RESUMEN
Oxidative stress critically contributes to the pathogenesis of a variety of neurodegenerative diseases such as multiple sclerosis. Astrocytes are the main regulators of oxidative homeostasis in the brain and dysregulation of these cells likely contributes to the accumulation of oxidative damage. The nuclear factor erythroid 2-related factor 2 (Nrf2) is the main transcriptional regulator of the anti-oxidant stress defense. In this study, we elucidate the effects of astrocytic Nrf2-activation on brain-intrinsic inflammation and lesion development. Cells deficient for the Nrf2 repressor kelch-like ECH-associated protein 1 (Keap1) are characterized by hyperactivation of Nrf2-signaling. Therefore, wild type mice and mice with a GFAP-specific Keap1-deletion were fed with 0.25% cuprizone for 1 or 3 weeks. Cuprizone intoxication induced pronounced oligodendrocyte loss, demyelination and reactive gliosis in wild type animals. In contrast, astrocyte-specific Nrf2-activation was sufficient to prevent oligodendrocyte loss and demyelination, to ameliorate brain intrinsic inflammation and to counteract axonal damage. Our results highlight the potential of the Nrf2/ARE system for the treatment of neuroinflammation in general and of multiple sclerosis in particular. © GLIA 2016;64:2219-2230.
Asunto(s)
Astrocitos/metabolismo , Enfermedades Desmielinizantes/etiología , Regulación de la Expresión Génica/fisiología , Esclerosis Múltiple/complicaciones , Esclerosis Múltiple/patología , Factor 2 Relacionado con NF-E2/metabolismo , Animales , Astrocitos/efectos de los fármacos , Encéfalo/diagnóstico por imagen , Encéfalo/metabolismo , Encéfalo/patología , Quimiocina CXCL10/genética , Quimiocina CXCL10/metabolismo , Cuprizona/toxicidad , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/efectos de los fármacos , Regulación de la Expresión Génica/genética , Proteína Ácida Fibrilar de la Glía/genética , Proteína Ácida Fibrilar de la Glía/metabolismo , Glutamato-Cisteína Ligasa/genética , Glutamato-Cisteína Ligasa/metabolismo , Hemo-Oxigenasa 1/genética , Hemo-Oxigenasa 1/metabolismo , Proteína 1 Asociada A ECH Tipo Kelch/genética , Proteína 1 Asociada A ECH Tipo Kelch/metabolismo , Proteínas de la Membrana/genética , Proteínas de la Membrana/metabolismo , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Inhibidores de la Monoaminooxidasa/toxicidad , Esclerosis Múltiple/inducido químicamente , Factor 2 Relacionado con NF-E2/genética , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/genética , Tiorredoxina Reductasa 1/genética , Tiorredoxina Reductasa 1/metabolismoRESUMEN
The effect of mannitol on the permeability of the endothelial monolayer was investigated. Endothelial cells from bovine major cerebral arteries were cultured on a polycarbonate membranes of the double chamber culture system. After the monolayers reached confluence, they were incubated with three kinds of mannitol solution either on the upper chamber or the lower chamber. Evan's blue conjugated bovine serum albumin was used as a marker of vasopermeability and added into the upper chamber solution. The density of the dye that passed through the monolayer was measured by a spectrophotometer. When the solution of the lower chamber was Hepes buffered salt solution (HBSS), permeability was maximum with the 20% mannitol solution in the upper chamber. When the solution of the lower chamber was 20% mannitol, permeability was maximum with HBSS in the upper chamber. When the solution of the lower chamber was 10% mannitol, permeability was minimum with the 10% mannitol solution in the upper chamber. These findings suggested that endothelial cells increase vasopermeability according to gradient of the concentration of mannitol between the intraluminal side and the abluminal side, and not due to the hyperosmolarity itself. Hyperosmolar urea made the endothelial cells shrink, while hyperosmolar mannitol solution did not induce such shrinkage. Therefore a difference in the mechanism of increasing vasopermeability by mannitol and urea was suggested.
Asunto(s)
Permeabilidad de la Membrana Celular/efectos de los fármacos , Endotelio Vascular/efectos de los fármacos , Manitol/farmacología , Animales , Bovinos , Células Cultivadas , Endotelio Vascular/citología , Concentración Osmolar , Urea/farmacologíaRESUMEN
Clavulanic acid, a potent beta-lactamase inhibitor, was studied in fixed combination with ticarcillin and used with tobramycin as empiric therapy for fever in the immunocompromised host. Fifty febrile episodes were evaluated in patients with hematologic malignancy and/or neutropenia. Eighty-one percent of evaluable infections treated with the study regimen of ticarcillin, clavulanic acid, and tobramycin responded. Seventy-four percent of evaluable infections treated with the control regimen of piperacillin, tobramycin, and vancomycin responded (p = 0.4). Resistance to piperacillin and ticarcillin were noted in 23.8 percent of 21 isolated organisms. Resistance to ticarcillin and clavulanic acid was noted in only one (4.7 percent) of the isolated organisms (p = 0.092). Untoward reactions, including rash, nephrotoxicity, and superinfection, were unusual and occurred with equal frequency in the study and control groups. Clavulanic acid in combination with ticarcillin was effective and safe in treating fever in the immunocompromised host.
