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2.
Rheumatology (Oxford) ; 46(6): 952-6, 2007 Jun.
Artículo en Inglés | MEDLINE | ID: mdl-17317716

RESUMEN

OBJECTIVES: To determine the safety and efficacy of a short course of fludarabine combined with cyclophoshamide in lupus nephritis. METHODS: A phase I/II open label pilot study. Thirteen patients with active proliferative lupus nephritis received monthly oral boluses of low-dose cyclophoshamide (0.5 gm/m(2) on day 1) and subcutaneous fludarabine (30 mg/m(2) on days 1-3) for 3-6 cycles. Concomitant prednisone was aggressively tapered from 0.5 mg/kg/day to a low-dose, alternate-day schedule. Patients were followed for at least 24 months after therapy. The primary outcome was the number of patients achieving renal remission defined as stable creatinine, proteinuria <1 gm/day and inactive urine sediment for at least 6 months. RESULTS: The study was terminated early because of bone marrow toxicity. Eleven patients who received at least three cycles were evaluated for efficacy. Ten patients improved markedly with seven patients achieving complete remission and three patients achieving partial remission. There were three serious haematological adverse events during the treatment with one death due to transfusion-associated graft vs host disease. Profound and prolonged CD4 (mean CD4: 98/microl at 7 months and 251/microl at 12 months) and CD20 lymphocytopenia was noted in most patients. Three patients developed Herpes zoster infections. CONCLUSIONS: A short course of low-dose fludarabine and cyclophoshamide can induce long-lasting remissions in patients with proliferative lupus nephritis, but severe myelosuppression limits its widespread use.


Asunto(s)
Ciclofosfamida/uso terapéutico , Inmunosupresores/uso terapéutico , Nefritis Lúpica/tratamiento farmacológico , Vidarabina/análogos & derivados , Adulto , Anciano , Recuento de Linfocito CD4 , Ciclofosfamida/efectos adversos , Esquema de Medicación , Quimioterapia Combinada , Femenino , Humanos , Inmunosupresores/efectos adversos , Linfopenia/inducido químicamente , Masculino , Persona de Mediana Edad , Neutropenia/inducido químicamente , Proyectos Piloto , Proteinuria/tratamiento farmacológico , Resultado del Tratamiento , Vidarabina/efectos adversos , Vidarabina/uso terapéutico
3.
Genetics ; 135(3): 741-53, 1993 Nov.
Artículo en Inglés | MEDLINE | ID: mdl-7904971

RESUMEN

The unc-4 gene of Caenorhabditis elegans encodes a homeodomain protein that defines synaptic input to ventral cord motor neurons. unc-4 mutants are unable to crawl backward because VA motor neurons are miswired with synaptic connections normally reserved for their sister cells, the VB motor neurons. These changes in connectivity are not accompanied by any visible effects upon neuronal morphology, which suggests that unc-4 regulates synaptic specificity but not axonal guidance or outgrowth. In an effort to identify other genes in the unc-4 pathway, we have devised a selection scheme for rare mutations that suppress the Unc-4 phenotype. We have isolated four, dominant, extragenic, allele-specific suppressors of unc-4(e2322ts), a temperature sensitive allele with a point mutation in the unc-4 homeodomain. Our data indicate that these suppressors are gain-of-function mutations in the previously identified unc-37 gene. We show that the loss-of-function mutation unc-37(e262) phenocopies the Unc-4 movement defect but does not prevent unc-4 expression or alter VA motor neuron morphology. These findings suggest that unc-37 functions with unc-4 to specify synaptic input to the VA motor neurons. We propose that unc-37 may be regulated by unc-4. Alternatively, unc-37 may encode a gene product that interacts with the unc-4 homeodomain.


Asunto(s)
Caenorhabditis elegans/genética , Genes de Helminto , Mutación , Alelos , Secuencia de Aminoácidos , Animales , Caenorhabditis elegans/crecimiento & desarrollo , Caenorhabditis elegans/fisiología , Femenino , Genes Dominantes , Genes Homeobox , Genes Supresores , Ligamiento Genético , Proteínas del Helminto/genética , Masculino , Modelos Genéticos , Datos de Secuencia Molecular , Neuronas Motoras/fisiología , Movimiento/fisiología , Proteínas del Tejido Nervioso/genética , Sistema Nervioso/crecimiento & desarrollo , Fenómenos Fisiológicos del Sistema Nervioso , Fenotipo , Sinapsis/fisiología
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