Human Nav1.6 Channels Generate Larger Resurgent Currents than Human Nav1.1 Channels, but the Navβ4 Peptide Does Not Protect Either Isoform from Use-Dependent Reduction

Voltage-gated sodium channels are responsible for the initiation and propagation of action potentials (APs). Two brain isoforms, Nav1.1 and Nav1.6, have very distinct cellular and subcellular expression. Specifically, Nav1.1 is predominantly expressed in the soma and proximal axon initial segment of fast-spiking GABAergic neurons, while Nav1.6 is found at the distal axon initial segment and nodes of Ranvier of both fast-spiking GABAergic and excitatory neurons. Interestingly, an auxiliary voltage-gated sodium channel subunit, Navβ4, is also enriched in the axon initial segment of fast-spiking GABAergic neurons. The C-terminal tail of Navβ4 is thought to mediate resurgent sodium current, an atypical current that occurs immediately following the action potential and is predicted to enhance excitability. To better understand the contribution of Nav1.1, Nav1.6 and Navβ4 to high frequency firing, we compared the properties of these two channel isoforms in the presence and absence of a peptide corresponding to part of the C-terminal tail of Navβ4. We used whole-cell patch clamp recordings to examine the biophysical properties of these two channel isoforms in HEK293T cells and found several differences between human Nav1.1 and Nav1.6 currents. Nav1.1 channels exhibited slower closed-state inactivation but faster open-state inactivation than Nav1.6 channels. We also observed a greater propensity of Nav1.6 to generate resurgent currents, most likely due to its slower kinetics of open-state inactivation, compared to Nav1.1. These two isoforms also showed differential responses to slow and fast AP waveforms, which were altered by the Navβ4 peptide. Although the Navβ4 peptide substantially increased the rate of recovery from apparent inactivation, Navβ4 peptide did not protect either channel isoform from undergoing use-dependent reduction with 10 Hz step-pulse stimulation or trains of slow or fast AP waveforms. Overall, these two channels have distinct biophysical properties that may differentially contribute to regulating neuronal excitability

Resurgent sodicum current modulation by auxiliary subunits in dorsal root ganglia neurons and potential implications in pain pathologies

Indiana University-Purdue University Indianapolis (IUPUI)Increased electrical activity in peripheral sensory neurons contributes to pain. A unique type of sodium current, fast resurgent current, is proposed to increase nerve activity and has been associated with pain pathologies. While sodium channel isoform Nav1.6 has been identified as the main carrier of fast resurgent currents, our understanding of how resurgent currents are modulated in sensory neurons is fairly limited. Thus the goal of this dissertation was to identify resurgent current modulators. In particular, we focused on sodium channel beta subunits (Navβs) and fibroblast growth factor homologous factors (FHFs) in dorsal root ganglion (DRG) neurons. We hypothesized that Navβ4 and FHF2B act as positive regulators by mediating resurgent currents and modulating Nav1.6 inactivation, respectively. In contrast, we hypothesized FHF2A negatively regulates resurgent current by increasing the probability of channels in inactivated states. Thus, the aims of this dissertation were to 1) determine if Navβ4 regulates fast resurgent currents in DRG neurons, 2) examine the effects of Navβ4 knockdown on resurgent currents, firing frequency and pain associated behavior in an inflammatory pain model and 3) determine if FHF2A and FHF2B functionally regulate Nav1.6 currents, including resurgent currents in DRG neurons. To examine the aims, we used biochemical, electrophysiological and behavioral assays. Our results suggest that Navβ4 is a positive regulator of resurgent currents: in particular, the C-terminus likely mediates these currents. Localized knockdown of Navβ4 decreased inflammation-induced enhancement of resurgent currents and neuronal excitability, and prevented the development of persistent pain associated behavior in an inflammatory pain model. FHF2B increased resurgent currents and delayed inactivation. In contrast, FHF2A limited resurgent currents; an effect that is mainly contributed by FHF2A's N-terminus activity that increased accumulation of channels in inactivated states. Interestingly, in an inflammatory pain model FHF2B was upregulated and FHFA isoforms were downregulated. Together these results suggest that FHF2A/B modulation might contribute to enhanced resurgent currents and increased neuronal excitability observed in the inflammatory pain model. Overall, our work has identified three resurgent current modulators FHF2A, FHF2B and Navβ4. Manipulation of these proteins or their activity might result in novel strategies for the study and treatment of pain

Intervención en las problemáticas psicosociales de los niños y jóvenes usuarios del Centro de Emergencias de la Fundación Niños de los Andes

