RESUMO
OBJECTIVES: Delirium is a serious complication following neurosurgical procedures. We hypothesise that the beneficial effect of music on a combination of delirium-eliciting factors might reduce delirium incidence following neurosurgery and subsequently improve clinical outcomes. DESIGN: Prospective randomised controlled trial. SETTING: Single centre, conducted at the neurosurgical department of the Erasmus Medical Center, Rotterdam, the Netherlands. PARTICIPANTS: Adult patients undergoing craniotomy were eligible. INTERVENTIONS: Patients in the intervention group received preferred recorded music before, during and after the operation until day 3 after surgery. Patients in the control group were treated according to standard of clinical care. PRIMARY AND SECONDARY OUTCOME MEASURES: Primary outcome was presence or absence of postoperative delirium within the first 5 postoperative days measured with the Delirium Observation Screening Scale (DOSS) and, in case of a daily mean score of 3 or higher, a psychiatric evaluation with the latest Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria. Secondary outcomes included anxiety, heart rate variability (HRV), depth of anaesthesia, delirium severity and duration, postoperative complications, length of stay and location of discharge. RESULTS: We enrolled 189 patients (music=95, control=94) from July 2020 through September 2021. Delirium, as assessed by the DOSS, was less common in the music (n=11, 11.6%) than in the control group (n=21, 22.3%, OR:0.49, p=0.048). However, after DSM-5 confirmation, differences in delirium were not significant (4.2% vs 7.4%, OR:0.47, p=0.342). Moreover, music increased the HRV (root mean square of successive differences between normal heartbeats, p=0.012). All other secondary outcomes were not different between groups. CONCLUSION: Our results support the efficacy of music in reducing the incidence of delirium after craniotomy, as found with DOSS but not after DSM-5 confirmation, substantiated by the effect of music on preoperative autonomic tone. Delirium screening tools should be validated and the long-term implications should be evaluated after craniotomy. TRIAL REGISTRATION NUMBER: Trialregister.nl: NL8503 and ClinicalTrials.gov: NCT04649450.
Assuntos
Delírio , Música , Neurocirurgia , Adulto , Humanos , Estudos Prospectivos , Delírio/etiologia , Delírio/prevenção & controle , Delírio/diagnóstico , Procedimentos Neurocirúrgicos/efeitos adversosRESUMO
INTRODUCTION: Delirium is a neurocognitive disorder characterised by an acute and temporary decline of mental status affecting attention, awareness, cognition, language and visuospatial ability. The underlying pathophysiology is driven by neuroinflammation and cellular oxidative stress.Delirium is a serious complication following neurosurgical procedures with a reported incidence varying between 4% and 44% and has been associated with increased length of hospital stay, increased amount of reoperations, increased costs and mortality.Perioperative music has been reported to reduce preoperative anxiety, postoperative pain and opioid usage, and attenuates stress response caused by surgery. We hypothesize that this beneficial effect of music on a combination of delirium eliciting factors might reduce delirium incidence following neurosurgery and subsequently improve clinical outcomes. METHODS: This protocol concerns a single-centred prospective randomised controlled trial with 6 months follow-up. All adult patients undergoing a craniotomy at the Erasmus Medical Center in Rotterdam are eligible. The music group will receive recorded music through an overear headphone before, during and after surgery until postoperative day 3. Patients can choose from music playlists, offered based on music importance questionnaires administered at baseline. The control group will receive standard of clinical careDelirium is assessed by the Delirium Observation Scale and confirmed by a delirium-expert psychiatrist according to the DSM-5 criteria. Risk factors correlated with the onset of delirium, such as cognitive function at baseline, preoperative anxiety, perioperative medication use, depth of anaesthesia and postoperative pain, and delirium-related health outcomes such as length of stay, daily function, quality of life (ie, EQ-5D, EORTC questionnaires), costs and cost-effectiveness are collected. ETHICS AND DISSEMINATION: This study is being conducted in accordance with the Declaration of Helsinki. The Medical Ethics Review Board of Erasmus University Medical Center Rotterdam, The Netherlands, approved this protocol. Results will be disseminated via peer-reviewed scientific journals and conference presentations. TRIAL REGISTRATION NUMBERS: NL8503 and NCT04649450.
