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Find video protocols related to scientific articles indexed in Pubmed.
Maternal PRKAA1 and EDNRA genotypes are associated with birth weight, and PRKAA1 with uterine artery diameter and metabolic homeostasis at high altitude.
Physiol. Genomics
PUBLISHED: 07-15-2014
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Low birth weight and intrauterine growth restriction (IUGR) increase the risk of mortality and morbidity during the perinatal period as well as in adulthood. Environmental and genetic factors contribute to IUGR, but the influence of maternal genetic variation on birth weight is largely unknown. We implemented a gene-by-environment study wherein we utilized the growth restrictive effects of high altitude. Multigenerational high-altitude residents (Andeans) are protected from altitude-associated IUGR compared with recent migrants (Europeans). Using a combined cohort of low- and high-altitude European and Andean women, we tested 63 single nucleotide polymorphisms (SNPs) from 16 natural selection-nominated candidate gene regions for associations with infant birth weight. We identified significant SNP associations with birth weight near coding regions for two genes involved in oxygen sensing and vascular control, PRKAA1 and EDNRA, respectively. Next, we identified a significant association for the PRKAA1 SNP with an intermediate phenotype, uterine artery diameter, which has been shown to be related to Andean protection from altitude-associated reductions in fetal growth. To explore potential functional relationships for the effect of maternal SNP genotype on birth weight, we evaluated the relationship between maternal PRKAA1 SNP genotype and gene expression patterns in general and, in particular, of key pathways involved in metabolic homeostasis that have been proposed to play a role in the pathophysiology of IUGR. Our observations suggest that maternal genetic variation within genes that regulate oxygen sensing, metabolic homeostasis, and vascular control influence fetal growth and birth weight outcomes and hence Andean adaptation to high altitude.
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Higher estrogen levels during pregnancy in Andean than European residents of high altitude suggest differences in aromatase activity.
J. Clin. Endocrinol. Metab.
PUBLISHED: 03-31-2014
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Uteroplacental hypoxia has been reported to lower estrogen levels in preeclampsia as the result of reduced aromatase activity.
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An Argonaute 2 switch regulates circulating miR-210 to coordinate hypoxic adaptation across cells.
Biochim. Biophys. Acta
PUBLISHED: 02-07-2014
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Complex organisms may coordinate molecular responses to hypoxia by specialized avenues of communication across multiple tissues, but these mechanisms are poorly understood. Plasma-based, extracellular microRNAs have been described, yet their regulation and biological functions in hypoxia remain enigmatic. We found a unique pattern of release of the hypoxia-inducible microRNA-210 (miR-210) from hypoxic and reoxygenated cells. This microRNA is also elevated in human plasma in physiologic and pathologic conditions of altered oxygen demand and delivery. Released miR-210 can be delivered to recipient cells, and the suppression of its direct target ISCU and mitochondrial metabolism is primarily evident in hypoxia. To regulate these hypoxia-specific actions, prolyl-hydroxylation of Argonaute 2 acts as a molecular switch that reciprocally modulates miR-210 release and intracellular activity in source cells as well as regulates intracellular activity in recipient cells after miR-210 delivery. Therefore, Argonaute 2-dependent control of released miR-210 represents a unique communication system that integrates the hypoxic response across anatomically distinct cells, preventing unnecessary activity of delivered miR-210 in normoxia while still preparing recipient tissues for incipient hypoxic stress and accelerating adaptation.
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AltitudeOmics: Rapid Hemoglobin Mass Alterations with Early Acclimatization to and De-Acclimatization from 5260 m in Healthy Humans.
PLoS ONE
PUBLISHED: 01-01-2014
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It is classically thought that increases in hemoglobin mass (Hbmass) take several weeks to develop upon ascent to high altitude and are lost gradually following descent. However, the early time course of these erythropoietic adaptations has not been thoroughly investigated and data are lacking at elevations greater than 5000 m, where the hypoxic stimulus is dramatically increased. As part of the AltitudeOmics project, we examined Hbmass in healthy men and women at sea level (SL) and 5260 m following 1, 7, and 16 days of high altitude exposure (ALT1/ALT7/ALT16). Subjects were also studied upon return to 5260 m following descent to 1525 m for either 7 or 21 days. Compared to SL, absolute Hbmass was not different at ALT1 but increased by 3.7±5.8% (mean ± SD; n?=?20; p<0.01) at ALT7 and 7.6±6.6% (n?=?21; p<0.001) at ALT16. Following descent to 1525 m, Hbmass was reduced compared to ALT16 (-6.0±3.7%; n?=?20; p?=?0.001) and not different compared to SL, with no difference in the loss in Hbmass between groups that descended for 7 (-6.3±3.0%; n?=?13) versus 21 days (-5.7±5.0; n?=?7). The loss in Hbmass following 7 days at 1525 m was correlated with an increase in serum ferritin (r?=?-0.64; n?=?13; p<0.05), suggesting increased red blood cell destruction. Our novel findings demonstrate that Hbmass increases within 7 days of ascent to 5260 m but that the altitude-induced Hbmass adaptation is lost within 7 days of descent to 1525 m. The rapid time course of these adaptations contrasts with the classical dogma, suggesting the need to further examine mechanisms responsible for Hbmass adaptations in response to severe hypoxia.
