RESUMO
BACKGROUND: Toxic neuropathies induced by cisplatin and other chemotherapeutic agents are important clinical problems because of their high incidence, their lack of effective treatment, and the fact that neuropathy represents a dose-limiting factor for these therapies. The pathogenic basis for toxic neuropathies induced by chemotherapeutic agents has not been completely elucidated. METHODS AND RESULTS: We investigated the hypothesis that experimental toxic neuropathy results from an antiangiogenic effect of these drugs, resulting in destruction of the vasa nervorum, and accordingly that the neuropathy could be prevented or reversed by locally administered VEGF gene transfer without augmenting tumor growth. In an animal model of cisplatin-induced neuropathy, nerve blood flow was markedly attenuated, and there was a profound reduction in the number of vasa nervorum associated with marked endothelial cell apoptosis, resulting in a severe peripheral neuropathy with focal axonal degeneration characteristic of ischemic neuropathy. After intramuscular gene transfer of naked plasmid DNA encoding VEGF-1 in animals with an established neuropathy, vascularity and blood flow returned to levels similar to those of control rats, peripheral nerve function was restored, and histological nerve architecture was normalized. Gene therapy administered in parallel with cisplatin chemotherapy completely attenuated endothelial cell apoptosis and inhibited destruction of nerve vasculature, deterioration of nerve function, and axonal degeneration. In a rat tumor model, VEGF gene transfer administered locally did not alter tumor growth or vascularity. CONCLUSIONS: These findings implicate microvascular damage as the basis for toxic neuropathy induced by cisplatin and suggest that local angiogenic gene therapy may constitute a novel prevention or treatment for this disorder without augmenting tumor growth or vascularization.
Assuntos
Cisplatino/efeitos adversos , Doenças do Sistema Nervoso Periférico/prevenção & controle , Fator A de Crescimento do Endotélio Vascular/administração & dosagem , Inibidores da Angiogênese/efeitos adversos , Animais , Apoptose , Endotélio Vascular/citologia , Terapia Genética , Humanos , Masculino , Neoplasias/irrigação sanguínea , Neoplasias/complicações , Neoplasias/tratamento farmacológico , Doenças do Sistema Nervoso Periférico/induzido quimicamente , Doenças do Sistema Nervoso Periférico/terapia , Ratos , Ratos Sprague-Dawley , Carga Tumoral/efeitos dos fármacos , Veias Umbilicais/citologia , Vasa Nervorum/efeitos dos fármacos , Fator A de Crescimento do Endotélio Vascular/uso terapêuticoRESUMO
Recent electrophysiological and histopathological reports point to motor neurons in the anterior horn of the spinal cord and the brainstem as targets of severe West Nile virus (WNV) infection. We report histopathological confirmation of this poliomyelitis-like syndrome in a patient with WNV infection in Massachusetts.
Assuntos
Tronco Encefálico/fisiopatologia , Tronco Encefálico/virologia , Poliomielite/virologia , Quadriplegia/virologia , Febre do Nilo Ocidental/virologia , Idoso , Humanos , Masculino , Vírus do Nilo Ocidental/isolamento & purificaçãoRESUMO
OBJECTIVE: To describe a case of pituitary apoplexy complicated by diabetes insipidus and to review management of patients with pituitary apoplexy and water excretion disturbances associated with transsphenoidal surgery. METHODS: We describe clinical, laboratory, and radiologic findings in a patient with pituitary apoplexy and central diabetes insipidus. RESULTS: A 74-year-old woman presented with severe headache and sudden loss of vision for 12 hours, accompanied by thirst and frequent urination. Visual field examination demonstrated bitemporal hemianopsia. Her laboratory findings were significant for a serum sodium level of 152 mEq/L and urine specific gravity of <1.005. A magnetic resonance imaging scan of her pituitary gland identified a 3.5-cm suprasellar mass compressing the optic chiasm. She subsequently underwent transsphenoidal pituitary surgery with subtotal resection of this mass. Microscopic evaluation of tumor tissue revealed a pituitary adenoma with evidence of recent infarct and hemorrhage. Her clinical and biochemical course was consistent with the triphasic response that may occur after pituitary surgery related to damage to the hypothalamus and supraopticohypophyseal tract. CONCLUSION: Pituitary apoplexy may be rarely associated with diabetes insipidus.