The Interactions of Temporal and Sensory Representations in the Basal Ganglia.

In rodents and primates, interval estimation has been associated with a complex network of cortical and subcortical structures where the dorsal striatum plays a paramount role. Diverse evidence ranging from individual neurons to population activity has demonstrated that this area hosts temporal-related neural representations that may be instrumental for the perception and production of time intervals. However, little is known about how temporal representations interact with other well-known striatal representations, such as kinematic parameters of movements or somatosensory representations. An attractive hypothesis suggests that somatosensory representations may serve as the scaffold for complex representations such as elapsed time. Alternatively, these representations may coexist as independent streams of information that could be integrated into downstream nuclei, such as the substantia nigra or the globus pallidus. In this review, we will revise the available information suggesting an instrumental role of sensory representations in the construction of temporal representations at population and single-neuron levels throughout the basal ganglia.

Receiver operating characteristic (ROC) to determine cut-off points of clinical and biomolecular markers to discriminate mortality in severe COVID-19 living at high altitude.

BACKGROUND: In 2020, Ecuador had one of the highest death rates because of COVID-19. The role of clinical and biomolecular markers in COVID disease prognosis, is still not well supported by available data. In order for these markers to have practical application in clinical decision-making regarding patient treatment and prognosis, it is necessary to know an optimal cut-off point, taking into consideration ethnic differences and geographic conditions. AIM: To determine the value of clinical and biomolecular markers, to predict mortality of patients with severe COVID-19 living at high altitude. METHODS: In this study, receiver operating characteristic (ROC) curves, area under the curve (AUC) of ROC, sensitivity, specificity and likelihood ratios were calculated to determine levels of clinical and biomolecular markers that best differentiate survivors versus non-survivors in severe COVID subjects that live at a high altitude setting. RESULTS: Selected cut-off values for ferritin (≥ 1225 ng/dl, p = 0.026), IL-6 (≥ 11 pg/ml, p = 0.005) and NLR (≥ 22, p = 0.008) at 24 h, as well as PaFiO2 (≤ 164 mmHg, p = 0.015), NLR (≥ 16, p = p = 0.013) and SOFA (≥ 6, p = 0.031) at 72 h, appear to have good discriminating power to differentiate survivors versus non-survivors. Additionally, odds ratios for ferritin (OR = 3.38); IL-6 (OR = 17.07); PaFiO2 (OR = 4.61); NLR 24 h (OR = 4.95); NLR 72 h (OR = 4.46), and SOFA (OR = 3.77) indicate increased risk of mortality when cut-off points were taken into consideration. CONCLUSIONS: We proposed a straightforward and understandable method to identify dichotomized levels of clinical and biomolecular markers that can discriminate between survivors and non-survivors patients with severe COVID-19 living at high altitudes.

The Central Medial Thalamic Nucleus Facilitates Bilateral Movement Execution in Rats.

Intralaminar thalamic nuclei, including the central medial nucleus (CMT), have been classically implicated in the control of attentional functional states such as sleep-wake transitions. In rodents, the CMT innervates large cortical and subcortical areas bilaterally, including sensorimotor regions of the cortex and striatum, but its contribution to motor function, which regularly develops in faster temporal scales than attentional states, is still far from being completely understood. Here, by using a novel behavioral protocol to evaluate bilateral coordination in rats, combined with electrophysiological recordings and optogenetic manipulations, we studied the contribution of the CMT to motor control and coordination. We found that optogenetic stimulation of the central region of the CMT produced bilateral recruitment of neural activity in the sensorimotor cortex and striatum. The same type of stimulations produced a significant increase in bilateral movement coordination of the forelimbs accompanied by a decrease in movement trajectory variability. Optogenetic inactivation of the CMT did not affect motor execution but significantly increased execution times, suggesting less interest in the task. Altogether, our results indicate that brief CMT activations create windows of synchronized bilateral cortico-striatal activity, suitable to facilitate motor coordination in temporal scales relevant for motor execution.