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AltitudeOmics: the integrative physiology of human acclimatization to hypobaric hypoxia and its retention upon reascent.
PLoS ONE
PUBLISHED: 01-01-2014
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An understanding of human responses to hypoxia is important for the health of millions of people worldwide who visit, live, or work in the hypoxic environment encountered at high altitudes. In spite of dozens of studies over the last 100 years, the basic mechanisms controlling acclimatization to hypoxia remain largely unknown. The AltitudeOmics project aimed to bridge this gap. Our goals were 1) to describe a phenotype for successful acclimatization and assess its retention and 2) use these findings as a foundation for companion mechanistic studies. Our approach was to characterize acclimatization by measuring changes in arterial oxygenation and hemoglobin concentration [Hb], acute mountain sickness (AMS), cognitive function, and exercise performance in 21 subjects as they acclimatized to 5260 m over 16 days. We then focused on the retention of acclimatization by having subjects reascend to 5260 m after either 7 (n?=?14) or 21 (n?=?7) days at 1525 m. At 16 days at 5260 m we observed: 1) increases in arterial oxygenation and [Hb] (compared to acute hypoxia: PaO2 rose 9±4 mmHg to 45±4 while PaCO2 dropped a further 6±3 mmHg to 21±3, and [Hb] rose 1.8±0.7 g/dL to 16±2 g/dL; 2) no AMS; 3) improved cognitive function; and 4) improved exercise performance by 8±8% (all changes p<0.01). Upon reascent, we observed retention of arterial oxygenation but not [Hb], protection from AMS, retention of exercise performance, less retention of cognitive function; and noted that some of these effects lasted for 21 days. Taken together, these findings reveal new information about retention of acclimatization, and can be used as a physiological foundation to explore the molecular mechanisms of acclimatization and its retention.
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AltitudeOmics: Cerebral autoregulation during ascent, acclimatization, and re-exposure to high altitude and its relation with acute mountain sickness.
J. Appl. Physiol.
PUBLISHED: 12-26-2013
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Cerebral autoregulation (CA) acts to maintain brain blood flow despite fluctuations in perfusion pressure. Acute hypoxia is thought to impair CA, but it is unclear if CA is affected by acclimatization or related to the development of acute mountain sickness (AMS). We assessed changes in CA using transfer function analysis of spontaneous fluctuations in radial artery blood pressure (indwelling catheter) and resulting changes in middle cerebral artery blood flow velocity (transcranial Doppler) in 21 active individuals at sea level (SL), upon arrival at 5,260 m (ALT1), after 16 days of acclimatization (ALT16), and upon re-exposure to 5,260m after 7 days at 1,525 m (POST7). The Lake Louise Questionnaire (LLQ) was used to evaluate AMS symptom severity. CA was impaired upon arrival at ALT1 (P<0.001) and did not change with acclimatization at ALT16 or upon re-exposure at POST7. CA was not associated with AMS symptoms (all R < 0.50, P > 0.05). These findings suggest that alterations in CA are an intrinsic consequence of hypoxia and are not directly related to the occurrence or severity of AMS.
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Inhibition of peroxisome proliferator-activated receptor ?: a potential link between chronic maternal hypoxia and impaired fetal growth.
FASEB J.
