Nitrous oxide induces hypothermia and TrkB activation: Maintenance of body temperature abolishes antidepressant-like effects in mice.

Recent studies indicate that nitrous oxide (N2O), a gaseous anesthetic and an NMDA (N-methyl-D-aspartate) receptor antagonist, produces rapid antidepressant effect in patients suffering from treatment-resistant depression. Our recent work implies that hypothermia and reduced energy expenditure are connected with antidepressant-induced activation of TrkB neurotrophin receptors - a key regulator of synaptic plasticity. In this study, we demonstrate that a brief exposure to N2O leads to a drop in body temperature following the treatment, which is linked to decreased locomotor activity; enhanced slow-wave electroencephalographic activity; reduced brain glucose utilization; and increased phosphorylation of TrkB, GSK3ß (glycogen synthase kinase 3ß), and p70S6K (a kinase downstream of mTor (mammalian target of rapamycin)) in the medial prefrontal cortex of adult male mice. Moreover, preventing the hypothermic response in a chronic corticosterone stress model of depression attenuated the antidepressant-like behavioral effects of N2O in the saccharin preference test. These findings indicate that N2O treatment modulates TrkB signaling and related neurotrophic signaling pathways in a temperature-dependent manner, suggesting that the phenomenon driving TrkB activation - altered thermoregulation and energy expenditure - is linked to antidepressant-like behavioral responses.

Linking Hypothermia and Altered Metabolism with TrkB Activation.

Many mechanisms have been proposed to explain acute antidepressant drug-induced activation of TrkB neurotrophin receptors, but several questions remain. In a series of pharmacological experiments, we observed that TrkB activation induced by antidepressants and several other drugs correlated with sedation, and most importantly, coinciding hypothermia. Untargeted metabolomics of pharmacologically dissimilar TrkB activating treatments revealed effects on shared bioenergetic targets involved in adenosine triphosphate (ATP) breakdown and synthesis, demonstrating a common perturbation in metabolic activity. Both activation of TrkB signaling and hypothermia were recapitulated by administration of inhibitors of glucose and lipid metabolism, supporting a close relationship between metabolic inhibition and neurotrophic signaling. Drug-induced TrkB phosphorylation was independent of electroencephalography slow-wave activity and remained unaltered in knock-in mice with the brain-derived neurotrophic factor (BDNF) Val66Met allele, which have impaired activity-dependent BDNF release, alluding to an activation mechanism independent from BDNF and neuronal activity. Instead, we demonstrated that the active maintenance of body temperature prevents activation of TrkB and other targets associated with antidepressants, including p70S6 kinase downstream of the mammalian target of rapamycin (mTOR) and glycogen synthase kinase 3ß (GSK3ß). Increased TrkB, GSK3ß, and p70S6K phosphorylation was also observed during recovery sleep following sleep deprivation, when a physiological temperature drop is known to occur. Our results suggest that the changes in bioenergetics and thermoregulation are causally connected to TrkB activation and may act as physiological regulators of signaling processes involved in neuronal plasticity.

Caracterización por Ultrasound Tissue Characterization de los tendones rotulianos de jugadores de baloncesto; comparación entre profesionales versus formativos y asintomáticos versus sintomáticos / Patellar tendon analysis by ultrasound tissue characterization; comparison between professional and amateur basketball players. Asymptomatic versus symptomatic

