Functional Characterization of a Familial ALS-Associated Missense TBK1 (p-Arg573Gly) Mutation in Patient-Derived Lymphoblasts.

The goal of this work was to elucidate the pathogenic mechanism of an ALS-associated missense mutation, p.Arg573Gly (R573G), in the TBK1 gene. In particular, we seek to analyze the influence of this variant on the cellular levels and the function of TBK1 in immortalized cells from an ALS patient. The patient (Code# E7) belonged to a Spanish family with autosomal dominant disease manifesting in the sixth decade as either dementia or ALS. Four control individuals without signs of neurological disease were also included in this study. Our results indicate that the R375G TBK1 mutation did not affect the levels of mRNA nor the total TBK1 content; however, we observed a significant decrease in the levels of TBK1 phosphorylation, which is essential for TBK1 activity, as well as a significant reduction in the phosphorylation of p62 and RIPK1, known substrates for TBK1. Lymphoblasts from the R573G TBK1 mutation carrier patient display pathological TDP-43 homeostasis, showing elevated levels of phosphorylated TDP-43 and accumulation of the protein in the cytosolic compartment. In addition, the functional decrease in TBK1 activity observed in the E7 patient did not alter the autophagy flux, but it seems to be enough to increase ROS levels as well as the expression of pro-inflammatory cytokine IL-6.

Los suplementos dietéticos y el anestesiólogo: resultados de investigación y estado del arte / Dietary supplements and the anesthesiologist: Research results and state of the art

RESUMEN Introducción: Hay una creciente tendencia mundial hacia el consumo de suplementos nutricionales. Los pacientes que consumen dichas sustancias y que van a ser llevados a cirugía tienen un riesgo potencial de presentar interacciones medicamentosas entre estas sustancias y los medicamentos del período perioperatorio. Objetivos: Realizar una caracterización sociodemográfica y determinar la prevalencia del consumo de suplementos nutricionales en personas que van a ser llevadas a cirugía; además, servir como guía de consulta para tomar conductas en la consulta preanestésica. Metodología: Se llevó a cabo un estudio observacional descriptivo de corte transversal, con pacientes que se presentaban a la consulta preanestésica, en 13 ciudades del país. A 1.130 pacientes se les interrogó acerca del consumo de estas sustancias. Resultados: La prevalencia de consumo fue de un 20,7%, siendo mayor en el sexo femenino, con un 62,8%, frente al sexo masculino; el consumo en personas mayores de 41 años fue del 63,2%; se automedicaron un 72,8%; a mayor edad, mayor consumo; entre los estratos medio y alto el consumo fue del 63%; a mayor nivel educativo, más consumo; el 36,6% piensan seguir consumiendo a pesar del procedimiento. Conclusiones: El alto índice de consumo de suplementos nutricionales en pacientes que van a someterse a una cirugía, las posibles interacciones con los medicamentos del perioperatorio y los efectos adversos de algunas hierbas medicinales deben poner en alerta el anestesiólogo que realiza la consulta preanestésica; es necesario incluir este tema en el interrogatorio y tomar conductas al respecto. Es aconsejable solicitar los empaques de los productos que consume.

ABSTRACT Background: There is a growing worldwide trend towards the consumption of nutritional supplements. Patients scheduled for surgery who are users of dietary supplements run the risk of interactions between these substances and drugs used in the perioperative period. Objectives: To conduct a socio-demographic characterization, and determine the prevalence of nutritional supplement use in people taken to surgery; to offer a reference guideline for use during pre-anesthetic consultation. Methods: The research team conducted an observational descriptive and cross-sectional study of patients presenting to the pre-anesthetic consultation in thirteen cities; 1130 patients were asked about the use of these substances. Results: The prevalence of use was 20.7%, higher among females at 62.8%, compared to males; consumption in people over 41 years was 63.2%; self-medication in 72.8%; increased consumption with age; in middle and high socioeconomic brackets, consumption was 63%; the higher the education, the higher the consumption; 36.6% plan to continue consumption despite the surgical procedure. Conclusions: The high rate of consumption of nutritional supplements in patients about to undergo surgery, possible drug interactions, and adverse effects of perioperative consumption of some herbs should trigger an alarm in the anesthesiologist performing the pre-anesthetic consultation; it is necessary to include this in the interview and act accordingly. We recommend always asking to see product packaging.