Assuntos
Delírio , Música , Neurocirurgia , Adulto , Delírio/etiologia , Delírio/prevenção & controle , Humanos , Procedimentos Neurocirúrgicos , Estudos Prospectivos , Qualidade de Vida , Ensaios Clínicos Controlados Aleatórios como AssuntoRESUMO
BACKGROUND: RASopathies are a group of disorders that result from mutations in genes coding for proteins involved in regulating the Ras-MAPK signaling pathway, and have an increased incidence of autism spectrum disorder (ASD). Legius syndrome is a rare RASopathy caused by loss-of-function mutations in the SPRED1 gene. The patient phenotype is similar to, but milder than, Neurofibromatosis type 1-another RASopathy caused by loss-of-function mutations in the NF1 gene. RASopathies exhibit increased activation of Ras-MAPK signaling and commonly manifest with cognitive impairments and ASD. Here, we investigated if a Spred1-/- mouse model for Legius syndrome recapitulates ASD-like symptoms, and whether targeting the Ras-MAPK pathway has therapeutic potential in this RASopathy mouse model. METHODS: We investigated social and communicative behaviors in Spred1-/- mice and probed therapeutic mechanisms underlying the observed behavioral phenotypes by pharmacological targeting of the Ras-MAPK pathway with the MEK inhibitor PD325901. RESULTS: Spred1-/- mice have robust increases in social dominance in the automated tube test and reduced adult ultrasonic vocalizations during social communication. Neonatal ultrasonic vocalization was also altered, with significant differences in spectral properties. Spred1-/- mice also exhibit impaired nesting behavior. Acute MEK inhibitor treatment in adulthood with PD325901 reversed the enhanced social dominance in Spred1-/- mice to normal levels, and improved nesting behavior in adult Spred1-/- mice. LIMITATIONS: This study used an acute treatment protocol to administer the drug. It is not known what the effects of longer-term treatment would be on behavior. Further studies titrating the lowest dose of this drug that is required to alter Spred1-/- social behavior are still required. Finally, our findings are in a homozygous mouse model, whereas patients carry heterozygous mutations. These factors should be considered before any translational conclusions are drawn. CONCLUSIONS: These results demonstrate for the first time that social behavior phenotypes in a mouse model for RASopathies (Spred1-/-) can be acutely reversed. This highlights a key role for Ras-MAPK dysregulation in mediating social behavior phenotypes in mouse models for ASD, suggesting that proper regulation of Ras-MAPK signaling is important for social behavior.
Assuntos
Transtorno do Espectro Autista , Neurofibromina 1 , Proteínas Adaptadoras de Transdução de Sinal/genética , Adulto , Animais , Humanos , Camundongos , Camundongos Knockout , Quinases de Proteína Quinase Ativadas por Mitógeno/genética , Quinases de Proteína Quinase Ativadas por Mitógeno/metabolismo , Neurofibromina 1/genética , Fenótipo , Comportamento SocialRESUMO
OBJECTIVE: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder that is associated with cognitive disabilities. Based on studies involving animals, the hypothesized cause of these disabilities results from increased activity of inhibitory interneurons that decreases synaptic plasticity. We obtained transcranial magnetic stimulation (TMS)-based measures of cortical inhibition, excitability and plasticity in individuals with NF1. METHODS: We included 32 NF1 adults and 32 neurotypical controls. Cortical inhibition was measured with short-interval intracortical inhibition (SICI) and cortical silent period (CSP). Excitability and plasticity were studied with intermittent theta burst stimulation (iTBS). RESULTS: The SICI and CSP response did not differ between NF1 adults and controls. The response upon iTBS induction was significantly increased in controls (70%) and in NF1 adults (83%). This potentiation lasted longer in controls than in individuals with NF1. Overall, the TMS response was significantly lower in NF1 patients (F(1, 41) = 7.552, p = 0.009). CONCLUSIONS: Individuals with NF1 may have reduced excitability and plasticity, as indicated by their lower TMS response and attenuation of the initial potentiated response upon iTBS induction. However, our findings did not provide evidence for increased inhibition in NF1 patients. SIGNIFICANCE: These findings have potential utility as neurophysiological outcome measures for intervention studies to treat cognitive deficits associated with NF1.
Assuntos
Excitabilidade Cortical/fisiologia , Potencial Evocado Motor/fisiologia , Córtex Motor/fisiopatologia , Neurofibromatose 1/fisiopatologia , Plasticidade Neuronal/fisiologia , Adolescente , Adulto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Ritmo Teta/fisiologia , Estimulação Magnética Transcraniana , Adulto JovemRESUMO
OBJECTIVE: To identify the clinical characteristics and genetic etiology of a family affected with hereditary spastic paraplegia (HSP). METHODS: Clinical, genetic, and functional analyses involving genome-wide linkage coupled to whole-exome sequencing in a consanguineous family with complicated HSP. RESULTS: A homozygous missense mutation was identified in the ACO2 gene (c.1240T>G p.Phe414Val) that segregated with HSP complicated by intellectual disability and microcephaly. Lymphoblastoid cell lines of homozygous carrier patients revealed significantly decreased activity of the mitochondrial aconitase enzyme and defective mitochondrial respiration. ACO2 encodes mitochondrial aconitase, an essential enzyme in the Krebs cycle. Recessive mutations in this gene have been previously associated with cerebellar ataxia. CONCLUSIONS: Our findings nominate ACO2 as a disease-causing gene for autosomal recessive complicated HSP and provide further support for the central role of mitochondrial defects in the pathogenesis of HSP.
