Descending Command Neurons in the Brainstem that Halt Locomotion.

The episodic nature of locomotion is thought to be controlled by descending inputs from the brainstem. Most studies have largely attributed this control to initiating excitatory signals, but little is known about putative commands that may specifically determine locomotor offset. To link identifiable brainstem populations to a potential locomotor stop signal, we used developmental genetics and considered a discrete neuronal population in the reticular formation: the V2a neurons. We find that those neurons constitute a major excitatory pathway to locomotor areas of the ventral spinal cord. Selective activation of V2a neurons of the rostral medulla stops ongoing locomotor activity, owing to an inhibition of premotor locomotor networks in the spinal cord. Moreover, inactivation of such neurons decreases spontaneous stopping in vivo. Therefore, the V2a "stop neurons" represent a glutamatergic descending pathway that favors immobility and may thus help control the episodic nature of locomotion.

Excitatory Spinal Lhx9-Derived Interneurons Modulate Locomotor Frequency in Mice.

Locomotion allows us to move and interact with our surroundings. Spinal networks that control locomotion produce rhythm and left-right and flexor-extensor coordination. Several glutamatergic populations, Shox2 non-V2a, Hb9-derived interneurons, and, recently, spinocerebellar neurons have been proposed to be involved in the mouse rhythm generating networks. These cells make up only a smaller fraction of the excitatory cells in the ventral spinal cord. Here, we set out to identify additional populations of excitatory spinal neurons that may be involved in rhythm generation or other functions in the locomotor network. We use RNA sequencing from glutamatergic, non-glutamatergic, and Shox2 cells in the neonatal mice from both sexes followed by differential gene expression analyses. These analyses identified transcription factors that are highly expressed by glutamatergic spinal neurons and differentially expressed between Shox2 neurons and glutamatergic neurons. From this latter category, we identified the Lhx9-derived neurons as having a restricted spinal expression pattern with no Shox2 neuron overlap. They are purely glutamatergic and ipsilaterally projecting. Ablation of the glutamatergic transmission or acute inactivation of the neuronal activity of Lhx9-derived neurons leads to a decrease in the frequency of locomotor-like activity without change in coordination pattern. Optogenetic activation of Lhx9-derived neurons promotes locomotor-like activity and modulates the frequency of the locomotor activity. Calcium activities of Lhx9-derived neurons show strong left-right out-of-phase rhythmicity during locomotor-like activity. Our study identifies a distinct population of spinal excitatory neurons that regulates the frequency of locomotor output with a suggested role in rhythm-generation in the mouse alongside other spinal populations.

Spinal glutamatergic neurons defined by EphA4 signaling are essential components of normal locomotor circuits.

EphA4 signaling is essential for the spatiotemporal organization of neuronal circuit formation. In mice, deletion of this signaling pathway causes aberrant midline crossing of axons from both brain and spinal neurons and the complete knock-outs (KOs) exhibit a pronounced change in motor behavior, where alternating gaits are replaced by a rabbit-like hopping gait. The neuronal mechanism that is responsible for the gait switch in these KO mice is not known. Here, using intersectional genetics, we demonstrate that a spinal cord-specific deletion of EphA4 signaling is sufficient to generate the overground hopping gait. In contrast, selective deletion of EphA4 signaling in forebrain neurons, including the corticospinal tract neurons, did not result in a change in locomotor pattern. The gait switch was attributed to the loss of EphA4 signaling in excitatory Vglut2+ neurons, which is accompanied by an increased midline crossing of Vglut2+ neurons in the ventral spinal cord. Our findings functionally define spinal EphA4 signaling in excitatory Vglut2+ neurons as required for proper organization of the spinal locomotor circuitry, and place these cells as essential components of the mammalian locomotor network.

Design and development of orally disintegrating films: A platform based on hydroxypropyl methylcellulose and guar gum.

From a design of experiments (DOE) performed under four independent variables, with the filmogenicity conditions and shortest disintegration time as the answers, a new oral disintegrating film (ODF) based on hydroxypropyl methylcellulose (HPMC) and guar gum (GG) with the essential oil of Plectranthus amboinicus L. (EOPA) was developed. Sixteen formulations were tested for filmogenicity, homogeneity, and viability. The better selected ODF required 230.1 s for complete disintegration. The retention rate of the EOPA was quantified using the nuclear magnetic resonance hydrogen technique (H1 NMR), which identified the presence of 0.14 % carvacrol. The scanning electron microscopy showed a smooth and homogeneous surface with the presence of small white dots. Through the disk diffusion test, the EOPA was able to inhibit the growth of clinical strains of the Candida genus and gram-positive and gram-negative bacterial strains. This work opens new perspectives for the development of antimicrobial ODFS used in clinical practice.

Spinal Hb9::Cre-derived excitatory interneurons contribute to rhythm generation in the mouse.

