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BACKGROUND AND OBJECTIVE: Heterozygous mutations in KCNA1 cause episodic ataxia type 1 (EA1), an ion channel disorder characterised by brief paroxysms of cerebellar dysfunction and persistent neuromyotonia. This paper describes four previously unreported families with EA1, with the aim of understanding the phenotypic spectrum associated with different mutations. METHODS: 15 affected individuals from four families underwent clinical, genetic and neurophysiological evaluation. The functional impact of new mutations identified in the KCNA1 gene was investigated with in vitro electrophysiology and immunocytochemistry. RESULTS: Detailed clinical documentation, dating back to 1928 in one family, indicates that all patients manifested episodic ataxia of varying severity. Four subjects from three families reported hearing impairment, which has not previously been reported in association with EA1. New mutations (R167M, C185W and I407M) were identified in three out of the four families. When expressed in human embryonic kidney cells, all three new mutations resulted in a loss of K(v)1.1 channel function. The fourth family harboured a previously reported A242P mutation, which has not been previously described in association with ataxia. CONCLUSIONS: The genetic basis of EA1 in four families is established and this report presents the earliest documented case from 1928. All three new mutations caused a loss of K(v)1.1 channel function. The finding of deafness in four individuals raises the possibility of a link between K(v)1.1 dysfunction and hearing impairment. Our findings broaden the phenotypic range associated with mutations in KCNA1.
Assuntos
Ataxia/diagnóstico , Ataxia/genética , Análise Mutacional de DNA , Triagem de Portadores Genéticos , Canal de Potássio Kv1.1/genética , Mioquimia/diagnóstico , Mioquimia/genética , Adolescente , Ataxia/fisiopatologia , Linhagem Celular Transformada , Cerebelo/fisiopatologia , Cromossomos Humanos Par 12/genética , Avaliação da Deficiência , Eletromiografia , Feminino , Humanos , Técnicas In Vitro , Síndrome de Isaacs/diagnóstico , Síndrome de Isaacs/genética , Síndrome de Isaacs/fisiopatologia , Masculino , Neurônios Motores/fisiologia , Mioquimia/fisiopatologia , Linhagem , Fenótipo , Análise de Sequência de DNA , Superfamília Shaker de Canais de Potássio/genética , Superfamília Shaker de Canais de Potássio/fisiologia , TransfecçãoRESUMO
The conventional concept of using nanocarriers to deliver chemotherapeutic drugs has advanced to accommodate additional diagnostic capability. Nanotheranostic agents (NTA), combining both treatment and diagnostic tools, are an ideal example of engineering-health integration for cancer management. Owing to the diverse materials used to construct NTAs, their safety, effectiveness, and diagnostic accuracy could vary substantially. This systematic review consolidated current NTAs incorporating 5-fluorouracil and elucidated their toxicity, anticancer efficacy, and imaging capability. Medline and Embase databases were searched up to March 18, 2022. The search, selection, and extraction were performed by the preferred reporting items for systematic reviews and meta-analysis (PRISMA) guidelines to ensure completeness and reproducibility. Original research papers involving 5-fluorouracil in the preparation of nanoparticles which reported their efficacy, toxicity, and diagnostic capability in animal cancer models were recruited. The quality of included studies was assessed using the Collaborative Approach to Meta-Analysis and Review of Animal Data from Experimental Studies (CAMARADES) checklist. Nine studies were eligible for the systematic review. There was no significant toxicity reported based on animal weight and organ histology. Complete tumor remission was observed in several animal models using chemo-thermal ablation with NTAs, proving the enhancement of 5-fluorouracil efficacy. In terms of imaging performance, the time to achieve maximum tumor image intensity correlates with the presence of targeting ligand on NTAs. The NTAs, which are composed of tumor-targeting ligands, hold promises for further development. Based on the input of current NTA research on cancer, this review proposed a checklist of parameters to recommend researchers for their future NTA testing, especially in animal cancer studies. Systematic Review Registration: website, identifier registration number.
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PURPOSE: To define the spectrum of the epileptic syndromes and epilepsies (other than the idiopathic epilepsies of childhood with occipital paroxysms) that can be associated with fixation-off sensitivity (FOS), delineate the electrographic types of FOS abnormalities and identify the patterns that can be associated with clinical seizures, and examine whether there may be a pure form of fixation-off sensitive epilepsy. METHODS: We reviewed the clinical and video EEG data of all our patients with FOS over the last 12 years. Children with idiopathic focal epilepsies and occipital EEG paroxysms were excluded. RESULTS: From January 1995 to December 2006, 19 of about 8,500 patients had had one or more video-EEGs with FOS, yielding an approximate incidence of 0.2%. From the 14 patients with full clinical and EEG data available, 12 had various epilepsies that included IGE phenotypes (7), symptomatic or probably symptomatic focal (3), cryptogenic generalised (1), and adult onset idiopathic photosensitive occipital (1), and two had no seizures. Seven patients (50%) were photosensitive. FOS EEG abnormalities were occipital in six patients, generalised in eight, and generalised with posterior emphasis in two patients. Seven of these patterns were associated with habitual seizures in seven patients, but actual FOS-induced seizures (absences) were documented with video EEG in only one patient; three others had some historical evidence suggesting that, under some circumstances, their FOS EEG abnormalities might generate clinical seizures. CONCLUSIONS: Despite the association of FOS with generalised and focal, symptomatic and cryptogenic and mild or pharmaco-resistant epilepsies, closer analysis of our data, and supportive evidence from functional imaging and physiological observations on alpha rhythm generation, disclose a prominent role of the occipital areas, even when FOS EEG abnormalities and seizures are ostensibly generalised. Although FOS appears to be of relatively low epileptogenicity, an electroclinical profile of pure FOS epilepsy may exist [Published with video sequences].