RESUMO
Scarce access to primary samples and lack of efficient protocols to generate oligodendrocytes (OLs) from human pluripotent stem cells (hPSCs) are hampering our understanding of OL biology and the development of novel therapies. Here, we demonstrate that overexpression of the transcription factor SOX10 is sufficient to generate surface antigen O4-positive (O4+) and myelin basic protein-positive OLs from hPSCs in only 22 days, including from patients with multiple sclerosis or amyotrophic lateral sclerosis. The SOX10-induced O4+ population resembles primary human OLs at the transcriptome level and can myelinate neurons in vivo. Using in vitro OL-neuron co-cultures, myelination of neurons by OLs can also be demonstrated, which can be adapted to a high-throughput screening format to test the response of pro-myelinating drugs. In conclusion, we provide an approach to generate OLs in a very rapid and efficient manner, which can be used for disease modeling, drug discovery efforts, and potentially for therapeutic OL transplantation.
Assuntos
Diferenciação Celular/genética , Oligodendroglia/metabolismo , Células-Tronco Pluripotentes/metabolismo , Fatores de Transcrição SOXE/genética , Esclerose Lateral Amiotrófica/genética , Esclerose Lateral Amiotrófica/terapia , Antígenos de Superfície/genética , Regulação da Expressão Gênica no Desenvolvimento , Humanos , Esclerose Múltipla/genética , Esclerose Múltipla/patologia , Esclerose Múltipla/terapia , Proteína Básica da Mielina/genética , Neurônios/patologia , Neurônios/transplante , Oligodendroglia/citologia , Oligodendroglia/transplante , Células-Tronco Pluripotentes/citologia , Células-Tronco Pluripotentes/transplante , Transcriptoma/genéticaRESUMO
BACKGROUND: Since postpartum psychosis has been linked to activation of the immune system, it has been hypothesized that infectious agents may be involved in the pathogenesis of this disorder. We therefore investigated whether exposure to pathogens that can infect the central nervous system is increased in patients with postpartum psychosis. METHODS: We measured the prevalence and titers of immunoglobulin G (IgG) and M (IgM) to herpes simplex virus type 1 (HSV-1) and 2 (HSV-2), Epstein-Barr virus (EBV), cytomegalovirus (CMV) and Toxoplasma Gondii (TG) in a cohort of patients with postpartum psychosis (n = 81) and compared these to matched postpartum controls. RESULTS: We did not find significant differences in seroprevalence or antibody titers for any of these pathogens. LIMITATIONS: Limitations of this study include the indirect measurement of infectious disease and the cross-sectional design. CONCLUSION: Our results do not support the hypothesis that exposure to these neurotropic pathogens is involved in postpartum psychosis.
Assuntos
Anticorpos Antiprotozoários/sangue , Anticorpos Antivirais/sangue , Transtornos Psicóticos/imunologia , Transtornos Psicóticos/virologia , Transtornos Puerperais/imunologia , Adulto , Estudos de Coortes , Estudos Transversais , Citomegalovirus/imunologia , Feminino , Herpesvirus Humano 1/imunologia , Herpesvirus Humano 2/imunologia , Herpesvirus Humano 4/imunologia , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Pessoa de Meia-Idade , Período Pós-Parto/imunologia , Período Pós-Parto/psicologia , Gravidez , Prevalência , Transtornos Psicóticos/epidemiologia , Transtornos Psicóticos/parasitologia , Transtornos Puerperais/epidemiologia , Transtornos Puerperais/parasitologia , Transtornos Puerperais/virologia , Estudos Soroepidemiológicos , Toxoplasma/imunologiaRESUMO
Recent Zika virus (ZIKV) infections have been associated with a range of neurological complications, in particular congenital microcephaly. Human neural progenitor cells (hNPCs) are thought to play an important role in the pathogenesis of microcephaly, and experimental ZIKV infection of hNPCs has been shown to induce cell death. However, the infection efficiency and rate of cell death have varied between studies, which might be related to intrinsic differences between African and Asian lineage ZIKV strains. Therefore, we determined the replication kinetics, including infection efficiency, burst size, and ability to induce cell death, of two Asian and two African ZIKV strains. African ZIKV strains replicated to higher titers in Vero cells, human glioblastoma (U87MG) cells, human neuroblastoma (SK-N-SH) cells, and hNPCs than Asian ZIKV strains. Furthermore, infection with Asian ZIKV strains did not result in significant cell death early after infection, whereas infection with African ZIKV strains resulted in high percentages of cell death in hNPCs. The differences between African and Asian lineage ZIKV strains highlight the importance of including relevant ZIKV strains to study the pathogenesis of congenital microcephaly and caution against extrapolation of experimental data obtained using historical African ZIKV strains to the current outbreak. Finally, the fact that Asian ZIKV strains infect only a minority of cells with a relatively low burst size together with the lack of early cell death induction might contribute to its ability to cause chronic infections within the central nervous system (CNS). IMPORTANCE The mechanism by which ZIKV causes a range of neurological complications, especially congenital microcephaly, is not well understood. The fact that congenital microcephaly is associated with Asian lineage ZIKV strains raises the question of why this was not discovered earlier. One possible explanation is that Asian and African ZIKV strains differ in their abilities to infect cells of the CNS and to cause neurodevelopmental problems. Here, we show that Asian ZIKV strains infect and induce cell death in human neural progenitor cells-which are important target cells in the development of congenital microcephaly-less efficiently than African ZIKV strains. These features of Asian ZIKV strains likely contribute to their ability to cause chronic infections, often observed in congenital microcephaly cases. It is therefore likely that phenotypic differences between ZIKV strains could be, at least in part, responsible for the ability of Asian ZIKV strains to cause congenital microcephaly.