Rhythm generating neurons are thought to be ipsilaterally-projecting excitatory neurons in the thoracolumbar mammalian spinal cord. Recently, a subset of Shox2 interneurons (Shox2 non-V2a INs) was found to fulfill these criteria and make up a fraction of the rhythm-generating population. Here we use Hb9::Cre mice to genetically manipulate Hb9::Cre-derived excitatory interneurons (INs) in order to determine the role of these INs in rhythm generation. We demonstrate that this line captures a consistent population of spinal INs which is mixed with respect to neurotransmitter phenotype and progenitor domain, but does not overlap with the Shox2 non-V2a population. We also show that Hb9::Cre-derived INs include the comparatively small medial population of INs which continues to express Hb9 postnatally. When excitatory neurotransmission is selectively blocked by deleting Vglut2 from Hb9::Cre-derived INs, there is no difference in left-right and/or flexor-extensor phasing between these cords and controls, suggesting that excitatory Hb9::Cre-derived INs do not affect pattern generation. In contrast, the frequencies of locomotor activity are significantly lower in cords from Hb9::Cre-Vglut2Δ/Δ mice than in cords from controls. Collectively, our findings indicate that excitatory Hb9::Cre-derived INs constitute a distinct population of neurons that participates in the rhythm generating kernel for spinal locomotion.

Spatiotemporal correlation of spinal network dynamics underlying spasms in chronic spinalized mice.

Spasms after spinal cord injury (SCI) are debilitating involuntary muscle contractions that have been associated with increased motor neuron excitability and decreased inhibition. However, whether spasms involve activation of premotor spinal excitatory neuronal circuits is unknown. Here we use mouse genetics, electrophysiology, imaging and optogenetics to directly target major classes of spinal interneurons as well as motor neurons during spasms in a mouse model of chronic SCI. We find that assemblies of excitatory spinal interneurons are recruited by sensory input into functional circuits to generate persistent neural activity, which interacts with both the graded expression of plateau potentials in motor neurons to generate spasms, and inhibitory interneurons to curtail them. Our study reveals hitherto unrecognized neuronal mechanisms for the generation of persistent neural activity under pathophysiological conditions, opening up new targets for treatment of muscle spasms after SCI.

Criteria for patient admission to an intensive care unit and related mortality rates.

OBJECTIVE: The aim of the study was to evaluate criteria used in clinical practice, for screening of patients for ICU admission. METHODS: Cohort prospective study in a tertiary hospital. Four groups were compared in relation to ICU admission by ranking priorities into groups 1, 2, 3 and 4; highest priority 1, lowest priority 4. RESULTS: Enrolled were 359 patients, 66 (53.2-75.0) years old. APACHE II was 23 (18-30). The ICU made available 70.4% of beds. Patients who were refused beds in the ICU were older, 66.2 ± 16.1 versus 61.9 ± 15.2 years of age (p= 0.02) and the priority 1 group had less refusal of beds, which means, 39.1% versus 23.8% had beds refused (p=0.01). The opposite occurred with priorities 3 and 4. Patients in priority 3 and 4 showed older ages, score system and more organ dysfunctions as well as more refusals of beds. ICU mortality rates were higher for priority groups 3 and 4 when compared to 1 and 2 priority groups, 86.7% versus 31.3% (p<0.001). CONCLUSION: Age, score system and organ dysfunctions were greater in priority groups 3 and 4 and these were related with refusal from the ICU. Patients refused admission to the ICU showed higher mortality rates and these remained higher among priority groups 3 and 4 even when patients were admitted to the ICU.

Critérios para admissão de pacientes na unidade de terapia intensiva e mortalidade / Criteria for patient admissiwwon in the intensive care unit and mortality rate

OBJETIVO: O objetivo do estudo foi avaliar os critérios utilizados na prática clínica, no processo de triagem de pacientes para admissão em UTI. MÉTODOS: Estudo de coorte prospectivo, em hospital terciário. Foram comparados quatro grupos diferentes de pacientes em relação à necessidade para admissão na UTI e divididos em prioridades 1, 2, 3 e 4, ou seja, prioridade 1 mais necessária até prioridade 4, menos necessária. RESULTADOS: Incluiu-se 359 pacientes, idade 66 (53,2-75,0) anos. APACHE II foi 23 (18-30). Obtevese 70,4 por cento de vagas cedidas na UTI. A idade foi maior nos pacientes para os quais foram recusadas vagas em UTI 66,2±16,1 vs 61,9±15,2 anos (p= 0,02) e a prioridade 1 apresentou mais vagas cedidas 39,1 por cento vs 23,8 por cento vagas recusadas (p=0,01), o contrário ocorreu com prioridades 3 e 4. Pacientes com prioridades 3 e 4 apresentaram maiores idade, escores prognósticos e mais disfunções orgânicas, assim como maiores taxas de recusas. Ocorreram altas mortalidades destes grupos na UTI, 86,7 por cento vs 31,3 por cento no grupo de prioridades 1 e 2 (p<0,001). CONCLUSÃO: A idade, o escore prognóstico e a disfunção orgânica são maiores nas categorias 3 e 4, sendo estas relacionadas com a recusa na UTI. Os pacientes recusados para admissão na UTI apresentam taxa de mortalidade elevada, que permanece alta entre pacientes prioridades 3 e 4, mesmo quando estes são admitidos na UTI.

