Masseter muscle thickness is predictive of cancer cachexia in patients with head and neck cancer.

BACKGROUND: Cancer cachexia is prevalent in head and neck cancer patients. The L3 skeletal muscle index (SMI) is often used to assess sarcopenia and cachexia but is infrequently able to be measured in this population. Masseter muscle thickness (MT) may serve as an alternative predictor of cachexia. METHODS: SMI and MT were calculated from 20 trauma (CTRL) and 40 cachectic (CA-CX) and non-cachectic (CA-NCX) head and neck cancer patients. Area Under the Curve of the Receiver Operating Characteristics (AUC-ROC) analysis was performed for SMI and MT. RESULTS: Both SMI and MT were significantly decreased in CA-CX patients (vs. CA-NCX mean difference -19.5 cm2/m2 and -2.06 mm, respectively) and significant predictors of CA-CX (AUC = 0.985 and 0.805, respectively). When analyzed by sex, the same findings were observed for MT in males and trended toward significance in females. CONCLUSIONS: Compared with SMI, MT is a good alternative prognostic biomarker to determine CA-CX status in HNC patients.

Fibroblast growth factor 21 is expressed and secreted from skeletal muscle following electrical stimulation via extracellular ATP activation of the PI3K/Akt/mTOR signaling pathway.

Fibroblast growth factor 21 (FGF21) is a hormone involved in the regulation of lipid, glucose, and energy metabolism. Although it is released mainly from the liver, in recent years it has been shown that it is a "myokine", synthesized in skeletal muscles after exercise and stress conditions through an Akt-dependent pathway and secreted for mediating autocrine and endocrine roles. To date, the molecular mechanism for the pathophysiological regulation of FGF21 production in skeletal muscle is not totally understood. We have previously demonstrated that muscle membrane depolarization controls gene expression through extracellular ATP (eATP) signaling, by a mechanism defined as "Excitation-Transcription coupling". eATP signaling regulates the expression and secretion of interleukin 6, a well-defined myokine, and activates the Akt/mTOR signaling pathway. This work aimed to study the effect of electrical stimulation in the regulation of both production and secretion of skeletal muscle FGF21, through eATP signaling and PI3K/Akt pathway. Our results show that electrical stimulation increases both mRNA and protein (intracellular and secreted) levels of FGF21, dependent on an extracellular ATP signaling mechanism in skeletal muscle. Using pharmacological inhibitors, we demonstrated that FGF21 production and secretion from muscle requires the activation of the P2YR/PI3K/Akt/mTOR signaling pathway. These results confirm skeletal muscle as a source of FGF21 in physiological conditions and unveil a new molecular mechanism for regulating FGF21 production in this tissue. Our results will allow to identify new molecular targets to understand the regulation of FGF21 both in physiological and pathological conditions, such as exercise, aging, insulin resistance, and Duchenne muscular dystrophy, all characterized by an alteration in both FGF21 levels and ATP signaling components. These data reinforce that eATP signaling is a relevant mechanism for myokine expression in skeletal muscle.

Mechanical Disturbance of Osteoclasts Induces ATP Release That Leads to Protein Synthesis in Skeletal Muscle through an Akt-mTOR Signaling Pathway.

Muscle and bone are tightly integrated through mechanical and biochemical signals. Osteoclasts are cells mostly related to pathological bone loss; however, they also start physiological bone remodeling. Therefore, osteoclast signals released during bone remodeling could improve both bone and skeletal muscle mass. Extracellular ATP is an autocrine/paracrine signaling molecule released by bone and muscle cells. Then, in the present work, it was hypothesized that ATP is a paracrine mediator released by osteoclasts and leads to skeletal muscle protein synthesis. RAW264.7-derived osteoclasts were co-cultured in Transwell® chambers with flexor digitorum brevis (FDB) muscle isolated from adult BalbC mice. The osteoclasts at the upper chamber were mechanically stimulated by controlled culture medium perturbation, resulting in a two-fold increase in protein synthesis in FDB muscle at the lower chamber. Osteoclasts released ATP to the extracellular medium in response to mechanical stimulation, proportional to the magnitude of the stimulus and partly dependent on the P2X7 receptor. On the other hand, exogenous ATP promoted Akt phosphorylation (S473) in isolated FDB muscle in a time- and concentration-dependent manner. ATP also induced phosphorylation of proteins downstream Akt: mTOR (S2448), p70S6K (T389) and 4E-BP1 (T37/46). Exogenous ATP increased the protein synthesis rate in FDB muscle 2.2-fold; this effect was blocked by Suramin (general P2X/P2Y antagonist), LY294002 (phosphatidylinositol 3 kinase inhibitor) and Rapamycin (mTOR inhibitor). These blockers, as well as apyrase (ATP metabolizing enzyme), also abolished the induction of FDB protein synthesis evoked by mechanical stimulation of osteoclasts in the co-culture model. Therefore, the present findings suggest that mechanically stimulated osteoclasts release ATP, leading to protein synthesis in isolated FDB muscle, by activating the P2-PI3K-Akt-mTOR pathway. These results open a new area for research and clinical interest in bone-to-muscle crosstalk in adaptive processes related to muscle use/disuse or in musculoskeletal pathologies.