PUBLISHED: 12-04-2013
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Chronic exposure to hypoxia raises the risk of pregnancy disorders characterized by maternal vascular dysfunction and diminished fetal growth. In an effort to identify novel pathways for these hypoxia-related effects, we assessed gene expression profiles of peripheral blood mononuclear cells (PBMCs) obtained from 43 female, high-altitude or sea-level residents in the nonpregnant state or during pregnancy (20 or 36 wk). Hypoxia-related fetal growth restriction becomes apparent between 25 and 29 wk of gestation and continues until delivery. Our sampling strategy was designed to capture changes occurring before (20 wk) and during (36 wk) the time frame of slowed fetal growth. PBMC gene expression profiles were generated using human gene expression microarrays and compared between altitudes. Biological pathways were identified using pathway analysis. Modest transcriptional differences were observed between altitudes in the nonpregnant state. Of the genes that were differentially expressed at high altitude vs. sea level during pregnancy (20 wk: 59 probes mapped to 41 genes; 36 wk: 985 probes mapped to 700 genes), several are of pathological relevance for fetal growth restriction. In particular, transcriptional changes were consistent with the negative regulation of peroxisome proliferator-activated receptor ? (PPAR?) at high altitude; such effects were accompanied by reduced birth weight (P <0.05) and head circumference (P <0.01) at high altitude vs. sea level. Our findings indicate that chronic exposure to hypoxia during pregnancy alters maternal gene expression patterns in general and, in particular, expression of key genes involved in metabolic homeostasis that have been proposed to play a role in the pathophysiology of fetal growth restriction.-Julian, C. G., Yang, I. V., Browne, V. A., Vargas, E., Rodriguez, C., Pedersen, B. S., Moore, L. G., Schwartz, D. A. Inhibition of peroxisome proliferator-activated receptor ?: a potential link between chronic maternal hypoxia and impaired fetal growth.
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Exploratory proteomic analysis of hypobaric hypoxia and acute mountain sickness and in humans.
J. Appl. Physiol.
PUBLISHED: 11-21-2013
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Our objective in this exploratory study was to identify novel biomarkers of importance for acute mountain sickness (AMS) using discovery-based proteomic methods. Peripheral blood samples were collected and AMS symptoms assessed in 20 healthy volunteers prior to (-15 hours [BL] and 0 hours; 1609 m; PB= 625mm Hg) and after a 9-hour exposure to hypobaric hypoxia (9 hours; 4875 m; PB= 425mm Hg). AMS status was assessed using the Lake Louise Questionnaire. Plasma samples were pooled according to AMS status at each time point. Protein composition of the samples was determined by a GeLC-MS/MS approach using two analytical platforms (LTQ-XL Linear Ion Trap Mass Spectrometer and a LTQ-FT Ultra Hybrid Mass Spectrometer) for technical replication. Spectral counting was used to make semi-quantitative comparisons of protein abundance between AMS-susceptible (AMS) and AMS-resistant (AMS•R) subjects with exposure to hypobaric hypoxia. After 9 hours of hypoxia the abundance of proteins with antioxidant properties (i.e., peroxiredoxin 6, glutathione peroxidase and sulfhydryl oxidase 1) rose in AMS but not AMS•R. Our exploratory analyses suggest that exposure to hypobaric hypoxia enhances enzymatic antioxidant systems in AMS vs. AMS•R which, we propose, may be an overcompensation for hypoxia-induced oxidant production. Based on our findings we 1) speculate that quenching oxidant activity may have adverse downstream effects that are of pathophysiological importance for AMS such as interrupting oxidant-sensitive cell signaling and gene transcription, and 2) question the existing assumption that increased oxidant production in AMS is pathological.
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AltitudeOmics: Effect of ascent and acclimatization to 5260 m on regional cerebral oxygen delivery.
Exp. Physiol.
PUBLISHED: 11-15-2013
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Cerebral hypoxemia associated with rapid ascent to high altitude can be life threatening; yet, with proper acclimatization, cerebral function can be maintained well enough for humans to thrive.
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Graduated effects of high-altitude hypoxia and highland ancestry on birth size.
Pediatr. Res.
PUBLISHED: 04-03-2013
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Background:We present a cohort of ca. 25,000 birth records from Bolivia of men and women who are currently adults. We used this cohort to test the hypothesis that high altitude reduces birth weight and that highland ancestry confers graduated protection against this effect.Methods:Birth records were obtained from obstetric clinics and hospitals in La Paz (3,600 m) and Santa Cruz (420 m). Only singleton, healthy term (>37?wk) pregnancies of nonsmoking mothers were included. Andean, Mestizo, or European ancestry was determined by validated analysis of parental surnames.Results:High altitude reduced body weight (3,396?±?3 vs. 3,090?±?6?g) and length (50.8?±?0 vs. 48.7?±?0?cm) at birth (P < 0.001). Highland ancestry partially protected against the effects of high altitude on birth weight (Andean = 3,148?±?15?g; Mestizo = 3,081?±?6?g; and European = 2,957?±?32?g; trend P < 0.001) but not on birth length. The effects of high-altitude pregnancy on birth size were similar for male and female babies.Conclusion:High altitude reduces birth weight and highland native ancestry confers graduated protection. Given previous studies linking reduced birth weight with increased risk of cardiovascular disease, further study is warranted to test whether adults from high-altitude pregnancy are at increased risk of developing cardiovascular disease.
