RESUMO
Genomic studies have identified hundreds of candidate genes near loci associated with risk for schizophrenia. To define candidates and their functions, we mutated zebrafish orthologs of 132 human schizophrenia-associated genes. We created a phenotype atlas consisting of whole-brain activity maps, brain structural differences, and profiles of behavioral abnormalities. Phenotypes were diverse but specific, including altered forebrain development and decreased prepulse inhibition. Exploration of these datasets identified promising candidates in more than 10 gene-rich regions, including the magnesium transporter cnnm2 and the translational repressor gigyf2, and revealed shared anatomical sites of activity differences, including the pallium, hypothalamus, and tectum. Single-cell RNA sequencing uncovered an essential role for the understudied transcription factor znf536 in the development of forebrain neurons implicated in social behavior and stress. This phenotypic landscape of schizophrenia-associated genes prioritizes more than 30 candidates for further study and provides hypotheses to bridge the divide between genetic association and biological mechanism.
Assuntos
Esquizofrenia/genética , Esquizofrenia/fisiopatologia , Animais , Encéfalo , Córtex Cerebral , Modelos Animais de Doenças , Regulação da Expressão Gênica/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Peixe-Zebra/genéticaRESUMO
KBG syndrome is a rare genetic disorder caused by heterozygous pathogenic variants in ANKRD11. Affected individuals have developmental delay, short stature, characteristic facial features, and other dysmorphic findings. To date, a spectrum of unspecific neuroradiological defects has been reported in KBG patients, such as cortical defects, white matter abnormalities, corpus callosum, and cerebellar vermis hypoplasia.Deep clinical and neuroradiological phenotyping and genotype of a patient presenting with mild cognitive and behavioral problems were obtained after written informed consent.We herein describe the first KBG patient presenting with cerebellar heterotopia, a heterogeneous malformation characterized by the presence of clusters of neurons within the white matter of cerebellar hemispheres.This novel association broadens the neuroradiological spectrum of KBG syndrome, and further prompts to investigate the potential functions of ANKRD11 in cerebellar development.
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Cerebelo , Humanos , Cerebelo/diagnóstico por imagem , Cerebelo/anormalidades , Cerebelo/patologia , Deficiência Intelectual/genética , Deficiência Intelectual/diagnóstico por imagem , Deficiência Intelectual/patologia , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/diagnóstico por imagem , Anormalidades Múltiplas/patologia , Imageamento por Ressonância Magnética , Masculino , Fácies , Doenças Renais Císticas/genética , Doenças Renais Císticas/diagnóstico por imagem , Doenças Renais Císticas/patologia , Feminino , Síndromes Neurocutâneas/diagnóstico por imagem , Síndromes Neurocutâneas/genética , Síndromes Neurocutâneas/patologia , Criança , Coristoma/diagnóstico por imagem , Coristoma/patologia , Doenças do Desenvolvimento Ósseo , Anormalidades DentáriasRESUMO
BACKGROUND: Attention deficit hyperactivity disorder (ADHD) is one of the more common neuropsychiatric disorders in women of reproductive age. Our objective was to compare perinatal outcomes between women with an ADHD diagnosis and those without. METHODS: A retrospective population-based cohort study utilizing the Healthcare Cost and Utilization Project, Nationwide Inpatient Sample (HCUP-NIS) United States database. The study included all women who either delivered or experienced maternal death from 2004 to 2014. Perinatal outcomes were compared between women with an ICD-9 diagnosis of ADHD and those without. RESULTS: Overall, 9,096,788 women met the inclusion criteria. Amongst them, 10,031 women had a diagnosis of ADHD. Women with ADHD, compared to those without, were more likely to be younger than 25 years of age; white; to smoke tobacco during pregnancy; to use illicit drugs; and to suffer from chronic hypertension, thyroid disorders, and obesity (p < 0.001 for all). Women in the ADHD group, compared to those without, had a higher rate of hypertensive disorders of pregnancy (HDP) (aOR 1.36, 95% CI 1.28-1.45, p < 0.001), cesarean delivery (aOR 1.19, 95% CI 1.13-1.25, p < 0.001), chorioamnionitis (aOR 1.34, 95% CI 1.17-1.52, p < 0.001), and maternal infection (aOR 1.33, 95% CI 1.19-1.5, p < 0.001). Regarding neonatal outcomes, patients with ADHD, compared to those without, had a higher rate of small-for-gestational-age neonate (SGA) (aOR 1.3, 95% CI 1.17-1.43, p < 0.001), and congenital anomalies (aOR 2.77, 95% CI 2.36-3.26, p < 0.001). CONCLUSION: Women with a diagnosis of ADHD had a higher incidence of a myriad of maternal and neonatal complications, including cesarean delivery, HDP, and SGA neonates.