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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.

KEY POINTS: Chronic mountain sickness (CMS) is a maladaptation syndrome encountered at high altitude (HA) characterised by severe hypoxaemia that carries a higher risk of stroke and migraine and is associated with increased morbidity and mortality. We examined if exaggerated oxidative‐inflammatory‐nitrosative stress (OXINOS) and corresponding decrease in vascular nitric oxide bioavailability in patients with CMS (CMS+) is associated with impaired cerebrovascular function and adverse neurological outcome. Systemic OXINOS was markedly elevated in CMS+ compared to healthy HA (CMS−) and low‐altitude controls. OXINOS was associated with blunted cerebral perfusion and vasoreactivity to hypercapnia, impaired cognition and, in CMS+, symptoms of depression. These findings are the first to suggest that a physiological continuum exists for hypoxaemia‐induced systemic OXINOS in HA dwellers that when excessive is associated with accelerated cognitive decline and depression, helping identify those in need of more specialist neurological assessment and targeted support. ABSTRACT: Chronic mountain sickness (CMS) is a maladaptation syndrome encountered at high altitude (HA) characterised by severe hypoxaemia that carries a higher risk of stroke and migraine and is associated with increased morbidity and mortality. The present cross‐sectional study examined to what extent exaggerated systemic oxidative‐inflammatory‐nitrosative stress (OXINOS), defined by an increase in free radical formation and corresponding decrease in vascular nitric oxide (NO) bioavailability, is associated with impaired cerebrovascular function, accelerated cognitive decline and depression in CMS. Venous blood was obtained from healthy male lowlanders (80 m, n = 17), and age‐ and gender‐matched HA dwellers born and bred in La Paz, Bolivia (3600 m) with (CMS+, n = 23) and without (CMS−, n = 14) CMS. We sampled blood for oxidative (electron paramagnetic resonance spectroscopy, HPLC), nitrosative (ozone‐based chemiluminescence) and inflammatory (fluorescence) biomarkers. We employed transcranial Doppler ultrasound to measure cerebral blood flow (CBF) and reactivity. We utilised psychometric tests and validated questionnaires to assess cognition and depression. Highlanders exhibited elevated systemic OXINOS (P < 0.05 vs. lowlanders) that was especially exaggerated in the more hypoxaemic CMS+ patients (P < 0.05 vs. CMS−). OXINOS was associated with blunted cerebral perfusion and vasoreactivity to hypercapnia, impaired cognition and, in CMS+, symptoms of depression. Collectively, these findings are the first to suggest that a physiological continuum exists for hypoxaemia‐induced OXINOS in HA dwellers that when excessive is associated with accelerated cognitive decline and depression, helping identify those in need of specialist neurological assessment and support.

Chronic mountain sickness (CMS) is often associated with vascular dysfunction, but the underlying mechanism is unknown. Sleep-disordered breathing (SDB) frequently occurs at high altitude. At low altitude, SDB causes vascular dysfunction. Moreover, in SDB, transient elevations of right-sided cardiac pressure may cause right-to-left shunting in the presence of a patent foramen ovale (PFO) and, in turn, further aggravate hypoxemia and pulmonary hypertension. We speculated that SDB and nocturnal hypoxemia are more pronounced in patients with CMS compared with healthy high-altitude dwellers, and are related to vascular dysfunction.We performed overnight sleep recordings, and measured systemic and pulmonary artery pressure in 23 patients with CMS (mean ± SD age, 52.8 ± 9.8 y) and 12 healthy control subjects (47.8 ± 7.8 y) at 3,600 m. In a subgroup of 15 subjects with SDB, we assessed the presence of a PFO with transesophageal echocardiography.The major new findings were that in patients with CMS, (1) SDB and nocturnal hypoxemia was more severe (P.01) than in control subjects (apnea-hypopnea index [AHI], 38.9 ± 25.5 vs 14.3 ± 7.8 number of events per hour [nb/h]; arterial oxygen saturation, 80.2% ± 3.6% vs 86.8% ± 1.7%, CMS vs control group), and (2) AHI was directly correlated with systemic blood pressure (r = 0.5216; P = .001) and pulmonary artery pressure (r = 0.4497; P = .024). PFO was associated with more severe SDB (AHI, 48.8 ± 24.7 vs 14.8 ± 7.3 nb/h; P = .013, PFO vs no PFO) and hypoxemia.SDB and nocturnal hypoxemia are more severe in patients with CMS than in control subjects and are associated with systemic and pulmonary vascular dysfunction. The presence of a PFO appeared to further aggravate SDB. Closure of the PFO may improve SDB, hypoxemia, and vascular dysfunction in patients with CMS.ClinicalTrials.gov; No.: NCT01182792; URL: www.clinicaltrials.gov.

International audience; Chronic mountain sickness (CMS) is a maladaptation syndrome encountered at high-altitude (HA) characterised by severe hypoxaemia that carries a higher risk of stroke and migraine and is associated with increased morbidity and mortality. The present cross-sectional study examined to what extent exaggerated systemic oxidative-nitrosative-inflammatory stress (OXINOS), defined by an increase in free radical formation and corresponding decrease in vascular nitric oxide (NO) bioavailability, is associated with impaired cerebrovascular function, accelerated cognitive decline and depression in CMS. Venous blood was obtained from healthy male lowlanders (80m,n= 17), and age and gender-matched HAdwellers born and bred in La Paz, Bolivia (3,600 m) with (CMS+, n= 23) and without (CMS-, n= 14) CMS. We sampled blood for oxidative (electron paramagnetic resonance spectroscopy, HPLC), nitrosative (ozone-based chemiluminescence), and inflammatory (fluorescence) biomarkers. We employed transcranial Doppler ultrasound to measure cerebral blood flow (CBF) and reactivity. We utilised psychometric tests and validated questionnaires to assess cognition and depression. Highlanders exhibited elevated systemic OXINOS (P< 0.05 vs. lowlanders) that was especially exaggerated in the more hypoxaemic CMS+ patients (P< 0.05 vs. CMS-). OXINOS was associated with blunted cerebral perfusion and vasoreactivity to hypercapnia, impaired cognition and in CMS+, symptoms of depression. Collectively, these findings are the first to suggest that a physiological continuum exists for hypoxaemia-induced OXINOS in HA dwellers that when excessive,is associated with accelerated cognitive decline and depression, helping identify those in need of specialist neurological assessment and support.