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Ritmo alfa , Epilepsia/etiologia , Fixação Ocular , Lobo Occipital/patologia , Lobo Occipital/fisiopatologia , Adolescente , Adulto , Encéfalo/patologia , Encéfalo/fisiopatologia , Criança , Eletroencefalografia , Epilepsia/complicações , Epilepsia/diagnóstico , Epilepsia/fisiopatologia , Feminino , Seguimentos , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
PURPOSE: The purpose of this study was to investigate virulence factors associated with maternal transmission of mutans streptococci (MS). METHODS: Saliva samples were collected from 10 mothers with active caries and their 2- to 5-year-old children. Ten MS colonies were isolated from each subject. Transmission of MS was identified by arbitrarily primed polymerase chain reactions. Biofilm formation and mutacin production of the isolates against Streptococcus gordonii 10558, Streptococcus sanguinis 10557, Streptococcus mutans 25175, and Streptococcus sobrinus 6715 were analyzed. RESULTS: All mothers and children had MS colonization. Only 7 of the 36 maternal genotypes (33 Streptococcus mutans genotypes and 3 Streptococcus sobrinus genotypes) were transmitted. Maternal transmission was found in 4 mother-child pairs, whereas 9 children had nonmaternal genotypes. There was no difference in biofilm formation between transmitted and nontransmitted genotypes (P>.05). Transmitted genotypes, however, produced more mutacin against Streptococcus sobrinus 6715 than nontransmitted genotypes. CONCLUSIONS: This pilot study showed that there may be nonmaternal as well as maternal mutans streptococci transmission.
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Transmissão Vertical de Doenças Infecciosas , Infecções Estreptocócicas/transmissão , Streptococcus mutans/isolamento & purificação , Adulto , Biofilmes , Criança , Feminino , Humanos , Masculino , Projetos Piloto , Reação em Cadeia da Polimerase , Fatores de RiscoRESUMO
Testosterone and estrogen are essential for male behaviors in vertebrates. How these two signaling pathways interact to control masculinization of the brain and behavior remains to be established. Circulating testosterone activates the androgen receptor (AR) and also serves as the source of estrogen in the brain. We have used a genetic strategy to delete AR specifically in the mouse nervous system. This approach permits us to determine the function of AR in sexually dimorphic behaviors in males while maintaining circulating testosterone levels within the normal range. We find that AR mutant males exhibit masculine sexual and territorial displays, but they have striking deficits in specific components of these behaviors. Taken together with the surprisingly limited expression of AR in the developing brain, our findings indicate that testosterone acts as a precursor to estrogen to masculinize the brain and behavior, and signals via AR to control the levels of male behavioral displays.
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Encéfalo/metabolismo , Receptores Androgênicos/metabolismo , Comportamento Sexual Animal/fisiologia , Territorialidade , Animais , Estrogênios/metabolismo , Masculino , Camundongos , Camundongos Transgênicos , Neurônios/metabolismo , Receptores Androgênicos/genética , Testosterona/metabolismoRESUMO
This review concentrates on the principles of the clinical and electroencephalogram diagnosis of idiopathic generalized epilepsies and their treatment. The electroclinical variability of the main seizure types is detailed and particular emphasis is placed on the differential diagnosis from other seizures and nonepileptic conditions that is essential for the optimal management of these patients. The authors review the various idiopathic generalized epilepsy subsyndromes and conditions that are included in both the 1989 International League Against Epilepsy classification system and the recently proposed International League Against Epilepsy scheme, but also syndromes and forms that have not been formally recognized. Finally, the authors describe the principles of antiepileptic drug treatment with the old and newer drugs, and their specific indications and contraindications in the various syndromes and seizure types.
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Anticonvulsivantes/uso terapêutico , Eletroencefalografia/métodos , Epilepsia Generalizada/diagnóstico , Epilepsia Generalizada/tratamento farmacológico , Epilepsias Mioclônicas/diagnóstico , Epilepsias Mioclônicas/fisiopatologia , Epilepsia Generalizada/fisiopatologia , Prova Pericial , HumanosRESUMO
To investigate the pathophysiology of neuropathy in Fabry disease, multiple nerve excitability properties of median motor axons in 20 patients with this disorder but without hyperkalemia were compared with 35 age-matched normal controls. In the patients, depolarizing threshold electrotonus was reduced (P < 0.0001) and superexcitability was reduced (P < 0.001), but late subexcitability was normal. These findings indicate that the axons were mildly depolarized, probably due to ischemia, and are consistent with the hypothesis that poor nerve perfusion in Fabry disease contributes to axonal damage.