Excessive mechanotransduction in sensory neurons causes joint contractures.

Distal arthrogryposis (DA) is a collection of rare disorders that are characterized by congenital joint contractures. Most DA mutations are in muscle- and joint-related genes, and the anatomical defects originate cell-autonomously within the musculoskeletal system. However, gain-of-function mutations in PIEZO2, a principal mechanosensor in somatosensation, cause DA subtype 5 (DA5) through unknown mechanisms. We show that expression of a gain-of-function PIEZO2 mutation in proprioceptive sensory neurons that mainly innervate muscle spindles and tendons is sufficient to induce DA5-like phenotypes in mice. Overactive PIEZO2 causes anatomical defects through increased activity within the peripheral nervous system during postnatal development. Furthermore, botulinum toxin (Botox) and a dietary fatty acid that modulates PIEZO2 activity reduce DA5-like deficits. This reveals a role for somatosensory neurons: Excessive mechanosensation within these neurons disrupts musculoskeletal development.

Vesicle-released glutamate is necessary to maintain muscle spindle afferent excitability but not dynamic sensitivity in adult mice.

KEY POINTS: Muscle spindle afferents are slowly adapting low threshold mechanoreceptors that report muscle length and movement information critical for motor control and proprioception. The rapidly adapting cation channel PIEZO2 has been identified as necessary for muscle spindle afferent stretch sensitivity, although the properties of this channel suggest that additional molecular elements are necessary for mediating the complex slowly adapting response of muscle spindle afferents. We report that glutamate increases muscle spindle afferent static sensitivity in an ex vivo mouse muscle nerve preparation, although blocking glutamate packaging into vesicles by the sole vesicular glutamate transporter, VGLUT1, either pharmacologically or by transgenic knockout of one allele of VGLUT1 decreases muscle spindle afferent static but not dynamic sensitivity. Our results confirm that vesicle-released glutamate is an important contributor to maintained muscle spindle afferent excitability and may suggest a therapeutic target for normalizing muscle spindle afferent function. ABSTRACT: Muscle spindle afferents are slowly adapting low threshold mechanoreceptors that have both dynamic and static sensitivity to muscle stretch. The exact mechanism by which these neurons translate muscle movement into action potentials is not well understood, although the PIEZO2 mechanically sensitive cation channel is essential for stretch sensitivity. PIEZO2 is rapidly adapting, suggesting the requirement for additional molecular elements to maintain firing during stretch. Spindle afferent sensory endings contain glutamate-filled synaptic-like vesicles that are released in a stretch- and calcium-dependent manner. Previous work has shown that glutamate can increase and a phospholipase-D coupled metabotropic glutamate antagonist can abolish firing during static stretch. Here, we test the hypothesis that vesicle-released glutamate is necessary for maintaining muscle spindle afferent excitability during static but not dynamic stretch. To test this hypothesis, we used a mouse muscle-nerve ex vivo preparation to measure identified muscle spindle afferent responses to stretch and vibration. In C57BL/6 adult mice, bath applied glutamate significantly increased the firing rate during the plateau phase of stretch but not during the dynamic phase of stretch. Blocking the packaging of glutamate into vesicles by the sole vesicular glutamate transporter, VGLUT1, either with xanthurenic acid or by using a transgenic mouse with only one copy of the VGLUT1 gene (VGLUT1+/- ), decreased muscle spindle afferent firing during sustained stretch but not during vibration. Our results suggest a model of mechanotransduction where calcium entering the PIEZO2 channel can cause the release of glutamate from synaptic-like vesicles, which then helps to maintain afferent depolarization and firing.

Morbimortalidad materna y neonatal asociada a embarazos múltiples en el hospital gineco obstétrico isidro ayora de quito en el año 2016 / Maternal and neonatal morbidity and mortality associated with multiple pregnancies in the gynecological obstetric hospital isidro ayora de quito in 2016

El número de embarazos múltiples a nivel mundial ha incrementado durante los últimos 20 a 30 años, debido a las técnicas de reproducción asistida (TRA) y al aumento de la edad materna para concebir; dado la importancia de las complicaciones maternas y fetales que se consideran de riesgo, se realizó un estudio analítico de corte transversal, que incluyó todos los embarazos múltiples y su desenlace en el Hospital Gineco Obstétrico Isidro Ayora (HGOIA) desde el 1 de enero hasta el 31 de diciembre del año 2016. Las patologías más frecuentes en madres con embarazo múltiple fueron: amenaza de parto pretérmino, IVU, vaginosis, preeclampsia y anemia; mientras que en los recién nacidos se encontró mayor número de ictericia, enfermedades respiratorias, tales como enfermedad de membrana hialina, taquipnea transitoria del RN, síndrome adaptativo, sepsis, malformaciones congénitas, hipoglucemia, entre otras. El segundo gemelo presentó mayor morbilidad respiratoria, mientras que la mortalidad fue mayor en el gemelo presentado.

The number of multiple pregnancies worldwild has increased during the last 20 to 30 years; it is considered a high risk pregnancy due to the fetal and maternal complications that it involves. It has been made an analytical transversal study that includes all the multiple pregnancies and its outcomes at "Hospital Gineco Obstétrico Isidro Ayora" (HGOIA) since January 1st to December 31th, 2016. The most common maternal pathologies were: risk of premature birth, urinary tract infections, vaginosis, preeclampsia and anemia. In new borns it has been found jaundice, respiratory diseases like hyaline membrane, transient tachypnea of the new born, adaptive sindrome, sepsis, congenital malformations, hypoglycemic, etc. Nonpresentig twins had more respiratory morbidity than presentig twins; whereas mortality was more frequent in presenting twins.