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Bases de Dados Factuais , Complicações na Gravidez , Resultado da Gravidez , Humanos , Feminino , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Gravidez , Adulto , Estudos Retrospectivos , Complicações na Gravidez/epidemiologia , Recém-Nascido , Resultado da Gravidez/epidemiologia , Estados Unidos/epidemiologia , Adulto Jovem , Cesárea/estatística & dados numéricos , Parto Obstétrico/estatística & dados numéricos , Hipertensão Induzida pela Gravidez/epidemiologiaRESUMO
Neuroimaging and other neurobiological evidences are increasingly introduced in criminal litigation, especially when a neuropsychiatric disorder is suspected. Evaluations of criminal competencies are the most common type of criminal forensic assessment in forensic psychiatry and psychology. Given this, it is critical for forensic evaluators to understand how neuropsychiatric disorders may affect a defendant's criminal competencies and how neurobiological data may be used in competency determinations. This paper reviews the use of neurobiological data, particularly neuroimaging, while considering the limitations and potential misuse of such data in criminal competency evaluations.
Assuntos
Criminosos , Competência Mental , Transtornos Mentais , Neuroimagem , Humanos , Encéfalo/diagnóstico por imagem , Encéfalo/fisiopatologia , Criminosos/psicologia , Psiquiatria Legal , Competência Mental/legislação & jurisprudência , Transtornos Mentais/diagnóstico por imagem , Transtornos Mentais/psicologiaRESUMO
INTRODUCTION: Previous research indicates that children with Paediatric Acute-onset Neuropsychiatric Syndrome (PANS) experience sensory reactivity differences that impact occupational performance. The purpose of this study was to determine whether there are differences in sensory reactivity in these children across two different time points; during exacerbation and during remission, using the Sensory Processing Measure (SPM) Home-Form. The study also sought to investigate whether children with PANS experience sensory differences during remission periods, when compared with SPM Home-Form norms. METHODS: A two-period bidirectional case-crossover design was used, and an online assessment was conducted to measure sensory reactivity. Parents of children aged 4.6 to 13.1 years with a diagnosis of PANS were recruited from various sites across Australia, USA, England, Ireland, Scotland, Canada, and New Zealand. The SPM Home-Form was used to measure sensory reactivity at two time points, when PANS was in remission (T-R) and in exacerbation (T-E). Study entry was permitted at either T-E or T-R. Participant exacerbation status was monitored over a maximum 12-month period, and a follow-up SPM Home-Form was sent when a change in exacerbation status was indicated. A linear mixed model was used to assess the difference between SPM Home-Form norm-referenced scores during exacerbation and remission. RESULTS: The study included 82 participants, with 80 providing data at study entry, and 27 providing data at follow-up. Results showed a statistically significant decline in performance across the SPM Home-Form domains of Hearing, Social Participation, Planning and Ideas, and Total Sensory Systems T-scores during exacerbation when compared with remission data. Results also demonstrated atypical sensory reactivity across Vision, Hearing, Touch, Balance and Motion, and Total Sensory Systems domains during periods of remission compared with SPM Home-Form norms. CONCLUSION: This study found that children with PANS experience significant sensory reactivity differences during exacerbation and remission across multiple sensory domains, with a decline in performance during exacerbation. Where there are occupational performance challenges, occupational therapists should consider administering sensory assessments so that effective intervention plans addressing the unique sensory reactivity needs of children with PANS can be developed.