OBJECTIVE: The aim of the study was to evaluate criteria used in clinical practice, for screening of patients for ICU admission. METHODS: Cohort prospective study in a tertiary hospital. Four groups were compared in relation to ICU admission by ranking priorities into groups 1, 2, 3 and 4; highest priority 1, lowest priority 4. RESULTS: Enrolled were 359 patients, 66 (53.2-75.0) years old. APACHE II was 23 (18-30). The ICU made available 70.4 percent of beds. Patients who were refused beds in the ICU were older, 66.2±16.1 versus 61.9±15.2 years of age (p= 0.02) and the priority 1 group had less refusal of beds, which means, 39.1 percent versus 23.8 percent had beds refused (p=0.01). The opposite occurred with priorities 3 and 4. Patients in priority 3 and 4 showed older ages, score system and more organ dysfunctions as well as more refusals of beds. ICU mortality rates were higher for priority groups 3 and 4 when compared to 1 and 2 priority groups, 86.7 percent versus 31.3 percent (p<0.001). CONCLUSION: Age, score system and organ dysfunctions were greater in priority groups 3 and 4 and these were related with refusal from the ICU. Patients refused admission to the ICU showed higher mortality rates and these remained higher among priority groups 3 and 4 even when patients were admitted to the ICU.

Benefícios da programação dos intervalos AV e VV na estimulação biventricular / The AV and VV interval program in the biventricular stimulation and its benefits

A insuficiência cardíaca crônica está frequentemente associada a distúbios de condução intra e interventricular, o que resulta em uma síndrome de baixo débito sistêmica. Para promover melhora dessa disfunção miocárdica, tanto nas formas agudas como crônica, é crucial restaurar a sincronia por meio do ajuste dos estímulos entre átrios e ventrículos, entre ventrículos e dentro do próprio ventrículo. Benefícios hemodinâmicos adicionais têm relação direta com a otimização dos intervalos AV e VV, medidas que devem ser individualizadas e programadas por meio do ecocardiograma (doppler pulsado). O objetivo desse artigo é discutir a importância dessa programação para o paciente submetido a TRC e como executá-la.

A criança com deficiência e as relações interpessoais numa brinquedoteca comunitária / Children with mental deficiency and interpersonal relationships in a community toy library

A sociedade contemporânea tem limitado o brincar das crianças sendo que as crianças com deficiência enfrentam, ainda, barreiras psicossociais. Uma brinquedoteca comunitária pode ser um local de enfrentamento das limitações ao brincar. O objetivo deste estudo foi descrever as relações interpessoais entre crianças com deficiência e crianças sem deficiência num contexto de brinquedoteca comunitária, e como esta pode influenciar essas relações. Observou-se durante 10 encontros um grupo de crianças sendo duas delas com deficiência mental. Utilizou-se como foco de coleta a descrição da situação lúdica que envolvesse a questão da deficiência, utilizando como categorias de coleta: tipo de brincadeira, estilo de interação e seu caráter social. Comparou-se um episódio com outro que envolvessem os mesmos participantes buscando identificar transformação ou não do tipo de interação de caráter social ou agonístico. Identificamos três contextos de interação que se mostraram significativos: de passagem, em brincadeiras paralelas e nas brincadeiras com o outro. As interações de passagem mostraram potencializar mais interações agonísticas, enquanto brincadeiras paralelas, mais interações pró-sociais. As situação de brincadeira de escolinha, de fantasia e jogos potencializaram mais interações pró-sociais, pelos próprios integrantes escolherem as brincadeiras e seus companheiros. As brincadeiras em que todos participavam, embora dessem visibilidade e participação grupal às crianças com deficiência, mostraram maior quantidade de interações agonísticas e pró-sociais. Concluiu-se que as crianças com deficiência conquistaram um lugar.

Contemporary society has been limiting the play activity of children. Children with mental deficiency also have to face psychosocial barriers. A community toy library can be a place where it is possible to face limitations while playing. The objective was to describe the interpersonal relationships among children with mental deficiency and children without deficiency in a context of community toy library, pointing out how this context can influence these relationships. Basic procedures were a group of children was observed during ten meetings. In this group, two children had mental deficiency. The description of the play situation that involved the issue of deficiency was used as collection focus. Categories of data collection were: type of game, interaction style and its social character. An episode was compared with another involving the same participants, aiming to identify transformation or not of the type of interaction of social or agonistic character. We identified three significant interaction contexts: passage interactions, interactions in parallel games and interactions in games with another child. It seems that the passage interactions potentialized more agonistic interactions, while the parallel games potentialized more pro-social interactions. Situations of school play, fantasies and games seemed to potentialize more pro-social interactions, because of the fact that the members of the group chose the games and their companions. Although games in which all children participated gave visibility and group participation to children with mental deficiency, they showed a larger amount of agonistic and pro-social interactions. As conclusions, Children with mental deficiency have conquered a place. A place to go, to play, to find children, to transform themselves, their relationships and the relationship of the others.