EPR spectroscopic evidence of iron-catalysed free radical formation in chronic mountain sickness: Dietary causes and vascular consequences.

Chronic mountain sickness (CMS) is a high-altitude (HA) maladaptation syndrome characterised by elevated systemic oxidative-nitrosative stress (OXNOS) due to a free radical-mediated reduction in vascular nitric oxide (NO) bioavailability. To better define underlying mechanisms and vascular consequences, this study compared healthy male lowlanders (80 m, n = 10) against age/sex-matched highlanders born and bred in La Paz, Bolivia (3600 m) with (CMS+, n = 10) and without (CMS-, n = 10) CMS. Cephalic venous blood was assayed using electron paramagnetic resonance spectroscopy and reductive ozone-based chemiluminescence. Nutritional intake was assessed via dietary recall. Systemic vascular function and structure were assessed via flow-mediated dilatation, aortic pulse wave velocity and carotid intima-media thickness using duplex ultrasound and applanation tonometry. Basal systemic OXNOS was permanently elevated in highlanders (P = <0.001 vs. lowlanders) and further exaggerated in CMS+, reflected by increased hydroxyl radical spin adduct formation (P = <0.001 vs. CMS-) subsequent to liberation of free 'catalytic' iron consistent with a Fenton and/or nucleophilic addition mechanism(s). This was accompanied by elevated global protein carbonylation (P = 0.046 vs. CMS-) and corresponding reduction in plasma nitrite (P = <0.001 vs. lowlanders). Dietary intake of vitamins C and E, carotene, magnesium and retinol were lower in highlanders and especially deficient in CMS + due to reduced consumption of fruit and vegetables (P = <0.001 to 0.028 vs. lowlanders/CMS-). Systemic vascular function and structure were also impaired in highlanders (P = <0.001 to 0.040 vs. lowlanders) with more marked dysfunction observed in CMS+ (P = 0.035 to 0.043 vs. CMS-) in direct proportion to systemic OXNOS (r = -0.692 to 0.595, P = <0.001 to 0.045). Collectively, these findings suggest that lifelong exposure to iron-catalysed systemic OXNOS, compounded by a dietary deficiency of antioxidant micronutrients, likely contributes to the systemic vascular complications and increased morbidity/mortality in CMS+. TRIAL REGISTRY: ClinicalTrials.gov; No: NCT01182792; URL: www.clinicaltrials.gov.

Genetic Variations in the TP53 Pathway in Native Americans Strongly Suggest Adaptation to the High Altitudes of the Andes.

The diversity of the five single nucleotide polymorphisms located in genes of the TP53 pathway (TP53, rs1042522; MDM2, rs2279744; MDM4, rs1563828; USP7, rs1529916; and LIF, rs929271) were studied in a total of 282 individuals belonging to Quechua, Aymara, Chivay, Cabanaconde, Yanke, Taquile, Amantani, Anapia, Uros, Guarani Ñandeva, and Guarani Kaiowá populations, characterized as Native American or as having a high level (> 90%) of Native American ancestry. In addition, published data pertaining to 100 persons from five other Native American populations (Surui, Karitiana, Maya, Pima, and Piapoco) were analyzed. The populations were classified as living in high altitude (≥ 2,500 m) or in lowlands (< 2,500 m). Our analyses revealed that alleles USP7-G, LIF-T, and MDM2-T showed significant evidence that they were selected for in relation to harsh environmental variables related to high altitudes. Our results show for the first time that alleles of classical TP53 network genes have been evolutionary co-opted for the successful human colonization of the Andes.

Determinación de distancia recorrida y variación de parámetros respiratorios y cardiovasculares, antes y después de la prueba de caminata de 6 minutos, en nativos y residentes permanentes de altura clínicamente sanos / Determiation of distance and change in respiratory and cardiovascular parameters before and after the 6 minutes walk test in native and permanent residents of clinically healthy altitude