Assuntos
Terapia Ocupacional , Humanos , Criança , Masculino , Feminino , Terapia Ocupacional/métodos , Pré-Escolar , Adolescente , Estudos Cross-Over , Sensação/fisiologia , Austrália , Doenças Autoimunes , Transtorno Obsessivo-CompulsivoRESUMO
Normal neural circuits and functions depend on proper neuronal differentiation, migration, synaptic plasticity, and maintenance. Abnormalities in these processes underlie various neurodevelopmental, neuropsychiatric, and neurodegenerative disorders. Neural development and maintenance are regulated by many proteins. Among them are Par3, Par6 (partitioning defective 3 and 6), and aPKC (atypical protein kinase C) families of evolutionarily conserved polarity proteins. These proteins perform versatile functions by forming tripartite or other combinations of protein complexes, which hereafter are collectively referred to as "Par complexes." In this review, we summarize the major findings on their biophysical and biochemical properties in cell polarization and signaling pathways. We next summarize their expression and localization in the nervous system as well as their versatile functions in various aspects of neurodevelopment, including neuroepithelial polarity, neurogenesis, neuronal migration, neurite differentiation, synaptic plasticity, and memory. These versatile functions rely on the fundamental roles of Par complexes in cell polarity in distinct cellular contexts. We also discuss how cell polarization may correlate with subcellular polarization in neurons. Finally, we review the involvement of Par complexes in neuropsychiatric and neurodegenerative disorders, such as schizophrenia and Alzheimer's disease. While emerging evidence indicates that Par complexes are essential for proper neural development and maintenance, many questions on their in vivo functions have yet to be answered. Thus, Par3, Par6, and aPKC continue to be important research topics to advance neuroscience.
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Polaridade Celular , Proteína Quinase C , Proteínas de Ciclo Celular/metabolismo , Polaridade Celular/fisiologia , Proteína Quinase C/metabolismo , Proteínas , Transdução de SinaisRESUMO
Microglia are so versatile that they not only provide immune surveillance for central nervous system, but participate in neural circuitry development, brain blood vessels formation, blood-brain barrier architecture, and intriguingly, the regulation of emotions and behaviors. Microglia have a profound impact on neuronal survival, brain wiring and synaptic plasticity. As professional phagocytic cells in the brain, they remove dead cell debris and neurotoxic agents via an elaborate mechanism. The functional profile of microglia varies considerately depending on age, gender, disease context and other internal or external environmental factors. Numerous studies have demonstrated a pivotal involvement of microglia in neuropsychiatric disorders, including negative affection, social deficit, compulsive behavior, fear memory, pain and other symptoms associated with major depression disorder, anxiety disorder, autism spectrum disorder and schizophrenia. In this review, we summarized the latest discoveries regarding microglial ontogeny, cell subtypes or state spectrum, biological functions and mechanistic underpinnings of emotional and behavioral disorders. Furthermore, we highlight the potential of microglia-targeted therapies of neuropsychiatric disorders, and propose outstanding questions to be addressed in future research of human microglia.
Assuntos
Transtorno do Espectro Autista , Microglia , Humanos , Sistema Nervoso Central , Encéfalo/fisiologia , Plasticidade NeuronalRESUMO
MOTIVATION: Rare variant-based analyses are beginning to identify risk genes for neuropsychiatric disorders and other diseases. However, the identified genes only account for a fraction of predicted causal genes. Recent studies have shown that rare damaging variants are significantly enriched in specific gene-sets. Methods which are able to jointly model rare variants and gene-sets to identify enriched gene-sets and use these enriched gene-sets to prioritize additional risk genes could improve understanding of the genetic architecture of diseases. RESULTS: We propose DECO (Integrated analysis of de novo mutations, rare case/control variants and omics information via gene-sets), an integrated method for rare-variant and gene-set analysis. The method can (i) test the enrichment of gene-sets directly within the statistical model, and (ii) use enriched gene-sets to rank existing genes and prioritize additional risk genes for tested disorders. In simulations, DECO performs better than a homologous method that uses only variant data. To demonstrate the application of the proposed protocol, we have applied this approach to rare-variant datasets of schizophrenia. Compared with a method which only uses variant information, DECO is able to prioritize additional risk genes. AVAILABILITY: DECO can be used to analyze rare-variants and biological pathways or cell types for any disease. The package is available on Github https://github.com/hoangtn/DECO.