Servicio Social ComunitarioEste trabajo se desarrolló en la FNA Centros de Emergencias, como opción de grado de Servicio Social Comunitario. Tuvo dos fases: fase 1 acercamiento a la institución y la población para encontrar problemáticas más relevantes y trabajar en la Fase 2 de intervención. La intervención se realizó implementando talleres en temas de toma de decisiones y consecuencias del consumo de SPA, orientado a la concientización de la problemática con el fin de restablecer en ellos su proyecto de vida y la de sus familias.Resumen 1. Descripción de la problemática 2. Contexto institucional, geográfico y poblacional 3. Justificación 4. Delimitación de la investigación 5. Objetivos de la evaluación de Necesidades 6. Objetivos de la Intervención 7. Marco Teórico 8. Marco Metodológico 9. Diseño metodológico de la investigación 10. Categoría de análisis 11.Matriz operativa del proyecto 12. Análisis del proceso 13. Conclusiones 14. Recomendaciones ReferenciasPregradoPsicólog

FHF2 isoforms differentially regulate Nav1.6-mediated resurgent sodium currents in dorsal root ganglion neurons

Nav1.6 and Nav1.6-mediated resurgent currents have been implicated in several pain pathologies. However, our knowledge of how fast resurgent currents are modulated in neurons is limited. Our study explored the potential regulation of Nav1.6-mediated resurgent currents by isoforms of fibroblast growth factor homologous factor 2 (FHF2) in an effort to address the gap in our knowledge. FHF2 isoforms colocalize with Nav1.6 in peripheral sensory neurons. Cell line studies suggest that these proteins differentially regulate inactivation. In particular, FHF2A mediates long-term inactivation, a mechanism proposed to compete with the open-channel blocker mechanism that mediates resurgent currents. On the other hand, FHF2B lacks the ability to mediate long-term inactivation and may delay inactivation favoring open-channel block. Based on these observations, we hypothesized that FHF2A limits resurgent currents, whereas FHF2B enhances resurgent currents. Overall, our results suggest that FHF2A negatively regulates fast resurgent current by enhancing long-term inactivation and delaying recovery. In contrast, FHF2B positively regulated resurgent current and did not alter long-term inactivation. Chimeric constructs of FHF2A and Navβ4 (likely the endogenous open channel blocker in sensory neurons) exhibited differential effects on resurgent currents, suggesting that specific regions within FHF2A and Navβ4 have important regulatory functions. Our data also indicate that FHFAs and FHF2B isoform expression are differentially regulated in a radicular pain model and that associated neuronal hyperexcitability is substantially attenuated by a FHFA peptide. As such, these findings suggest that FHF2A and FHF2B regulate resurgent current in sensory neurons and may contribute to hyperexcitability associated with some pain pathologies

El juego de roles: una estrategia lúdico pedagógica para potenciar las habilidades del pensamiento lógico-matemático en los niños y niñas entre los cinco y siete años del Liceo Comercial Nuevo Alejandrino

Potenciar las habilidades del pensamiento lógico matemático a través del juego de roles, en los niños y niñas entre los cinco y siete años del Liceo Comercial Nuevo Alejandrino.Partiendo de la importancia del pensamiento lógico matemático para el desenvolvimiento en las distintas actividades de la vida cotidiana y de la responsabilidad que tiene la escuela de potenciar el desarrollo de los educandos y enriquecer el contexto educativo, se da inicio a este proyecto de investigación, el cual tiene como finalidad diseñar una estrategia lúdica y pedagógica, para potenciar las habilidades lógico matemáticas en los estudiantes del grado primero de la institución educativa Liceo Comercial Nuevo Alejandrino

Navβ4 regulates fast resurgent sodium currents and excitability in sensory neurons

