Boosting neuregulin 1 type-III expression hastens SMA motor axon maturation.

Intercellular communication between axons and Schwann cells is critical for attaining the complex morphological steps necessary for axon maturation. In the early onset motor neuron disease spinal muscular atrophy (SMA), many motor axons are not ensheathed by Schwann cells nor grow sufficiently in radial diameter to become myelinated. These developmentally arrested motor axons are dysfunctional and vulnerable to rapid degeneration, limiting efficacy of current SMA therapeutics. We hypothesized that accelerating SMA motor axon maturation would improve their function and reduce disease features. A principle regulator of peripheral axon development is neuregulin 1 type III (NRG1-III). Expressed on axon surfaces, it interacts with Schwann cell receptors to mediate axon ensheathment and myelination. We examined NRG1 mRNA and protein expression levels in human and mouse SMA tissues and observed reduced expression in SMA spinal cord and in ventral, but not dorsal root axons. To determine the impact of neuronal NRG1-III overexpression on SMA motor axon development, we bred NRG1-III overexpressing mice to SMA∆7 mice. Neonatally, elevated NRG1-III expression increased SMA ventral root size as well as axon segregation, diameter, and myelination resulting in improved motor axon conduction velocities. NRG1-III was not able to prevent distal axonal degeneration nor improve axon electrophysiology, motor behavior, or survival of older mice. Together these findings demonstrate that early SMA motor axon developmental impairments can be ameliorated by a molecular strategy independent of SMN replacement providing hope for future SMA combinatorial therapeutic approaches.

Síntomas de hipoacusia y exposición al ruido recreativo en jóvenes universitarios, Barranquilla, Colombia / Hearing loss symptoms and leisure noise exposure in university students in Barranquilla, Colombia

RESUMEN Objetivo Investigar la participación de estudiantes universitarios en actividades de ocio productoras de ruido y la relación entre los niveles de exposición semanal al ruido recreativo y síntomas de hipoacusia auto reportados, en la ciudad de Barranquilla, Colombia. Método Se realizó un estudio transversal mediante encuesta virtual, basada en el Cuestionario de Exposición al Ruido, más 11 preguntas de síntomas auditivos, a una muestra aleatoria de 730 sujetos. El nivel de exposición semanal al ruido recreativo se estimó a partir del tiempo dedicado al total de actividades recreativas reportadas por los participantes y su evaluación subjetiva de la intensidad de ruido producida por cada actividad, transformada en niveles de ruido continuo equivalente. La asociación entre la exposición al ruido recreativo y la presencia de síntomas de hipoacusia se analizó mediante la prueba de Chi-cuadrado. Resultados El 93% de los participantes manifestó al menos un síntoma de hipoacusia y la mitad reportó cuatro o más. El síntoma más frecuente de hipoacusia asociada al ruido fue el tinnitus (72%). El 55% tenía una exposición semanal de ruido por encima de 85 dBA y en éstos la prevalencia de síntomas de hipoacusia fue mayor (p < 0.05). Conclusión Se sugiere la presencia de deterioro auditivo en gran parte la población universitaria, asociado con altas dosis de exposición semanal al ruido recreativo. Es necesario fortalecer los programas de promoción de la salud auditiva en la academia, y desde los servicios de salud, la valoración objetiva y periódica de la audición.

ABSTRACT Purpose The aim of this study was to investigate the total weekly exposure to leisure noise among university students and to assess its association with self-reported symptoms of hypoacusis. Methods This is a cross-sectional survey. An online questionnaire based on the "Noise Exposure Questionnaire", plus 11 questions regarding hearing loss were sent to 730 randomly selected students. Participants self-reported time spent on different leisure noise activities and their subjective evaluation of the loudness of these activities, converted into equivalent noise levels, were used to estimate weekly noise exposure levels that were compared to occupational noise limits (> 85 dBA = hazardous). Inference statistics was applied to relate hearing symptoms and "likely or having some degree of hearing loss" with hazardous weekly leisure noise exposure levels. Results Ninety-three percent of the participants reported at least one hypoacusis symptom. The most frequent sound-related ear symptom was tinnitus (72%). Fifty-five percent of the individuals presented weekly exposure to noise >85 dBA. Symptoms of hearing loss were more prevalent in those exposed to weekly noise levels >85 dBA. Conclusion This study suggests that there may be hearing loss caused by exposure to high levels of leisure noise in a large part of the study population. Health promotion of hearing conservation should be emphasized at university level. Objective repeated measurement of hearing acuity should be part of integral health services for the youth population.

