Editorial: Carotid body: a new target for rescuing neural control of cardiorespiratory balance in disease.

The carotid body (CB) is in charge of adjusting ventilatory and cardiovascular function during changes in arterial blood gases. Regardless this essential function, the CB has been implicated in the sensing of other physiological signals such as changes in blood flow and glucose levels. More important, malfunction of the CB chemoreceptors has been associated with the progression and deterioration of several disease states such as hypertension, heart failure, renal failure, insulin resistance, diabetes and sleep apnea. Although the mechanisms involved in the alterations of the CB function in pathophysiology are currently under intense research, the development of therapeutic approaches to restore normal CB chemoreflex function remains unsolved. Recent studies showing the effect of CB denervation in pathophysiology have unveiled a key role of these arterial chemoreceptors in the development of autonomic imbalance and respiratory disturbances, and suggest that targeting the CB could represent a novel strategy to improve disease outcome. Unfortunately, classical pharmacotherapy intended to normalize CB function may be hard to establish since several cellular pathways are involved in the CB dysfunction. Augmented levels of angiotensin II, endothelin-1, cytokines and free radicals along with decreases in nitric oxide had all been related to the CB dysfunction. Moreover, changes in expression of angiotensin receptors, nitric oxide synthases and cytokines that take place within the CB tissue in pathological states also contribute to the enhanced CB chemoreflex drive. It has been shown in heart failure, hypertension and obstructive sleep apnea that the CB becomes tonically hyper-reactive. During the progression of the disease this CB chemosensory facilitation process induces central nervous system plasticity. The altered autonomic-respiratory control leads to increased cardiorespiratory distress and the deterioration of the condition. The focus of this e-book will be to cover the role of the CB in pathophysiology and to provide new evidence of the pathways involved in the maladaptive potentiation of the CB chemoreflex function. In memory of Professor Mashiko Shirahata and Professor Constancio Gonzalez

Intermittent Hypoxia-Induced Carotid Body Chemosensory Potentiation and Hypertension Are Critically Dependent on Peroxynitrite Formation

Oxidative stress is involved in the development of carotid body (CB) chemosensory potentiation and systemic hypertension induced by chronic intermittent hypoxia (CIH), the main feature of obstructive sleep apnea. We tested whether peroxynitrite (ONOO−), a highly reactive nitrogen species, is involved in the enhanced CB oxygen chemosensitivity and the hypertension during CIH. Accordingly, we studied effects of Ebselen, an ONOO− scavenger, on 3-nitrotyrosine immunoreactivity (3-NT-ir) in the CB, the CB chemosensory discharge, and arterial blood pressure (BP) in rats exposed to CIH. Male Sprague-Dawley rats were exposed to CIH (5% O2, 12 times/h, 8 h/day) for 7 days. Ebselen (10 mg/kg/day) was administrated using osmotic minipumps and BP measured with radiotelemetry. Compared to the sham animals, CIH-treated rats showed increased 3-NT-ir within the CB, enhanced CB chemosensory responses to hypoxia, increased BP response to acute hypoxia, and hypertension. Rats treated with Ebselen and exposed to CIH displayed a significant reduction in 3-NT-ir levels (60.8 ± 14.9 versus 22.9 ± 4.2 a.u.), reduced CB chemosensory response to 5% O2 (266.5 ± 13.4 versus 168.6 ± 16.8 Hz), and decreased mean BP (116.9 ± 13.2 versus 82.1 ± 5.1 mmHg). Our results suggest that CIH-induced CB chemosensory potentiation and hypertension are critically dependent on ONOO− formation

