The effect of anesthetic preconditioning with sevoflurane on intracellular signal-transduction pathways and apoptosis, in a lung autotransplant experimental model / O efeito do pré-condicionamento anestésico com sevoflurano sobre as vias de transdução de sinal intracelular e a apoptose, em modelo experimental de autotransplante pulmonar

Abstract Background: Anesthetic pre-conditioning attenuates inflammatory response during ischemia-reperfusion lung injury. The molecular mechanisms to explain it are not fully understood. The aim of our investigation was to analyze the molecular mechanism that explain the anti-inflammatory effects of anesthetic pre-conditioning with sevoflurane focusing on its effects on MAPKs (mitogen-activated protein kinases), NF-κB (nuclear factor kappa beta) pathways, and apoptosis in an experimental lung autotransplant model. Methods: Twenty large white pigs undergoing pneumonectomy plus lung autotransplant were divided into two 10-member groups on the basis of the anesthetic received (propofol or sevoflurane). Anesthetic pre-conditioning group received sevoflurane 3% after anesthesia induction and it stopped when one-lung ventilation get started. Control group did not receive sevoflurane in any moment during the whole study period. Intracellular signal-transduction pathways (MAPK family), transcription factor (NF-κB), and apoptosis (caspases 3 and 9) were analyzed during experiment. Results: Pigs that received anesthetic pre-conditioning with sevoflurane have shown significant lower values of MAPK-p38, MAPK-P-p38, JNK (c-Jun N-terminal kinases), NF-κB p50 intranuclear, and caspases (p < 0.05) than pigs anesthetized with intravenous propofol. Conclusions: Lung protection of anesthetic pre-conditioning with sevoflurane during experimental lung autotransplant is, at least, partially associated with MAPKs and NF κB pathways attenuation, and antiapoptotic effects.

Resumo Justificativa: O pré-condicionamento anestésico atenua a resposta inflamatória durante a lesão de isquemia-reperfusão do pulmão. Os mecanismos moleculares para explicá-lo não são totalmente compreendidos. O objetivo de nossa investigação foi analisar o mecanismo molecular que explica os efeitos anti-inflamatórios do pré-condicionamento anestésico com sevoflurano, enfocar seus efeitos sobre as proteínas quinases ativadas por mitógenos (MAPKs), o fator nuclear kappa beta (NF-κB) e a apoptose em modelo experimental de autotransplante pulmonar. Métodos: Vinte porcos Large White submetidos à pneumonectomia e autoimplante de pulmão foram divididos em dois grupos de 10 membros com base no anestésico recebido (propofol ou sevoflurano). O grupo de pré-condicionamento anestésico recebeu sevoflurano a 3% após a indução da anestesia, que foi descontinuado quando a ventilação monopulmonar foi iniciada. O grupo controle não recebeu sevoflurano em qualquer momento durante todo o período do estudo. As vias de transdução de sinal intracelular (família MAPK), o fator de transcrição (NF-κB) e a apoptose (caspases 3 e 9) foram analisados durante o experimento. Resultados: Os suínos que receberam pré-condicionamento anestésico com sevoflurano apresentaram valores mais baixos de MAPK-p38, MAPK-P-p38, c-Jun N-terminal quinases (JNK), NF-κB p50 intranuclear e caspases (p < 0,05) do que os suínos anestesiados com propofol intravenoso. Conclusões: A proteção pulmonar do pré-condicionamento anestésico com sevoflurano durante o autotransplante pulmonar experimental está, pelo menos, parcialmente associada à atenuação das vias de MAPKs e NF κB e aos efeitos antiapoptóticos.

Mediciones de adiposidad intraabdominal por ultrasonido y factores asociados con riesgo cardiovascular en niños obesos / Ultrasound measurements of intra-abdominal adiposity and factors associated with cardiovascular risk in obese children