RESUMO
The directed differentiation of patient-derived induced pluripotent stem cells into cell-type specific neurons has inspired the development of therapeutic discovery for neurodegenerative diseases. Many forms of ataxia result from degeneration of cerebellar Purkinje cells, but thus far it has not been possible to efficiently generate Purkinje neuron (PN) progenitors from human or mouse pluripotent stem cells, let alone to develop a methodology for in vivo transplantation in the adult cerebellum. Here, we present a protocol to obtain an expandable population of cerebellar neuron progenitors from mouse embryonic stem cells. Our protocol is characterized by applying factors that promote proliferation of cerebellar progenitors. Cerebellar progenitors isolated in culture from cell aggregates contained a stable subpopulation of PN progenitors that could be expanded for up to 6 passages. When transplanted into the adult cerebellum of either wild-type mice or a strain lacking Purkinje cells (L7cre-ERCC1 knockout), GFP-labeled progenitors differentiated in vivo to establish a population of calbindin-positive cells in the molecular layer with dendritic trees typical of mature PNs. We conclude that this protocol may be useful for the generation and maturation of PNs, highlighting the potential for development of a regenerative medicine approach to the treatment of cerebellar neurodegenerative diseases.
Assuntos
Diferenciação Celular , Cerebelo/citologia , Células-Tronco Embrionárias/citologia , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Células de Purkinje/citologia , Células de Purkinje/metabolismo , Potenciais de Ação , Fatores Etários , Animais , Biomarcadores , Técnicas de Cultura de Células , Células Cultivadas , Meios de Cultura , Feminino , Imunofluorescência , Expressão Gênica , Genes Reporter , Imunofenotipagem , Masculino , Camundongos , Transplante de Células-TroncoRESUMO
A recent phase 1 trial of the fatty acid amide hydrolase (FAAH) inhibitor BIA 10-2474 led to the death of one volunteer and produced mild-to-severe neurological symptoms in four others. Although the cause of the clinical neurotoxicity is unknown, it has been postulated, given the clinical safety profile of other tested FAAH inhibitors, that off-target activities of BIA 10-2474 may have played a role. Here we use activity-based proteomic methods to determine the protein interaction landscape of BIA 10-2474 in human cells and tissues. This analysis revealed that the drug inhibits several lipases that are not targeted by PF04457845, a highly selective and clinically tested FAAH inhibitor. BIA 10-2474, but not PF04457845, produced substantial alterations in lipid networks in human cortical neurons, suggesting that promiscuous lipase inhibitors have the potential to cause metabolic dysregulation in the nervous system.