The peopling of the Andean highlands above 2500m in elevation was a complex process that included cultural, biological and genetic adaptations. Here we present a time series of ancient whole genomes from the Andes of Peru, dating back to 7,000 calendar years before present (BP), and compare them to 64 new genome-wide genetic variation datasets from both high and lowland populations. We infer three significant features: a split between low and high elevation populations that occurred between 9200-8200 BP; a population collapse after European contact that is significantly more severe in South American lowlanders than in highland populations; and evidence for positive selection at genetic loci related to starch digestion and plausibly pathogen resistance after European contact. Importantly, we do not find selective sweep signals related to known components of the human hypoxia response, which may suggest more complex modes of genetic adaptation to high altitude.One Sentence SummaryAncient DNA from the Andes reveals a complex picture of human adaptation from early settlement to the colonial period.

Background By combining the chick embryo model with incubation at high altitude (HA), the effects of chronic hypoxia on fetal growth, fetal cardiac and aortic wall remodeling and systemic arterial blood pressure at adulthood were reported. Using non-invasive functional echocardiography, here we investigated the in vivo effects of HA hypoxia on the pulmonary circulation at adulthood in male and female chickens. Methods and results Chick embryos were incubated, hatched and raised at sea level (SL) or at HA. At 6 months of age, functional echocardiography was performed and the body and heart weights were taken. Heart weight was heavier in males but not in female HA chickens compared to their same sex SL counterparts. Similarly, male but not female HA chickens had greater in vivo right ventricular wall thickness compared to their same sex SL counterparts. The tricuspid pressure gradient was greatly enhanced in HA male and HA female chickens. However, the increment in the tricuspid pressure gradient was greater in HA males than in HA females. The pulmonary artery diameter was also enhanced in HA males than in SL males. In contrast, HA did not affect this variable in female chickens. Conclusions The data show that chronic hypoxia during development at HA is associated with echocardiocraphic indices of pulmonary hypertension at adulthood in a highly sex-dependent manner.

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 Monge9s 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 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)

Acute exposure to high altitude stimulates free radical formation in lowlanders, yet whether this persists during chronic exposure in healthy, well-adapted and maladapted highlanders suffering from chronic mountain sickness (CMS) remains to be established.Oxidative-nitrosative stress (as determined by the presence of the biomarkers ascorbate radical [A •- ], via electron paramagnetic resonance spectroscopy, and nitrite [NO 2 2 ], via ozone-based chemiluminescence) was assessed in venous blood of 25 male highlanders in Bolivia living at 3,600 m with CMS (n 5 13, CMS 1 ) and without CMS (n 5 12, CMS 2 ). Twelve age- and activity-matched, healthy, male lowlanders were examined at sea level and during acute hypoxia. We also measured fl ow-mediated dilatation (FMD), arterial stiffness defined by augmentation index normalized for a heart rate of 75 beats/min (AIx-75), and carotid intima-media thickness (IMT).Compared with normoxic lowlanders, oxidative-nitrosative stress was moderately increased in the CMS 2 group ( P , .05), as indicated by elevated A •- (3,191 457 arbitrary units [AU] vs 2,640 445 AU) and lower NO 2 2 (206 55 nM vs 420 128 nM), whereas vascular function remained preserved. This was comparable to that observed during acute hypoxia in lowlanders in whom vascular dysfunction is typically observed. In contrast, this response was markedly exaggerated in CMS 1 group (A •- , 3,765 429 AU; NO 2 2 , 148 50 nM) compared with both the CMS 2 group and lowlanders ( P , .05). This was associated with systemic vascular dysfunction as indicated by lower ( P , .05 vs CMS 2 ) FMD (4.2% 0.7% vs 7.6% 1.7%) and increased AIx-75 (23% 8% vs 12% 7%) and carotid IMT (714 127 m M vs 588 94 m M).Healthy highlanders display a moderate, sustained elevation in oxidative-nitrosative stress that, unlike the equivalent increase evoked by acute hypoxia in healthy lowlanders, failed to affect vascular function. Its more marked elevation in patients with CMS may contribute to systemic vascular dysfunction.

Studies of high-altitude populations, and in particular of maladapted subgroups, may provide important insight into underlying mechanisms involved in the pathogenesis of hypoxemia-related disease in general. Chronic mountain sickness (CMS) is a major public health problem in mountainous regions of the world affecting many millions of high-altitude dwellers. It is characterized by exaggerated chronic hypoxemia, erythrocytosis, and mild pulmonary hypertension. In later stages these patients often present with right heart failure and are predisposed to systemic cardiovascular disease, but the underlying mechanisms are poorly understood. Here, we present recent new data providing insight into underlying mechanisms that may cause these complications.