Assuntos
Predisposição Genética para Doença/genética , Mutação , Transtornos do Neurodesenvolvimento/genética , Esquizofrenia/genética , Biologia de Sistemas/métodos , Estudos de Casos e Controles , Simulação por Computador , Análise Mutacional de DNA/métodos , Humanos , Modelos Estatísticos , Mapeamento de Interação de Proteínas/métodos , Mapas de Interação de Proteínas/genéticaRESUMO
PURPOSE: The aim of the study was to examine the possible relation between adolescent ADHD and high BMI, studying also eating behavior and physical activity. METHODS: The data were collected from the Northern Finland Birth Cohort 1986. The follow-up at the age of 16 consisted of a self-assessment form and clinical examination where height and weight were measured and questionnaires on physical activity and eating habits was completed. ADHD diagnosis was based on a diagnostic interview with adolescents and parents according to DSM-IV-TR criteria. The participants were divided into the following study groups: individuals with adolescent ADHD (n = 90), those with only childhood ADHD (n = 40), and community controls (n = 269). RESULTS: Results showed no significant differences in BMI, but adolescents with ADHD seemed to have unhealthier eating habits than controls; they ate less often vegetables and breakfast, devoured more often, and consumed more fast food, soft drinks, sweets, and potato crisps daily. Individuals with adolescent ADHD reported light exercise more often but strenuous exercise more seldom than controls. Those with only childhood ADHD did not significantly differ from community controls regarding health behaviors. CONCLUSIONS: There was no relation between ADHD and high BMI but adolescents with ADHD had unhealthier eating habits than those without ADHD. It is conceivable that unhealthy eating behaviors in adolescence might be a risk factor for the development of later overweight; however, the longitudinal associations between ADHD, unhealthy eating behaviors and overweight have not been considered in the present study and remain to be examined further.
Assuntos
Transtorno do Deficit de Atenção com Hiperatividade , Humanos , Adolescente , Criança , Transtorno do Deficit de Atenção com Hiperatividade/epidemiologia , Transtorno do Deficit de Atenção com Hiperatividade/complicações , Sobrepeso/epidemiologia , Comportamento Alimentar , Exercício Físico , Fatores de RiscoRESUMO
Autism spectrum disorder (ASD) is a neurodevelopmental condition characterized by the early onset of communication and behavioral problems. ASD is highly heritable; however, environmental factors also play a considerable role in this disorder. A significant part of both syndromic and idiopathic autism cases could be attributed to disorders caused by mammalian target of rapamycin (mTOR)-dependent translation deregulation. This narrative review analyzes both bioinformatic and experimental evidence that connects mTOR signaling to the maternal autoantibody-related (MAR) autism spectrum and autoimmune neuropsychiatric disorders simultaneously. In addition, we reconstruct a network presenting the interactions between the mTOR signaling and eight MAR ASD genes coding for ASD-specific maternal autoantibody target proteins. The research discussed in this review demonstrates novel perspectives and validates the need for a subtyping of ASD on the grounds of pathogenic mechanisms. The utter necessity of designing ELISA-based test panels to identify all antibodies related to autism-like behavior is also considered.
Assuntos
Transtorno do Espectro Autista/patologia , Efeitos Tardios da Exposição Pré-Natal/patologia , Serina-Treonina Quinases TOR/metabolismo , Transtorno do Espectro Autista/classificação , Transtorno do Espectro Autista/imunologia , Transtorno do Espectro Autista/metabolismo , Autoanticorpos/metabolismo , Criança , Biologia Computacional/métodos , Feminino , Humanos , Gravidez , Efeitos Tardios da Exposição Pré-Natal/classificação , Efeitos Tardios da Exposição Pré-Natal/imunologia , Efeitos Tardios da Exposição Pré-Natal/metabolismo , Transdução de SinaisRESUMO
Fahr's disease is a rare clinical neurodegenerative entity, occurring mainly in 4th or 5th decade, showing gradually progressive bilateral symmetric calcifications in basal ganglia, subcortical white matter, thalami or cerebellum, which can lead to movement disorder and/or neuropsychiatric manifestations. We present two cases in the same family; a 68-year-old brother had involuntary jerky movements of hand and dysarthria for 10 years while the 44-year-old sister had right lower limb spasticity and decreased vision for 2 years. The serial MRI scans showed slow progression in the bilateral subcortical white matter and cerebellar dentate nuclei calcifications along with surrounding reactive gliosis.