Assuntos
Amidoidrolases/antagonistas & inibidores , Analgésicos/farmacologia , Ansiolíticos/farmacologia , Óxidos N-Cíclicos/farmacologia , Neurônios/efeitos dos fármacos , Piridinas/farmacologia , Analgésicos/efeitos adversos , Analgésicos/química , Analgésicos/metabolismo , Ansiolíticos/efeitos adversos , Ansiolíticos/química , Ansiolíticos/metabolismo , Linhagem Celular Tumoral , Ensaios Clínicos Fase I como Assunto , Reações Cruzadas , Óxidos N-Cíclicos/efeitos adversos , Óxidos N-Cíclicos/química , Óxidos N-Cíclicos/metabolismo , Humanos , Neurônios/metabolismo , Mapas de Interação de Proteínas , Piridazinas/farmacologia , Piridazinas/uso terapêutico , Piridinas/efeitos adversos , Piridinas/química , Piridinas/metabolismo , Ureia/análogos & derivados , Ureia/farmacologia , Ureia/uso terapêuticoRESUMO
RASopathies, characterized by germline mutations in genes encoding proteins of the RAS-ERK signaling pathway, show overlapping phenotypes, which manifest themselves with a varying severity of intellectual disability. However, it is unclear to what extent they share the same downstream pathophysiology that underlies the cognitive deficits. Costello syndrome (CS) is a rare RASopathy caused by activating mutations in the HRAS gene. Here we investigated the mechanisms underlying the cognitive deficits of HRas G12V/G12V mice. HRas G12V/G12V mice showed robust upregulation of ERK signaling, neuronal hypertrophy, increased brain volume, spatial learning deficits, and impaired mGluR-dependent long-term depression (LTD). In contrast, long-term potentiation (LTP), which is affected in other RASopathy mouse models was unaffected. Treatment with lovastatin, a HMG-CoA-Reductase inhibitor which has been shown to rescue the behavioral phenotypes of mouse models of NF1 and Noonan syndrome, was unable to restore ERK signaling and the cognitive deficits of HRas G12V/G12V mice. Administration of a potent mitogen-activated protein kinase (MEK) inhibitor rescued the ERK upregulation and the mGluR-LTD deficit of HRas G12V/G12V mice, but failed to rescue the cognitive deficits. Taken together, this study indicates that the fundamental molecular and cellular mechanisms underlying the cognitive aspects of different RASopathies are remarkably distinct, and may require disease specific treatments.
Assuntos
Disfunção Cognitiva/fisiopatologia , Síndrome de Costello/fisiopatologia , Mutação de Sentido Incorreto , Proteínas Proto-Oncogênicas p21(ras)/genética , Animais , Encéfalo/patologia , Depressão , Modelos Animais de Doenças , Hipertrofia , Sistema de Sinalização das MAP Quinases , Camundongos , Neurônios/patologiaRESUMO
Presynaptic terminals are metabolically active and accrue damage through continuous vesicle cycling. How synapses locally regulate protein homeostasis is poorly understood. We show that the presynaptic lipid phosphatase synaptojanin is required for macroautophagy, and this role is inhibited by the Parkinson's disease mutation R258Q. Synaptojanin drives synaptic endocytosis by dephosphorylating PI(4,5)P2, but this function appears normal in SynaptojaninRQ knock-in flies. Instead, R258Q affects the synaptojanin SAC1 domain that dephosphorylates PI(3)P and PI(3,5)P2, two lipids found in autophagosomal membranes. Using advanced imaging, we show that SynaptojaninRQ mutants accumulate the PI(3)P/PI(3,5)P2-binding protein Atg18a on nascent synaptic autophagosomes, blocking autophagosome maturation at fly synapses and in neurites of human patient induced pluripotent stem cell-derived neurons. Additionally, we observe neurodegeneration, including dopaminergic neuron loss, in SynaptojaninRQ flies. Thus, synaptojanin is essential for macroautophagy within presynaptic terminals, coupling protein turnover with synaptic vesicle cycling and linking presynaptic-specific autophagy defects to Parkinson's disease.
Assuntos
Autofagossomos/metabolismo , Autofagia , Proteínas do Tecido Nervoso/metabolismo , Monoéster Fosfórico Hidrolases/metabolismo , Terminações Pré-Sinápticas/enzimologia , Terminações Pré-Sinápticas/metabolismo , Substituição de Aminoácidos , Animais , Proteínas Relacionadas à Autofagia/análise , Células Cultivadas , Drosophila , Humanos , Proteínas de Membrana/análise , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/genética , Doença de Parkinson/patologia , Fosfatos de Fosfatidilinositol/metabolismo , Monoéster Fosfórico Hidrolases/genéticaRESUMO
Hepatitis E virus (HEV), as a hepatotropic virus, is supposed to exclusively infect the liver and only cause hepatitis. However, a broad range of extrahepatic manifestations (in particular, idiopathic neurological disorders) have been recently reported in association with its infection. In this study, we have demonstrated that various human neural cell lines (embryonic stem cell-derived neural lineage cells) induced pluripotent stem cell-derived human neurons and primary mouse neurons are highly susceptible to HEV infection. Treatment with interferon-α or ribavirin, the off-label antiviral drugs for chronic hepatitis E, exerted potent antiviral activities against HEV infection in neural cells. More importantly, in mice and monkey peripherally inoculated with HEV particles, viral RNA and protein were detected in brain tissues. Finally, patients with HEV-associated neurological disorders shed the virus into cerebrospinal fluid, indicating a direct infection of their nervous system. Thus, HEV is neurotropic in vitro, and in mice, monkeys, and possibly humans. These results challenge the dogma of HEV as a pure hepatotropic virus and suggest that HEV infection should be considered in the differential diagnosis of idiopathic neurological disorders.