Hearing loss symptoms and leisure noise exposure in university students in Barranquilla, Colombia. / Síntomas de hipoacusia y exposición al ruido recreativo en jóvenes universitarios, Barranquilla, Colombia.

PURPOSE: The aim of this study was to investigate the total weekly exposure to leisure noise among university students and to assess its association with self-reported symptoms of hypoacusis. METHODS: This is a cross-sectional survey. An online questionnaire based on the "Noise Exposure Questionnaire", plus 11 questions regarding hearing loss were sent to 730 randomly selected students. Participants self-reported time spent on different leisure noise activities and their subjective evaluation of the loudness of these activities, converted into equivalent noise levels, were used to estimate weekly noise exposure levels that were compared to occupational noise limits (> 85 dBA = hazardous). Inference statistics was applied to relate hearing symptoms and "likely or having some degree of hearing loss" with hazardous weekly leisure noise exposure levels. RESULTS: Ninety-three percent of the participants reported at least one hypoacusis symptom. The most frequent sound-related ear symptom was tinnitus (72%). Fifty-five percent of the individuals presented weekly exposure to noise >85 dBA. Symptoms of hearing loss were more prevalent in those exposed to weekly noise levels >85 dBA. CONCLUSION: This study suggests that there may be hearing loss caused by exposure to high levels of leisure noise in a large part of the study population. Health promotion of hearing conservation should be emphasized at university level. Objective repeated measurement of hearing acuity should be part of integral health services for the youth population.

OBJETIVO: Investigar la participación de estudiantes universitarios en actividades de ocio productoras de ruido y la relación entre los niveles de exposición semanal al ruido recreativo y síntomas de hipoacusia auto reportados, en la ciudad de Barranquilla, Colombia. MÉTODO: Se realizó un estudio transversal mediante encuesta virtual, basada en el Cuestionario de Exposición al Ruido, más 11 preguntas de síntomas auditivos, a una muestra aleatoria de 730 sujetos. El nivel de exposición semanal al ruido recreativo se estimó a partir del tiempo dedicado al total de actividades recreativas reportadas por los participantes y su evaluación subjetiva de la intensidad de ruido producida por cada actividad, transformada en niveles de ruido continuo equivalente. La asociación entre la exposición al ruido recreativo y la presencia de síntomas de hipoacusia se analizó mediante la prueba de Chi-cuadrado. RESULTADOS: El 93% de los participantes manifestó al menos un síntoma de hipoacusia y la mitad reportó cuatro o más. El síntoma más frecuente de hipoacusia asociada al ruido fue el tinnitus (72%). El 55% tenía una exposición semanal de ruido por encima de 85 dBA y en éstos la prevalencia de síntomas de hipoacusia fue mayor (p < 0.05). CONCLUSIÓN: Se sugiere la presencia de deterioro auditivo en gran parte la población universitaria, asociado con altas dosis de exposición semanal al ruido recreativo. Es necesario fortalecer los programas de promoción de la salud auditiva en la academia, y desde los servicios de salud, la valoración objetiva y periódica de la audición.

Gene-Targeting Therapeutics for Neurological Disease: Lessons Learned from Spinal Muscular Atrophy.

The last few decades have seen an explosion in identification of genes that cause monogenetic neurological diseases, as well as advances in gene-targeting therapeutics. Neurological conditions that were once considered incurable are now increasingly tractable. At the forefront is the motor neuron disease spinal muscular atrophy (SMA), historically the leading inherited cause of infant mortality. In the last 5 years, three SMA treatments have been approved by the US Food and Drug Administration (FDA): intrathecally delivered splice-switching antisense oligonucleotide (nusinersen), systemically delivered AAV9-based gene replacement therapy (onasemnogene abeparvovec), and an orally bioavailable, small-molecule, splice-switching drug (risdiplam). Despite this remarkable progress, clinical outcomes in patients are variable. Therapeutic optimization will require improved understanding of drug pharmacokinetics and target engagement in neurons, potential toxicities, and long-term effects. We review current progress in SMA therapeutics, clinical trials, shortcomings of current treatments, and implications for the treatment of other neurogenetic diseases.