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Little effect of gestation at 3,100 m on fetal fat accretion or the fetal circulation.
Am. J. Hum. Biol.
PUBLISHED: 02-20-2013
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While chronic hypoxia has been recognized as the principal causative factor for decreasing birth weight at high altitude, unknown is whether fetal fat accretion and vascular function are affected.
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Andean and Tibetan patterns of adaptation to high altitude.
Am. J. Hum. Biol.
PUBLISHED: 01-24-2013
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High-altitude hypoxia, or decreased oxygen levels caused by low barometric pressure, challenges the ability of humans to live and reproduce. Despite these challenges, human populations have lived on the Andean Altiplano and the Tibetan Plateau for millennia and exhibit unique circulatory, respiratory, and hematological adaptations to life at high altitude. We and others have identified natural selection candidate genes and gene regions for these adaptations using dense genome scan data. One gene previously known to be important in cellular oxygen sensing, egl nine homolog 1 (EGLN1), shows evidence of positive selection in both Tibetans and Andeans. Interestingly, the pattern of variation for this gene differs between the two populations. Continued research among Tibetan populations has identified statistical associations between hemoglobin concentration and single nucleotide polymorphism (SNP) genotype at EGLN1 and a second gene, endothelial PAS domain protein 1 (EPAS1).
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Sleep-disordered breathing and oxidative stress in preclinical chronic mountain sickness (excessive erythrocytosis).
Respir Physiol Neurobiol
PUBLISHED: 01-21-2013
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Chronic mountain sickness (CMS) is considered to be a loss of ventilatory acclimatization to high altitude (>2500m) resulting in marked arterial hypoxemia and polycythemia. This case-control study explores the possibility that sleep-disordered breathing (SDB) and associated oxidative stress contribute to the etiology of CMS. Nocturnal respiratory and [Formula: see text] patterns were measured using standard polysomnography techniques and compared between male high-altitude residents (aged 18-25) with preclinical CMS (excessive erythrocytosis (EE), n=20) and controls (n=19). Measures of oxidative stress and antioxidant status included isoprostanes (8-iso-PGF2alpha), superoxide dismutase and ascorbic acid. EE cases had a greater apnea-hypopnea index, a higher frequency of apneas (central and obstructive) and hypopneas during REM sleep, and lower nocturnal [Formula: see text] compared to controls. 8-iso-PGF2alpha was greater in EE than controls, negatively associated with nocturnal [Formula: see text] , and positively associated with hemoglobin concentration. Mild sleep-disordered breathing and oxidative stress are evident in preclinical CMS, suggesting that the resolution of nocturnal hypoxemia or antioxidant treatment may prevent disease progression.
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Potential role for elevated maternal enzymatic antioxidant status in Andean protection against altitude-associated SGA.
J. Matern. Fetal. Neonatal. Med.
PUBLISHED: 11-30-2011
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Oxidative stress has been implicated in the uteroplacental ischemia characteristic of preeclampsia and small-for-gestational-age (SGA) birth, both of which are more common at high (>2500 m) vs low altitude. Since Andeans are protected relative to Europeans from the altitude-associated rise in SGA, we asked whether alterations in maternal antioxidant status or oxidative stress contributed to their protection. Enzymatic antioxidant (erythrocyte catalase and superoxide dismutase [SOD]) activity and a plasma marker of lipid peroxidation (8-iso-PGF2?) were measured during pregnancy and in the non-pregnant state in Andean or European residents of low (400 m) or high altitude (3600-4100 m). Pregnancy and altitude increased catalase and/or SOD activity to a greater extent in Andeans than Europeans. 8-iso-PGF2? levels were independent of altitude and pregnancy. SOD was lower in mothers of SGA infants at weeks 20 and 36. Our findings are consistent with the possibility that elevated enzymatic antioxidant activity contributes to Andean protection against altitude-associated SGA.
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Acute mountain sickness, inflammation, and permeability: new insights from a blood biomarker study.
