RESUMO
The recent cloning of two GABA(B) receptor subunits, GABA(B1) and GABA(B2), has raised the possibility that differences in GABA(B) receptor subunit composition may give rise to pharmacologically or functionally distinct receptors. If present, such molecular diversity could permit the selective targeting of GABA(B) receptor subtypes specifically involved in pathologies such as drug addiction, spasticity, pain, and epilepsy. To address these issues we have developed a GABA(B1) subunit knockout mouse using gene targeting techniques. In the brains of GABA(B1) null mice, all pre- and postsynaptic GABA(B) receptor function was absent demonstrating that the GABA(B1) subunit is essential for all GABA(B) receptor-mediated mechanisms. Despite this, GABA(B1) null mice appeared normal at birth, although by postnatal week four their growth was retarded and they developed a generalized epilepsy that resulted in premature death. In addition, GABA(B1) heterozygote animals showed enhanced prepulse inhibition responses compared to littermate controls, suggesting that GABA(B1) deficient mice exhibit increased sensorimotor gating mechanisms. These data suggest that GABA(B) receptor antagonists may be of benefit in the treatment of psychiatric and neurological disorders in which attentional processing is impaired.
Assuntos
Sistema Nervoso Central/anormalidades , Epilepsia/congênito , Camundongos Knockout/anormalidades , Inibição Neural/genética , Neurônios/metabolismo , Receptores de GABA-B/deficiência , Potenciais de Ação/efeitos dos fármacos , Potenciais de Ação/fisiologia , Animais , Baclofeno/farmacologia , Comportamento Animal/fisiologia , Sistema Nervoso Central/metabolismo , Sistema Nervoso Central/fisiopatologia , Regulação para Baixo/genética , Epilepsia/genética , Epilepsia/fisiopatologia , Agonistas GABAérgicos/farmacologia , Marcação de Genes/métodos , Heterozigoto , Camundongos , Camundongos Knockout/anatomia & histologia , Camundongos Knockout/metabolismo , Neurônios/citologia , Fenótipo , RNA Mensageiro/metabolismo , Ensaio Radioligante , Receptores de GABA-B/genética , Receptores de GABA-B/metabolismo , Reflexo de Sobressalto/efeitos dos fármacos , Reflexo de Sobressalto/fisiologia , Convulsões/congênito , Convulsões/genética , Convulsões/fisiopatologia , Sinapses/efeitos dos fármacos , Sinapses/metabolismo , Sinapses/ultraestrutura , Transmissão Sináptica/efeitos dos fármacos , Transmissão Sináptica/genética , Ácido gama-Aminobutírico/metabolismoRESUMO
We reviewed the clinical and fine-needle aspiration (FNA) findings in 20 patients with poorly differentiated carcinomas presenting initially as parotid or as submandibular masses. There were 11 primary tumors and nine metastatic malignancies in 14 males and six females ranging in age from 39 to 89 yr (median = 66). The tumor types included three primary carcinomas with oncocytic features, three additional cases of high-grade parotid carcinoma, one case of primary neuroendocrine carcinoma, two examples of malignant mixed tumor, one high-grade mucoepidermoid carcinoma, and a single example of malignant lymphoepithelial lesion. Six patients with metastatic carcinoma had previous diagnoses of malignancy. In the three remaining individuals, primary carcinomas of the lung (two cases), and an unknown primary site presented initially as parotid masses. Five examples of metastatic squamous cell carcinoma, one metastatic basal cell carcinoma, and two metastatic renal cell carcinomas were identified. One parotid lymphoepithelioma was interpreted cytologically as an atypical lymphoproliferative process suggestive of Hodgkin's disease. Nineteen cases (95%) were correctly classified as carcinoma at the time of FNA. High-grade carcinomas aspirated from the parotid may be primary, but are frequently metastatic to either the gland, or to an intraparotid lymph node. Our experience indicates that some metastatic carcinomas present at this site, without a previous history of malignancy. Distinguishing primary from metastatic lesions has important therapeutic implications.