Background: Cardiovascular risk factors are commonly present in obese children. Aim: To evaluate the association among radiological measurements of intra-abdominal adipose tissue, and cardiovascular risk factors, in prepuberal obese children. Patients and Methods: We evaluated 30 obese (body mass index > p95) children aged 6 to 12 years (15 males). Anthropometry and blood pressure were measured. Subcutaneous and intra-abdominal fat thickness and fat area were measured by ultrasound (US) and computed tomography. Serum insulin, glucose and lipid profile were measured in a fasting blood sample. Homeostasis model assessment (HOMA) was calculated as an index of insulin resistance. Results: There was a significant correlation between US intra-abdominal fat thickness and HOMA (r = 0.47, p < 0.01), serum triglycerides (r = 0.46, p < 0.05) and with positive criteria for metabolic syndrome (r = 0.66, p < 0.01). A receiver operating curve (ROC) analysis showed that, above a cut-off of 45 mm for intra-abdominal fat thickness, US was able to identify insulin resistance with a sensibility and specificity of 79 and 69 percent respectively and metabolic syndrome with sensibility and specificity of 100 and 67 percent respectively. US and computed tomography measurements for intra-abdominal fat thickness were significantly correlated (r= 0.62, p < 0.01). Conclusions: US measurements of intra-abdominal fat thickness identify obesity-associated damage in childhood. Age-specific measurements of intra-abdominal adipose tissue may improve the detection power of this approach.

Lactancia materna en la prevención de la obesidad / Breastfeeding on obesity prevention

El ambiente intrauterino y los primeros años de vida, son fundamentales para la programación de una serie de situaciones en nuestro organismo. Son muchas las teorías que indican que la lactancia materna (LM) puede tener beneficio en la prevención de la obesidad. Esto hace referencia a que la LM posee una serie de componentes hormonales, que favorecen la maduración o la forma de interpretación de ciertas áreas del cerebro, que tienen que ver con los mecanismos de saciedad y hambre. Existen estudios bastante clásicos que demuestran cómo ésta se regula en el niño alimentado con LM, y la impor tancia que el lo representa, en consideración del efecto de la insulina en la formación de tejido adiposo. La variedad metodológica de los estudios sobre LM hace compleja una buena homologación de los resultados, e incluso hasta indicar que la LM es perjudicial. En conclusión, la LM parece disminuir el riesgo de obesidad hacia la vida adulta; sin que los mecanismos biológicos de estas asociaciones estén totalmente definidos; y además del efecto directo de los nutrientes, existen otros mecanismos que podrían explicar esta asociación.

The intrauterine environment and early life are fundamental to programming a series of situations in our body. There are many theories that suggest that breastfeeding (BF) can have benefits in preventing obesity. This refers to the BF has a number of hormonal components that promote maturation or manner of interpretation of certain brain areas, which have to do with the mechanisms of satiety and hunger. There are enough classic studies showing how it is regulated in the BF, and the importance it represents, in consideration of the effect of insulin in adipose tissue formation. The variety methodological studies complicates BF approval good results, and even indicate that the BF is harmful. In conclusion, the BF seems to decrease the risk of obesity into adulthood, but the biological mechanisms of these associations to be fully defined, and in addition to the direct effect of nutrients, there are other mechanisms that could explain this association.

Interacción entre los polimorfismos del receptor ß1 y ß2 adrenérgico como predictor de riesgo de insuficiencia cardiaca crónica / Interactions between ß1 and ß2 adrenergic receptor polymorphisms as risk factors for chronic heart failure

Background: ß adrenergic receptors (AR) are highly polymorphic and important regulators of cardiovascular homeostasis. Among these, ß1 and ß2 AR regulate cardiac contractility and frequency and are important pharmacological targets. Aim: To evaluate genotype and gene-gene interaction between ß1-AR Arg389Gly and ß2-AR ArglSGly GlnZ7Gly and Thrl 64Ile polymorphisms, as risk factors for HF. Material and methods: Eighty chronic HF patients and eighty-eight controls matched by age and sex were genotyped for ß1 -AR Arg389Gly ß2-AR ArgWGly, GlnZ7Glu and Thr164Ile polymorphisms. Results: The presence of ß2-AR Glu afiele was a risk predictor for HF (odds ratio (OR) =2.81; 95 percent confidence intervals (CI) =1.49-5.31). Interactions that increased the risk for HF were found in patients carrying at least one of the ß2-AR Glu and ß2-AR Gly allele (OR =3.81; 95 percent CI =1.50-0.70) and ß2-AR Glu and ß1 -AR Gly allele combination (OR =5.51; 95 percent CI =2.19-13.86). Furthermore, the frequency of ß2-AR Glu allele was higher among patients with a history ofacute myocardial infarction (with infarction: 0.534, without: 0.313, p =0.01). Conclusions: ß2-AR Glu allele could be a risk predictor for HF. This risk could be enhanced by the additional presence of ß2-AR GlyW or ß1-AR Arg389 alleles. The frequency of ß2-AR Gln27 Glu allele was higher among patients with a history of myocardial infarction.