BACKGROUND: Increased electrical activity in peripheral sensory neurons including dorsal root ganglia (DRG) and trigeminal ganglia neurons is an important mechanism underlying pain. Voltage gated sodium channels (VGSC) contribute to the excitability of sensory neurons and are essential for the upstroke of action potentials. A unique type of VGSC current, resurgent current (INaR), generates an inward current at repolarizing voltages through an alternate mechanism of inactivation referred to as open-channel block. INaRs are proposed to enable high frequency firing and increased INaRs in sensory neurons are associated with pain pathologies. While Nav1.6 has been identified as the main carrier of fast INaR, our understanding of the mechanisms that contribute to INaR generation is limited. Specifically, the open-channel blocker in sensory neurons has not been identified. Previous studies suggest Navβ4 subunit mediates INaR in central nervous system neurons. The goal of this study was to determine whether Navβ4 regulates INaR in DRG sensory neurons. RESULTS: Our immunocytochemistry studies show that Navβ4 expression is highly correlated with Nav1.6 expression predominantly in medium-large diameter rat DRG neurons. Navβ4 knockdown decreased endogenous fast INaR in medium-large diameter neurons as measured with whole-cell voltage clamp. Using a reduced expression system in DRG neurons, we isolated recombinant human Nav1.6 sodium currents in rat DRG neurons and found that overexpression of Navβ4 enhanced Nav1.6 INaR generation. By contrast neither overexpression of Navβ2 nor overexpression of a Navβ4-mutant, predicted to be an inactive form of Navβ4, enhanced Nav1.6 INaR generation. DRG neurons transfected with wild-type Navβ4 exhibited increased excitability with increases in both spontaneous activity and evoked activity. Thus, Navβ4 overexpression enhanced INaR and excitability, whereas knockdown or expression of mutant Navβ4 decreased INaR generation. CONCLUSION: INaRs are associated with inherited and acquired pain disorders. However, our ability to selectively target and study this current has been hindered due to limited understanding of how it is generated in sensory neurons. This study identified Navβ4 as an important regulator of INaR and excitability in sensory neurons. As such, Navβ4 is a potential target for the manipulation of pain sensations

Efecto de lo videojuego sobre el rendimiento de la prueba de conocimiento a los estudiantes de la disciplina " práctica profesional y ética en fisioterapia " de la Universidad de Brasilia

O presente estudo teve como objetivo avaliar o efeito de longo prazo do vídeo game educacional (VGE) no desempenho em teste de conhecimentos específicos (TCE), opinião de satisfação com a disciplina (SAT) e percepção de aprendizagem dos conteúdos (PA) de uma disciplina da graduação em fisioterapia da Universidade de Brasília. Trata-se de um ensaio clínico randomizado com dois grupos: Grupo Experimental (GE): aulas presencias e uso semanal do VGE extraclasse; Grupo Controle (GC): apenas aulas presenciais. As aulas presenciais ocorreram uma vez por semana com ambos os grupos presentes. Os alunos do GE precisaram acessar a plataforma do VGE uma vez por semana. Após 17 semanas foram aplicados os instrumentos de avaliação das variáveis dependentes: (I) TCE; (2) SAT; (3) PA. Utilizamos o teste t Student para comparar as médias do TCE entre os grupos e frequências absolutas e relativas para reportar as escalas SAT e PA. Os dados foram analisados com nível de significância 5%. A amostra foi composta por um total de 71 alunos (22,83 [±3,35] anos de idade), sendo 62 indivíduos do sexo feminino (87,3%) e 09 do sexo masculinos (12,7%). Houve diferença estatisticamente significante entre GE e GC no TCE (p = 0.006), apresentando o GE maior média que o GC. Em relação aos desfechos secundários O GE apresentou 100% das respostas nas categorias 4 e 5, enquanto, o GC também apresentou respostas na categoria 3. Os resultados da pesquisa indicaram que o VGE foi capaz de melhorar o desempenho em teste de conhecimentos específicos. Os resultados de opinião parecem indicar que a utilização do VGE pode aumentar a satisfação com a disciplina e a percepção de aprendizados do conteúdo.The current study had the objective of evaluate the long term effect of the educational video game (EVG) in the specific knowledge test (SKT) performance, opinion of satisfaction with the discipline (SAT) and learning perception of the subject matter (LP) of a graduation discipline in the Physiotherapy course of the University of Brasília (UNB). This study is a randomized clinical trial with two groups: Experimental Group (EG): Attending instead presential classes with extra time for EVG. Control Group (CG): only attending regular timeclasses. The classes occurred once a week with the presence of both groups. Students allocated in EG needed to access the EVG platform once a week. After 17 weeks, the assessment tools were applied for the dependent variables: (I) SKT, (2) SAT and (3) LP. The Student t test was used to compare the SKT means between groups and for the absolute and relative frequencies, were used to report SAT and LP scales. The data was analyzed with statistical significance of 5%. The sample consisted of a total of 71 students (22,83 [±3,35] years old), including 62 females (87,3%) and 9 males (12,7%) individuals. There was a significant statistical difference between EG and CG in SKT (p=0.006), with the EG having higher means than CG. Regarding the secondary endpoints EG had 100% answers in categories 4 and 5, while the GC also showed responses in category 3. The study results points that de EVG was able to improve the performance in the SKT. The SAT results may indicate that the use of the EVG can increase the satisfaction with the discipline and the learning perception of the subject matter.El estudio tuvo como objetivo evaluar el efecto a largo plazo del videojuego educativo (VJE) en la realización de la prueba de conocimientos específicos (TCE), opinión de la satisfacción con la disciplina (SAT) y la percepción de los contenidos de aprendizaje (PCA) del curso de graduación en fisioterapia en la Universidad de Brasilia. Se trata de un ensayo clínico aleatorizado con dos grupos: grupo experimental (GE): clases presenciales y uso semanal de VJE extra clase; Grupo control (GC): sólo las clases presenciales. Las clases ocurrieran una vez por semana con los dos grupos presentes. Los estudiantes del grupo GE necesitaban acesar a la plataforma VJE una vez a la semana. Después de 17 semanas, se aplicaron los instrumentos de evaluación de las variables dependientes: TCE (I); (2) SAT; (3) PCA. Se utilizó el Test t de Student para comparar las medias del TCE entre los grupos y las frecuencias absolutas y relativas, para informar las escalas del SAT y PCA. Los datos se analizaron con nivel de significación de 5%. La muestra estuvo constituida por un total de 71 estudiantes (22,83 [± 3,35] años), 62 mujeres (87,3%) y 09 hombres (12,7%). No hubo diferencias significativas entre GE y GC en el TCE (p = 0,006), con GE teniendo medias superiores a GC. Mientras los criterios de valoración secundarios GE tuvo 100% de las respuestas en las categorías 4 y 5, mientras que el GC también mostró respuestas en la categoría 3. Los resultados indicaron que el VJE fue capaz de mejorar el rendimiento en la prueba de conocimientos específicos. Los resultados de laopiniones parecen indicar que la utilización del VJE puede aumentar la satisfacción con la disciplina y la percepción de los contenidos de aprendizaje