Toxina Botulínica tipo A para el bruxismo del sueño en adultos / Botulinum toxin type A for sleep bruxism in adults

RESUMEN: Introducción: El bruxismo del sueño es un comportamiento que se caracteriza por la actividad repetitiva de los músculos masticadores. Varias terapias para el manejo del bruxismo del sueño se centran en la relajación de los músculos involucrados, incluyendo la inyección intramuscular de Toxina Botulínica tipo A (BoNTA). A pesar de que se ha comprobado la efectividad de esta terapia frente al dolor subjetivo, cuando se asocia a bruxismo del sueño, es necesario determinarla frente a desenlaces objetivos, tanto a nivel craneofacial como sistémico. Además, se debe evaluar también la seguridad de esta intervención frente a eventos adversos tales como afecciones estéticas, debilidad masticatoria y pérdida ósea mandibular, entre otros. Métodos: Realizamos una búsqueda en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante el cribado de múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, analizamos los datos de los estudios primarios, realizamos un meta-análisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. Resultados y conclusiones: Identificamos 11 revisiones sistemáticas que en conjunto incluyeron 9 estudios primarios, de los cuales, 8 corresponden a ensayos aleatorizados. Concluimos que la inyección intramuscular de toxina botulínica tipo A podría disminuir el dolor en reposo, presentar poca o nula diferencia en dolor durante la masticación y mejorar la autoevaluación del bruxismo, pero la certeza de la evidencia es baja. Por otra parte, no es posible establecer con claridad si el uso de Toxina Botulínica Tipo A disminuye el número de eventos de bruxismo, ya que la certeza de la evidencia ha sido evaluada como muy baja. Finalmente y a pesar de la evidencia existente respecto de los potenciales eventos adversos producto de la intervención con Toxina Botulínica Tipo A en los músculos masticatorios, los ensayos clínicos fallan en evaluarlos y reportarlos.

ABSTRACT: Introduction: The sleep bruxism is a behavior that impacts the craniofacial musculoskeletal system characterized by repetitive activity of the masticatory muscles. Several management strategies for sleep bruxism are focused of the relaxation of the involved masticatory muscles, including the intramuscular injection of botulinum toxin type A (BoNTA). Although the effectiveness of BoNTA for myofascial pain, when related with the sleep bruxism in adult patients, it is necessary to determine its effectiveness using objective outcomes at both craniofacial and systemic levels. In addition, it is necessary to determine the safety of this intervention in the context of adverse events such as aesthetic alterations, reduced masticatory function, mandibular bone loss among others. Methods: A search was performed using Epistemonikos, the biggest database for systematic reviews in health, with is maintained by screening of multiple sources of information, including MEDLINE, EMBASE, Cochrane, among others. Data from systematic reviews were extracted, and analysis of the primary studies was performed, including a meta-analysis and a summary of findings table using GRADE assessment. Results and conclusions: 11 systematic reviews were identified, and 9 primary studies were included. 8 out of these 9 studies corresponded to randomized clinical trials. We conclude that the intramuscular injection of BoNTA may reduce the pain during rest and results in either little or none difference in pain during mastication, when pain is associated with sleep bruxism in adult patients. Also, low evidence is determined for auto-report and subjective evaluation of sleep bruxism among adult patients. Additionally, it is not possible to determine if the BoNTA intervention is effective to reduce the bruxism events due to the low evidence. Finally, although evidence regarding adverse events such as mandibular bone loss after BoNTA intervention in masticatory muscles has been published at preclinical and clinical levels, the clinical trials fail to consider and to report these outcomes.

Infiltración de resina y barniz de flúor para el tratamiento de caries interproximales no cavitadas en dentición temporal / Resin infiltration plus fluoride varnish for non-cavitated proximal caries in primary dentition

RESUMEN: Introducción: Con el fin de prevenir la progresión de la caries interproximal no cavitada en dientes temporales, se ha generalizado el uso de estrategias mínimamente invasivas como la aplicación de sellantes, barniz de flúor o la resina infiltrante, ya sea combinadas o como monoterapia. Pese a lo anterior, hay incertidumbre con relación al efecto de la infiltración de resina en combinación con el barniz de flúor en dientes temporales. Métodos: Realizamos una búsqueda en Epistemonikos, la mayor base de datos de revisiones sistemáticas en salud, la cual es mantenida mediante el cribado de múltiples fuentes de información, incluyendo MEDLINE, EMBASE, Cochrane, entre otras. Extrajimos los datos desde las revisiones identificadas, analizamos los datos de los estudios primarios, realizamos un metaanálisis y preparamos una tabla de resumen de los resultados utilizando el método GRADE. Resultados y conclusiones: Se identificaron nueve revisiones sistemáticas que en conjunto incluyeron tres estudios primarios que corresponden a ensayos clínicos aleatorizados. Se concluye que la infiltración de resina probablemente reduce el riesgo de la progresión de la caries interproximal no cavitada en dientes temporales. No se encontraron estudios que evaluaran los eventos adversos. Palabras claves: caries, infiltración de resina, caries interproximal, barniz de flúor, tratamiento mínimamente invasivo, Epistemonikos, GRADE.