Assuntos
Encéfalo/virologia , Vírus da Hepatite E/patogenicidade , Hepatite E/patologia , Neurônios/virologia , Adulto , Idoso , Animais , Antivirais/farmacologia , Encéfalo/patologia , Linhagem Celular Tumoral , Líquido Cefalorraquidiano/virologia , Feminino , Síndrome de Guillain-Barré/virologia , Hepatite E/tratamento farmacológico , Humanos , Interferon-alfa/farmacologia , Fígado/patologia , Fígado/virologia , Macaca mulatta , Masculino , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Neurônios/patologia , RNA Viral/análise , Ribavirina/farmacologia , Replicação Viral/efeitos dos fármacos , Eliminação de Partículas ViraisRESUMO
Affective psychoses are a group of severe psychiatric disorders, including schizoaffective disorder and bipolar I disorder, together affecting â¼1% of the population. Despite their high heritability, the molecular genetics and neurobiology of affective psychosis remain largely elusive. Here, we describe the identification of a structural genetic variant segregating with affective psychosis in a family with multiple members suffering from bipolar I disorder or schizoaffective disorder, bipolar type. A balanced translocation involving chromosomes 6 and 15 was detected by karyotyping and fluorescence in-situ hybridization (FISH). Using whole-genome sequencing, we rapidly delineated the translocation breakpoints as corresponding intragenic events disrupting BCL2L10 and PNLDC1. These data warrant further consideration for BCL2L10 and PNLDC1 as novel candidates for affective psychosis. © 2016 The Authors. American Journal of Medical Genetics Part B: Neuropsychiatric Genetics Published by Wiley Periodicals, Inc.
Assuntos
Transtornos Psicóticos Afetivos/genética , Proteínas Proto-Oncogênicas c-bcl-2/genética , Adulto , Transtorno Bipolar/genética , Cromossomos Humanos Par 15/genética , Cromossomos Humanos Par 6/genética , Citogenética/métodos , Exorribonucleases , Feminino , Humanos , Hibridização in Situ Fluorescente , Cariotipagem , Masculino , Linhagem , Proteínas Proto-Oncogênicas c-bcl-2/metabolismo , Transtornos Psicóticos/genética , Esquizofrenia/genética , Análise de Sequência de DNA , Translocação Genética/genéticaRESUMO
STUDY QUESTION: Does adrenocorticotropic hormone (ACTH) induce gonadotropin release in premenopausal women? SUMMARY ANSWER: Administration of ACTH stimulates gonadotropin release, most likely by stimulation of the production of cortisol, in premenopausal women. WHAT IS KNOWN ALREADY: In animal models, acute activation of the hypothalamic-pituitary-adrenal (HPA) axis has been shown to induce gonadotropin release in the presence of sufficiently high estrogen levels. However, it is unknown whether the HPA axis has a similar influence on gonadotropin release in humans. STUDY DESIGN, SIZE, DURATION: This study had a mixed factorial design. A total of 60 healthy female participants participated in the experimental study. PARTICIPANTS/MATERIALS, SETTING, METHODS: The study sample comprised three distinct hormonal-based populations according to their levels of progesterone (PROG) and estradiol (E2): (i) low-PROG-low-E2, (ii) low-PROG-high-E2 and (iii) high-PROG-high-E2 women. A low dose (1 µg) of ACTH was administered to all study participants. Serum steroid and gonadotropin concentrations were measured prior to, and at 30 and 90 minutes after, intravenous ACTH administration. MAIN RESULTS AND THE ROLE OF CHANCE: Mean serum cortisol levels increased significantly following ACTH administration in all groups (P < 0.001). Similarly, the serum levels of 17-OH-PROG, androstenedione, dehydroepiandrosterone and testosterone increased significantly in all groups (P < 0.01). The low-PROG-high-E2 and high-PROG-high-E2 groups exhibited a significant increase in LH and FSH levels (P < 0.001), whereas the low-PROG-low-E2 group demonstrated blunted LH and FSH responses to ACTH administration (P < 0.05). LIMITATIONS, REASONS FOR CAUTION: Testing was performed during the luteal phase of the natural menstrual cycle. Testing during the follicular phase might have elicited premature, or more pronounced, LH surges in response to ACTH administration. WIDER IMPLICATIONS OF THE FINDINGS: Our findings suggest a novel mechanism by which the adrenal cortex functions as a mediator of gonadotropin release. These findings contribute to a greater understanding of the influence of acute stress on reproductive endocrinology. STUDY FUNDING/COMPETING INTERESTS: Funding was received from the Erasmus University Medical Center. The authors have no conflicts of interest. TRIAL REGISTRATION NUMBER: EudraCT Number 2012-005640-14.