J. Appl. Physiol.
PUBLISHED: 06-02-2011
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The pathophysiology of acute mountain sickness (AMS) is unknown. One hypothesis is that hypoxia induces biochemical changes that disrupt the blood-brain barrier (BBB) and, subsequently, lead to the development of cerebral edema and the defining symptoms of AMS. This study explores the relationship between AMS and biomarkers thought to protect against or contribute to BBB disruption. Twenty healthy volunteers participated in a series of hypobaric hypoxia trials distinguished by pretreatment with placebo, acetazolamide (250 mg), or dexamethasone (4 mg), administered using a randomized, double-blind, placebo-controlled, crossover design. Each trial included peripheral blood sampling and AMS assessment before (-15 and 0 h) and during (0.5, 4, and 9 h) a 10-h hypoxic exposure (barometric pressure = 425 mmHg). Anti-inflammatory and/or anti-permeability [interleukin (IL)-1 receptor agonist (IL-1RA), heat shock protein (HSP)-70, and adrenomedullin], proinflammatory (IL-6, IL-8, IL-2, IL-1?, and substance P), angiogenic, or chemotactic biomarkers (macrophage inflammatory protein-1?, VEGF, TNF-?, monocyte chemotactic protein-1, and matrix metalloproteinase-9) were assessed. AMS-resistant subjects had higher IL-1RA (4 and 9 h and overall), HSP-70 (0 h and overall), and adrenomedullin (overall) compared with AMS-susceptible subjects. Acetazolamide raised IL-1RA and HSP-70 compared with placebo in AMS-susceptible subjects. Dexamethasone also increased HSP-70 and adrenomedullin in AMS-susceptible subjects. Macrophage inflammatory protein-1? was higher in AMS-susceptible than AMS-resistant subjects after 4 h of hypoxia; dexamethasone minimized this difference. Other biomarkers were unrelated to AMS. Resistance to AMS was accompanied by a marked anti-inflammatory and/or anti-permeability response that may have prevented downstream pathophysiological events leading to AMS. Conversely, AMS susceptibility does not appear to be related to an exaggerated inflammatory response.
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Effects of acetazolamide and dexamethasone on cerebral hemodynamics in hypoxia.
J. Appl. Physiol.
PUBLISHED: 03-10-2011
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Previous attempts to detect global cerebral hemodynamic differences between those who develop headache, nausea, and fatigue following rapid exposure to hypoxia [acute mountain sickness (AMS)] and those who remain healthy have been inconclusive. In this study, we investigated the effects of two drugs known to reduce symptoms of AMS to determine if a common cerebral hemodynamic mechanism could explain the prophylactic effect within individuals. With the use of randomized, placebo-controlled, double-blind, crossover design, 20 healthy volunteers were given oral acetazolamide (250 mg), dexamethasone (4 mg), or placebo every 8 h for 24 h prior to and during a 10-h exposure to a simulated altitude of 4,875 m in a hypobaric chamber, which included 2 h of exercise at 50% of altitude-specific VO(2max). Cerebral hemodynamic parameters derived from ultrasound assessments of dynamic cerebral autoregulation and vasomotor reactivity were recorded 15 h prior to and after 9 h of hypoxia. AMS symptoms were scored using the Lake Louise Questionnaire (LLQ). It was found that both drugs prevented AMS in those who became ill on placebo (~70% decrease in LLQ), yet a common cerebral hemodynamic mechanism was not identified. Compared with placebo, acetazolamide reduced middle cerebral artery blood flow velocity (11%) and improved dynamic cerebral autoregulation after 9 h of hypoxia, but these effects appeared independent of AMS. Dexamethasone had no measureable cerebral hemodynamic effects in hypoxia. In conclusion, global cerebral hemodynamic changes resulting from hypoxia may not explain the development of AMS.
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High-end arteriolar resistance limits uterine artery blood flow and restricts fetal growth in preeclampsia and gestational hypertension at high altitude.
Am. J. Physiol. Regul. Integr. Comp. Physiol.