Microbiota y sepsis

La sepsis es la respuesta desordenada del organismo a la infección y se caracteriza por un daño a los órganos que puede ser irreversible y mortal. El microbioma intestinal regula a un grupo de mecanismos homeostáticos en el huésped, como la función inmunológica y la protección de la barrera intestinal, la pérdida de la estructura y la función microbiana intestinal normal; además, se ha asociado con el inicio de enfermedades de características diversas. La evidencia reciente ha demostrado un nexo entre el microbioma intestinal y la sepsis: la alteración del microbioma intestinal aumenta la susceptibilidad a la sepsis a través de varios mecanismos como la expansión de bacterias intestinales patógenas, la respuesta proinflamatoria marcada y la disminución de la formación de productos microbianos beneficiosos como los ácidos grasos de cadena corta. Una vez establecida la sepsis, la alteración del microbioma intestinal empeora y aumenta la susceptibilidad a la disfunción del órgano terminal. Existen pruebas limitadas de que las terapias basadas en microbiomas (que incluyen a probióticos y a la descontaminación digestiva selectiva) pueden disminuir el riesgo de sepsis y mejorar sus resultados en poblaciones de pacientes seleccionadas, pero las preocupaciones sobre la seguridad causan una aceptación limitada. Si bien gran parte de la evidencia que vincula el microbioma intestinal y la sepsis se ha establecido en estudios preclínicos, aún es necesaria la evidencia clínica en distintas áreas.

Sepsis is the body's overwhelming response to an infection. It is characterized by damage to the organs that may be irreversible and life-threatening. The gastrointestinal microbiome regulates a series of homeostatic mechanisms in the host, such as the immune function and the protection of the intestinal barrier, and the loss of normal intestinal microbial structure and function. Moreover, it has been associated with the onset of diseases of diverse characteristics. Recent evidence has shown a link between the gastrointestinal microbiome and sepsis: the alteration of the gastrointestinal microbiome increases the susceptibility to sepsis through various mechanisms, including the expansion of pathogenic intestinal bacteria, marked pro-inflammatory response and decreased production of beneficial microbial products such as short-chain fatty acids. Once sepsis is established, the alteration of the gastrointestinal microbiome worsens and the susceptibility to end-organ dysfunction increases. There is limited evidence that microbiome-based therapies, which include probiotics and selective digestive decontamination, can decrease the risk of sepsis and improve its outcomes in selected patient populations. However, safety concerns generate limited acceptance. While much of the evidence linking the gastrointestinal microbiome and sepsis has been established in preclinical studies, clinical evidence is still necessary in many areas.

The diversity and coexistence of extracellular mitochondria in circulation: A friend or foe of the immune system.

The diversity and coexistence of extracellular mitochondria may have a key role in the maintenance of health and progression of disease. Studies report that active mitochondria can be found physiologically outside of cells and circulating in the blood without inducing an inflammatory response. In addition, inactive or harmed mitochondria have been recognized as activators of immune cells, as they play an essential role in diseases characterized by the metabolic deregulation of these cells, such as sepsis. In this review we analyze key aspects regarding the existence of a diversity of extracellular mitochondria, their coexistence in body fluids and their effects on various immune cells. Additionally, we introduce models of how extracellular mitochondria could be interacting to maintain health and affect disease prognosis. Unwrapped mitochondria (freeMitos) can exist as viable, active, inactive or harmed organelles. Mitochondria can also be found wrapped in a membrane (wrappedMitos) that may differ depending on the cell of origin. Mitochondrial fragments can also be present in various body fluids as DAMPs, as mtDNA enclosed in vesicles or as circulating-cell-free mtDNA (ccf-mtDNA). Interestingly, the great quantity of evidence regarding the levels of ccf-mtDNA and their correlation with aging and disease allows for the identification of the diversity, but not type, of extracellular mitochondria. The existence of a diversity of mitochondria and their effects on immune cells opens a new concept in the biomedical field towards the understanding of health, the progression of disease and the development of mitochondria as therapeutic agents.