Adiposidad visceral y su asociación con lípidos séricos e insulinemis en adolescentes obesas / Visceral adiposity and its association with serum lipids in female obese teenagers

Background: Increased visceral or abdominal adipose tissue in children and adults is strongly associated with metabolic and a variety of chronic diseases. Aim: To study the association between visceral or external body measurements of adiposity with blood lipids, glucose and insulin levels, in obese female adolescents. Material and methods: In a cross-sectional study, 47 obese female adolescents (body mass index (BMI) >95th percentile) aged 10 to 15 years, were analyzed. Weight, height, BMI, Tanner pubertal stages, skinfold thickness, waist circumference, waist-to-hip ratio, fasting and 120 min post prandial blood glucose, serum insulin, and lipid profile were studied. Visceral fat was assessed by computed tomography at the L4-L5 level, measuring the fat area or the length of a straight drawn line between the spine and the internal border of the rectus abdominus muscle. Results: No association between lipid profile and BMI or external body measurements (skinfold thickness, waist circumference, waist-to-hip ratio) was observed. Total serum cholesterol >170 mg/dL was positively associated with the straight line over 63 mm (a cut-off obtained by ROC analysis (RR 2.64; 1.15-6.08). This association was statistically significant in girls in Tanner I + II (n =21; Fisher, p <0.023), but not with Tanner III + IV (n =26) stages. Increased cholesterol (>170 mg/dL) was also positively associated with a serum insulin >17 uU/mL in the Tanner I + II group (Fisher p<0.05), but not with the homeostasis model assessment of insulin resistance (HOMA). Conclusions: No external body measurement of adiposity was associated to increased serum cholesterol in these obese female adolescents. Increased total cholesterol (>170 mg/dL) was associated with visceral fat (evaluated through the straight line spina-rectus abdominus muscle), and also with a serum insulin >17 uU/ml in those teenagers with Tanner I or II pubertal stages.

La actividad de metaloproteinasa-9 se asocia a estrés oxidativo en el síndrome coronario agudo / Metalloproteinase-9 activity is associated with oxidative stress in acute coronary syndrome

Antecedentes: La metaloproteinasas (MMPs) son enzimas proteolíticas que participan en la inestabilidad de la placa aterosclerótica. En cultivos celulares, la actividad de metaloproteinasas-2 y 9 (MMP-2 y MMP-9) aumenta en presencia de radicales libres del oxígeno. En una experiencia preliminar en pacientes con síndrome coronario agudo (SCA) hemos encontrado una posible asociación entre ambos fenómenos. Objetivo: Evaluar la relación entre actividad de enzimas de degradación de la matriz extracelular y estrés oxidativo (EO) en el SCA. Métodos: Estudiamos en forma prospectiva a 40 pacientes con SCA sin supradesnivel del segmento ST, puntaje TIMI ≥ 3 y alteraciones al electrocardiograma o elevación de Troponina I, que no presentaran un proceso inflamatorio. Se midió actividad de MMP-2 y MMP-9 (por zimografía en geles), malondialdehido (MDA) (mediante sustancias reactivas al ácido tiobarbitúrico) y PCR ultrasensible (PCRus) (ELISA), al ingreso y al quinto día. Se utilizó test t de Student para muestras pareadas y correlación lineal de Pearson. Resultados: De los 40 pacientes, 31 fueron hombres, la edad promedio fue 61+/-12 (38-85) años, todos con elevación de Troponina I. El puntaje TIMI fue de 4 (3-7). El 85 por ciento de los pacientes presentaron elevación de PCRus al ingreso (15,0+/-28,7 mg/L) y ésta aumentó al día 5 (35,3+/-38 mg/L, p=0,01); los niveles plasmáticos de MDA se encontraron elevados al ingreso (1,54+/-0,75 µM/L) y descendieron al quinto día (1,04+/-0,32 µM/L, p<0,0001). Al quinto día, la actividad de MMP-9 cayó a un 74+/-27 por ciento del valor basal (p<0,0001). No se observó cambio en la actividad de MMP-2. Se demostró una correlación positiva entre las fracciones de cambio de MDA y MMP-9 (r=0,43, p<0,0001). Conclusiones: En pacientes con SCA se observa un aumento precoz en el grado de inflamación, actividad de MMP-9 y de EO...

