectivos , Telômero/ultraestrutura , Via de Sinalização Wnt , beta Catenina/genéticaRESUMO
The neuroprotective effect of Edaravone in young hydrocephalic rats associated with a CSF derivation system was evaluated. The drug has already been shown to be beneficial in experimental hydrocephalus, but the combination of this drug with shunt surgery has not yet been investigated. Fifty-seven-day-old Wistar rats submitted to hydrocephalus by injection of kaolin in the cisterna magna were used and divided into five groups: control (n = 10), hydrocephalic (n = 10), hydrocephalic treated with Edaravone (20 mg/kg/day) (n = 10), hydrocephalic treated with shunt (n = 10) and hydrocephalic treated with shunt and Edaravone (n = 10). Administration of the Edaravone was started 24 h after hydrocephalus induction (P1) and continued until the experimental endpoint (P21). The CSF shunt surgery was performed seven days after hydrocephalus induction (P7). Open-field tests, histological evaluation by hematoxylin and eosin, immunohistochemistry by Caspase-3 and GFAP, and ELISA biochemistry by GFAP were performed. Edaravone reduced reactive astrogliosis in the corpus callosum and germinal matrix (p < 0.05). When used alone or associated with CSF shunt surgery, the drug decreased the cell death process (p < 0.0001) and improved the morphological aspect of the astroglia (p < 0.05). The results showed that Edaravone associated with CSF bypass surgery promotes neuroprotection in young hydrocephalic rats by reducing reactive astrogliosis and decreasing cell death.
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Astrócitos , Neuroproteção , Animais , Apoptose , Astrócitos/metabolismo , Edaravone/metabolismo , Edaravone/farmacologia , Ratos , Ratos WistarRESUMO
BACKGROUND: Meningiomas are the most frequent primary central nervous system (CNS) tumors. Their geographical and ethnic characteristics need to be known, in order to enable rational treatment. OBJECTIVE: To investigate clinical and epidemiological aspects in a series of patients with meningiomas. METHODS: Retrospective analysis on the demographic profile, location and histopathology of 993 patients with meningiomas (768 operated and 225 not operated). RESULTS: Meningiomas represented 43.8% of the primary CNS tumors; 6.8% were multiple tumors (14.7% with neurofibromatosis 2) and 0.6% were radiation-induced tumors. The mean ages were 53.0 and 63.9 years for operated and non-operated patients and the female/male ratios were 3.2:1 and 6.3:1. Diagnosis was made later among females. The peak incidences were in the 6th and 7th decades respectively for operated and non-operated patients. The incidence was low at early ages and higher among patients aged 70+ years. The meningiomas were intracranial in 96.5% and most were WHO grade I (88.9%) and transitional. In the spinal canal (3.5%), they occurred mainly in the dorsal region (all grade I; mostly transitional). The racial distribution was 1.0% in Asian-Brazilians, 87% in Caucasians and 12% in African-Brazilians. 83.4% and 51.6% of the patients were estimated to be recurrence-free at 10 and 20 years, and the mortality rate was 3%. CONCLUSIONS: Most of the demographic data were similar to what has been observed in other western centers. Differences were higher incidence of meningiomas, female and older predominance in non-operated patients, predominance in Caucasian, and higher association with neurofibromatosis 2.
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Neoplasias Meníngeas , Meningioma , Neurofibromatose 2 , Feminino , Humanos , Masculino , Neoplasias Meníngeas/epidemiologia , Meningioma/epidemiologia , Pessoa de Meia-Idade , Recidiva Local de Neoplasia , Estudos RetrospectivosRESUMO
Myelomeningocele (MMC), the commonest type of spina bifida (SB), occurs due to abnormal development of the neural tube and manifest as failure of the complete fusion of posterior arches of the spinal column, leading to dysplastic growth of the spinal cord and meninges. It is associated with several degrees of motor and sensory deficits below the level of the lesion, as well as skeletal deformities, bladder and bowel incontinence, and sexual dysfunction. These children might develop varying degrees of neuropsychomotor delay, partly due to the severity of the injuries that affect the nervous system before birth, partly due to the related cerebral malformations (notably hydrocephalus-which may also lead to an increase in intracranial pressure-and Chiari II deformity). Traditionally, MMC was repaired surgically just after birth; however, intrauterine correction of MMC has been shown to have several potential benefits, including better sensorimotor outcomes (since exposure to amniotic fluid and its consequent deleterious effects is shortened) and reduced rates of hydrocephalus, among others. Fetal surgery for myelomeningocele, nevertheless, would not have been made possible without the development of experimental models of this pathological condition. Hence, the aim of the current article is to provide an overview of the animal models of MMC that were used over the years and describe how this knowledge has been translated into the fetal treatment of MMC in humans.