PUBLISHED: 02-16-2011
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The reduction in infant birth weight and increased frequency of preeclampsia (PE) in high-altitude residents have been attributed to greater placental hypoxia, smaller uterine artery (UA) diameter, and lower UA blood flow (Q(UA)). This cross-sectional case-control study determined UA, common iliac (CI), and external iliac (EI) arterial blood flow in Andeans residing at 3,600-4,100 m, who were either nonpregnant (NP, n = 23), or experiencing normotensive pregnancies (NORM; n = 155), preeclampsia (PE, n = 20), or gestational hypertension (GH, n = 12). Pregnancy enlarged UA diameter to ~0.62 cm in all groups, but indices of end-arteriolar vascular resistance were higher in PE or GH than in NORM. Q(UA) was lower in early-onset (?34 wk) PE or GH than in NORM, but was normal in late-onset (>34 wk) illness. Left Q(UA) was consistently greater than right in NORM, but the pattern reversed in PE. Although Q(CI) and Q(EI) were higher in PE and GH than NORM, the fraction of Q(CI) distributed to the UA was reduced 2- to 3-fold. Women with early-onset PE delivered preterm, and 43% had stillborn small for gestational age (SGA) babies. Those with GH and late-onset PE delivered at term but had higher frequencies of SGA babies (GH=50%, PE=46% vs. NORM=15%, both P < 0.01). Birth weight was strongly associated with reduced Q(UA) (R(2) = 0.80, P < 0.01), as were disease severity and adverse fetal outcomes. We concluded that high end-arteriolar resistance, not smaller UA diameter, limited Q(UA) and restricted fetal growth in PE and GH. These are, to our knowledge, the first quantitative measurements of Q(UA) and pelvic blood flow in early- vs. late-onset PE in high-altitude residents.
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Humans at high altitude: hypoxia and fetal growth.
Respir Physiol Neurobiol
PUBLISHED: 02-13-2011
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High-altitude studies offer insight into the evolutionary processes and physiological mechanisms affecting the early phases of the human lifespan. Chronic hypoxia slows fetal growth and reduces the pregnancy-associated rise in uterine artery (UA) blood flow. Multigenerational vs. shorter-term high-altitude residents are protected from the altitude-associated reductions in UA flow and fetal growth. Presently unknown is whether this fetal-growth protection is due to the greater delivery or metabolism of oxygen, glucose or other substrates or to other considerations such as mechanical factors protecting fragile fetal villi, the creation of a reserve protecting against ischemia/reperfusion injury, or improved placental O(2) transfer as the result of narrowing the A-V O(2) difference and raising uterine P(v)O?. Placental growth and development appear to be normal or modified at high altitude in ways likely to benefit diffusion. Much remains to be learned concerning the effects of chronic hypoxia on embryonic development. Further research is required for identifying the fetoplacental and maternal mechanisms responsible for transforming the maternal vasculature and regulating UA blood flow and fetal growth. Genomic as well as epigenetic studies are opening new avenues of investigation that can yield insights into the basic pathways and evolutionary processes involved.
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High altitude during pregnancy.
Clin. Chest Med.
PUBLISHED: 02-01-2011
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One of the greatest physiologic challenges during pregnancy is to maintain an adequate supply of oxygenated blood to the uteroplacental circulation for fetal development. This challenge is magnified under conditions of limited oxygen availability. High altitude impairs fetal growth, increases the incidence of preeclampsia, and, as a result, significantly increases the risk of perinatal and/or maternal morbidity and mortality. This review summarizes the clinical consequences and physiologic challenges that emerge when pregnancy and high altitude coincide and highlights the adaptations that serve to protect oxygenation and fetal growth under conditions of chronic hypoxia.
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Lowland origin women raised at high altitude are not protected against lower uteroplacental O2 delivery during pregnancy or reduced birth weight.
Am. J. Hum. Biol.
PUBLISHED: 01-21-2011
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Maternal physiologic responses to pregnancy promoting fetal oxygen and nutrient delivery are important determinants of reproductive success. Incomplete physiologic compensation for reduced oxygen availability at high altitude (?2,500 m) compromises fetal growth. Populations of highland (e.g., Andeans, Tibetans) compared with lowland origin groups (e.g., Europeans, Han Chinese) are protected from this altitude-associated decrease in birth weight; here we sought to determine whether maternal development at high altitude-rather than highland ancestry-contributed to the protection of birth weight and uterine artery (UA) blood flow during pregnancy.
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Do cytokines contribute to the Andean-associated protection from reduced fetal growth at high altitude?