Background: Metalloproteinases are proteolytic enzymes that participate in atherosclerotic plaque instability. In cellular cultures there is increased activity of metalloproteinases-2 and 9 (MMP-2 and MMP-9) in the presence of free oxygen radicals. In a preliminary experience in patients with acute coronary syndrome (ACS) we have found a possible association between both phenomena. Objective: To evaluate the relation between activity of matrix degradation proteins and oxidative stress (OS) in acute coronary syndrome. Methods: Fourty patients with non-ST segment elevation acute coronary syndrome were prospectively studied. All had a TIMI risk score ≥ 3, ischemic changes on electrocardiogram or Troponin I elevation, without a concomitant inflammatory condition. We determined MMP-2 and MMP-9 activities (gel zymography), malondialdehyde (MDA) (thiobarbituric acid reactive species) and high sensitive C reactive protein (hsCRP) plasma levels at admission and 5 days later. Paired samples Student’ t test and Pearson’s lineal correlation were used for statistical analysis. Results: Of the 40 patients, 31 were male, mean age 61+/-12 years old (range 38-85), all of them with Troponin I elevation. The TIMI risk score was 4 (3-7). 85 percent presented hsCRP elevation (15.0+/-28,7 mg/L at admission and 35.3+/-38 mg/L at day 5). MDA plasma levels were increased at admission (1,54+/-0,75 µM/L) and diminished at day 5 (1,04+/-0,32 µM/L, p<0,0001). Compared to basal values, MMP-9 activity decreased to 74+/- 27 percent at day 5, (p<0,001). No significant change was observed in MMP-2 activity between both measurements. A significant positive correlation was found between change fractions of MDA levels and MMP-9 activity (r=0,43, p<0,0001). Conclusions: In patients with ACS we observed an early increase in inflammation markers, MMP-9 activity and OS. The correlation demonstrated between MMP-9 activity and OS suggests a common role of both phenomena in the pathophysiology...

Inflamación y estrés oxidativo en el síndrome coronario agudo: ¿dos fenómenos relacionados? / Inflammation and oxidative stress in acute coronary syndromes: two related phenomena?

Antecedentes: Hemos descrito un incremento en el estrés oxidativo (EO) en pacientes con síndrome coronario agudo (SCA), relacionado con el fenómeno de isquemia-reperfusión. La inflamación es otra potencial fuente de especies reactivas de oxígeno. Objetivo: Evaluar la relación entre inflamación, determinada mediante proteína C reactiva ultrasensible (PCRus) y enzimas de la matriz extracelular, y el nivel de estrés oxidativo en el SCA. Métodos: se estudió en forma prospectiva a pacientes con SCA sin supradesnivel del segmento ST de alto riesgo. Se determinó niveles de PCRus al ingreso, actividad de metaloproteinasa-9 (MMP-9), niveles séricos de malondialdehido (MDA), y de péptido natriurético cerebral (proBNP), al primer y quinto día, estableciendo la correlación entre estas variables en el tiempo. Resultados: Se incluyó a 10 pacientes: 7 hombres, edad 63±10 años (50-80 años), 8 con elevación de enzimas miocárdicas. El puntaje TIMI fue 5 (3-6). Todos presentaron elevación de PCRus antes de las 24 horas (26,5±51 mg/L). Los niveles de MMP-9 estaban normales y los niveles plasmáticos de MDA estaban elevados al ingreso (1,25±0,55μM/L). Tanto MMP-9 como MDA disminuyeron en forma significativa al quinto día (p=0,02 y p=0,009 respectivamente). Hubo una estrecha correlación entre la disminución de MDA y MMP-9 (r=0,95, p<0,05). No hubo correlación entre la modificación de los valores de MDA y proBNP (r=0,36) ni entre MMP-9 y proBNP (r=0,33). Conclusión: En el SCA habría inicialmente aumento de la inflamación y EO. Las reducciones de ambos fenómenos parecen estar relacionadas. Estos hechos apoyan la asociación entre inflamación y EO en el SCA.