Although it is accepted that impaired placental perfusion in complicated pregnancy can slow fetal growth and programme an increased risk of cardiovascular dysfunction at adulthood, the relative contribution of reductions in fetal nutrition and in fetal oxygenation as the triggering stimulus remains unclear. By combining high altitude (HA) with the chick embryo model, we have previously isolated the direct effects of HA hypoxia on embryonic growth and cardiovascular development before hatching. This study isolated the effects of developmental hypoxia on cardiovascular function measuredin vivoin conscious adult male and female chickens. Chick embryos were incubated, hatched and raised at sea level (SL, nine males and nine females) or incubated, hatched and raised at HA (seven males and seven females). At 6 months of age, vascular catheters were inserted under general anaesthesia. Five days later, basal blood gas status, basal cardiovascular function and cardiac baroreflex responses were investigated. HA chickens had significantly lower basal arterial PO2and haemoglobin saturation, and significantly higher haematocrit than SL chickens, independent of the sex of the animal. HA chickens had significantly lower arterial blood pressure than SL chickens, independent of the sex of the animal. Although the gain of the arterial baroreflex was decreased in HA relative to SL male chickens, it was increased in HA relative to SL female chickens. We show that development at HA lowers basal arterial blood pressure and alters baroreflex sensitivity in a sex-dependent manner at adulthood.

The APOE/C1/C4/C2 gene cluster presents high relevance in lipid metabolism and, therefore, has important epidemiological implications. Here, we study for the first time the variation patterns of 25 polymorphisms (10 short tandem repeats, STRs, and 15 single nucleotide polymorphismas, SNPs) in two native Andean samples from Bolivia (45 Aymaras and 45 Quechuas) as well as one European sample (n = 41) as external reference. We estimated diversity parameters, linkage disequilibrium patterns, population structure, and possible selective effects. In general, diversity was low and could be partly attributed to selection (probably due to its physiological importance), since the APOE/C1/C4/C2 region was highly conserved compared to the flanking genes in both Bolivians and Europeans. Moreover, the lower gene diversity in Bolivians compared to Europeans for some markers might indicate different demographic histories. Regarding the APOE isoforms, in addition to ɛ3 (94%) and ɛ4 (5%), isoform ɛ2 (1%) was also detected in Bolivians. In relation to previous hypotheses, our results support that genetic drift or founder effects rather than selection for increased cholesterol absorption are the main factors that have shaped the distribution of APOE isoforms observed in South America.

Background Chronic mountain sickness (CMS) is an important public health problem and is characterized by exaggerated hypoxemia, erythrocytosis, and pulmonary hypertension. While pulmonary hypertension is a leading cause of morbidity and mortality in patients with CMS, it is relatively mild and its underlying mechanisms are not known. We speculated that during mild exercise associated with daily activities, pulmonary hypertension in CMS is much more pronounced. Methods We estimated pulmonary artery pressure by using echocardiography at rest and during mild bicycle exercise at 50 W in 30 male patients with CMS and 32 age-matched, healthy control subjects who were born and living at an altitude of 3,600 m. Results The modest, albeit significant difference of the systolic right-ventricular-to-right-atrial pressure gradient between patients with CMS and controls at rest (30.3 ± 8.0 vs 25.4 ± 4.5 mm Hg, P 5 .002) became more than three times larger during mild bicycle exercise (56.4 ± 19.0 vs 39.8 ± 8.0 mm Hg, P Conclusions Measurements of pulmonary artery pressure at rest greatly underestimate pulmonary artery pressure during daily activity in patients with CMS. The marked pulmonary hypertension during mild exercise associated with daily activity may explain why this problem is a leading cause of morbidity and mortality in patients with CMS.

Testosterone (T) plays a key role in the increase and maintenance of muscle mass and bone density in adult men. Life history theory predicts that environmental stress may prompt a reallocation of such investments to those functions critical to survival. We tested this hypothesis in two studies of rural Bolivian adult men by comparing free T levels and circadian rhythms during late winter, which is especially severe, to those in less arduous seasons. For each pair of salivary T(AM)/T(PM) samples (collected in a approximately 12-h period), circadian rhythm was considered classic (C(CLASSIC)) if T(AM)110%T(PM), reverse (C(REVERSE)) if T(PM)110%T(AM), and flat (C(FLAT)) otherwise. We tested the hypotheses that mean T(AM)mean T(PM) and that mean T(LW)mean T(OTHER) (LW = late winter, OTHER = other seasons). In Study A, of 115 T(PM)-T(AM) pairs, 51% = C(CLASSIC), 39% = C(REVERSE), 10% = C(FLAT); in Study B, of 184 T(AM)-T(PM) pairs, 55% = C(CLASSIC), 33% = C(REVERSE), 12% = C(FLAT). Based on fitting linear mixed models, in both studies T(OTHER-AM)T(OTHER-PM) (A: P = 0.035, B: P = 0.0005) and T(OTHER-AM)T(LW-AM) (A: P = 0.054, B: P = 0.007); T(PM) did not vary seasonally, and T diurnality was not significant during late winter. T diurnality varied substantially between days within an individual, between individuals and between seasons, but neither T levels nor diurnality varied with age. These patterns may reflect the seasonally varying but unscheduled, life-long, strenuous physical labor that typifies many non-industrialized economies. These results also suggest that single morning samples may substantially underestimate peak circulating T for an individual and, most importantly, that exogenous signals may moderate diurnality and the trajectory of age-related change in the male gonadal axis.