Reprod Sci
PUBLISHED: 09-14-2010
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Pro- versus anti-inflammatory cytokine balance is important for successful pregnancy. Chronic hypoxia alters cytokine levels and increases the frequency of fetal growth restriction (FGR). Multigenerational Andean (AND) versus shorter duration European (EUR) high-altitude (HA) residents are protected from altitude-associated FGR. To address whether ancestry group differences in cytokine levels were involved, we conducted serial studies in 56 low-altitude ([LA]; 400 m; n = 29 AND and n = 27 EUR) and 42 HA residents (3600-4100 m; n = 19 ANDs and n = 23 EURs). Pregnancy raised pro- (interleukin 1? [IL-1?]) and anti- (IL-10) inflammatory cytokines and HA lowered IL-6 and tumor necrosis factor-? (TNF-?) near term. There were no ancestry group differences in cytokine levels at any time, but HA reduced IL-1? in ANDs only near term. Higher IL-1? levels correlated with uterine artery (UA) blood flow at 20 weeks in ANDs at HA, suggesting that IL-1? may play a role in AND protection from altitude-associated reductions in fetal growth.
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Do anti-angiogenic or angiogenic factors contribute to the protection of birth weight at high altitude afforded by Andean ancestry?
Reprod Sci
PUBLISHED: 07-02-2010
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This prospective study was designed to determine whether variation in angiogenic (placental growth factor [PlGF]) and/or anti-angiogenic (soluble fms-like tyrosine kinase [sFlt-1]) factors contribute to the protective effect of highland ancestry (Andean) from altitude-associated reductions in fetal growth.
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Identifying signatures of natural selection in Tibetan and Andean populations using dense genome scan data.
PLoS Genet.
PUBLISHED: 01-04-2010
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High-altitude hypoxia (reduced inspired oxygen tension due to decreased barometric pressure) exerts severe physiological stress on the human body. Two high-altitude regions where humans have lived for millennia are the Andean Altiplano and the Tibetan Plateau. Populations living in these regions exhibit unique circulatory, respiratory, and hematological adaptations to life at high altitude. Although these responses have been well characterized physiologically, their underlying genetic basis remains unknown. We performed a genome scan to identify genes showing evidence of adaptation to hypoxia. We looked across each chromosome to identify genomic regions with previously unknown function with respect to altitude phenotypes. In addition, groups of genes functioning in oxygen metabolism and sensing were examined to test the hypothesis that particular pathways have been involved in genetic adaptation to altitude. Applying four population genetic statistics commonly used for detecting signatures of natural selection, we identified selection-nominated candidate genes and gene regions in these two populations (Andeans and Tibetans) separately. The Tibetan and Andean patterns of genetic adaptation are largely distinct from one another, with both populations showing evidence of positive natural selection in different genes or gene regions. Interestingly, one gene previously known to be important in cellular oxygen sensing, EGLN1 (also known as PHD2), shows evidence of positive selection in both Tibetans and Andeans. However, the pattern of variation for this gene differs between the two populations. Our results indicate that several key HIF-regulatory and targeted genes are responsible for adaptation to high altitude in Andeans and Tibetans, and several different chromosomal regions are implicated in the putative response to selection. These data suggest a genetic role in high-altitude adaption and provide a basis for future genotype/phenotype association studies necessary to confirm the role of selection-nominated candidate genes and gene regions in adaptation to altitude.
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Identifying positive selection candidate loci for high-altitude adaptation in Andean populations.
Hum. Genomics
PUBLISHED: 12-30-2009
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High-altitude environments (>2,500 m) provide scientists with a natural laboratory to study the physiological and genetic effects of low ambient oxygen tension on human populations. One approach to understanding how life at high altitude has affected human metabolism is to survey genome-wide datasets for signatures of natural selection. In this work, we report on a study to identify selection-nominated candidate genes involved in adaptation to hypoxia in one highland group, Andeans from the South American Altiplano. We analysed dense microarray genotype data using four test statistics that detect departures from neutrality. Using a candidate gene, single nucleotide polymorphism-based approach, we identified genes exhibiting preliminary evidence of recent genetic adaptation in this population. These included genes that are part of the hypoxia-inducible transcription factor ( HIF ) pathway, a biochemical pathway involved in oxygen homeostasis, as well as three other genomic regions previously not known to be associated with high-altitude phenotypes. In addition to identifying selection-nominated candidate genes, we also tested whether the HIF pathway shows evidence of natural selection. Our results indicate that the genes of this biochemical pathway as a group show no evidence of having evolved in response to hypoxia in Andeans. Results from particular HIF -targeted genes, however, suggest that genes in this pathway could play a role in Andean adaptation to high altitude, even if the pathway as a whole does not show higher relative rates of evolution. These data suggest a genetic role in high-altitude adaptation and provide a basis for genotype/phenotype association studies that are necessary to confirm the role of putative natural selection candidate genes and gene regions in adaptation to altitude.
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Evolutionary adaptation to high altitude: a view from in utero.