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Malformação de Arnold-Chiari , Terapias Fetais , Hidrocefalia , Meningomielocele , Disrafismo Espinal , Animais , Feminino , Humanos , Hidrocefalia/etiologia , Meningomielocele/complicações , Gravidez , Disrafismo Espinal/complicaçõesRESUMO
ABSTRACT Background: Meningiomas are the most frequent primary central nervous system (CNS) tumors. Their geographical and ethnic characteristics need to be known, in order to enable rational treatment. Objective: To investigate clinical and epidemiological aspects in a series of patients with meningiomas. Methods: Retrospective analysis on the demographic profile, location and histopathology of 993 patients with meningiomas (768 operated and 225 not operated). Results: Meningiomas represented 43.8% of the primary CNS tumors; 6.8% were multiple tumors (14.7% with neurofibromatosis 2) and 0.6% were radiation-induced tumors. The mean ages were 53.0 and 63.9 years for operated and non-operated patients and the female/male ratios were 3.2:1 and 6.3:1. Diagnosis was made later among females. The peak incidences were in the 6th and 7th decades respectively for operated and non-operated patients. The incidence was low at early ages and higher among patients aged 70+ years. The meningiomas were intracranial in 96.5% and most were WHO grade I (88.9%) and transitional. In the spinal canal (3.5%), they occurred mainly in the dorsal region (all grade I; mostly transitional). The racial distribution was 1.0% in Asian-Brazilians, 87% in Caucasians and 12% in African-Brazilians. 83.4% and 51.6% of the patients were estimated to be recurrence-free at 10 and 20 years, and the mortality rate was 3%. Conclusions: Most of the demographic data were similar to what has been observed in other western centers. Differences were higher incidence of meningiomas, female and older predominance in non-operated patients, predominance in Caucasian, and higher association with neurofibromatosis 2.
RESUMO Antecedentes: Meningiomas são os tumores mais frequentes do sistema nervoso central (SNC). Suas características étnicas e geográficas precisam ser conhecidas para o seu tratamento racional. Objetivo: Investigar aspectos clínicos e epidemiológicos de uma série de pacientes com meningiomas. Métodos: Análise retrospectiva demográfica de 993 pacientes com meningiomas (768 operados e 225 tratados conservadoramente) Resultados: Meningiomas constituíram 43.8% dos tumores primários do SNC. 0.8% deles eram múltiplos (14,7% com neurofibromatose 2) e 0,6% eram radioinduzidos. A idade média e o índice mulheres/homens foram respectivamente 53,0 e 63,9 anos e 3.2:1 e 6.3:1 para pacientes operados e não operados. O diagnóstico foi mais tardio em mulheres. Ocorreram picos de incidências na 6ª e na 7ª décadas respectivamente para pacientes operados e não operados. A incidência foi menor na infância e maior após 70 anos. Meningiomas predominaram no crânio (96.5%), a maioria grau I da OMS, subtipo transicional. Do total, 3.5% ocorreram no canal raquídeo, principalmente na região torácica, todos grau I, a maioria transicional. Em relação à distribuição racial, 1.0% dos meningiomas ocorreu em amarelos, 87% em brancos e 12% em negros. As taxas de sobrevida sem recorrência foram 83.4% e 51.6% em 10 e 20 anos e a mortalidade operatória foi 3%. Conclusões: A maioria dos dados demográficos observados foi similar aos de outros centros ocidentais. As diferenças observadas foram maior incidência, predominância em mulheres e idosos nos pacientes não operados e em caucasianos, e maior associação com neurofibromatose 2.