First-in-human evaluation of [11C]PS13, a novel PET radioligand, to quantify cyclooxygenase-1 in the brain.

PURPOSE: This study assessed whether the newly developed PET radioligand [11C]PS13, which has shown excellent in vivo selectivity in previous animal studies, could be used to quantify constitutive levels of cyclooxygenase-1 (COX-1) in healthy human brain. METHODS: Brain test-retest scans with concurrent arterial blood samples were obtained in 10 healthy individuals. The one- and unconstrained two-tissue compartment models, as well as the Logan graphical analysis were compared, and test-retest reliability and time-stability of total distribution volume (VT) were assessed. Correlation analyses were conducted between brain regional VT and COX-1 transcript levels provided in the Allen Human Brain Atlas. RESULTS: In the brain, [11C]PS13 showed highest uptake in the hippocampus and occipital cortex. The pericentral cortex also showed relatively higher uptake compared with adjacent neocortices. The two-tissue compartment model showed the best fit in all the brain regions, and the results from the Logan graphical analysis were consistent with those from the two-tissue compartment model. VT values showed excellent test-retest variability (range 6.0-8.5%) and good reliability (intraclass correlation coefficient range 0.74-0.87). VT values also showed excellent time-stability in all brain regions, confirming that there was no radiometabolite accumulation and that shorter scans were still able to reliably measure VT. Significant correlation was observed between VT and COX-1 transcript levels (r = 0.82, P = 0.007), indicating that [11C]PS13 binding reflects actual COX-1 density in the human brain. CONCLUSIONS: These results from the first-in-human evaluation of the ability of [11C]PS13 to image COX-1 in the brain justifies extending the study to disease populations with neuroinflammation. CLINICAL TRIAL REGISTRATION: NCT03324646 at https://clinicaltrials.gov/ . Registered October 30, 2017. Retrospectively registered.

Catecholaminergic axons in the neocortex of adult mice regrow following brain injury.

Serotonin axons in the adult rodent brain can regrow and recover their function following several forms of injury including controlled cortical impact (CCI), a neocortical stab wound, or systemic amphetamine toxicity. To assess whether this capacity for regrowth is unique to serotonergic fibers, we used CCI and stab injury models to assess whether fibers from other neuromodulatory systems can also regrow following injury. Using tyrosine-hydoxylase (TH) immunohistochemistry we measured the density of catecholaminergic axons before and at various time points after injury. One week after CCI injury we observed a pronounced loss, across cortical layers, of TH+ axons posterior to the site of injury. One month after CCI injury the same was true of TH+ axons both anterior and posterior to the site of injury. This loss was followed by significant recovery of TH+ fiber density across cortical layers, both anterior and posterior to the site of injury, measured three months after injury. TH+ axon loss and recovery over weeks to months was also observed throughout cortical layers using the stab injury model. Double label immunohistochemistry revealed that nearly all TH+ axons in neocortical layer 1/2 are also dopamine-beta-hyroxylase+ (DBH+; presumed norepinephrine), while TH+ axons in layer 5 are a mixture of DBH+ and dopamine transporter+ types. This suggests that noradrenergic axons can regrow following CCI or stab injury in the adult mouse neocortex and leaves open the question of whether dopaminergic axons can do the same.

Evaluation of Two Potent and Selective PET Radioligands to Image COX-1 and COX-2 in Rhesus Monkeys.