Am. J. Hum. Biol.
PUBLISHED: 04-16-2009
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A primary focus within biological anthropology has been to elucidate the processes of evolutionary adaptation. Frisancho helped to move anthropology towards more mechanistic explanations of human adaptation by drawing attention to the importance of the functional relevance of human variation. Using the natural laboratory of high altitude, he and others asked whether the unique physiology of indigenous high-altitude residents was the result of acclimatization, developmental plasticity, and/or genetic adaptation in response to the high-altitude environment. We approach the question of human adaptation to high altitude from a somewhat unique vantage point; namely, by examining physiological characteristics-pregnancy and pregnancy outcome-which are closely associated with reproductive fitness. Here we review the potent example of high-altitude native populations resistance to hypoxia-associated reductions in birth weight, which is often associated with higher infant morbidity and mortality at high altitude. With the exception of two recent publications, these comparative birth weight studies have utilized surnames, self-identification, and/or linguistic characteristics to assess ancestry, and none have linked advantageous phenotypes to specific genetic variations. Recent advancements in genetic and statistical tools have enabled us to assess individual ancestry with higher resolution, identify the genetic basis of complex phenotypes and to infer the effect of natural selection on specific gene regions. Using these technologies our studies are now directed to determine the genetic variations that underlie the mechanisms by which high-altitude ancestry protects fetal growth and, in turn, to further our understanding of evolutionary processes involved in human adaptation to high altitude.
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Augmented uterine artery blood flow and oxygen delivery protect Andeans from altitude-associated reductions in fetal growth.
Am. J. Physiol. Regul. Integr. Comp. Physiol.
PUBLISHED: 02-25-2009
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The effect of high altitude on reducing birth weight is markedly less in populations of high- (e.g., Andeans) relative to low-altitude origin (e.g., Europeans). Uterine artery (UA) blood flow is greater during pregnancy in Andeans than Europeans at high altitude; however, it is not clear whether such blood flow differences play a causal role in ancestry-associated variations in fetal growth. We tested the hypothesis that greater UA blood flow contributes to the protection of fetal growth afforded by Andean ancestry by comparing UA blood flow and fetal growth throughout pregnancy in 137 Andean or European residents of low (400 m; European n = 28, Andean n = 23) or high (3,100-4,100 m; European n = 51, Andean n = 35) altitude in Bolivia. Blood flow and fetal biometry were assessed by Doppler ultrasound, and maternal ancestry was confirmed, using a panel of 100 ancestry-informative genetic markers (AIMs). At low altitude, there were no ancestry-related differences in the pregnancy-associated rise in UA blood flow, fetal biometry, or birth weight. At high altitude, Andean infants weighed 253 g more than European infants after controlling for gestational age and other known influences. UA blood flow and O(2) delivery were twofold greater at 20 wk in Andean than European women at high altitude, and were paralleled by greater fetal size. Moreover, variation in the proportion of Indigenous American ancestry among individual women was positively associated with UA diameter, blood flow, O(2) delivery, and fetal head circumference. We concluded that greater UA blood flow protects against hypoxia-associated reductions in fetal growth, consistent with the hypothesis that genetic factors enabled Andeans to achieve a greater pregnancy-associated rise in UA blood flow and O(2) delivery than European women at high altitude.
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Role of cytokines in altitude-associated preeclampsia.
Pregnancy Hypertens
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BACKGROUND: Preeclampsia (PE) is more common at high than low altitude and contributes to the altitude-related decline in birth weight. Since inflammatory markers are implicated in PE, we asked if such markers differed in PE vs. normotensive pregnant (NORM) women residing at high altitude (3600-4100 m), and were related to uterine artery blood flow (UA BF) or fetal growth. METHODS: Subjects were 33 Andean pregnant residents of Bolivia, comprising six with early-onset PE (? 34 wk), 12 with late-onset PE (> 34 wk), and 15 gestational-age matched NORM. Maternal pro- and anti-inflammatory cytokines were measured using a multiplex bead-based assay and UA BF by Doppler ultrasound. RESULTS: PE compared to NORM women had higher levels of the pro-inflammatory cytokines IL-6 and IL-8 as well as higher levels of the anti-inflammatory cytokine IL-1ra, but only IL-6 levels were higher when gestational age was controlled. Women with early- vs. late-onset PE had higher TNF? levels, and higher IL-6 was negatively correlated with birth weight in all women at ? 34 wk. We suggest that pro-inflammatory factors influence both the timing and severity of PE at high altitude.
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JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

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