Objetivo: Determinar la distancia recorrida y la variación de parámetros respiratorios y cardiovasculares antes y después de la prueba de caminata de los 6 minutos (PC6M) en nativos y residentes permanentes de la altura clínicamente sanos. Metodología: El tipo de estudio responde a un diseño de investigación pre y post test. Se trabajó con 64 personas, 33 mujeres y 31 varones, clínicamente sanos entre los 20 y 30 años, previo consentimiento informado y se procedió de acuerdo al protocolo internacionalmente establecido. El examen consistió en medir la distancia que cada participante podía caminar en 6 minutos. Como fue establecido y aplicando métodos no invasivos, se evaluó la presencia de disnea, las variaciones de frecuencia cardíaca, frecuencia respiratoria y saturación de oxígeno (SO2) al inicio, al final y a los 5 minutos de la prueba. Todos los datos obtenidos se anotaron en las planillas correspondientes y posteriormente fueron transcritas a una base informatizada de datos para su análisis estadístico. Resultados: Se encontraron diferencias significativas en la frecuencia cardíaca y la saturación de oxígeno. La FC incremento en ambos grupos después de la caminata y se mantuvo a los 5 minutos de recuperación. La SaO2 post caminata disminuyó en el sexo femenino, mientras que en el sexo masculino se incrementó. Las mujeres refirieron disnea muy débil, por su lado, los varones no presentaron disnea. Se compararon los valores obtenidos en nuestros participantes con valores de referencia existentes (Enright -población norteamericana y Osses - población chilena), obteniéndose resultados significativamente menores. Conclusión: La PC6M es totalmente factible pero las fórmulas utilizadas a nivel del mar, no pueden ser aplicadas en nuestro medio y se requiere el estudio de una muestra poblacional estadísticamente admisible, para obtener fórmulas que permitan valores de referencia para la altura.

Objective: Determine the distance and the variation of respiratory and cardiovascular parameters before and after the walk test 6 minutes (6MWD) in native and permanent residents of the clinically healthy altitude. Methodology: The type of study design responds to a pre and post test research. We worked with 64 people, 33 women and 31 men, clinically healthy between 20 and 30 years, previous informed consent proceeded according to internationally established protocol. The test consisted of measuring the distance each participant could walk in 6 minutes. As established and applying non-invasive methods, the presence of dyspnea was assessed, changes in heart rate, respiratory rate and oxygen saturation (SO2) at the beginning, end and at 5 minutes of the test. All data were recorded immediately in the relevant forms and subsequently transcribed in a computerized data basis for statistical analysis. Results: Significant differences in heart rate and oxygen saturation were found between groups. Heart rate increased in both groups after the hike and kept at 5 minutes of recovery. Post hike a SaO2 decreased in females, while in males, increased. Women reported weak dyspnea and men showed no dyspnea. We compared the values obtained in our participants with the existing reference values (Enright - norteamerican population and Osses - chilean population) and significantly lower results being obtained. Conclusion: The 6MWT is entirely feasible but the formulas used at sea level, can't be applied in our study and a statistically acceptable sample population is required to obtain formulas to reference values for altitude.

RV contractility and exercise-induced pulmonary hypertension in chronic mountain sickness: a stress echocardiographic and tissue Doppler imaging study.

OBJECTIVES: The aim of this study was to evaluate right ventricular (RV) and left ventricular function and pulmonary circulation in chronic mountain sickness (CMS) patients with rest and stress echocardiography compared with healthy high-altitude (HA) dwellers. BACKGROUND: CMS or Monge's disease is defined by excessive erythrocytosis (hemoglobin >21 g/dl in males, 19 g/dl in females) and severe hypoxemia. In some cases, a moderate or severe increase in pulmonary pressure is present, suggesting a similar pathogenesis of pulmonary hypertension. METHODS: In La Paz (Bolivia, 3,600 m sea level), 46 CMS patients and 40 HA dwellers of similar age were evaluated at rest and during semisupine bicycle exercise. Pulmonary artery pressure (PAP), pulmonary vascular resistance, and cardiac function were estimated by Doppler echocardiography. RESULTS: Compared with HA dwellers, CMS patients showed RV dilation at rest (RV mid diameter: 36 ± 5 mm vs. 32 ± 4 mm, CMS vs. HA, p = 0.001) and reduced RV fractional area change both at rest (35 ± 9% vs. 43 ± 9%, p = 0.002) and during exercise (36 ± 9% vs. 43 ± 8%, CMS vs. HA, p = 0.005). The RV systolic longitudinal function (RV-S') decreased in CMS patients, whereas it increased in the control patients (p < 0.0001) at peak stress. The RV end-systolic pressure-area relationship, a load independent surrogate of RV contractility, was similar in CMS patients and HA dwellers with a significant increase in systolic PAP and pulmonary vascular resistance in CMS patients (systolic PAP: 50 ± 12 mm Hg vs. 38 ± 8 mm Hg, CMS vs. HA, p < 0.0001; pulmonary vascular resistance: 2.9 ± 1 mm Hg/min/l vs. 2.2 ± 1 mm Hg/min/l, p = 0.03). Both groups showed comparable systolic and diastolic left ventricular function both at rest and during stress. CONCLUSIONS: Comparable RV contractile reserve in CMS and HA suggests that the lower resting values of RV function in CMS may represent a physiological adaptation to chronic hypoxic conditions rather than impaired RV function. (Chronic Mountain Sickness, Systemic Vascular Function [CMS]; NCT01182792).