Assuntos
Doenças dos Gânglios da Base , Calcinose , Doenças Neurodegenerativas , Idoso , Doenças dos Gânglios da Base/diagnóstico por imagem , Calcinose/diagnóstico , Calcinose/diagnóstico por imagem , Humanos , Imageamento por Ressonância Magnética , Masculino , Doenças Neurodegenerativas/diagnóstico , Doenças Neurodegenerativas/diagnóstico por imagemRESUMO
Causal genes and variants within genome-wide association study (GWAS) loci can be identified by integrating GWAS statistics with expression quantitative trait loci (eQTL) and determining which variants underlie both GWAS and eQTL signals. Most analyses, however, consider only the marginal eQTL signal, rather than dissect this signal into multiple conditionally independent signals for each gene. Here we show that analyzing conditional eQTL signatures, which could be important under specific cellular or temporal contexts, leads to improved fine mapping of GWAS associations. Using genotypes and gene expression levels from post-mortem human brain samples (n = 467) reported by the CommonMind Consortium (CMC), we find that conditional eQTL are widespread; 63% of genes with primary eQTL also have conditional eQTL. In addition, genomic features associated with conditional eQTL are consistent with context-specific (e.g., tissue-, cell type-, or developmental time point-specific) regulation of gene expression. Integrating the 2014 Psychiatric Genomics Consortium schizophrenia (SCZ) GWAS and CMC primary and conditional eQTL data reveals 40 loci with strong evidence for co-localization (posterior probability > 0.8), including six loci with co-localization of conditional eQTL. Our co-localization analyses support previously reported genes, identify novel genes associated with schizophrenia risk, and provide specific hypotheses for their functional follow-up.
Assuntos
Estudo de Associação Genômica Ampla , Córtex Pré-Frontal/patologia , Locos de Características Quantitativas/genética , Esquizofrenia/genética , Células Cultivadas , Epigênese Genética , Genoma Humano , HumanosRESUMO
Autism spectrum disorder (ASD) comprises a group of neurodevelopmental disorders characterized by social deficits and stereotyped behaviors. Despite intensive research, its etiopathogenesis remains largely unclear. Although studies consistently reported dopaminergic anomalies, a coherent dopaminergic model of ASD was lacking until recently. In 2017, we provided a theoretical framework for a "dopamine hypothesis of ASD" which proposed that autistic behavior arises from a dysfunctional midbrain dopaminergic system. Namely, we hypothesized that malfunction of 2 critical circuits originating in the midbrain, that is, the mesocorticolimbic and nigrostriatal pathways, generates the core behavioral features of ASD. Moreover, we provided key predictions of our model along with testing means. Since then, a notable number of studies referenced our work and numerous others provided support for our model. To account for these developments, we review all these recent data and discuss their implications. Furthermore, in the light of these new insights, we further refine and reconceptualize our model, debating on the possibility that various etiologies of ASD converge upon a dysfunctional midbrain dopaminergic system. In addition, we discuss future prospects, providing new means of testing our hypothesis, as well as its limitations. Along these lines, we aimed to provide a model which, if confirmed, could provide a better understanding of the etiopathogenesis of ASD along with new therapeutic strategies.