Rol de la apoptosis en la sepsis / The role of apoptosis in sepsis

RESUMEN La sepsis es una entidad potencialmente mortal a causa de la disfunción multiorgánica que genera una respuesta alterada del huésped frente a la infección y que culmina, luego de varios procesos, en un estado de inmunosupresión. Hoy en día, existen varias estrategias de manejo de la sepsis para disminuir el impacto multisistémico y mejorar la supervivencia, pero ninguna ha mostrado una clara eficacia. Es por esto que los últimos estudios se centran en aclarar y buscar alternativas terapéuticas basadas en el análisis de la fisiopatología molecular, con la finalidad de entrar en un periodo tardío de inmunosupresión continúa, conocida también como parálisis inmune. La apoptosis es un mecanismo molecular y fisiológico, cuya homeostasis es alterada en presencia de sepsis y que elimina células clave de la inmunidad innata y adaptativa, lo que conlleva a un mayor riesgo de infección secundaria, muchas veces fatal. Varios estudios post mortem han confirmado que la apoptosis de las células inmunes inducida por sepsis es un factor protagonista en la génesis de la inmunosupresión relacionada a la sepsis. Se cree que las estrategias terapéuticas dirigidas a regular la apoptosis podrían mejorar la supervivencia. Este es un artículo de revisión que describirá el rol fisiopatológico del fenómeno apoptótico en la sepsis y su repercusión en la evolución de esta entidad.

ABSTRACT Sepsis is a life-threatening entity caused by a multiorgan dysfunction that generates a dysregulated host response to infection and, after several processes, results in immunosuppression. Today, there are several sepsis management strategies to reduce its multisystemic effect and improve survival, but none of them have shown clear efficacy. Therefore, latest studies focus on clarifying and seeking therapeutic alternatives based on the analysis of the molecular pathophysiology of sepsis, in order to enter a late period of continuous immunosuppression also known as immunoparalysis. Apoptosis is a molecular and physiological mechanism, whose homeostasis is altered by the presence of sepsis. It causes the elimination of key cells of innate and adaptive immunity, which leads to an increased risk of-and often fatal- secondary infection. Several postmortem studies have confirmed that sepsis-induced immune cell apoptosis is a leading factor in the genesis of sepsis-related immunosuppression. It is believed that therapeutic strategies aimed at regulating apoptosis could improve survival. This review article describes the pathophysiological role of the apoptotic phenomenon in sepsis and its effect on the evolution of this entity.

Glicocálix endotelial: relevancia clínica y enfoque traslacional / Endothelial glycocalyx: clinical relevance and translational approach

El glicocálix endotelial es una estructura sin forma definida que recubre la capa luminal del endotelio vascular y que está constituido, principalmente, por tres elementos: proteoglicanos, glucosaminoglicanos y glicoproteínas. Cumple distintas funciones, como regular la permeabilidad vascular a las moléculas y líquidos, la transducción de las fuerzas mecánicas de tensión y las cascadas de fibrinólisis y coagulación vascular; además, protege de la adhesión leucocitaria, plaquetaria y de patógenos. Los determinantes de lesión del glicocálix pueden ser de varios tipos, por ejemplo, incremento las fuerzas de tensión, especies reactivas de oxígeno (O2), aumento, a nivel plasmático, de sustancias como el sodio (hipernatremia), glucosa (hiperglicemia) y colesterol (hipercolesterolemia), y las moléculas proinflamatorias. Cualquiera de las noxas citadas, individualmente o combinadas, lesionan el glicocálix y la disfunción resultante se expresará clínicamente como disfunción endotelial, aumento de la permeabilidad vascular, paso de lipoproteínas al subendotelio, activación de la coagulación o aumento de la adhesión de plaquetas y leucocitos al endotelio.

Endothelial glycocalyx is an undefined structure covering the luminal layer of the vascular endothelium and consisting mainly of three elements: proteoglycans, glycosaminoglycans and glycoproteins. It has different functions, such as the regulation of vascular permeability to liquids and molecules; transduction of the mechanical forces of vascular tension; regulation of coagulation and fibrinolysis cascades; and protection of leukocyte, platelet and pathogen adhesion. The determinants of a glycocalyx lesion can be of several types­e.g., increased tensile forces; reactive oxygen (O2) species; increased plasma level of substances such as sodium (hypernatremia), glucose (hyperglycemia) and cholesterol (hypercholesterolemia); and pro-inflammatory molecules. Any of the above-mentioned noxas, alone or combined, injure the glycocalyx. Its dysfunction will be clinically expressed as endothelial dysfunction, increased vascular permeability, filtration of lipoproteins to the subendothelium, activation of coagulation, or increased adhesion of leukocytes and platelets to the endothelium.