The partial contributions of reductions in fetal nutrition and oxygenation to slow fetal growth and a developmental origin of cardiovascular disease remain unclear. By combining high altitude with the chick embryo model, we have previously isolated the direct effects of high-altitude hypoxia on growth. This study isolated the direct effects of high-altitude hypoxia on cardiovascular development. Fertilized eggs from sea-level or high-altitude hens were incubated at sea level or high altitude. Fertilized eggs from sea-level hens were also incubated at high altitude with oxygen supplementation. High altitude promoted embryonic growth restriction, cardiomegaly and aortic wall thickening, effects which could be prevented by incubating eggs from high-altitude hens at sea level or by incubating eggs from sea-level hens at high altitude with oxygen supplementation. Embryos from high-altitude hens showed reduced effects of altitude incubation on growth restriction but not on cardiovascular remodeling. The data show that: (1) high-altitude hypoxia promotes embryonic cardiac and vascular disease already evident prior to hatching and that this is associated with growth restriction; (2) the effects can be prevented by increased oxygenation; and (3) the effects are different in embryos from sea-level or high-altitude hens.

There is evidence that high altitude populations may be better protected from hypoxic pulmonary hypertension than low altitude natives, but the underlying mechanism is incompletely understood. In Tibetans, increased pulmonary respiratory NO synthesis attenuates hypoxic pulmonary hypertension. It has been speculated that this mechanism may represent a generalized high altitude adaptation pattern, but direct evidence for this speculation is lacking. We therefore measured systolic pulmonary-artery pressure (Doppler chocardiography) and exhaled nitric oxide (NO) in 34 healthy, middle-aged Bolivian high altitude natives and in 34 age- and sex-matched, well-acclimatized Caucasian low altitude natives living at high altitude (3600 m). The mean+/-SD systolic right ventricular to right atrial pressure gradient (24.3+/-5.9 vs. 24.7+/-4.9 mmHg) and exhaled NO (19.2+/-7.2 vs. 22.5+/-9.5 ppb) were similar in Bolivians and Caucasians. There was no relationship between pulmonary-artery pressure and respiratory NO in the two groups. These findings provide no evidence that Bolivian high altitude natives are better protected from hypoxic pulmonary hypertension than Caucasian low altitude natives and suggest that attenuation of pulmonary hypertension by increased respiratory NO synthesis may not represent a universal adaptation pattern in highaltitude populations.

Invasive studies suggest that healthy children living at high altitude display pulmonary hypertension, but the data to support this assumption are sparse. Nitric oxide (NO) synthesized by the respiratory epithelium regulates pulmonary artery pressure, and its synthesis was reported to be increased in Aymara high-altitude dwellers. We hypothesized that pulmonary artery pressure will be lower in Aymara children than in children of European ancestry at high altitude, and that this will be related to increased respiratory NO. We therefore compared pulmonary artery pressure and exhaled NO (a marker of respiratory epithelial NO synthesis) between large groups of healthy children of Aymara (n = 200; mean +/- SD age, 9.5 +/- 3.6 years) and European ancestry (n = 77) living at high altitude (3,600 to 4,000 m). We also studied a group of European children (n = 29) living at low altitude. The systolic right ventricular to right atrial pressure gradient in the Aymara children was normal, even though significantly higher than the gradient measured in European children at low altitude (22.5 +/- 6.1 mm Hg vs 17.7 +/- 3.1 mm Hg, p < 0.001). In children of European ancestry studied at high altitude, the pressure gradient was 33% higher than in the Aymara children (30.0 +/- 5.3 mm Hg vs 22.5 +/- 6.1 mm Hg, p < 0.0001). In contrast to what was expected, exhaled NO tended to be lower in Aymara children than in European children living at the same altitude (12.4 +/- 8.8 parts per billion [ppb] vs 16.1 +/- 11.1 ppb, p = 0.06) and was not related to pulmonary artery pressure in either group. Aymara children are protected from hypoxic pulmonary hypertension at high altitude. This protection does not appear to be related to increased respiratory NO synthesis.

Studies of high-altitude populations, and in particular of maladapted subgroups, may provide important insight into underlying mechanisms involved in the pathogenesis of hypoxemia-related disease in general. Chronic mountain sickness (CMS) is a major public health problem in mountainous regions of the world affecting many millions of high-altitude dwellers. It is characterized by exaggerated chronic hypoxemia, erythrocytosis, and mild pulmonary hypertension. In later stages these patients often present with right heart failure and are predisposed to systemic cardiovascular disease, but the underlying mechanisms are poorly understood. Here, we present recent new data providing insight into underlying mechanisms that may cause these complications.

Objective To assess whether exposure to high altitude induces cognitive dysfunction in young healthy European children and adolescents during acute, short-term exposure to an altitude of 3450 m and in an age-matched European population permanently living at this altitude. Study design We tested executive function (inhibition, shifting, and working memory), memory (verbal, short-term visuospatial, and verbal episodic memory), and speed processing ability in: (1) 48 healthy nonacclimatized European children and adolescents, 24 hours after arrival at high altitude and 3 months after return to low altitude; (2) 21 matched European subjects permanently living at high altitude; and (3) a matched control group tested twice at low altitude. Results Short-term hypoxia significantly impaired all but 2 (visuospatial memory and processing speed) of the neuropsychological abilities that were tested. These impairments were even more severe in the children permanently living at high altitude. Three months after return to low altitude, the neuropsychological performances significantly improved and were comparable with those observed in the control group tested only at low altitude. Conclusions Acute short-term exposure to an altitude at which major tourist destinations are located induces marked executive and memory deficits in healthy children. These deficits are equally marked or more severe in children permanently living at high altitude and are expected to impair their learning abilities.

