RESUMO
In contrast to drugs established to treat neonatal seizures, levetiracetam shows little neurotoxicity in experimental animal models and has good safety records in adults and children. Here, we present results from a survey on the off-label use of levetiracetam in newborn infants among neonatologists and pediatric neurologists in German university hospitals.
Assuntos
Anticonvulsivantes/uso terapêutico , Doenças do Recém-Nascido/tratamento farmacológico , Piracetam/análogos & derivados , Espasmos Infantis/tratamento farmacológico , Anticonvulsivantes/efeitos adversos , Uso de Medicamentos/estatística & dados numéricos , Alemanha , Inquéritos Epidemiológicos , Hospitais Universitários/estatística & dados numéricos , Humanos , Recém-Nascido , Levetiracetam , Uso Off-Label , Piracetam/efeitos adversos , Piracetam/uso terapêuticoRESUMO
Focal and symmetric necrotic lesions of the brainstem are thought to result from fetal hypotension or cardiac arrest in the perinatal period and thus occur in the course of postnatal intensive care rather than in utero. Here, we report for the first time on brainstem necrosis in a preterm stillborn demonstrating that brainstem necrosis occurs already in utero. The preterm stillborn of 28 weeks gestation of a mother that suffered from HELLP-syndrome was severely affected by a fetal hydrops with bilateral pleural effusions and lung hypoplasia. Bilateral tegmental brainstem necrosis and thalamic lesions were detected.
Assuntos
Tronco Encefálico/patologia , Hidropisia Fetal/patologia , Nascimento Prematuro , Natimorto , Tálamo/patologia , Adulto , Feminino , Síndrome HELLP/diagnóstico , Humanos , Recém-Nascido , Masculino , Necrose/diagnóstico , Necrose/patologia , GravidezRESUMO
Although the role of microglial activation in neural injury remains controversial, there is increasing evidence for a detrimental effect in the immature brain, which may occur in response to release of neurotoxic substances including pro-inflammatory cytokines. However, the signaling mechanisms involved in microglial-induced neuronal cell death are unclear. Microglia isolated from the brains of wild-type (WT) or MyD88 knockout (KO) mice were exposed to PBS or the TLR4-ligand LPS (100 ng/mL) for 2, 6, 14, or 24 h, and the microglia-conditioned medium (MCM) collected. Detection of multiple inflammatory molecules in MCM was performed using a mouse 22-plex cytokine microbead array kit. Primary neuronal cultures were supplemented with the 14 or 24 h MCM, and the degree of neuronal apoptosis examined after exposure for 24 h. Results showed a rapid and sustained elevation in multiple inflammatory mediators in the MCM of WT microglia exposed to LPS, which was largely inhibited in MyD88 KO microglia. There was a significant increase in apoptotic death measured at 24 h in cultured neurons exposed to CM from either 14 or 24 h LPS-stimulated WT microglia (p<.05 vs. WT control). By contrast, there was no increase in apoptotic death in cultured neurons exposed to CM from 14 or 24 h LPS-stimulated MyD88 KO microglia (p=.15 vs. MyD88 KO control). These data suggest that MyD88-dependent activation of microglia by LPS causes release of factors directly toxic to neurons.
Assuntos
Citocinas/metabolismo , Microglia/metabolismo , Fator 88 de Diferenciação Mieloide/metabolismo , Neurônios/metabolismo , Análise de Variância , Animais , Apoptose/efeitos dos fármacos , Apoptose/imunologia , Encéfalo/imunologia , Encéfalo/metabolismo , Células Cultivadas , Técnicas de Cocultura , Citocinas/imunologia , Lipopolissacarídeos/farmacologia , Camundongos , Camundongos Knockout , Microglia/efeitos dos fármacos , Microglia/imunologia , Fator 88 de Diferenciação Mieloide/genética , Fator 88 de Diferenciação Mieloide/imunologia , Neurônios/efeitos dos fármacos , Neurônios/imunologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/imunologiaRESUMO
In this article, we review the clinical, neuropathological and genetic aspects of distal spinal-muscular atrophy 1 (DSMA1; MIM#604320), formerly designated as autosomal recessive spinal muscular atrophy with respiratory distress type 1 (SMARD1) and also known as distal hereditary-motor neuropathy type 6 (dHMN6 or HMN6).
Assuntos
Atrofia Muscular Espinal/diagnóstico , Diagnóstico Diferencial , Feminino , Humanos , Recém-Nascido , Atrofia Muscular Espinal/genética , Gravidez , Diagnóstico Pré-Natal , Síndrome do Desconforto Respiratório do Recém-Nascido/etiologiaAssuntos
Mutação de Sentido Incorreto/genética , Miopatias da Nemalina/etiologia , Miopatias da Nemalina/genética , Canal de Liberação de Cálcio do Receptor de Rianodina/genética , Adolescente , Afeganistão/etnologia , Feminino , Humanos , Imageamento por Ressonância Magnética , Músculo Esquelético/patologia , Miopatias da Nemalina/patologiaRESUMO
Severe side effects of chemotherapy in pediatric patients with acute lymphoblastic leukemia are rare, but well-known. We present two pediatric patients who developed ascending motoric paraplegia (AMP) following intrathecal chemotherapy. Both patients suffered from progressive weakness of their lower extremities, neurogenic bladder dysfunction, autonomous neural dysregulation and minor sensory deficits. Despite an initially similar clinical picture, progression and outcome were fairly different. There is convincing evidence that AMP is caused by spinal cord toxicity of intrathecally applied toxic agents such as cytarabin and/or methotrexate leading to spinal demyelinisation as demonstrated by elevated myelin basic protein in cerebrospinal fluid.