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Humanos , Masculino , Feminino , Neurofibromatose 2 , Neoplasias Meníngeas/epidemiologia , Meningioma/epidemiologia , Estudos Retrospectivos , Pessoa de Meia-Idade , Recidiva Local de NeoplasiaRESUMO
PURPOSES: Demonstrate that transcranial ultrasonography (TUS) scanning is viable and useful as a diagnostic method in experimental hydrocephalus, as well as to compare measurements of cerebral and ventricular width obtained from TUS scans of hydrocephalic rats with post-mortem anatomical specimens, aiming for the development of accurate criteria to establish ventricular enlargement and progression of hydrocephalus subsequently. METHODS: Thirty-five male Wistar rats were used. Following hydrocephalus induction, they underwent a transcranial ultrasound scan to measure cerebral and ventricular dimensions, in the fourth and 21 post-induction days. By the end of the experiments, measurements obtained from TUS scans were compared with actual values as seen in the post-mortem specimens of each animal. RESULTS: Ventricular dilation could be clearly visualized in hydrocephalic animals. We performed intraclass correlation coefficient and linear regression analyses that have demonstrated a precise correlation between measurements of TUS scans and post-mortem specimens; we have found a similarity of 0,95 for the cerebral diameter and 0,97 for ventricular width. CONCLUSIONS: Transcranial ultrasonography is a useful and reliable diagnostic tool for experimental hydrocephalus; also, it can be used to assess the progression of ventriculomegaly in animal models of hydrocephalus.
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Hidrocefalia , Animais , Ventrículos Cerebrais/diagnóstico por imagem , Hidrocefalia/diagnóstico por imagem , Masculino , Projetos Piloto , Ratos , Ratos Wistar , UltrassonografiaRESUMO
BACKGROUND: Chronic constriction injury (CCI) is a model of neuropathic pain induced by four loose ligatures around the sciatic nerve. This work aimed to investigate the sensory, affective, cognitive, and motor changes induced by an adaptation of the CCI model by applying a single ligature around the sciatic nerve. METHODS: Mechanical allodynia was measured from day 1 to day 28 postsurgery by the von Frey test. The beam walking test (BWT) was conducted weekly until 28 days after surgery. Anxiety- and depression-like behaviors, and cognitive performance were assessed through the open field (OF), forced swimming (FS), and novel object recognition (NOR) tests, respectively, 21 days after surgery. RESULTS: The two CCI models, both Bennett and Xie's model (four ligatures of the sciatic nerve) and a modification of it (one ligature), induced mechanical allodynia, increased immobility in the FS, and reduced recognition index in the NOR. The exploratory behavior and time spent in the central part of the arena decreased, while the defensive behavior increased in the OF. The animals subjected to the two CCI models showed motor alterations in the BWT; however, autotomy was observed only in the group with four ligatures and not in the group with a single ligature. CONCLUSIONS: Overall these results demonstrate that our adapted CCI model, using a single ligature around the sciatic nerve, induces sensory, affective, cognitive, and motor alterations comparable to the CCI model with four ligatures without generating autotomy. This adaptation to the CCI model may therefore represent an appropriate and more easily performed model for inducing neuropathic pain and study underlying mechanisms and effective treatments.
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Disfunção Cognitiva , Mononeuropatias , Neuralgia , Animais , Constrição , Modelos Animais de Doenças , Hiperalgesia/epidemiologia , Neuralgia/epidemiologia , Neuralgia/etiologia , Ratos , Nervo IsquiáticoRESUMO
PURPOSE: Somatic mutations on H3 histone are currently considered a genetic hallmark for midline pediatric high-grade gliomas (HGGs). Yet, different tumor histologies have been occasionally described to carry these mutations. Since histone modifications can lead to major epigenetic changes with direct impact on prognosis and treatment, we thought to investigate the occurrence of H3F3A K27M and G34R/V mutations in a cohort of pediatric tumors which included HGGs, low-grade gliomas, ependymomas, medulloblastomas, and a series of rare brain tumor lesions of different histologies. METHODS: A total of 82 fresh-frozen pediatric brain tumor samples were evaluated. PCR or RT-PCR followed by Sanger sequencing for the exon 2 of H3F3A (containing both K27 and G34 hotspots) were obtained and aligned to human genome. Loss of trimethylation mark (H3K27me3) in H3F3A/K27M-mutant samples was confirmed by immunohistochemistry. RESULTS: We found H3F3A/K27M mutation in 2 out of 9 cases of HGGs; no H3F3A/K27M mutations were detected in low-grade gliomas (27), ependymomas (n = 10), medulloblastomas (n = 21), or a series of rare pediatric brain tumors which included meningiomas, dysembryoplastic neuroepithelial tumors (DNETs), central nervous system (CNS) germ-cell tumors, choroid plexus tumors, cortical hamartoma, subcortical tubers, and schwannomas (n = 15). H3F3A/G34R/V mutation was not observed in any of the samples. CONCLUSIONS: Our investigation reinforces the low frequency of H3F3A somatic mutations outside the HGG setting. Interestingly, an atypical focal brainstem glioma carrying H3F3A K27M mutation that showed protracted clinical course with late-onset tumor progression was identified.