Introducción: La ecografía convencional permite identificar los cambios macroscópicos que se producen en el tendón patológico, sin embargo, estos cambios no se correlacionan bien con los síntomas o la respuesta al tratamiento. La Ultrasound Tissue Characterization (UTC) evalúa la estructura del tendón en 3 dimensiones y la clasifica en 4 eco-tipos. El objetivo de este estudio fue investigar la estructura del tendón rotuliano de jugadores de baloncesto utilizando la técnica de la UTC y estudiar las diferencias entre jugadores profesionales y formativos, comparando la pierna dominante con la pierna no dominante, y sintomáticos con asintomáticos. Material y métodos: Un total de 40 tendones rotulianos (20 jugadores de baloncesto) se incluyeron en el estudio. La estructura del tendón rotuliano (proximal, medial y distal) se cuantificó mediante UTC en el inicio de la pretemporada. La fiabilidad inter e intraobservador se estudió mediante el coeficiente de correlación intraclase (CCI). Resultados: La edad media de los 10 jugadores profesionales y la de los 10 jugadores formativos fue de 28,1 años (DE 4,5) y 17,6 (DE 1,13), respectivamente. El espesor del tendón rotuliano fue mayor en los jugadores profesionales (p < 0,05), en la pierna dominante (p < 0,05) y en los tendones sintomáticos (p < 0,05). No se encontraron diferencias significativas para los eco-tipos, excepto en el caso del eco-tipo II del tendón rotuliano derecho en la porción proximal entre los jugadores profesionales y los académicos (p = 0,05), y en los eco-tipo III y IV del tendón derecho en su porción proximal entre los jugadores sintomáticos y los asintomáticos (p < 0,05). Se encontró una buena-alta fiabilidad con estas técnicas (CCI = 0,80-0,99). Conclusiones: Se ha caracterizado el patrón ecográfico de los tendones rotulianos de jugadores de baloncesto utilizando UTC. El espesor del tendón rotuliano es mayor en los jugadores profesionales que en los jugadores académicos. También se ha observado mayor grosor de los tendones sintomáticos que de los asintomáticos. No hubo diferencias importantes en el patrón de UTC entre los jugadores profesionales y los académicos ni entre los sintomáticos y los asintomáticos (AU)

Introduction: Conventional ultrasound helps to identify the macroscopic changes produced in the injured tendon. However, these changes do not correlate well with the symptoms or the response to treatment. The ‘characterization of tissues by ultrasound’ (UTC) evaluates the structure of the tendon in 3 dimensions and classifies it into 4 echo-types. The aim of this study was to investigate the structure of the patellar tendon in basketball players using the UTC technique, and to study the differences between professional and amateur players by comparing the dominant leg with the non-dominant one, and the asymptomatic with the asymptomatic ones. Material and methods: The study included 40 patellar tendons (20 basketball players). The structure of the patellar tendon (proximal, medial, and distal) was quantified by means of UTC at the beginning of the pre-season. The within and between observer reliability was measured using the intraclass correlation coefficient (ICC). Results: The mean ages of the 10 professional players and 10 amateur players were 28.1 years (SD 4.5) and 17.6 years (SD 1.3), respectively. The thickness of the patellar tendon was greater in the professional players (P < .05), in the dominant leg (P < .05), and in symptomatic tendons (P < .05). There were no significant differences in the echo-types, except in the case of echotype II in the proximal portion of the right patellar tendon, between professional and amateur players (P = .05). Similarly, there was a difference in echo-type III and IV of the proximal portion of the right tendon between symptomatic and asymptomatic players (P < .05). A good, high reliability was found with these techniques (ICC = .80-.99). Conclusions: The ultrasound pattern of the patellar tendons of basketball players has been characterised using UTC. The thickness of the tendon is greater in professional players than in amateur players. It has also been observed that the symptomatic tendons are thicker than in asymptomatic ones. There were no significant differences in the UTC patterns between professional and amateur players, or between symptomatic and asymptomatic ones (AU)

Amine-reactive PEGylated nanoparticles for potential bioconjugation.

Water-dispersible PEGylated nanoparticles (NPs) presenting amine-reactive conjugation sites at their surfaces were synthesized and their ability to react with amines was demonstrated. An amphiphilic block copolymer bearing an N-succinimidyl ester at its water-soluble end was synthesized by the consecutive controlled radical polymerization of poly(ethylene glycol) methacrylate and styrene from a functional halide initiator. After purification of the copolymer, NPs of approximately 40 nm were obtained by a self-assembly process in water. The reactivity of the NPs was evidenced by reacting them with primary amines, including a fluorescent dye. The activated ester remained stable throughout all synthetic steps and a nearly quantitative coupling efficiency was obtained.

Stress fractures of the metacarpal bones in adolescent tennis players: a case series.