[Pheochromocytoma in multiple endocrine neoplasia 2A associated with pulmonary tuberculosis presenting as abdominal pain: a case report and literature review]. / Feocromocitoma en neoplasia endocrina múltiple IIA asociado a tuberculosis pulmonar presentada como abdomen agudo: reporte de caso y revisión de la literatura.

Pheochromocytoma is a catecholamine-producing neoplasm that may occur sporadically or associated with hereditary diseases, such as multiple endocrine neoplasia. The classic symptoms are headache, sweating, and palpitations and are attributed to the sympathetic nervous system activity, usually presenting as paroxysms. On the other hand, pulmonary tuberculosis is an infectious disease considered a public health problem in many countries, whose incidence depends on risk factors such as immunosuppression. It is well known that endocrine-tumor diseases such as multiple endocrine neoplasia can predispose to chronic inflammation and immunosuppression. We report the case of a 38-year-old male patient who had an episode of arterial hypertension and abdominal pain as the first symptoms of a pheochromocytoma associated with multiple endocrine neoplasia type 2A. The patient developed pulmonary tuberculosis simultaneously, but we managed to treat both entities and achieve a favorable clinical course.

El feocromocitoma constituye una neoplasia productora de catecolaminas que se presenta de forma esporádica o asociada a enfermedades de transmisión hereditaria, como la neoplasia endocrina múltiple. Los síntomas clásicos como la cefalea, sudoración y palpitaciones son atribuidos a la actividad del sistema nervioso simpático y suelen presentarse en forma de paroxismos. La tuberculosis pulmonar es una enfermedad infecciosa que constituye un problema de salud pública en muchos países, cuya incidencia depende de algunos factores incluyendo la inmunosupresión que generan las enfermedades endocrino-tumorales como la antes descrita. Presentamos el caso de un paciente masculino de 38 años que acude a emergencia por presentar un paroxismo de hipertensión arterial y dolor abdominal, como manifestaciones iniciales de un feocromocitoma en el contexto de una neoplasia endocrina múltiple de tipo IIA. El paciente desarrolló de forma concomitante tuberculosis pulmonar; no obstante, se logró tratar ambas entidades consiguiendo una evolución clínica favorable.

Aclaramiento del lactato: revisión de la literatura / Lactate clearance: review of the literature

Cuando hablamos del aclaramiento de lactato debemos conocer con claridad la complejidad del proceso, pues abarca todo el metabolismo del lactato desde su producción hasta su remoción: a este proceso se ha denominado equilibrio reversible de lactato. Este concepto que permitirá entender mejor los procesos dinámicos de su metabolismo no como producto final o de desecho (según, tradicionalmente, se nos ha hecho creer) sino, más bien, como un producto intermedio que ejerce funciones específicas y bien definidas que lo convierten no sólo en indicador de perfusión tisular sino en un indicador global del metabolismo celular.

When we talk about lactate clearance we have to be clear about the complexity of the process, since it involves the metabolism of lactate from its production to its removal what has been called reversible lactate equilibrium, this concept that will allow us to better understand the dynamic processes of its metabolism not as a final product or waste, as we have traditionally been led to believe, but rather as an intermediate product with specific and welldefined functions that make it not only an indicator of tissue perfusion, but a global indicator of metabolism cell

Fisiología, bioquímica y metabolismo del ácido láctico: revisión de la literatura / Physiology, biochemistry and metabolism of lactic acid: review of the literature