Substituted N-(Biphenyl-4′-yl)methyl (R)-2-Acetamido-3-methoxypropionamides: Potent Anticonvulsants That Affect Frequency (Use) Dependence and Slow Inactivation of Sodium Channels

, We prepared 13 derivatives of N-(biphenyl-4′-yl)methyl (R)-2-acetamido-3-methoxypropionamide that differed in type and placement of a R-substituent in the terminal aryl unit. We demonstrated that the R-substituent impacted the compound’s whole animal and cellular pharmacological activities. In rodents, select compounds exhibited excellent anticonvulsant activities and protective indices (PI = TD50/ED50) that compared favorably with clinical antiseizure drugs. Compounds with a polar, aprotic R-substituent potently promoted Na+ channel slow inactivation and displayed frequency (use) inhibition of Na+ currents at low micromolar concentrations. The possible advantage of affecting these two pathways to decrease neurological hyperexcitability is discussed

Factores de riesgo psicosocial en los estudiantes de medicina de la Universidad de La Sabana durante en el marco del desarrollo del COVID-19

     El presente artículo tiene la característica de encontrarse enfocado hacia la identificación, análisis y descripción de los factores de riesgo psicosociales generados en el marco de la pandemia de Covid-19 en los estudiantes de medicina de la Universidad de La Sabana, que ejercen sus clases prácticas, rotaciones, internados o residencias en la Clínica Universidad de La Sabana – Chía. Teniendo en cuenta que los profesionales de la salud han sido permanentemente vulnerables a las afectaciones psicosociales, en esta ocasión se agrega a esta dificultad, el comportamiento y las manifestaciones de un estudiante que enfrenta su vida académica y laboral encaminada a ser parte de este personal o que ya ejerce allí de ciertas maneras. El propósito de este estudio es dar un enfoque de descripción de comportamientos psicosociales que han sufrido los estudiantes de medicina frente a la educación remota o virtual y después de un lapso de tiempo transcurrido enfrentarse a su vida laboral sin prácticas o sin referentes hospitalarios presenciales (Barbosa, Cortes & Marroquín, 2022)

Documental tres días de terror: reflexión de los episodios terroristas que padecieron los habitantes de la vereda Alto Palmar en el municipio de Viotá, Cundinamarca.

Uno de los principales problemas alrededor de la historia bélica de nuestro país, es quizá el silencio por parte de cada una de las víctimas que han estado inmersas, bien sea directa o indirectamente, en el núcleo de lo que hoy en día se puede denominar como la historia trágica de una Colombia que muy pocos conocen, y de la que por ende muy pocos hablan. En palabras del periodista Germán Castro Caycedo (2014, p. 88): “Colombia (después de los conflictos internos en Oriente medio) es el laboratorio de experimentación de las nuevas guerras en América Latina”, y está lleva más 50 años