We sequenced the genomes of a ∼7,000-year-old farmer from Germany and eight ∼8,000-year-old hunter-gatherers from Luxembourg and Sweden. We analysed these and other ancient genomes1,2,3,4 with 2,345 contemporary humans to show that most present-day Europeans derive from at least three highly differentiated populations: west European hunter-gatherers, who contributed ancestry to all Europeans but not to Near Easterners; ancient north Eurasians related to Upper Palaeolithic Siberians3, who contributed to both Europeans and Near Easterners; and early European farmers, who were mainly of Near Eastern origin but also harboured west European hunter-gatherer related ancestry. We model these populations’ deep relationships and show that early European farmers had ∼44% ancestry from a ‘basal Eurasian’ population that split before the diversification of other non-African lineages., Instituto Multidisciplinario de Biología Celular

Defining the range of normal hematocrit and hemoglobin levels in residents of high altitude is required to diagnose chronic mountain sickness (CMS) and other conditions defined, in part, by hematocrit or hemoglobin values. We studied 1,934 healthy, young (aged 15 to 29 yr) male and female residents of Potosí, Bolivia (4000 m), to determine the average and normal range of hemoglobin and hematocrit values, defining normal as within 2 standard deviations of the mean or encompassing 95% of the observed variation. Male hematocrit averaged 52.7% and hemoglobin averaged 17.3 m/dL whole blood. The corresponding female values were 48.3% and 15.8 g/dL whole blood, respectively. The range of normal values was 45% to 61% for hematocrit and 13 to 21 g/dL for hemoglobin in the men and 41% to 56% for hematocrit and 12 to 19 g/dL for hemoglobin in the women. These data indicate that hematocrit values above 61% in men or 56% in women and hemoglobin values above 21 g/dL whole blood in men or 19 g/dL whole blood in women are outside the normal range.

A range of variation in percent of oxygen saturation of arterial hemoglobin (SaO2) among healthy individuals at a given high altitude indicates differences in physiological hypoxemia despite uniform ambient hypoxic stress. In populations native to the Tibetan plateau, a significant portion of the variance is attributable to additive genetic factors, and there is a major gene influencing SaO2. To determine whether there is genetic variance in other high-altitude populations, we designed a study to test the hypothesis that additive genetic factors contribute to phenotypic variation in SaO2 among Aymara natives of the Andean plateau, a population geographically distant from the Tibetan plateau and with a long, separate history of high-altitude residence. The average SaO2 of 381 Aymara at 3,900-4,000 m was 92+/-0.15% (SEM) with a range of 84-99%. The average was 2.6% higher than the average SaO2 of a sample of Tibetans at 3,800-4,065 m measured with the same techniques. Quantitative genetic analyses of the Aymara sample detected no significant variance attributable to genetic factors. The presence of genetic variance in SaO2 in the Tibetan sample and its absence in the Aymara sample indicate there is potential for natural selection on this trait in the Tibetan but not the Aymara population.

Elevated hemoglobin concentrations have been reported for high-altitude sojourners and Andean high-altitude natives since early in the 20th century. Thus, reports that have appeared since the 1970s describing relatively low hemoglobin concentration among Tibetan high-altitude natives were unexpected. These suggested a hypothesis of population differences in hematological response to high-altitude hypoxia. A case of quantitatively different responses to one environmental stress would offer an opportunity to study the broad evolutionary question of the origin of adaptations. However, many factors may confound population comparisons. The present study was designed to test the null hypothesis of no difference in mean hemoglobin concentration of Tibetan and Aymara native residents at 3,800–4,065 meters by using healthy samples that were screened for iron deficiency, abnormal hemoglobins, and thalassemias, recruited and assessed using the same techniques. The hypothesis was rejected, because Tibetan males had a significantly lower mean hemoglobin concentration of 15.6 gm/dl compared with 19.2 gm/dl for Aymara males, and Tibetan females had a mean hemoglobin concentration of 14.2 gm/dl compared with 17.8 gm/dl for Aymara females. The Tibetan hemoglobin distribution closely resembled that from a comparable, sea-level sample from the United States, whereas the Aymara distribution was shifted toward 3–4 gm/dl higher values. Genetic factors accounted for a very high proportion of the phenotypic variance in hemoglobin concentration in both samples (0.86 in the Tibetan sample and 0.87 in the Aymara sample). The presence of significant genetic variance means that there is the potential for natural selection and genetic adaptation of hemoglobin concentration in Tibetan and Aymara high-altitude populations. Am J Phys Anthropol 106:385–400, 1998. © 1998 Wiley-Liss, Inc.

Newcomers acclimatizing to high altitude and adult male Tibetan high altitude natives have increased ventilation relative to sea level natives at sea level. However, Andean and Rocky Mountain high altitude natives have an intermediate level of ventilation lower than that of newcom- ers and Tibetan high altitude natives although generally higher than that of sea level natives at sea level. Because the reason for the relative hypoventila- tion of some high altitude native populations was unknown, a study was designed to describe ventilation from adolescence through old age in samples of Tibetan and Andean high altitude natives and to estimate the relative genetic and environmental influences. This paper compares resting ventila- tion and hypoxic ventilatory response (HVR) of 320 Tibetans 9-82 years of age and 542 Bolivian Aymara 13-94 years of age, native residents at 3,800-4,065 m. Tibetan resting ventilation was roughly 1.5 times higher and Tibetan HVR was roughly double that of Aymara. Greater duration of hypoxia (older age) was not an important source of variation in resting ventilation or HVR in either sample. That is, contrary to previous studies, neither sample acquired hypoventilation in the age ranges under study. Within populations, greater severity of hypoxia (lower percent of oxygen saturation of arterial hemoglo- bin) was associated with slightly higher resting ventilation among Tibetans and lower resting ventilation and HVR among Aymara women, although the associations accounted for just 2-7% of the variation. Between populations, the Tibetan sample was more hypoxic and had higher resting ventilation and HVR. Other systematic environmental contrasts did not appear to elevate Tibetan or depress Aymara ventilation. There was more intrapopulation genetic variation in these traits in the Tibetan than the Aymara sample. Thirty-five percent of the Tibetan, but none of the Aymara, resting ventilation variance was due to genetic differences among individuals. Thirty-one percent of the Tibetan HVR, but just 21% of the Aymara, HVR variance was due to

