RESUMO
Motoneurons (MNs) control muscle activity by releasing the neurotransmitter acetylcholine (ACh) at the level of neuromuscular junctions. ACh is packaged into synaptic vesicles by the vesicular ACh transporter (VAChT), and disruptions in its release can impair muscle contraction, as seen in congenital myasthenic syndromes (CMS). Recently, VAChT gene mutations were identified in humans displaying varying degrees of myasthenia. Moreover, mice with a global deficiency in VAChT expression display several characteristics of CMS. Despite these findings, little is known about how a long-term decrease in VAChT expression in vivo affects MNs structure and function. Using Cre-loxP technology, we generated a mouse model where VAChT is deleted in select groups of MNs (mnVAChT-KD). Molecular analysis revealed that the VAChT deletion was specific to MNs and affected approximately 50% of its population in the brainstem and spinal cord, with alpha-MNs primarily targeted (70% in spinal cord). Within each animal, the cell body area of VAChT-deleted MNs was significantly smaller compared to MNs with VAChT preserved. Likewise, muscles innervated by VAChT-deleted MNs showed atrophy while muscles innervated by VAChT-containing neurons appeared normal. In addition, mnVAChT KD mice had decreased muscle strength, were hypoactive, leaner and exhibited kyphosis. This neuromuscular dysfunction was evident at 2 months of age and became progressively worse by 6 months. Treatment of mutants with a cholinesterase inhibitor was able to improve some of the motor deficits. As these observations mimic what is seen in CMS, this new line could be valuable for assessing the efficacy of potential CMS drugs.
Assuntos
Acetilcolina/genética , Neurônios Motores/metabolismo , Síndromes Miastênicas Congênitas/genética , Proteínas Vesiculares de Transporte de Acetilcolina/genética , Acetilcolina/metabolismo , Animais , Modelos Animais de Doenças , Humanos , Camundongos , Neurônios Motores/patologia , Contração Muscular/genética , Contração Muscular/fisiologia , Músculo Esquelético/metabolismo , Músculo Esquelético/fisiologia , Síndromes Miastênicas Congênitas/metabolismo , Síndromes Miastênicas Congênitas/patologia , Junção Neuromuscular/genética , Junção Neuromuscular/metabolismo , Neurotransmissores/genética , Medula Espinal/metabolismo , Medula Espinal/fisiologia , Transmissão Sináptica/genética , Vesículas Sinápticas/metabolismoRESUMO
ABSTRACT Rare clinical case of acute lymphocytic leukemia (ALL) associated with toxoplasmosis affecting a 23-year-old male patient with progressive dyspnea. Chest computed tomography revealed expansive lesions indicating right supraclavicular fossa lymph node enlargement and right pleural effusion. Toxoplasmosis serology was performed: positive for immunoglobulin G [(IgG) 180.6] and positive for immunoglobulin M [(IgM) 0.98]. Therefore, treatment for the infection was initiated and immunohistochemistry of left cervical lymph node revealed ALL. Consequently, chemotherapy treatment was introduced at an oncology center. The diagnosis of toxoplasmosis allowed treatment to be administered, preventing the worsening of the condition caused by chemotherapy-induced immunosuppression.
RESUMEN Reportamos un caso clínico raro de leucemia linfocítica aguda (LLA) asociada a toxoplasmosis en un paciente masculino de 23 años con cuadro de disnea progresiva. La tomografía de tórax reveló lesiones expansivas, indicando agrandamiento de los ganglios linfáticos en fosa supraclavicular derecha y derrame pleural a la derecha. Examen serológico para toxoplasmosis: inmunoglobulinas G (IgG) e inmunoglobulinas M (IgM) positivas - 180,6 y 0,98, respectivamente. Se inició el tratamiento de la infección; la inmunohistoquímica de ganglio linfático cervical izquierdo reveló LLA. Se llevó a cabo la quimioterapia en un hospital oncológico. El diagnóstico de toxoplasmosis permitió hacer el tratamiento, impidiendo que la inmunosupresión inducida por la quimioterapia agravara el cuadro clínico.
RESUMO Relatamos um caso clínico raro de leucemia linfoblástica aguda (LLA) associada à toxoplasmose em um paciente do sexo masculino, 23 anos, com quadro de dispneia progressiva. A tomografia de tórax revelou lesões expansivas, indicando linfonodomegalias em fossa supraclavicular direita e derrame pleural à direita. Sorologia realizada para toxoplasmose: imunoglobulinas da classe G (IgG) e da classe M (IgM) positivas - 180,6 e 0,98, respectivamente. Tratamento para a infecção foi iniciado; estudo imuno-histoquímico de linfonodo cervical esquerdo foi realizado, revelando LLA. Institui-se tratamento quimioterápico em centro oncológico. O diagnóstico de toxoplasmose permitiu que o tratamento fosse feito, impedindo que a imunossupressão induzida pela quimioterapia agravasse o quadro clínico.
RESUMO
Estados de imunossupressão têm provocado mudanças na história natural da doença de Chagas com descrição de reativação da doença em pacientes com a Síndrome de Imunodeficiência Adquirida (AIDS), durante transplantes de órgãos e em quimioterapia de malignidades hematológicas. É relatado caso de reativação de doença de Chagas com meningoencefalite durante quimioterapia de linfoma não Hodgkin não relacionado a transplante de células-tronco hematopoéticas com tardia detecção de Trypanosoma cruzi em sangue e líquido cefalorraquidiano. Apesar de tratamento específico com benzonidazol, paciente morreu após oito dias. Alta suspeição clínica com abordagens diagnósticas sensíveis é fundamental para diagnóstico precoce e início de tratamento com objetivo de diminuir mortalidade.
Immunosuppression has caused changes in the natural history of Chagas' disease with reports of reactivation of the disease in acquired immune deficiency syndrome (AIDS) and organ transplant patients and during chemotherapy treatment in patients with hematological malignances. We report on a case of reactivation of Chagas' disease in a patient with meningoencephalitis during chemotherapy for non-Hodgkin's lymphoma without any relation to hematopoietic stem-cell transplantation and with late detection of Trypanosoma cruzi in blood and cerebrospinal fluid. Despite specific treatment with benznidazole, the patient died 8 days later. High clinical suspicion and sensitive diagnostic methods are fundamental for early diagnosis and initiation of treatment in order to minimize mortality.