Assuntos
Antimetabólitos Antineoplásicos/administração & dosagem , Injeções Espinhais/efeitos adversos , Metotrexato/administração & dosagem , Paraplegia/induzido quimicamente , Leucemia-Linfoma Linfoblástico de Células Precursoras/tratamento farmacológico , Doença Aguda , Administração Oral , Adolescente , Antimetabólitos Antineoplásicos/efeitos adversos , Antimetabólitos Antineoplásicos/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Criança , Progressão da Doença , Eletroencefalografia , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Mercaptopurina/administração & dosagem , Mercaptopurina/uso terapêutico , Metotrexato/efeitos adversos , Metotrexato/uso terapêutico , Paraplegia/sangue , Paraplegia/diagnóstico , Fatores de TempoRESUMO
Epilepsy is the most common neurological disorder in young humans. Antiepileptic drugs (AEDs) which are used to treat seizures in infants, children and pregnant women can cause cognitive impairment, microcephaly and birth defects. Ion channels, neurotransmitters and second messenger systems constitute molecular targets of AEDs. The same targets regulate brain processes essential both for propagation of seizures and for learning, memory and emotional behavior. Thus, AEDs can influence brain function and brain development in undesired ways. Here we review mechanisms of action of AEDs, examine clinical evidence for their adverse effects in the developing human brain, and present studies on cognitive and behavioral effects in animal models. Furthermore, we discuss mechanisms responsible for adverse effects of AEDs in the developing mammalian brain, including interference with cell proliferation and migration, axonal arborization, synaptogenesis, synaptic plasticity and physiological apoptotic cell death.
Assuntos
Anticonvulsivantes/efeitos adversos , Encéfalo/efeitos dos fármacos , Epilepsia/tratamento farmacológico , Animais , Anticonvulsivantes/farmacologia , Anticonvulsivantes/uso terapêutico , Apoptose , Encéfalo/embriologia , Encéfalo/crescimento & desenvolvimento , Encéfalo/patologia , Humanos , Neurônios/efeitos dos fármacos , Neurônios/patologiaRESUMO
The identification of an ever increasing number of gene defects in patients with neuromuscular disorders has disclosed both marked phenotype and genotype variability and considerable disease overlap. In order to offer an economic strategy to characterise the molecular defect in patients with unclassified neuromuscular disorders, we designed DNA marker sets for linkage analysis of 62 distinct neuromuscular disorders gene loci, including all known muscular dystrophies, congenital myopathies, congenital myasthenic syndromes and myotonias. Genotyping of marker loci of 140 clinically well-characterised families with unclassified neuromuscular disorders reduced the number of candidates to one or two genes in 49 % of the families. Subsequent mutation analysis and genome-wide scans enabled the determination of the genetic defect in 31 % of the families including the identification of a new gene and a new mutation in an unexpected candidate gene. This highlights the effective application of this approach both for diagnostic strategies as well as for the identification of new loci and genes.
Assuntos
Heterogeneidade Genética , Técnicas de Diagnóstico Molecular/métodos , Proteínas Musculares/genética , Doenças Neuromusculares/diagnóstico , Doenças Neuromusculares/genética , Análise Mutacional de DNA/métodos , Bases de Dados Genéticas/estatística & dados numéricos , Diagnóstico Diferencial , Saúde da Família , Genótipo , Humanos , Técnicas de Diagnóstico Molecular/economia , Doenças Neuromusculares/classificaçãoRESUMO
The developing mammalian brain experiences a period of rapid growth during which various otherwise innocuous environmental factors cause widespread apoptotic neuronal death. To gain insight into developmental events influenced by a premature exposure to high oxygen levels and identify proteins engaged in neurodegenerative and reparative processes, we analyzed mouse brain proteome changes at P7, P14 and P35 caused by an exposure to hyperoxia at P6. Changes detected in the brain proteome suggested that hyperoxia leads to oxidative stress and apoptotic neuronal death. These changes were consistent with results of histological and biochemical evaluation of the brains, which revealed widespread apoptotic neuronal death and increased levels of protein carbonyls. Furthermore, we detected changes in proteins involved in synaptic function, cell proliferation and formation of neuronal connections, suggesting interference of oxidative stress with these developmental events. These effects are age-dependent, as they did not occur in mice subjected to hyperoxia in adolescence.