BACKGROUND: There are 12 reported cases of metacarpal stress fractures in athletes, with only 4 of them involving the second metacarpal. PURPOSE: The authors describe stress fracture of the second metacarpal bone in teenaged tennis players and the relationship with sport intensity and type of grip used. They also demonstrate that magnetic resonance imaging is the diagnostic study of choice to differentiate this entity from the most common cause of pain in this region of the hand in tennis players-the carpal boss. STUDY DESIGN: Case series; Level of evidence, 4. METHODS: Seven adolescent tennis players (mean age, 16.5 years; 6 female, 1 male) with dorsal hand pain produced by playing tennis were examined by radiographs and initial magnetic resonance imaging. In 2 cases, bone scintigraphy was performed. In the first 2 cases, the presumptive diagnosis was a carpal boss, but with this experience, the diagnostic evaluation of the last 5 cases was oriented toward a stress reaction at this level. Radiologic follow-up was performed. The authors also evaluated the grip type used by each tennis player. RESULTS: Clinical evaluation and imaging studies resulted in a diagnosis of stress injury of the second metatarsal in 6 of 7 cases, with the seventh case involving the third metacarpal. Initial imaging was positive in 3 cases, revealing an increased signal in the marrow without hairline crack and cortical thickening of the shaft or simply an increased signal in the marrow. In all cases, there was a history of recent increase in the sport training load. Six of the 7 tennis players were using a semi-Western or Western grip. CONCLUSION: Stress fractures of the second metacarpal are characteristic of adolescent tennis players and are associated with an increased intensity of tennis play and may be associated with use of the semi-Western or Western grip. Magnetic resonance imaging is the most useful tool for obtaining a definitive diagnosis.

[Stability of NT-ProBNP in patients with systolic heart failure]. / Estabilidad de NT-proBNP en pacientes con insuficiencia cardiaca sistólica.

Natriuretic peptides are extremely useful in the diagnosis and prognosis of patients with heart failure. However, it is not clear whether their values are stable. We carried out a prospective study of 30 consecutive ambulatory patients (mean age, 62.6 [12.2] years) with stable systolic heart failure, as determined by the 6-minute walk test, who were in New York Heart Association class II or III and who had a left ventricular ejection fraction <30% (mean ejection fraction, 24.2% [6.68%]). At baseline, the mean N-terminal pro-brain natriuretic peptide (NT-proBNP) level and the mean distance walked in 6 minutes were 2237.3 pg/mL and 348.26 m, respectively. At 3-month follow-up, the corresponding values were 2096.2 pg/mL and 372.05 m, respectively. No significant difference was observed in NT-proBNP level or in distance walked in 6 minutes between baseline and 3 months (P=.8). Overall, there was a good correlation (r=0.94; P< .001) between the plasma NT-proBNP level at baseline and at 3 months in patients with stable chronic heart failure due to systolic dysfunction in New York Heart Association class II or III.

Estabilidad de NT-proBNP en pacientes con insuficiencia cardiaca sistólica / Stability of NT-ProBNP in patients with systolic heart failure

Los péptidos natriuréticos tienen un alto valor diagnóstico y pronóstico en pacientes con insuficiencia cardiaca, pero desconocemos la estabilidad de sus valores. Determinamos en 2 visitas ambulatorias los valores de N terminal pro-BNP (NT-proBNP) de 30 pacientes consecutivos con insuficiencia cardiaca estable [New York Heart Association (NYHA) II-III] (test 6 min) por disfunción sistólica [función ventricular izquierda deprimida (FEVI) < 30%] separadas entre sí 3 meses. Tenían una edad media de 62,6 ± 12,2 años y una fracción de eyección del 24,2 ± 6,68%. No encontramos diferencias significativas entre los valores basales del NT-proBNP como test de los 6 min (2.237,3 pg/ml y 348,26 m) y a los 3 meses (2.096,2 pg/ml y 372,05 m). El coeficiente de correlación intraclase entre los valores basales y a los 3 meses de NT-proBNP fue de 0,94 (p < 0,001). Existe una buena correlación entre los valores basales y a los 3 meses de las concentraciones plasmáticas de NT-proBNP en pacientes con insuficiencia cardiaca crónica estable (NYHA II-III) por disfunción sistólica