Assuntos
Transtorno do Espectro Autista , Dopamina , HumanosRESUMO
Distal 1q21.1 microdeletions have shown highly variable clinical expressivity and incomplete penetrance, with affected individuals manifesting a broad spectrum of nonspecific features. The goals of this study were to better describe the phenotypic spectrum of patients with distal 1q21.1 microdeletions and to compare the clinical features among affected individuals. We performed a retrospective chart review of 47 individuals with distal 1q21.1 microdeletions tested at a large clinical genetic testing laboratory, with most patients being clinically evaluated in the same children's hospital. Health information such as growth charts, results of imaging studies, developmental history, and progress notes were collected. Statistical analysis was performed using Fisher's exact test to compare clinical features among study subjects. Common features in our cohort include microcephaly (51.2%), seizures (29.8%), developmental delay (74.5%), failure to thrive (FTT) (68.1%), dysmorphic features (63.8%), and a variety of congenital anomalies such as cardiac abnormalities (23.4%) and genitourinary abnormalities (19.1%). Compared to prior literature, we found that seizures, brain anomalies, and FTT were more prevalent among our study cohort. Females were more likely than males to have microcephaly (p = 0.0199) and cardiac abnormalities (p = 0.0018). Based on existing genome-wide clinical testing results, at least a quarter of the cohort had additional genetic findings that may impact the phenotype of the individual. Our study represents the largest cohort of distal 1q21.1 microdeletion carriers available in the literature thus far, and it further illustrates the wide spectrum of clinical manifestations among symptomatic individuals. These results may allow for improved genetic counseling and management of affected individuals. Future studies may help to elucidate the underlying molecular mechanisms impacting the phenotypic variability observed with this microdeletion.
Assuntos
Anormalidades Múltiplas/genética , Cardiopatias Congênitas/genética , Deficiência Intelectual/genética , Megalencefalia/genética , Microcefalia/genética , Anormalidades Múltiplas/diagnóstico , Anormalidades Múltiplas/fisiopatologia , Adolescente , Adulto , Criança , Pré-Escolar , Deleção Cromossômica , Cromossomos Humanos Par 1/genética , Variações do Número de Cópias de DNA/genética , Deficiências do Desenvolvimento/complicações , Deficiências do Desenvolvimento/genética , Deficiências do Desenvolvimento/fisiopatologia , Insuficiência de Crescimento/complicações , Insuficiência de Crescimento/genética , Insuficiência de Crescimento/fisiopatologia , Feminino , Aconselhamento Genético , Testes Genéticos/métodos , Cardiopatias Congênitas/complicações , Cardiopatias Congênitas/diagnóstico , Cardiopatias Congênitas/fisiopatologia , Humanos , Lactente , Deficiência Intelectual/complicações , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/fisiopatologia , Masculino , Megalencefalia/complicações , Megalencefalia/diagnóstico , Megalencefalia/fisiopatologia , Microcefalia/complicações , Microcefalia/diagnóstico , Microcefalia/fisiopatologia , Linhagem , Convulsões/complicações , Convulsões/genética , Convulsões/fisiopatologia , Adulto JovemRESUMO
Neuroserpin is a serine protease inhibitor of the nervous system required for normal synaptic plasticity and regulating cognitive, emotional and social behavior in mice. The high expression level of neuroserpin detected at late stages of nervous system formation in most regions of the brain points to a function in neurodevelopment. In order to evaluate the contribution of neuroserpin to brain development, we investigated developmental neurogenesis and neuronal differentiation in the hippocampus of neuroserpin-deficient mice. Moreover, synaptic reorganization and composition of perineuronal net were studied during maturation and stabilization of hippocampal circuits. We showed that absence of neuroserpin results in early termination of neuronal precursor proliferation and premature neuronal differentiation in the first postnatal weeks. Additionally, at the end of the critical period neuroserpin-deficient mice had changed morphology of dendritic spines towards a more mature phenotype. This was accompanied by increased protein levels and reduced proteolytic cleavage of aggrecan, a perineuronal net core protein. These data suggest a role for neuroserpin in coordinating generation and maturation of the hippocampus, which is essential for establishment of an appropriate neuronal network.