Assuntos
Hormônio Adrenocorticotrópico/farmacologia , Androstenodiona/sangue , Hormônio Foliculoestimulante/sangue , Sistema Hipotálamo-Hipofisário/efeitos dos fármacos , Hormônio Luteinizante/sangue , 17-alfa-Hidroxiprogesterona/sangue , Adolescente , Adulto , Desidroepiandrosterona/sangue , Estradiol/sangue , Feminino , Voluntários Saudáveis , Humanos , Hidrocortisona/sangue , Sistema Hipófise-Suprarrenal/efeitos dos fármacos , Progesterona/sangue , Testosterona/sangue , Adulto JovemRESUMO
OBJECTIVE: Significant immunological alterations have been observed in women with first-onset affective psychosis during the postpartum period. Recent studies have highlighted the possibility that a subset of patients with first-onset severe psychiatric episodes might suffer from undiagnosed autoimmune encephalitis. Therefore, the authors performed a three-step immunohistochemistry-based screening for CNS autoantibodies in a large cohort of patients with postpartum psychosis and matched postpartum comparison subjects. METHOD: Ninety-six consecutive patients with postpartum psychosis and 64 healthy postpartum women were included. Screening for antibodies in patient serum was performed using immunohistochemistry. Samples showing any staining were further examined by immunocytochemistry using live hippocampal neurons and cell-based assays to test for anti-N-methyl-d-aspartate (NMDA) receptor antibodies. Cell-based assays for all other known CNS antigens were performed in those samples with immunocytochemistry labeling but negative for NMDA receptor antibodies. RESULTS: Four patients (4%) with neuropil labeling suggestive for extracellular antigen reactivity were identified. Serum samples from all four patients showed clear extracellular labeling of live hippocampal neurons. Two women had the specific staining pattern characteristic for anti-NMDA receptor antibody positivity, which was confirmed by cell-based assays. Neither patient with anti-NMDA receptor antibody positivity had evidence of an ovarian teratoma. The other two patients tested negative by cell-based assays for all known CNS antigens. None of the matched postpartum comparison subjects had confirmed neuronal surface antibodies. The two patients with anti-NMDA receptor antibodies both showed extrapyramidal symptoms following initiation of treatment with low-dose haloperidol. CONCLUSIONS: In patients with acute psychosis during the postpartum period, systematic screening for anti-NMDA receptor autoantibodies should be considered. The acute onset of severe atypical psychiatric symptoms in young female patients should raise the index of suspicion for anti-NMDA receptor encephalitis, particularly in the setting of neurological symptoms, including extrapyramidal side effects of antipsychotic treatment.
Assuntos
Encefalite/diagnóstico , Doença de Hashimoto/diagnóstico , Transtornos Psicóticos/diagnóstico , Transtornos Puerperais/diagnóstico , Adulto , Animais , Autoanticorpos/imunologia , Estudos de Casos e Controles , Encefalite/etiologia , Feminino , Doença de Hashimoto/etiologia , Hipocampo/imunologia , Humanos , Período Pós-Parto , Transtornos Psicóticos/etiologia , Transtornos Psicóticos/imunologia , Transtornos Puerperais/imunologia , Ratos/imunologia , Receptores de N-Metil-D-Aspartato/imunologia , Adulto JovemRESUMO
Angiotensin-induced vasodilation, involving type 2 receptor (AT2R)-induced generation of nitric oxide (NO; by endothelial NO synthase) and endothelium-derived hyperpolarizing factors, may be limited to women. To distinguish the contribution of female sex hormones and chromosomes to AT2R function and endothelium-derived hyperpolarizing factor-mediated vasodilation, we made use of the four-core genotype model, where the testis-determining Sry gene has been deleted (Y(-)) from the Y chromosome, allowing XY(-) mice to develop a female gonadal phenotype. Simultaneously, by incorporating the Sry gene onto an autosome, XY(-)Sry and XXSry transgenic mice develop into gonadal male mice. Four-core genotype mice underwent a sham or gonadectomy (GDX) operation, and after 8 weeks, iliac arteries were collected to assess vascular function. XY(-)Sry male mice responded more strongly to angiotensin than XX female mice, and the AT2R antagonist PD123319 revealed that this was because of a dilator AT2R-mediated effect occurring exclusively in XX female mice. The latter could not be demonstrated in XXSry male and XY(-) female mice nor in XX female mice after GDX, suggesting that it depends on both sex hormones and chromosomes. Indeed, treating C57bl/6 GDX male mice with estrogen could not restore angiotensin-mediated, AT2R-dependent relaxation. To block acetylcholine-induced relaxation of iliac arteries obtained from four-core genotype XX mice, both endothelial NO synthase and endothelium-derived hyperpolarizing factor inhibition were required, whereas in four-core genotype XY animals, endothelial NO synthase inhibition alone was sufficient. These findings were independent of gonadal sex and unaltered after GDX. In conclusion, AT2R-induced relaxation requires both estrogen and the XX chromosome sex complement, whereas only the latter is required for endothelium-derived hyperpolarizing factors.