El ácido láctico o lactato es un marcador bioquímico cuyo rol biológico ha ido adquiriendo mayor importancia a medida que entendemos su comportamiento bioquímico, fisiológico, metabólico y fisiopatológico. Inicialmente fue visto como un sustrato nocivo y luego, paulatinamente entendido como una vía vital de supervivencia celular y sustrato energético en condiciones extremas y aún normales (sistema nervioso central). Actualmente es un objetivo de resucitación hemodinámica, tan importante, que su descenso o ascenso luego de reanimación hemodinámica predice alta morbilidad y mortalidad. En esta revisión tenemos el propósito de facilitar el entendimiento del metabolismo del lactato y, por tanto, de la glucosa (ambas sustancias comparten paralelismos bioquímicos y metabólicos), recalcar la importancia del hígado y del músculo esquelético y alcanzar enfoques traslacionales sobre el tema.(AU)

Lactic acid or lactate is a biochemical marker whose biological role has become more important as we understand its biochemical, physiological, metabolic and pathophysiological behavior. Initially it was seen as a harmful substrate and then, gradually understood as a vital way of cell survival and energy substrate in extreme and still normal conditions (central nervous system). Currently, it is an important hemodynamic resuscitation objective, that its descent or rise after hemodynamic resuscitation predicts high morbidity and mortality. In this review we will try to facilitate the understanding of lactate metabolism and, therefore, of glucose (both substances share biochemical and metabolic parallelisms), emphasize the importance of the liver and skeletal muscle and achieve translational approaches on the subject.(AU)

Utilidad del score air en el diagnóstico y pronóstico de apendicitis aguda / Utility of the score air in the diagnosis and prognosis of acute appendicitis

Antecedente: la apendicitis aguda (AA) es la causa más común de urgencias quirúrgicas en el mundo; se estima un riesgo de padecerla durante la vida del 7% y un número de apendicetomías negativas entre 5 y 10%. Objetivo: evaluar la validez del Score AIR (respuesta inflamatoria por apendicitis) como herramienta diagnostica en pacientes con sospecha de apendicitis aguda. Metodología: se realizó un diseño epidemiológico, analítico, transversal de período, en pacientes que acudieron al Hospital Dr. Gustavo Domínguez Z., con sospecha de apendicitis aguda, entre julio y diciembre de 2015, mediante la aplicación del Score AIR más correlación con hallazgos histopatológicos. Los datos fueron ingresados en el paquete estadístico SPSS versión 21 para su análisis. Resultados: el presente estudio incluyó 210 pacientes con sospecha de apendicitis aguda, 108 mujeres y 102hombres con una edad promedio de 24.4 años; a la validación con los hallazgos histopatológicos el Score presentó una S:98.47%, E: 61.54%, VPP: 97.48%, VPN 72.72%, RV+:2.56, RV-:0.024; las muestras analizadas fueron fases necróticas con 48.57% seguidas de fases supurativas; puntajes altos de AIR se relacionaron con fases avanzadas de apendicitis con un rango de evolución entre 16 y 24 horas y cifras elevadas de leucocitosis, neutrofilia y PCR mostraron relación directa con las fases complicadas de apendicitis. Conclusión: el Score AIR sirve como herramienta de diagnóstico y pronóstico de apendicitis aguda.

Background: Acute appendicitis is the most common cause of surgical emergencies in the world, the risk of suffering during the life of 7%, is estimated a number of negative appendectomies from 5 to 10%. Objective: To evaluate the validity of AIR Score as diagnostic tool in patients with suspected acute appendicitis. Materials and Methods: A design analytical epidemiological transverse period was made in patients who attended to Dr. Gustavo Dominguez Z. Hospital with suspected acute appendicitis, between July and December 2015, applying Score AIR more correlation with histopathologic findings. The data were entered into SPSS version 21 for analysis. Results: This study included 210 patients with suspected acute appendicitis, 108 women and 102 men with an average age of 24.4 years; the Score validation with histopathological findings presented a S:98.47%, E: 61.54%, VPP:97.48%, VPN 72.72%, RV+:2.56, RV-:0.024;samples analyzed were necrotic phases in 48.57% followed with suppurative phases; high AIR scores were associated with advanced stages of appendicitis range hours of evolution between 16 and 24 hours and high levels of leukocytosis, neutrophilia and PCR showed direct relationship with the complicated stages of appendicitis. Conclusion: AIR Score serves as a tool for Diagnosis and Prognosis of Acute Appendicitis