This study assessed whether the newly developed PET radioligands 11C-PS13 and 11C-MC1 could image constitutive levels of cyclooxygenase (COX)-1 and COX-2, respectively, in rhesus monkeys. Methods: After intravenous injection of either radioligand, 24 whole-body PET scans were performed. To measure enzyme-specific uptake, scans of the 2 radioligands were also performed after administration of a nonradioactive drug preferential for either COX-1 or COX-2. Concurrent venous samples were obtained to measure parent radioligand concentrations. SUVs were calculated from 10 to 90 min. Results:11C-PS13 showed specific uptake in most organs, including spleen, gastrointestinal tract, kidneys, and brain, which was blocked by COX-1, but not COX-2, preferential inhibitors. Specific uptake of 11C-MC1 was not observed in any organ except the ovaries and possibly kidneys. Conclusion: The findings suggest that 11C-PS13 has adequate signal in monkeys to justify its extension to human subjects. In contrast, 11C-MC1 is unlikely to show significant signal in healthy humans, though it may be able to do so in inflammatory conditions.

Efectos adversos de la terapia antitrombótica en reemplazos articulares / Adverse effects of antithrombotic therapy in arthroplasty surgery

Introducción: la enfermedad tromboembólica es la complicación más frecuente en el reemplazo total de rodilla y/o cadera. Sin profilaxis, la incidencia de la enfermedad tromboembólica en los pacientes sometidos a estas cirugías se incrementa hasta en un 50% y en el 90% de los pacientes con embolia pulmonar sintomática los coágulos provienen de las extremidades inferiores. Materiales y métodos: se diseñó un estudio tipo serie de casos con los pacientes a los que se les realizó reemplazo total de cadera o rodilla primario en el Centro Médico Imbanaco de Cali entre junio de 2009 y junio de 2010, y a quienes se les medicó como profilaxis antitrombótica clexane o rivaroxaban en un esquema extendido por 30 días. Resultados: se seleccionaron 251 pacientes, de los cuales 9 (3,6%) presentaron efectos adversos, siendo los más frecuentes las flictenas y la equimosis de la zona operatoria, con 4 pacientes. Dos pacientes presentaron infección del sitio operatorio, 2 tuvieron intolerancia al medicamento y 1 presentó necrosis grasa de la zona operatoria. Se encontraron 6 eventos adversos en pacientes medicados con clexane y 3 en pacientes que recibieron rivaroxaban. Todos los pacientes con eventos adversos eran obesos. Discusión: el porcentaje y tipo de eventos adversos fue similar a lo reportado en la literatura mundial. Es necesario realizar un trabajo con un tamaño de muestra mayor y un diseño que permita establecer factores de riesgo para la presentación de eventos adversos con el uso de rivaroxaban o clexane como medicamentos antitrombóticos.

Curso básico de entrenamiento en habilidades para cirugía endoscópica: grado de satisfacción de los profesionales en formación / Basic course in skills training for endoscopic surgey: satisfaction of undergraduate students

Introducción: El Curso Básico de Entrenamiento en Habilidades para Cirugía Endoscópica desarrollado por el Centro Latinoamericano de Investigación y Entrenamiento en Cirugía de Mínima Invasión (CLEMI) suministra al estudiante las herramientas necesarias para el aprendizaje de conceptos básicos en cirugía mínimamente invasiva. El objetivo de este estudio es conocer el grado de satisfacción de los profesionales en formación con el curso. Materiales y métodos: entre los meses de junio y octubre del año 2008, se realizaron 7 cursos básicos con un total de 40 estudiantes. Se elaboraron dos encuestas que los estudiantes diligenciaron antes y después del curso. Las encuestas exploraron el perfil del estudiante, sus expectativas con respecto al curso y su grado de satisfacción. Resultados: de los 40 encuestados, 36 (90%) eran especialistas en ortopedia, ginecología, urología y cirugía general. El 69,6% de los que habían recibido entrenamiento en cirugía de mínima invasión, lo hizo con pacientes. El 100% de los estudiantes le confirieron una importancia máxima a los objetivos esencialmente prácticos del curso que corresponden al desarrollo de habilidades y destrezas en espacios bidimensionales, triangulación y precisión así como disección, corte y sutura en plantillas y modelos anatómicos de animales no vivos. El 97% de los profesionales estuvo satisfecho con el cumplimiento de los objetivos del curso. Discusión: el curso básico es un proyecto innovador en Latinoamérica que busca satisfacer las necesidades de entrenamiento de los cirujanos de las diferentes especialidades. Los resultados muestran el cumplimiento de las expectativas de formación demandadas por los profesionales.