The peopling of the Americas has been the subject of extensive genetic, archaeological and linguistic research; however, central questions remain unresolved. One contentious issue is whether the settlement occurred by means of a single migration or multiple streams of migration from Siberia. The pattern of dispersals within the Americas is also poorly understood. To address these questions at a higher resolution than was previously possible, we assembled data from 52 Native American and 17 Siberian groups genotyped at 364,470 single nucleotide polymorphisms. Here we show that Native Americans descend from at least three streams of Asian gene flow. Most descend entirely from a single ancestral population that we call First American. However, speakers of Eskimog-Aleut languages from the Arctic inherit almost half their ancestry from a second stream of Asian gene flow, and the Na-Dene-speaking Chipewyan from Canada inherit roughly one-tenth of their ancestry from a third stream. We show that the initial peopling followed a southward expansion facilitated by the coast, with sequential population splits and little gene flow after divergence, especially in South America. A major exception is in Chibchan speakers on both sides of the Panama isthmus, who have ancestry from both North and South America. © 2012 Macmillan Publishers Limited. All rights reserved. Fil: Reich, David. Harvard Medical School; Estados Unidos. Massachusetts Institute of Technology; Estados Unidos Fil: Patterson, Nick. Massachusetts Institute of Technology; Estados Unidos Fil: Campbell, Desmond. Colegio Universitario de Londres; Reino Unido. The University Of Hong Kong; Hong Kong Fil: Tandon, Arti. Harvard Medical School; Estados Unidos. Massachusetts Institute of Technology; Estados Unidos Fil: Mazieres, Stéphane. Colegio Universitario de Londres; Reino Unido Fil: Ray, Nicolas. Universidad de Ginebra; Suiza Fil: Parra, Maria V.. Colegio Universitario de Londres; Reino Unido. Universidad de Antioquia; Colombia Fil: Rojas, Winston. Colegio Universitario de Londres; Reino Unido. Universidad de Antioquia; Colombia Fil: Duque, Constanza. Universidad de Antioquia; Colombia. Colegio Universitario de Londres; Reino Unido Fil: Mesa, Natalia. Universidad de Antioquia; Colombia. Colegio Universitario de Londres; Reino Unido Fil: García, Luis F.. Universidad de Antioquia; Colombia Fil: Triana, Omar. Universidad de Antioquia; Colombia Fil: Blair, Silvia. Universidad de Antioquia; Colombia Fil: Maestre, Amanda. Universidad de Antioquia; Colombia Fil: Dib, Juan C.. Fundación Salud Para El Tró Pico; Colombia Fil: Bravi, Claudio Marcelo. Colegio Universitario de Londres; Reino Unido. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina Fil: Bailliet, Graciela. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina Fil: Corach, Daniel. Universidad de Buenos Aires; Argentina Fil: Hünemeier, Tábita. Colegio Universitario de Londres; Reino Unido. Universidade Federal do Rio Grande do Sul; Brasil Fil: Bortolini, Maria Cátira. Universidade Federal do Rio Grande do Sul; Brasil Fil: Salzano, Francisco M.. Universidade Federal do Rio Grande do Sul; Brasil Fil: Petzl Erler, María Luiza. Universidade Federal do Paraná; Brasil Fil: Acuña Alonzo, Victor. National Institute Of Anthropology And History; México Fil: Aguilar Salinas, Carlos. Instituto Nacional de la Nutrición Salvador Zubiran; México Fil: Canizales-Quinteros, Samuel. Universidad Nacional Autónoma de México; México Fil: Tusié Luna, Teresa. Universidad Nacional Autónoma de México; México Fil: Riba, Laura. Universidad Nacional Autónoma de México; México Fil: Rodríguez Cruz, Maricela. Umae Hospital de Pediatría Centro Medico Nacional Siglo Xxi; México Fil: Lopez Alarcón, Mardia. Umae Hospital de Pediatría Centro Medico Nacional Siglo Xxi; México Fil: Coral Vazquez, Ramón. Instituto Politécnico Nacional; México

Chronic mountain sickness (CMS) is a major public health problem in mountainous regions of the world. In its more advanced stages, exercise intolerance is often found, but the underlying mechanism is not known. Recent evidence indicates that exercise-induced pulmonary hypertension is markedly exaggerated in CMS. We speculated that this problem may cause pulmonary fluid accumulation and aggravate hypoxemia during exercise.We assessed extravascular lung water (chest ultrasonography), pulmonary artery pressure, and left ventricular function in 15 patients with CMS and 20 control subjects at rest and during exercise at 3,600 m.Exercise at high altitude rapidly induced pulmonary interstitial fluid accumulation in all patients but one (14 of 15) with CMS and further aggravated the preexisting hypoxemia. In contrast, in healthy high-altitude dwellers exercise did not induce fluid accumulation in the majority of subjects (16 of 20) (P = .002 vs CMS) and did not alter arterial oxygenation. Exercise-induced pulmonary interstitial fluid accumulation and hypoxemia in patients with CMS was accompanied by a more than two times larger increase of pulmonary artery pressure than in control subjects (P.001), but no evidence of left ventricular dysfunction. Oxygen inhalation markedly attenuated the exercise-induced pulmonary hypertension (P.01) and interstitial fluid accumulation (P.05) in patients with CMS but had no detectable effects in control subjects.To our knowledge, these findings provide the first direct evidence that exercise induces rapid interstitial lung fluid accumulation and hypoxemia in patients with CMS that appear to be related to exaggerated pulmonary hypertension. We suggest that this problem contributes to exercise intolerance in patients with CMS.ClinicalTrials.gov; No.: NCT01182792; URL: www.clinicaltrials.gov.