Assuntos
Neoplasias Encefálicas , Neoplasias Cerebelares , Glioma , Histonas/genética , Neoplasias Meníngeas , Neoplasias Encefálicas/genética , Criança , Glioma/genética , Humanos , Mutação/genéticaRESUMO
Glioblastoma (GBM) is the most common primary malignant neoplasm of the central nervous system and, despite the standard therapy; the patients' prognoses remain dismal. The miRNA expression profiles have been associated with patient prognosis, suggesting that they may be helpful for tumor diagnosis and classification as well as predictive of tumor response to treatment. We described the microRNA expression profile of 29 primary GBM samples (9 pediatric GBMs) and 11 non-neoplastic white matter samples as controls (WM) by microarray analysis and we performed functional in vitro assays on these 2 most differentially expressed miRNAs. Hierarchical clustering analysis showed 3 distinct miRNA profiles, two of them in the GBM samples and a group consisting only of cerebral white matter. When adult and pediatric GBMs were compared to WM, 37 human miRNAs were found to be differentially expressed, with miR-10b-5p being the most overexpressed and miR-630 the most underexpressed. The overexpression of miR-630 was associated with reduced cell proliferation and invasion in the U87 GBM cell line, whereas the inhibition of miR-10b-5p reduced cell proliferation and colony formation in the U251 GBM cell line, suggesting that these miRNAs may act as tumor-suppressive and oncogenic miRNAs, respectively. The present study highlights the distinct epigenetic profiling of adult and pediatric GBMs and underscores the biological importance of mir-10b-5p and miR-630 for the pathobiology of these lethal tumors.
Assuntos
Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Glioblastoma/metabolismo , MicroRNAs/biossíntese , RNA Neoplásico/biossíntese , Adolescente , Adulto , Idoso , Linhagem Celular Tumoral , Criança , Pré-Escolar , Feminino , Glioblastoma/patologia , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
OBJECTIVE: Drebrins are crucial for synaptic function and dendritic spine development, remodeling, and maintenance. In temporal lobe epilepsy (TLE) patients, a significant hippocampal synaptic reorganization occurs, and synaptic reorganization has been associated with hippocampal hyperexcitability. This study aimed to evaluate, in TLE patients, the hippocampal expression of drebrin using immunohistochemistry with DAS2 or M2F6 antibodies that recognize adult (drebrin A) or adult and embryonic (pan-drebrin) isoforms, respectively. METHODS: Hippocampal sections from drug-resistant TLE patients with hippocampal sclerosis (HS; TLE, n = 33), of whom 31 presented with type 1 HS and two with type 2 HS, and autopsy control cases (n = 20) were assayed by immunohistochemistry and evaluated for neuron density, and drebrin A and pan-drebrin expression. Double-labeling immunofluorescences were performed to localize drebrin A-positive spines in dendrites (MAP2), and to evaluate whether drebrin colocalizes with inhibitory (GAD65) and excitatory (VGlut1) presynaptic markers. RESULTS: Compared to controls, TLE patients had increased pan-drebrin in all hippocampal subfields and increased drebrin A-immunopositive area in all hippocampal subfields but CA1. Drebrin-positive spine density followed the same pattern as total drebrin quantification. Confocal microscopy indicated juxtaposition of drebrin-positive spines with VGlut1-positive puncta, but not with GAD65-positive puncta. Drebrin expression in the dentate gyrus of TLE cases was associated negatively with seizure frequency and positively with verbal memory. TLE patients with lower drebrin-immunopositive area in inner molecular layer (IML) than in outer molecular layer (OML) had a lower seizure frequency than those with higher or comparable drebrin-immunopositive area in IML compared with OML. SIGNIFICANCE: Our results suggest that changes in drebrin-positive spines and drebrin expression in the dentate gyrus of TLE patients are associated with lower seizure frequency, more preserved verbal memory, and a better postsurgical outcome.