Maladaptive myelination promotes generalized epilepsy progression.

Activity-dependent myelination can fine-tune neural network dynamics. Conversely, aberrant neuronal activity, as occurs in disorders of recurrent seizures (epilepsy), could promote maladaptive myelination, contributing to pathogenesis. In this study, we tested the hypothesis that activity-dependent myelination resulting from absence seizures, which manifest as frequent behavioral arrests with generalized electroencephalography (EEG) spike-wave discharges, promote thalamocortical network hypersynchrony and contribute to epilepsy progression. We found increased oligodendrogenesis and myelination specifically within the seizure network in two models of generalized epilepsy with absence seizures (Wag/Rij rats and Scn8a+/mut mice), evident only after epilepsy onset. Aberrant myelination was prevented by pharmacological seizure inhibition in Wag/Rij rats. Blocking activity-dependent myelination decreased seizure burden over time and reduced ictal synchrony as assessed by EEG coherence. These findings indicate that activity-dependent myelination driven by absence seizures contributes to epilepsy progression; maladaptive myelination may be pathogenic in some forms of epilepsy and other neurological diseases.

mTORC1 underlies age-related muscle fiber damage and loss by inducing oxidative stress and catabolism.

Aging leads to skeletal muscle atrophy (i.e., sarcopenia), and muscle fiber loss is a critical component of this process. The mechanisms underlying these age-related changes, however, remain unclear. We show here that mTORC1 signaling is activated in a subset of skeletal muscle fibers in aging mouse and human, colocalized with fiber damage. Activation of mTORC1 in TSC1 knockout mouse muscle fibers increases the content of morphologically abnormal mitochondria and causes progressive oxidative stress, fiber damage, and fiber loss over the lifespan. Transcriptomic profiling reveals that mTORC1's activation increases the expression of growth differentiation factors (GDF3, 5, and 15), and of genes involved in mitochondrial oxidative stress and catabolism. We show that increased GDF15 is sufficient to induce oxidative stress and catabolic changes, and that mTORC1 increases the expression of GDF15 via phosphorylation of STAT3. Inhibition of mTORC1 in aging mouse decreases the expression of GDFs and STAT3's phosphorylation in skeletal muscle, reducing oxidative stress and muscle fiber damage and loss. Thus, chronically increased mTORC1 activity contributes to age-related muscle atrophy, and GDF signaling is a proposed mechanism.

Smad3 initiates oxidative stress and proteolysis that underlies diaphragm dysfunction during mechanical ventilation.

Prolonged use of mechanical ventilation (MV) leads to atrophy and dysfunction of the major inspiratory muscle, the diaphragm, contributing to ventilator dependence. Numerous studies have shown that proteolysis and oxidative stress are among the major effectors of ventilator-induced diaphragm muscle dysfunction (VIDD), but the upstream initiator(s) of this process remain to be elucidated. We report here that periodic diaphragm contraction via phrenic nerve stimulation (PNS) substantially reduces MV-induced proteolytic activity and oxidative stress in the diaphragm. We show that MV rapidly induces phosphorylation of Smad3, and PNS nearly completely prevents this effect. In cultured cells, overexpressed Smad3 is sufficient to induce oxidative stress and protein degradation, whereas inhibition of Smad3 activity suppresses these events. In rats subjected to MV, inhibition of Smad3 activity by SIS3 suppresses oxidative stress and protein degradation in the diaphragm and prevents the reduction in contractility that is induced by MV. Smad3's effect appears to link to STAT3 activity, which we previously identified as a regulator of VIDD. Inhibition of Smad3 suppresses STAT3 signaling both in vitro and in vivo. Thus, MV-induced diaphragm inactivity initiates catabolic changes via rapid activation of Smad3 signaling. An early intervention with PNS and/or pharmaceutical inhibition of Smad3 may prevent clinical VIDD.

Treino de marcha com pistas visuais no paciente com doença de Parkinson / Training of gait visual clues in the pattient with Parkinson's disease

Os distúrbios da marcha são um dos sintomas primários da doença de Parkinson (DP). Devido a uma alteração no circuito da base - área motora suplementar, a marcha na DP fica comprometida na execução do movimento, já que as sugestões rítmicas internas não estão sendo fornecidas corretamente. Nos últimos anos, surgiram relatos promissores dos programas fisioterapêuticos cpmbinados a pistas visuais para o tratamento da marcha. Foram selecionados 16 pacientes com DP, de ambos os sexos do Serviço de Fisioterapia e Terapia Ocupacional do Hospital de Clínicas da UNICAMP, ramdomizados em dois grupos para tratamento. Oito no grupo de estudo (20 sessões de treino de marcha com pistas visuais, mais fisioterapia convencional) e oito no grupo controle (20 sessões) de fisioterapia convencional. Avaliados no início do tratamento, ao seu término e após 30 dias. Instrumentos utilizados. Escala Estimativa daD oença de Parkinson (updrs), Medida de Independência Funcional (MIF), Escala de Equilíbrio de Berg e Avaliação Funcional da Marcha. Aplicado o teste t-student, com p-valor <0,05 mostrando significãncia. observou-se no grupo de estudo um aumento da velocidade da marcha, comprimento do passo e cadência. Além da melhora no equilíbrio e independência nas atividades funcionais, imediatamente após as 20 sessões. Nos pacientes do grupo controle não foi observado melhora. O estudo demonstrou que o treino de marcha com pistas visuais é um meio poderoso para melhorar a marcha na DP