Assuntos
Espinhas Dendríticas/metabolismo , Neurogênese , Neuropeptídeos/metabolismo , Serpinas/metabolismo , Animais , Linhagem Celular , Proliferação de Células , Células Cultivadas , Espinhas Dendríticas/fisiologia , Hipocampo/citologia , Hipocampo/embriologia , Hipocampo/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Células-Tronco Neurais/citologia , Células-Tronco Neurais/metabolismo , Células-Tronco Neurais/fisiologia , Neuropeptídeos/genética , Serpinas/genética , NeuroserpinaRESUMO
OBJECTIVE: To examine caregiver satisfaction with treatments for pediatric autoimmune neuropsychiatric disorder associated with streptococcus (PANDAS) and how symptom frequency changes over time. METHODS: A list was created for PANDAS subjects seen at the Georgetown Pediatric Otolaryngology clinic from 2015 to 2018. Questionnaires were distributed to caregivers able to be contacted; 62% responded (n = 60). Subjects were placed in groups based on treatments reported: tonsillectomy and adenoidectomy (T&A, n = 28), T&A and intravenous immunoglobulin (IVIG, n = 22), or nonsurgical treatment(s) (n = 10). Caregivers reported frequencies for each of 10 associated symptoms from time of treatment to 12 months and also expressed their satisfaction with treatment. RESULTS: Patients were treated with antibiotics (n = 60, 100%), T&A (83.3%), IVIG (40%), Rituximab (15%), steroids (20%), and/or plasma exchange (10%). Caregivers for 66% (n = 33) of surgical patients identified T&A as the most effective treatment, and 80% would choose the operation again. No difference in median caregiver satisfaction level was found among the groups (n = 0.196). There was no significant difference in frequency for any of the symptoms (all p > 0.05) except choreiform movement (p = 0.0296). CONCLUSION: Caregivers reported a decreasing frequency of symptoms over time regardless of treatment and had no difference in satisfaction. T&A was the most preferred treatment and the most impactful on symptoms for surgical patients. Given the challenges of immunologic therapies, T&A in combination with antibiotics should be considered as an early intervention for PANDAS.
Assuntos
Adenoidectomia , Doenças Autoimunes/cirurgia , Cuidadores/psicologia , Pais/psicologia , Satisfação Pessoal , Infecções Estreptocócicas/cirurgia , Tonsilectomia , Adolescente , Adulto , Antibacterianos/uso terapêutico , Doenças Autoimunes/complicações , Criança , Pré-Escolar , Terapia Combinada , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Pessoa de Meia-Idade , Infecções Estreptocócicas/complicações , Fatores de TempoRESUMO
Despite extensive efforts to combat cigarette smoking/tobacco use, it still remains a leading cause of global morbidity and mortality, killing more than eight million people each year. While tobacco smoking is a major risk factor for non-communicable diseases related to the four main groups-cardiovascular disease, cancer, chronic lung disease, and diabetes-its impact on neuropsychiatric risk is rather elusive. The aim of this review article is to emphasize the importance of smoking as a potential risk factor for neuropsychiatric disease and to identify central pathophysiological mechanisms that may contribute to this relationship. There is strong evidence from epidemiological and experimental studies indicating that smoking may increase the risk of various neuropsychiatric diseases, such as dementia/cognitive decline, schizophrenia/psychosis, depression, anxiety disorder, and suicidal behavior induced by structural and functional alterations of the central nervous system, mainly centered on inflammatory and oxidative stress pathways. From a public health perspective, preventive measures and policies designed to counteract the global epidemic of smoking should necessarily include warnings and actions that address the risk of neuropsychiatric disease.
Assuntos
Transtornos de Ansiedade/induzido quimicamente , Fumar/efeitos adversos , Fumar Tabaco/efeitos adversos , Animais , Humanos , Estresse Oxidativo/efeitos dos fármacos , Fatores de Risco , Transdução de Sinais/efeitos dos fármacosRESUMO
Mitochondria are regarded as the metabolic centers of cells and are integral in many other cell processes, including the immune response. Each mitochondrion contains numerous copies of mitochondrial DNA (mtDNA), a small, circular, and bacterial-like DNA. In response to cellular damage or stress, mtDNA can be released from the mitochondrion and trigger immune and inflammatory responses. mtDNA release into the cytosol or bloodstream can occur as a response to hypoxia, sepsis, traumatic injury, excitatory cytotoxicity, or drastic mitochondrial membrane potential changes, some of which are hallmarks of neurodegenerative and mood disorders. Released mtDNA can mediate inflammatory responses observed in many neurological and mood disorders by driving the expression of inflammatory cytokines and the interferon response system. The current understanding of the role of mtDNA release in affective mood disorders and neurodegenerative diseases will be discussed.