Asunto(s)
Infecciones Bacterianas/tratamiento farmacológico , Ácidos Clavulánicos/administración & dosificación , Fiebre/tratamiento farmacológico , Tolerancia Inmunológica , Penicilinas/administración & dosificación , Piperacilina/uso terapéutico , Ticarcilina/administración & dosificación , Ácido Clavulánico , Ácidos Clavulánicos/efectos adversos , Ensayos Clínicos como Asunto , Combinación de Medicamentos , Humanos , Recuento de Leucocitos , Neutrófilos , Ticarcilina/efectos adversosAsunto(s)
Meningitis por Haemophilus/tratamiento farmacológico , Meningitis Meningocócica/tratamiento farmacológico , Moxalactam/uso terapéutico , Adolescente , Niño , Preescolar , Femenino , Haemophilus influenzae/efectos de los fármacos , Humanos , Lactante , Masculino , Pruebas de Sensibilidad Microbiana , Moxalactam/farmacología , Neisseria meningitidis/efectos de los fármacosRESUMEN
Foi avaliada a eficacia do moxalactam no tratamento de meningites em criancas, causadas por H. influenzae (27 casos) e N.meningitidis (6 casos). Dos 33 doentes tratados na dose de 100mg/Kg de peso (dose de ataque) e 50mg de 12/12 horas por via venosa, 32 curaram-se. A tolerancia ao produto foi muito boa, havendo alteracoes transitorias de transaminases e fosfatase alcalina; em um caso, houve hematoma posapendectomia, provavelmente relacionado ao uso deste antibiotico. Os niveis sericos e liquoricos do produto foram elevados; as concentracoes no liquor excederam de muito a concentracao bactericida minima dos germes infectantes. O moxalactam se mostrou seguro e eficaz como terapia primaria da meningite causada por H. influenzae e N.meningitidis em criancas
Asunto(s)
Lactante , Preescolar , Niño , Adolescente , Humanos , Masculino , Femenino , Meningitis por Haemophilus , Meningitis Meningocócica , MoxalactamRESUMEN
Eighty-one rabbits were inoculated with known concentrations of type III pneumococci by cisternal puncture and then started on antibiotic therapy the following day. Aliquots of cerebrospinal fluid were sampled at regular intervals both before and after therapy and then analyzed for bacterial titer and leukocyte count. These data were used to examine the interrelationships of inoculum size, leukocyte count, and bacterial titer to each other and their effects both univariately and multivariately on outcome. Inoculum size was the most important single variable affecting outcome, followed in order by the pretherapeutic bacterial titer and leukocyte count. Higher leukocyte counts early in the course of the disease prior to therapy were associated with a favorable outcome. Continued leukocyte elevation after therapy was associated with a poor prognosis. No correlations were found between inoculum size and subsequent bacterial titers; however, the bacterial titer immediately prior to therapy correlated negatively with the level of the early white cell response. The best prognostic information was obtained from the multivariate analysis of inoculum size and pretherapeutic white cell response.
Asunto(s)
Líquido Cefalorraquídeo/microbiología , Recuento de Leucocitos , Meningitis Neumocócica/tratamiento farmacológico , Animales , Meningitis Neumocócica/líquido cefalorraquídeo , Pronóstico , ConejosRESUMEN
In 90 patients a total of 100 reconstructions of the carotid artery had been performed between 1972 and 1977. No patient died from the operation, 3 suffered central nervous complications, and 33 had transitory defects of cranial nerves. These defects were reversible in all but two patients. After an average observation period of 20 months 11 patients had died (6 from cardiac infarction, 2 from stroke, and 3 from unknown reasons). Of the 31 patients with clinical stage II, 24 were without symptoms, 5 had only rare transient ischaemic attacks, and two patients had the same frequency of attacks as preoperatively. Among the 39 stage III patients 35 showed complete or partial regression of symptoms whereas 4 had had repeat strokes. 55 of the 59 corrected stenoses were patent as shown by Doppler ultrasound. In contrast attempts to correct complete internal carotid artery occlusions showed unsatisfactory results.