RESUMEN
Familial hemiplegic migraine (FHM) is a rare autosomal dominantly inherited subtype of migraine, in which hemiparesis occurs during the aura. The majority of the families carry mutations in the CACNA1A gene on chromosome 19p13 (FHM1). About 20% of FHM families is linked to chromosome 1q23 (FHM2), and has mutations in the ATP1A2 gene, encoding the alpha2-subunit of the Na,K-ATPase. Mutation analysis in a Dutch and a Turkish family with pure FHM revealed two novel de novo missense mutations, R593W and V628M, respectively. Cellular survival assays support the hypothesis that both mutations are disease-causative. The identification of the first de novo mutations underscores beyond any doubt the involvement of the ATP1A2 gene in FHM2.
Asunto(s)
Hemiplejía/genética , Trastornos Migrañosos/genética , Mutación , ATPasa Intercambiadora de Sodio-Potasio/genética , Secuencia de Aminoácidos , Cromosomas Humanos Par 1 , Femenino , Células HeLa , Humanos , Masculino , Persona de Mediana Edad , Datos de Secuencia Molecular , Homología de Secuencia de Aminoácido , ATPasa Intercambiadora de Sodio-Potasio/metabolismoRESUMEN
OBJECTIVE: We studied the interaction between valproate (VPA) and ethosuximide (ESM) in diminishing the incidence of absence-like spike-wave discharges (SWDs) in the EEG of WAG/Rij rats. METHODS: VPA, ESM, their combination and saline were evaluated in 16 rats. The doses of VPA ranged from 0 to 280 mg/kg and the doses of ESM ranged from 0 to 40 mg/kg. For the drug combination, a fixed weight ratio of 7/1 VPA/ESM was used. The incidence of SWDs in the EEG was determined for the period of 15-75 min after injection and compared to the incidence of SWDs prior to injection. The sigmoid-E(max) equation was fitted to the data. Isobolic analysis, on 50% effect, was used to assess the character of the drug interaction. RESULTS: The parameters for diminishing the incidence of the SWDs were: VPA: ED(50): 121mg/kg; ESM: ED(50): 21.5mg/kg; VPA/ESM: ED(50): 112/16 mg/kg. Isobolic analysis showed that a higher drug load was needed of the combination than of the individual drugs to achieve a 50% reduction of SWDs: factor 1.67; P = 0.012. CONCLUSION: The interaction between valproate and ethosuximide was shown to be infra-additive in diminishing the incidence of SWDs in WAG/Rij rats.
Asunto(s)
Potenciales de Acción/efectos de los fármacos , Etosuximida/farmacología , Ácido Valproico/farmacología , Potenciales de Acción/fisiología , Animales , Relación Dosis-Respuesta a Droga , Combinación de Medicamentos , Masculino , RatasRESUMEN
In the history of Dutch neurology Muskens has a place in his own right. Elderly neurologists still attest to the special fame of Muskens. He held a strong opinion on developing the specialty of neurology independent of psychiatry. At the same time he maintained that surgery of the nervous system also should be included in the realm of neurology. These views met with considerable opposition from colleagues and led to Muskens' isolation. To the field of epileptology he contributed both clinical and experimental neurological studies. With Donath he was the co-founder of the International League Against Epilepsy in 1909. In addition he held a lifelong interest in the pathophysiology of forced movements, which he studied both in human pathology and in experimental studies throughout the vertebrate series. This resulted in his magnum opus on the supravestibular system in 1935. His scientific work was well received in scientific societies all over Europe.