Assuntos
DNA Mitocondrial/genética , Mitocôndrias/genética , Doenças Neurodegenerativas/genética , Animais , Citosol/metabolismo , Humanos , Mutação , Doenças Neurodegenerativas/imunologiaRESUMO
BACKGROUND: Obsessive-Compulsive Disorder (OCD) is a chronic neuropsychiatric disorder associated with unpleasant thoughts or mental images, making the patient repeat physical or mental behaviors to relieve discomfort. 40-60% of patients do not respond to Serotonin Reuptake Inhibitors, including fluvoxamine therapy. INTRODUCTION: The aim of the study is to identify the predictors of fluvoxamine therapy in OCD patients by Bayesian Ordinal Quantile Regression Model. METHODS: This study was performed on 109 patients with OCD. Three methods, including Bayesian ordinal quantile, probit, and logistic regression models, were applied to identify predictors of response to fluvoxamine. The accuracy and weighted kappa were used to evaluate these models. RESULTS: Our result showed that rs3780413 (mean=-0.69, sd=0.39) and cleaning dimension (mean=-0.61, sd=0.20) had reverse effects on response to fluvoxamine therapy in Bayesian ordinal probit and logistic regression models. In the 75th quantile regression model, marital status (mean=1.62, sd=0.47) and family history (mean=1.33, sd=0.61) had a direct effect, and cleaning (mean=-1.10, sd=0.37) and somatic (mean=-0.58, sd=0.27) dimensions had reverse effects on response to fluvoxamine therapy. CONCLUSION: Response to fluvoxamine is a multifactorial problem and can be different in the levels of socio-demographic, genetic, and clinical predictors. Marital status, familial history, cleaning, and somatic dimensions are associated with response to fluvoxamine therapy.
RESUMO
BACKGROUND: Growing evidence has shown that alterations in the gut microbiota composition were associated with a variety of neuropsychiatric conditions. However, whether such associations reflect causality remains unknown. We aimed to reveal the causal relationships among gut microbiota, metabolites, and neuropsychiatric disorders including Alzheimer's disease (AD), major depressive disorder (MDD), and schizophrenia (SCZ). METHODS: A two-sample bi-directional Mendelian randomization analysis was performed by using genetic variants from genome-wide association studies as instrumental variables for gut microbiota, metabolites, AD, MDD, and SCZ, respectively. RESULTS: We found suggestive associations of host-genetic-driven increase in Blautia (OR, 0.88; 95%CI, 0.79-0.99; P = 0.028) and elevated γ-aminobutyric acid (GABA) (0.96; 0.92-1.00; P = 0.034), a downstream product of Blautia-dependent arginine metabolism, with a lower risk of AD. Genetically increased Enterobacteriaceae family and Enterobacteriales order were potentially associated with a higher risk of SCZ (1.09; 1.00-1.18; P = 0.048), while Gammaproteobacteria class (0.90; 0.83-0.98; P = 0.011) was related to a lower risk for SCZ. Gut production of serotonin was potentially associated with an increased risk of SCZ (1.07; 1.00-1.15; P = 0.047). Furthermore, genetically increased Bacilli class was related to a higher risk of MDD (1.07; 1.02-1.12; P = 0.010). In the other direction, neuropsychiatric disorders altered gut microbiota composition. CONCLUSIONS: These data for the first time provide evidence of potential causal links between gut microbiome and AD, MDD, and SCZ. GABA and serotonin may play an important role in gut microbiota-host crosstalk in AD and SCZ, respectively. Further investigations in understanding the underlying mechanisms of associations between gut microbiota and AD, MDD, and SCZ are required.