Fútbol en la altura en Bolivia / football at altitude in Bolivia

El presente trabajo se realizó en razón del tercer veto emitido por la FIFA, de jugar partidos eliminatorios para Copas Mundiales de Fútbol en alturas por encima de los 2500 m. Los objetivos del estudio se basaron en las preocupaciones de la FIFA por la preservación de la salud de los jugadores de fútbol y por la garantía de oportunidades iguales respecto al rendimiento físico cuando se juega a gran altura. En consecuencia se hizo un estudio comparativo entre un equipo de fútbol aclimatado a la altura de la Paz (3600 m) (equipo HAT; 10 jugadores) y otro equipo que vivía y entrenaba en una altura cercana a nivel del mar (60 m) (equipo LAT; 10 jugadores). Ambos equipos fueron estudiados en los laboratorios del Instituto Boliviano de Biología de Altura (IBBA) y en altura cercana al nivel del mar (Hotel América; Santa Cruz, 420m). La salud fue evaluada aplicando el cuestionario de Lake Louise para establecer la presencia de Enfermedad Aguda de Altura (EAA), así como mediante pruebas funcionales respiratorias y estimación de la presión arterial pulmonar sistólica(PAPs) mediante Eco Doppler. El rendimiento físico fue evaluado mediante prueba de esfuerzo máximo en rampa conmedición del consumo máximo de oxígeno (VO2max) y parámetros relacionados. Los resultados mostraron valores delVO2max algo mayores en la altura en HAT que en LAT. PAPs fue significativamente mayor a gran altura en ambos equipos. Proponemos un tiempo de aclimatación de 72 horas previa a los partidos de fútbol en La Paz en base a las estadísticas elaboradas que toman en cuenta el resultado de los partidos en relación con el tiempo de estadía en La Paz.

The present study was conducted as response to the third veto by FIFA against playing eliminatory football games forFIFA World Cups at altitudes above 2500 m. The aim of the study took into account FIFA ́s preoccupations with regard tothe health of the football players and concerning igual opportunities for physical performance when playing at high altitude. Consequently, a comparative study was conducted of two football teams, one acclimatized to the altitude of La Paz (3600m) (HAT, 10 players), and the second one living and training at an altitude close to sealevel (60 m) (LAT, 10 players). Bothteams were examined in the laboratories of he Instituto Boliviano de Biología de Altura (IBBA) and at an altitude close tosealevel (Hotel América, Santa Cruz, 420 m). Health was assessed applying the Lake Louise scoring system for AcuteAltitude Sickness as well as by measuring pulmonary function and by assessing systolic pulmonary artery pressure (PAPs)using theEcho Doppler technique. The physical capacity was measured by a progressive maximal exercise test on atreadmillwith determination of the maximal oxygen uptake (VO2max) andrelated parmeters. The results I howed a VO2max somwht higher at high altitude in HAT than in LAT. PAPs was significantly higher at high than at low altitude in bothteams. Wepropose an acclimatization time of 72 hours previous to football games in La Paz based on statistics that tookinto account the results of the games in relation to the time of the stay in La Paz.

El ambiente de la altura / The environment of the height

Este documento trata del ambiente en la altura y sus diferentes factores que intervienen en el mismo, la falta de oxígeno en la altura se conoce como mal de altura, mal de puna o soroche. Junto a la disminución de la presión de oxígeno en el aire ambiente, se deben también tomar en cuenta otros elelmentos físicos que caracterizan a la altura. Entre ellos la menor densidad del aire, la temperatura ambiental, al respecto se conoce que, especialmente en el invierno, las variaciones de temperatura ambiente en el curso de un mismo día son muy significativas. por otra parte en la altura existe una mayor sequedad del aire, con un aumento moderado del grado de humendad en las estaciones de lluvia. Finalmente en la altura existe una mayor cantidad de radiaciones solares no ionizantes, especialmente de las radiaciones ultravioleta.