Generación de grafos inducidos por la ley de potencia

157 p.Los grafos y la ley de potencia están estrechamente relacionados en el mundo real. Por ejemplo en una red social, la relación de amigos o seguidores globales de un individuo obedecen la distribución de ley de potencia. Este tipo de redes son muy estudiadas en la actualidad, pero no se proporciona acceso a estas, porque los datos son un recurso crítico y sensible. Esto ha llevado a la creación de métodos que generan grafos sintéticos que reproducen las características de grafos reales. Entre dichos métodos se encuentran R-MAT y R3MAT, donde el primero tiene problemas del uso de memoria y al segundo le toma mucho tiempo generar la distribución de aristas por su funcionamiento recursivo. Por esto, el problema que se enfrenta en esta memoria es mejorar el tiempo de producción de un grafo sintético manteniendo las propiedades de la ley de potencia. Para esto, se usa una metodología de investigación cuantitativa de cuatro fases. Es muy relevante en esta memoria la función de probabilidad de la ley de potencia, P(x = k) = C x k-t que en el contexto de grafos indica la fracción de nodos que deben tener k vecinos para que esta estructura mantenga la distribución de la ley de potencia. Para la generación de grafos sintéticos, en los métodos de esta memoria se utiliza directamente la función de probabilidad de la ley de potencia para aproximar la cantidad de nodos que deben existir por el número de vecinos, con el fin de mantener dicha propiedad en las estructuras generadas. Como resultado, se han obtenido tres métodos que generan grafos con distribución de la ley de potencia con los cuales se han generado grafos de hasta 250 millones de nodos llegando a generar m as de tres mil millones de aristas en algunos casos. Mediante las evaluaciones experimentales que se realizan para comparar uno de los métodos propuestos con otros algoritmos existentes, se comprobó una reducción del tiempo de generación con respecto a estos métodos alternativos. También se probó que efectivamente los grafos generados mantienen la propiedad de la ley de potencia por medio de la visualización de la distribución del número de nodos que se genera para los valores de k vecinos posibles. Finalmente, se logró obtener un método que reduce el tiempo de generación y que produce un grafo que mantiene la propiedad de distribución de la ley de potencia

Ventilatory and Autonomic Regulation in Sleep Apnea Syndrome: A Potential Protective Role for Erythropoietin?

Obstructive sleep apnea (OSA) is the most common form of sleep disordered breathing and is associated with wide array of cardiovascular morbidities. It has been proposed that during OSA, the respiratory control center (RCC) is affected by exaggerated afferent signals coming from peripheral/central chemoreceptors which leads to ventilatory instability and may perpetuate apnea generation. Treatments focused on decreasing hyperactivity of peripheral/central chemoreceptors may be useful to improving ventilatory instability in OSA patients. Previous studies indicate that oxidative stress and inflammation are key players in the increased peripheral/central chemoreflex drive associated with OSA. Recent data suggest that erythropoietin (Epo) could also be involved in modulating chemoreflex activity as functional Epo receptors are constitutively expressed in peripheral and central chemoreceptors cells. Additionally, there is some evidence that Epo has anti-oxidant/anti-inflammatory effects. Accordingly, we propose that Epo treatment during OSA may reduce enhanced peripheral/central chemoreflex drive and normalize the activity of the RCC which in turn may help to abrogate ventilatory instability. In this perspective article we discuss the potential beneficial effects of Epo administration on ventilatory regulation in the setting of OSA

Cumprimento das medidas de reparo e construção de uma cultura de paz no Equador e Chile