Chronic mountain sickness (CMS) is a major public health problem characterized by exaggerated hypoxemia and erythrocytosis. In more advanced stages, patients with CMS often present with functional and structural changes of the pulmonary circulation, but there is little information on the systemic circulation. In patients with diseases associated with chronic hypoxemia at low altitude, systemic vascular function is altered. We hypothesized that patients with CMS have systemic vascular dysfunction that may predispose them to increased systemic cardiovascular morbidity.To test this hypothesis, we assessed systemic endothelial function (by flow-mediated dilation [FMD]), arterial stiffness, and carotid intima-media thickness and arterial oxygen saturation (Sao(2)) in 23 patients with CMS without additional classic cardiovascular risk factors and 27 age-matched healthy mountain dwellers born and permanently living at 3,600 m. For some analyses, subjects were classified according to baseline Sao(2) quartiles; FMD of the highest quartile subgroup (Sao(2) ≥ 90%) was used as a reference value for post hoc comparisons.Patients with CMS had marked systemic vascular dysfunction as evidenced by impaired FMD (CMS, 4.6% ± 1.2%; control subjects, 7.6% ± 1.9%; P.0001), greater pulse wave velocity (10.6 ± 2.1 m/s vs 8.4 ± 1.0 m/s, P.001), and greater carotid intima-media thickness (690 ± 120 μm vs 570 ± 110 μm, P = .001). A positive relationship existed between Sao(2) and FMD (r = 0.62, P.0001). Oxygen inhalation improved (P.001) but did not normalize FMD in patients with CMS, although it normalized FMD in hypoxemic control subjects (Sao(2)90%) and had no detectable effect in normoxemic control subjects (Sao(2) ≥ 90%).Patients with CMS show marked systemic vascular dysfunction. Structural and functional alterations contribute to this problem that may predispose these patients to premature cardiovascular disease.ClinicalTrials.gov; No.: NCT01182792; URL: www.clinicaltrials.gov.

Salinas, Carlo E., Mercedes Villena, Carlos E. Blanco, and Dino A. Giusssani. Adrenocortical suppression in highland chick embryos is restored during incubation at sea level. High Alt. Med. Biol. 12:79-87, 2011.-By combining the chick embryo model with incubation at high altitude, this study tested the hypothesis that development at high altitude is related to a fetal origin of adrenocortical but not adrenomedullary suppression and that hypoxia is the mechanism underlying the relationship. Fertilized eggs from sea-level or high altitude hens were incubated at sea level or high altitude. Fertilized eggs from sea-level hens were also incubated at altitude with oxygen supplementation. At day 20 of incubation, embryonic blood was taken for measurement of plasma corticotropin, corticosterone, and PO2. Following biometry, the adrenal glands were collected and frozen for measurement of catecholamine content. Development of chick embryos at high altitude led to pronounced adrenocortical blunting, but an increase in adrenal catecholamine content. These effects were similar whether the fertilized eggs were laid by sea-level or high altitude hens. The effects of high altitude on the stress axes were completely prevented by incubation at high altitude with oxygen supplementation. When chick embryos from high altitude hens were incubated at sea level, plasma hormones and adrenal catecholamine content were partially restored toward levels measured in sea-level chick embryos. There was a significant correlation between adrenocortical blunting and elevated adrenal catecholamine content with both asymmetric growth restriction and fetal hypoxia. The data support the hypothesis tested and provide evidence to isolate the direct contribution of developmental hypoxia to alterations in the stress system.

We thank Lazdam et al and Yuan et al for their interesting comments on our study.1 Lazdam et al point out that in our study, birth weight in offspring of mothers with preeclampsia was significantly lower than in controls, and suggest that the vascular impairment in offspring was caused by a combination of the independent effects of preeclampsia and intrauterine growth restriction rather than by preeclampsia per se. To test this hypothesis, we performed a subgroup analysis of 15 offspring of mothers with preeclampsia and 15 controls matched for birth weight (3080±291 versus 3077±398 g; P =0.98). We found that the difference in flow-mediated dilation between birth-weight-matched offspring of preeclampsia and controls (6.4%±1.3% versus 8.9%±1.2%; P