Assuntos
Encéfalo/metabolismo , Estresse Oxidativo/fisiologia , Proteínas/análise , Proteoma/análise , Animais , Apoptose/fisiologia , Western Blotting , Encéfalo/citologia , Encéfalo/crescimento & desenvolvimento , Córtex Cerebral/química , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/metabolismo , Proteínas do Domínio Duplacortina , Eletroforese em Gel Bidimensional , Hipóxia/fisiopatologia , Proteínas de Filamentos Intermediários/análise , Proteínas de Filamentos Intermediários/genética , Camundongos , Camundongos Endogâmicos C57BL , Proteínas Associadas aos Microtúbulos/análise , Proteínas Associadas aos Microtúbulos/genética , Modelos Neurológicos , Proteínas do Tecido Nervoso/análise , Proteínas do Tecido Nervoso/genética , Nestina , Neurônios/química , Neurônios/citologia , Neurônios/metabolismo , Neuropeptídeos/análise , Neuropeptídeos/genética , Proteínas/genética , Proteoma/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , Reação em Cadeia da Polimerase Via Transcriptase ReversaAssuntos
Actinas/genética , Predisposição Genética para Doença , Mutação de Sentido Incorreto , Miopatias Congênitas Estruturais/diagnóstico , Miopatias Congênitas Estruturais/genética , Adolescente , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Miopatias Congênitas Estruturais/patologia , LinhagemRESUMO
The triple A syndrome (MIM#231550) is a rare autosomal recessive disorder characterized by adrenocorticotropic hormone (ACTH) resistant adrenal failure, achalasia, alacrima, and a variety of neurological and dermatological features. The triple A syndrome is caused by mutations in the AAAS gene, which encodes a protein known as ALADIN (ALacrima Achalasia aDrenal Insufficiency Neurologic disorder). ALADIN is a new WD-repeat protein that has no significant homology to any previously identified WD-repeat protein. It has been shown that it colocalizes with nuclear pore complexes (NPCs), a finding that strongly suggests an involvement of ALADIN in nucleocytoplasmic transport. An investigation of 110 families with triple A syndrome disclosed mutation hot spots including Q15K (exon 1), and S293P (exon 8), which occur in 17 and 21 families from different geographical regions, respectively. The variable phenotype of all patients cannot be correlated with the localization and the nature of the ALADIN mutations. Thus, modifying genes/factors may be involved in the progression of this neurodegenerative disease. The lack of AAAS mutations in eight patients and negative linkage to chromosome 12q13 in three families are suggestive of genetic heterogeneity. To examine the cellular localization of ALADIN mutants causing triple A syndrome, we investigated nine different ALADIN-mutants: 2 nonsense (W84X, Q456X), 2 frameshift (F157fsX171, G397fsX414) and 5 point mutations (Q15K, L25P, H160R, S263P, L381R) by transfection experiments with green fluorescence protein. Mutants were predominantly localized in the cytoplasm, but also found in the nucleus indicating that ALADIN is essential for NPC targeting. To investigate physiological functions of ALADIN in vivo, we generated and analysed Aaas-/- knockout mice by homologous recombination in embryonic stem cells. Surprisingly, required animals lack any gross abnormality in adrenal and nervous system function. Further studies have to investigate the role of ALADIN at NPCs and to identify interacting proteins. Functional analyses of ALADIN may permit further understanding of its role for adrenocortical function and neurodevelopment.
Assuntos
Doenças das Glândulas Suprarrenais/genética , Gastroenteropatias/genética , Doenças do Aparelho Lacrimal/genética , Mutação , Poro Nuclear/genética , Proteínas/genética , Doenças das Glândulas Suprarrenais/metabolismo , Hormônio Adrenocorticotrópico , Animais , Modelos Animais de Doenças , Resistência a Medicamentos , Gastroenteropatias/metabolismo , Humanos , Doenças do Aparelho Lacrimal/metabolismo , Camundongos , Camundongos Knockout/genética , Proteínas do Tecido Nervoso , Complexo de Proteínas Formadoras de Poros Nucleares , Proteínas/metabolismo , Frações Subcelulares/metabolismo , Síndrome , Distribuição TecidualRESUMO
The triple A syndrome (MIM*231550) is a rare autosomal recessive disorder characterized by adrenocorticotropic hormone (ACTH) resistant adrenal failure, achalasia, alacrima and a variety of neurological and dermatological features. Adrenal insufficiency usually presents in the first decade of life, however in some patients it may occur later in life or may even lack completely. Recently, we and others identified a novel gene on chromosome 12q13, designated AAAS (Achalasia-Addisonianism-Alacrima-Syndrome gene) which is mutated in patients with triple A syndrome. We investigated n=84 families including 111 patients with clinically suggested triple A syndrome and identified homozygous or compound heterozygous AAAS mutations in 78 families. Genotype/phenotype analyses revealed a highly variable occurrence, age of onset and severity of all clinical symptoms between patients with the same AAAS mutation. The obvious lack of a genotype/phenotype relationship is suggestive of modifying genes/factors which need to be determined. The AAAS protein function is unknown. With four WD repeats it belongs to the family of WD repeat-containing proteins which may exhibit a high degree of functional diversity. The subcellular localization of the protein and the determination of its putative binding partners will shed light on the role of the AAAS protein for the development and function of the adrenal gland and other neuroendocrine structures.