Assuntos
Acetilcolina/fisiologia , Estrogênios/fisiologia , Relaxamento Muscular/fisiologia , Músculo Liso Vascular/fisiologia , Receptor Tipo 2 de Angiotensina/fisiologia , Cromossomo X/fisiologia , Acetilcolina/farmacologia , Angiotensina II/farmacologia , Animais , Feminino , Genes sry/genética , Genótipo , Artéria Ilíaca/efeitos dos fármacos , Artéria Ilíaca/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Modelos Animais , Relaxamento Muscular/efeitos dos fármacos , Músculo Liso Vascular/efeitos dos fármacos , Óxido Nítrico/metabolismo , Fenótipo , Fatores Sexuais , Vasodilatação/efeitos dos fármacos , Vasodilatação/fisiologiaRESUMO
OBJECTIVE: A case-control study to investigate the effect of the menstrual cycle on trigeminal nerve-induced vasodilation in healthy women and patients with menstrually related migraine (MRM). METHODS: Using a laser-Doppler imager, we compared the vasodilator effects of capsaicin application and electrical stimulation (ES) on the forehead skin, a trigeminal nerve-innervated dermatome, in premenopausal patients with MRM (n = 22), healthy controls (n = 20), and postmenopausal women without migraine (n = 22). Blood samples were collected for female sex hormone measurements. RESULTS: Dermal blood flow (DBF) responses to capsaicin were higher in controls during days 1-2 than during days 19-21 of their menstruation cycle (mean Emax ± SEM: 203 ± 28 AU vs 156 ± 27 AU [p = 0.031] for 0.06 mg/mL capsaicin and 497 ± 25 AU vs 456 ± 24 AU [p = 0.009] for 6.0 mg/mL capsaicin). In contrast, patients with MRM demonstrated DBF responses without significant cycle-dependent variability (days 1-2 vs days 19-21: Emax 148 ± 20 AU vs 154 ± 20 AU [p = 0.788] for 0.06 mg/mL capsaicin and 470 ± 17 AU vs 465 ± 20 AU [p = 0.679] for 6.0 mg/mL capsaicin). DBF responses to ES were not different between either patients with MRM or controls, at either occasion. Estradiol levels on days 19-21 of the menstrual cycle were higher in healthy controls (mean ± SEM: 75 ± 8 pg/mL) than in patients with MRM (52 ± 4 pg/mL, p = 0.014). In postmenopausal women, DBF responses to capsaicin and ES, as well as estradiol levels at both visits, were all significantly reduced compared to patients with MRM and controls (in all cases, p < 0.05). CONCLUSIONS: Our study provides evidence for a reduced menstrual cyclicity of both estradiol levels and the trigeminovascular vasodilator system in patients with MRM.
Assuntos
Capsaicina/farmacologia , Estimulação Elétrica , Distúrbios Menstruais/fisiopatologia , Transtornos de Enxaqueca/fisiopatologia , Periodicidade , Fármacos do Sistema Sensorial/farmacologia , Pele/irrigação sanguínea , Nervo Trigêmeo/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Adulto , Idoso , Estudos de Casos e Controles , Estrogênios/sangue , Feminino , Testa , Humanos , Pessoa de Meia-Idade , Progesterona/sangue , Adulto JovemRESUMO
BACKGROUND: Postpartum psychosis is a life-threatening psychiatric emergency, which often occurs without significant premorbid symptoms. Although many studies have postulated an involvement of the immune and endocrine systems in the onset of postpartum psychosis, the specific aetiological factors have remained unknown. AIMS: To examine the hypothesis that autoimmune thyroid dysfunction may be associated with the onset of postpartum psychosis. METHOD: Thirty-one consecutive primiparous women with no prior psychiatric history were referred to our in-patient unit for postpartum psychosis. The control group (n = 117) comprised primiparous women with consecutive deliveries at a community practice. Blood samples were obtained from all participants at 4 weeks and 9 months postpartum. Thyroperoxidase antibody levels were quantified as immunological measures of autoimmune thyroid disease (AITD). Thyroid-stimulating hormone and free thyroxine levels were measured to assess clinical thyroid dysfunction. RESULTS: At 4 weeks postpartum and prior to the initiation of mood stabiliser therapy, 19% of women with postpartum psychosis had AITD compared with only 5% in the control group. Women with both postpartum psychosis and AITD had a dramatically higher risk of progression to clinical thyroid dysfunction (67%) than control participants with AITD (20%). CONCLUSIONS: Women with postpartum psychosis are at higher risk not only of AITD but also of clinical thyroid failure. These data implicate thyroid function as an important clinical outcome in patients with postpartum psychosis. Further, AITD represents a potentially strong aetiological factor for the development of postpartum psychosis. Therefore, screening for thyroperoxidase antibodies is warranted in patients with postpartum psychosis.