RESUMO
Volatile anesthetics like halothane and enflurane are of interest to clinicians and neuroscientists because of their ability to preferentially disrupt higher functions that make up the conscious state. All volatiles were once thought to act identically; if so, they should be affected equally by genetic variants. However, mutations in two distinct genes, one in Caenorhabditis and one in Drosophila, have been reported to produce much larger effects on the response to halothane than enflurane [1, 2]. To see whether this anesthesia signature is adventitious or fundamental, we have identified orthologs of each gene and determined the mutant phenotype within each species. The fly gene, narrow abdomen (na), encodes a putative ion channel whose sequence places it in a unique family; the nematode gene, unc-79, is identified here as encoding a large cytosolic protein that lacks obvious motifs. In Caenorhabditis, mutations that inactivate both of the na orthologs produce an Unc-79 phenotype; in Drosophila, mutations that inactivate the unc-79 ortholog produce an na phenotype. In each organism, studies of double mutants place the genes in the same pathway, and biochemical studies show that proteins of the UNC-79 family control NA protein levels by a posttranscriptional mechanism. Thus, the anesthetic signature reflects an evolutionarily conserved role for the na orthologs, implying its intimate involvement in drug action.
Assuntos
Anestesia Geral , Caenorhabditis elegans/metabolismo , Drosophila melanogaster/metabolismo , Canais Iônicos/metabolismo , Anestésicos Inalatórios/farmacologia , Animais , Evolução Biológica , Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/genética , Proteínas de Caenorhabditis elegans/metabolismo , Citosol/química , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Drosophila melanogaster/genética , Enflurano/farmacologia , Halotano/farmacologia , Canais Iônicos/genética , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Dados de Sequência Molecular , Mutação , FenótipoRESUMO
We present the first case report of successful cardiac surgery in a child with idiopathic infantile arterial calcification (IIAC), a disease that is generally lethal within the first 6 months of life. This 27-month-old Hispanic American boy with IIAC successfully underwent cardiothoracic surgery for severe pulmonary valve (PV) stenosis after unsuccessful balloon valvotomy in the cardiac catheterization laboratory.
Assuntos
Estenose da Valva Pulmonar/cirurgia , Calcinose/cirurgia , Pré-Escolar , Humanos , Masculino , Resultado do Tratamento , Calcificação Vascular , Doenças Vasculares/cirurgiaRESUMO
The discovery of the phenomenon of anesthesia over 150 years ago was a watershed event that revolutionized the practice of medicine. Despite their annual use in millions of patients, the mechanism by which volatile anesthetics produce reversible loss of consciousness remains a mystery. The inherent problems in studying loss of consciousness in humans are legion. However, multiple model organisms are currently being exploited to apply the powerful tools of modern molecular genetics to this question. Mutants in yeast, nematodes, fruit flies and mice have been produced that display abnormalities in their response to volatile anesthetics. Each organism possesses unique advantages and difficulties as a model system, and each reveals different molecules that control its response to anesthetics. Nonetheless, the accumulating body of genetic evidence points to multiple targets for volatile anesthetics. Not only will understanding how volatile anesthetics work yield better and safer anesthetics, but, in addition, these remarkable compounds may ultimately serve as probes to understand the nature of consciousness itself.