The objective of this work is to identify how the impacts of the Truth Commissions Reports in Chile and Ecuador have promoted compliance with comprehensive reparation measures and their relationship with the construction of the Culture of Peace (CP). Two studies were carried out: the first one, whose objective was to design and validate the content, an instrument to measure the perception of a culture of peace. The second one seeks to evaluate the knowledge of integral reparation measures as an intervening variable between the attitudes towards the work of the Commissions and the state functions of the CP. The implications of the lack of compliance with comprehensive reparation measures and their relationship with the construction of CP in post-conflict societies are discussed.El objetivo de este trabajo consiste en identificar cómo los impactos de los Informes de Comisiones de Verdad en Chile y Ecuador han promovido el cumplimiento de medidas de reparación integral y su relación con la construcción de la Cultura de Paz (CP). Se realizaron dos estudios: el primero, cuyo objetivo fue diseñar y validar el contenido un instrumento para medir la percepción de cultura de paz. El segundo, busca evaluar el conocimiento de medidas de reparación integral como variable interviniente entre las actitudes al trabajo de las Comisiones y las funciones estatales de CP. Se discuten las implicancias de la falta de cumplimiento de medidas de reparación integral y su relación con la construcción de CP en sociedades posconflictos. L’objectif de ce travail est d’identifier comment les impacts des rapports des commissions de vérité au Chili et en Équateur ont favorisé le respect des mesures de réparation globales et leur relation avec la construction de la culture de la paix (CP). Deux études ont été menées: la première, dont l’objectif était de concevoir et valider le contenu, un instrument pour mesurer la perception d’une culture de la paix. Le second vise à évaluer la connaissance des mesures de réparation intégrale comme variable intermédiaire entre les attitudes à l’égard du travail des commissions et les fonctions étatiques du CP. Les implications du non-respect des mesures de réparation globales et leur relation avec la construction de CP dans les sociétés sortant d’un conflit sont discutées.O objetivo deste trabalho é identificar como os impactos dos Relatórios da Comissão da Verdade no Chile e no Equador promoveram o cumprimento de medidas integrais de reparação e sua relação com a construção da Cultura de Paz (CP). Foram realizados dois estudos: o primeiro, cujo objetivo era projetar e validar o conteúdo, um instrumento para medir a percepção de uma cultura de paz. A segunda busca avaliar o conhecimento das medidas de reparação integral como uma variável interveniente entre as atitudes em relação ao trabalho das Comissões e as funções estatais do CP. São discutidas as implicações da falta de cumprimento de medidas abrangentes de reparação e sua relação com a construção da CP nas sociedades pós-conflito

Differences in the immune response elicited by two immunization schedules with an inactivated SARS-CoV-2 vaccine in a randomized phase 3 clinical trial

BACKGROUND: The development of vaccines to control the COVID-19 pandemic progression is a worldwide priority. CoronaVac® is an inactivated SARS-CoV-2 vaccine approved for emergency use with robust efficacy and immunogenicity data reported in trials in China, Brazil, Indonesia, Turkey, and Chile. METHODS: This study is a randomized, multicenter, and controlled phase 3 trial in healthy Chilean adults aged ≥18 years. Volunteers received two doses of CoronaVac® separated by two (0-14 schedule) or four weeks (0-28 schedule). 2,302 volunteers were enrolled, 440 were part of the immunogenicity arm, and blood samples were obtained at different times. Samples from a single center are reported. Humoral immune responses were evaluated by measuring the neutralizing capacities of circulating antibodies. Cellular immune responses were assessed by ELISPOT and flow cytometry. Correlation matrixes were performed to evaluate correlations in the data measured. RESULTS: Both schedules exhibited robust neutralizing capacities with the response induced by the 0-28 schedule being better. No differences were found in the concentration of antibodies against the virus and different variants of concern between schedules. Stimulation of PBMCs with MPs induced the secretion of IFN-g and the expression of activation induced markers for both schedules. Correlation matrixes showed strong correlations between neutralizing antibodies and IFN-g secretion. CONCLUSIONS: Immunization with CoronaVac® in Chilean adults promotes robust cellular and humoral immune responses. The 0-28 schedule induced a stronger humoral immune response than the 0-14 schedule. FUNDING: Ministry of Health, Government of Chile, Confederation of Production and Commerce & Millennium Institute on Immunology and Immunotherapy, Chile. CLINICAL TRIAL NUMBER: NCT04651790

Nitric oxide and carotid body chemoreception

Nitric oxide (NO) has been proposed as an inhibitory modulator of carotid body chemosensory responses to hypoxia. It is believed that NO modulates carotid chemoreception by several mechanisms, which include the control of carotid body vascular tone and oxygen delivery and reduction of the excitability of chemoreceptor cells and petrosal sensory neurons. In addition to the well-known inhibitory effect, we found that NO has a dual (dose-dependent) effect on carotid chemoreception depending on the oxygen pressure level. During hypoxia, NO is primarily an inhibitory modulator of carotid chemoreception, while in normoxia NO increased the chemosensory activity. This excitatory effect produced by NO is likely mediated by an impairment of mitochondrial electron transport and oxidative phosphorylation, which increases the chemosensory activity. The recent findings that mitochondria contain an isoform of NO synthase, which produces significant amounts of NO for regulating their own respiration, suggest that NO may be important for the regulation of mitochondrial energy metabolism and oxygen sensing in the CB