ABSTRACT: Introduction: Minimally invasive techniques are widely used in non-cavitated interproximal caries treatment in primary dentition. Sealants, fluoride varnish, or resin infiltration can be applied in conjunction or as monotherapy. There is uncertainty regarding the effect of resin infiltration in conjunction with fluoride varnish in primary dentition. Methods: We searched in Epistemonikos, the largest database of systematic reviews in health, which is maintained by screening multiple information sources, including MEDLINE, EMBASE, Cochrane, among others. We extracted data from the systematic reviews, reanalyzed data of primary studies, conducted a meta-analysis and generated a summary of findings table using the GRADE approach. Results and conclusions: We identified 9 systematic reviews including three studies overall, of which all were randomized trials. We conclude that resin infiltration plus fluoride varnish probably decreases the risk of progression of non-cavitated interproximal caries in primary dentition. No studies were found that looked at adverse effects.

Three-dimensional assessment of enamel and dentine in mouse molar teeth during masseter muscle hypofunction / Evaluación tridimensional del esmalte y la dentina de dientes molares de ratones durante la hipofunción del músculo masetero

Background: Mouse molar is a widely used model for teeth development. However, the effect of masticatory function on enamel and dentine in adult individuals remains poorly understood. As reported, the unilateral masseter hypofunction induced by botulinum toxin type A (BoNTA) resulted in mandibular bone damage and signs of unilateral chewing in adult mice. Objective: We aimed to assess the amount of enamel and dentine in the first molar (M1) during the unilateral masseter hypofunction in mice, using high-resolution X-ray microtomography (µCT) as threedimensional approach. Materials and methods: Mandibles of adult BALB/c mice, located either in a Control-group (without intervention) or a BoNTA-group, were ex-vivo scanned using µCT. Treated individuals received each one BoNTA intervention in the right masseter, and saline solution in the left masseter (intra-individual control). Enamel and dentine from M1 were segmented, and volume, thickness and mesial root length were quantified. Results: Enamel volume from treated side resulted unchanged after 2 weeks of unilateral masseter hypofunction. No differences for enamel volume were found between both sides of control individuals, and between these and samples from hypofunctional side in BoNTA-group. Enamel volume from saline-injected side was reduced when compared with experimental side (p<0,01). No differences in dentine volume, thickness of enamel and dentine, and mesial root length were found for any group. Conclusion: The amount of enamel in hypofunctional molars remains unaffected after unilateral BoNTA intervention in the masseter, but contralateral side showed reduced enamel volume. Therefore, increased functional wearing during unilateral chewing after BoNTA intervention should be considered.

Introducción: El molar de ratón es utilizado como modelo de estudio en el desarrollo dental. El efecto de la función masticatoriasobre el tejido dental en individuos adultos aún se comprende. En ratones adultos, la hipofunción unilateral del masetero inducida por toxina botulínica tipo A (BoNTA) resultó en daño óseo mandibular y signos de masticación unilateral. Objetivo: Evaluamos la cantidad de esmalte y dentina en el primer molar (M1) durante la hipofunción unilateral del músculo masetero en ratones mediante análisis con microtomografía (µCT). Materiales y métodos: Las mandíbulas de ratones BALB/c adultos, del grupo Control (sin intervención) o el grupo BoNTA, fueron escaneadas ex-vivo con µCT. Los individuos tratados se inyectaron con BoNTA en el masetero derecho y con solución salina en el masetero izquierdo (control intra-individuo). El volumen y grosor de esmalte y dentina del M1, y la longitud de la raíz mesial fueron medidos. Resultados: No hubo cambios en el volumen del esmalte del lado tratado con BoNTA y en ambos lados del grupo Control, 2 semanas post-intervención. El esmalte del lado control intra-individuo se redujo comparado con el lado experimental (p< 0,01). No hubo cambios en el volumen de dentina, el grosor de esmalte y dentina o en longitud de la raíz mesial de ambos grupos. Conclusión: La cantidad de esmalte en los molares hipofuncionales no se afecta después de la inyección unilateral de BoNTA en masetero, pero si se reduce en el lado contralateral. Por lo tanto, se debe considerar un desgaste dental asimétrico durante esta intervención.