Natriuretic peptides are extremely useful in the diagnosis and prognosis of patients with heart failure. However, it is not clear whether their values are stable. We carried out a prospective study of 30 consecutive ambulatory patients (mean age, 62.6 [12.2] years) with stable systolic heart failure, as determined by the 6-minute walk test, who were in New York Heart Association class II or III and who had a left ventricular ejection fraction <30% (mean ejection fraction, 24.2% [6.68%]). At baseline, the mean N-terminal pro-brain natriuretic peptide (NT-proBNP) level and the mean distance walked in 6 minutes were 2237.3 pg/mL and 348.26 m, respectively. At 3-month follow-up, the corresponding values were 2096.2 pg/mL and 372.05 m, respectively. No significant difference was observed in NT-proBNP level or in distance walked in 6 minutes between baseline and 3 months (P=.8). Overall, there was a good correlation (r=0.94; P<.001) between the plasma NT-proBNP level at baseline and at 3 months in patients with stable chronic heart failure due to systolic dysfunction in New York Heart Association class II or III

Productividad laboral relacionada con la salud en una población laboral: resultados del estudio Impala / No disponible

Objetivos: Realizar un estudio comparativo del impacto de distintas enfermedades en la productividad laboral relacionada con la salud. Metodología: Un cuestionario, incluyendo las medidas de productividad laboral del Índice IMPALA y número de días equivalentes a días de trabajo perdidos (LWDE), fue enviado por correo y cumplimentado por empleados de la empresa Pfizer en España. Se evaluaron diferencias en el grado de impacto laboral entre sujetos con/sin distintas características y antecedentes de enfermedades y no-toma/toma actual de tratamiento mediante pruebas estadísticas UMann- Whitney y Kruskal-Wallis. Resultados: En una muestra de 399 sujetos valorables, de 35,8+6,5 años (media desviación típica), 63,7% hombres, se observó menor productividad laboral según el Índice IMPALA en sujetos con antecedentes de alguna enfermedad, y en particular de migraña y trastornos mentales, y algún tratamiento (p<0,05). Según LWDE se observaron mayores pérdidas laborales en sujetos con antecedentes de alguna patología (media desviación típica: 1,9+6,2 días) y/o toma de algún tratamiento (2,7+6,8), versus sujetos sin antecedentes (0,2+1,0) y/o sin tratamiento (1,4+6,2) (p<0,05), y, específicamente, en sujetos con antecedentes de patologías mentales (6,1+12,7), respiratorias (4,0+10,0), digestivas (3,6+10,5) y migraña (2,6+3,3) (p<0,05). Conclusiones: El impacto negativo en la productividad laboral de diferentes enfermedades fue distinto, destacando en patologías mentales, respiratorias, digestivas y migraña

Objectives: To compare the impact of several diseases in work productivity related to health. Methods: A questionnaire, including the measures of work productivity of IMPALA Index and lost workday equivalents (LWDE), was sent by mail and fulfilled by employees of the Pfizer company in Spain. Differences in the degree of work impact between subjects with and without determined characteristics, history of several diseases and current treatment, were assessed by means of U-Mann-Whitney and Kruskal-Wallis statistical tests. Results: In a sample of 399 valuable subjects, 35.8+6.5 years (mean standard deviation), 63.7% of men, worst work productivity Index IMPALA scores were observed among subjects with history of some disease, and particularly among subjects with history of migraine and mental disorders, and some current treatment (p<0.05). In terms of LWDE, greater work losses were found among subjects with history of some disease (average standard deviation: 1.9+6.2 days) and/or taking some treatment (2.7+6.8), versus subjects without history of any disease (0.2+1.0) and/or any treatment (1.4+6.2) (p<0.05), and specifically, in subjects with history of mental (6.1+12.7), respiratory (4.0+10.0) and digestive (3.6+10.5) illnesses and migraine (2.6+3.3) (p<0.05). Conclusions: The negative impact in the work productivity of different illnesses varied, standing out in mental, respiratory, digestive diseases and migraine