Two Bolivian samples belonging to the two main Andean linguistic groups (Aymaras and Quechuas) were studied for mtDNA and Y-chromosome uniparental markers to evaluate sex-specific differences and give new insights into the demographic processes of the Andean region. mtDNA-coding polymorphisms, HVI-HVII control regions, 17 Y-STRs, and three SNPs were typed in two well-defined populations with adequate size samples. The two Bolivian samples showed more genetic differences for the mtDNA than for the Y-chromosome. For the mtDNA, 81% of Aymaras and 61% of Quechuas presented haplogroup B2. Native American Y-chromosomes were found in 97% of Aymaras (89% hg Q1a3a and 11% hg Q1a3*) and 78% of Quechuas (100% hg Q1a3a). Our data revealed high diversity values in the two populations, in agreement with other Andean studies. The comparisons with the available literature for both sets of markers indicated that the central Andean area is relatively homogeneous. For mtDNA, the Aymaras seemed to have been more isolated throughout time, maintaining their genetic characteristics, while the Quechuas have been more permeable to the incorporation of female foreigners and Peruvian influences. On the other hand, male mobility would have been widespread across the Andean region according to the homogeneity found in the area. Particular genetic characteristics presented by both samples support a past common origin of the Altiplano populations in the ancient Aymara territory, with independent, although related histories, with Peruvian (Quechuas) populations. Fil: Gayà Vidal, Magdalena. Universidad de Barcelona; España Fil: Moral, Pedro. Universidad de Barcelona; España Fil: Saenz Ruales, Nancy. Université Paul Sabatier; Francia Fil: Gerbault, Pascale. Universite de Toulouse Iii Paul Sabatier; Francia Fil: Tonasso, Laure. Université Paul Sabatier; Francia Fil: Villena, Mercedes. Universidad Mayor de San Andres; Bolivia Fil: Vasquez, René. Universidad Autonoma Tomas Frias; Bolivia Fil: Bravi, Claudio Marcelo. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata. Instituto Multidisciplinario de Biología Celular. Provincia de Buenos Aires. Gobernación. Comisión de Investigaciones Científicas. Instituto Multidisciplinario de Biología Celular. Universidad Nacional de La Plata. Instituto Multidisciplinario de Biología Celular; Argentina Fil: Dugoujon, Jean Michel. Université Paul Sabatier; Francia

Background— Adverse events in utero may predispose to cardiovascular disease in adulthood. The underlying mechanisms are unknown. During preeclampsia, vasculotoxic factors are released into the maternal circulation by the diseased placenta. We speculated that these factors pass the placental barrier and leave a defect in the circulation of the offspring that predisposes to a pathological response later in life. The hypoxia associated with high-altitude exposure is expected to facilitate the detection of this problem. Methods and Results— We assessed pulmonary artery pressure (by Doppler echocardiography) and flow-mediated dilation of the brachial artery in 48 offspring of women with preeclampsia and 90 offspring of women with normal pregnancies born and permanently living at the same high-altitude location (3600 m). Pulmonary artery pressure was roughly 30% higher (mean±SD, 32.1±5.6 versus 25.3±4.7 mm Hg; P P r =−0.61, P Conclusions— Preeclampsia leaves a persistent defect in the systemic and the pulmonary circulation of the offspring. This defect predisposes to exaggerated hypoxic pulmonary hypertension already during childhood and may contribute to premature cardiovascular disease in the systemic circulation later in life.

Thirty-two polymorphic Alu insertions (18 autosomal and 14 from the X chromosome) were studied in 192 individuals from two Amerindian populations of the Bolivian Altiplano (Aymara and Quechua speakers: the two main Andean linguistic groups), to provide relevant information about their genetic relationships and demographic processes. The main objective was to determine from genetic data whether the expansion of the Quechua language into Bolivia could be associated with demographic (Inca migration of Quechua-speakers from Peru into Bolivia) or cultural (language imposition by the Inca Empire) processes. Allele frequencies were used to assess the genetic relationships between these two linguistic groups. Our results indicated that the two Bolivian samples showed a high genetic similarity for both sets of markers and were clearly differentiated from the two Peruvian Quechua samples available in the literature. Additionally, our data were compared with the available literature to determine the genetic and linguistic structure, and East–West differentiation in South America. The close genetic relationship between the two Bolivian samples and their differentiation from the Quechua-speakers from Peru suggests that the Quechua language expansion in Bolivia took place without any important demographic contribution. Moreover, no clear geographical or linguistic structure was found for the Alu variation among South Amerindians. Am. J. Hum. Biol., 2010. © 2009 Wiley-Liss, Inc.

The compelling evidence linking small size at birth with later cardiovascular disease has renewed and amplified scientific and clinical interests into the determinants of fetal growth. It is accepted that genes and nutrition control fetal growth; however, prior to this study, it had been impossible to isolate the effect of increases and decreases in fetal oxygenation on the regulation of prenatal growth. We investigated the role of oxygen in the control of fetal growth in the chicken because in contrast to mammals, the effects on the fetus of changes in oxygenation could be isolated, by assessing them directly without alteration to the maternal or placental physiology or maternal nutrition during development. The data show that incubation at high altitude of fertilized eggs laid by sea level hens markedly restricted fetal growth. Incubation at high altitude of fertilized eggs laid by high altitude hens also restricted fetal growth, but to a lesser extent compared to eggs laid by sea level hens. By contrast, incubation at sea level of fertilized eggs laid by high altitude hens not only restored, but enhanced, fetal growth relative to sea level controls. Incubation at high altitude of sea level eggs with oxygen supplementation completely prevented the high altitude-induced fetal growth restriction. Thus, fetal oxygenation, independent of maternal nutrition during development, has a predominant role in the control of fetal growth. Further, prolonged high altitude residence confers protection against the deleterious effects of hypoxia on fetal growth.

Studies of high-altitude populations, and in particular of maladapted subgroups, may provide important insight into underlying mechanisms involved in the pathogenesis of hypoxemia-related disease states in general. Over the past decade, studies involving short-term hypoxic exposure have greatly advanced our knowledge regarding underlying mechanisms and predisposing events of hypoxic pulmonary hypertension. Studies in high altitude pulmonary edema (HAPE)-prone subjects, a condition characterized by exaggerated hypoxic pulmonary hypertension, have provided evidence for the central role of pulmonary vascular endothelial and respiratory epithelial nitric oxide (NO) for pulmonary artery pressure homeostasis. More recently, it has been shown that pathological events during the perinatal period (possibly by impairing pulmonary NO synthesis), predispose to exaggerated hypoxic pulmonary hypertension later in life. In an attempt to translate some of this new knowledge to the understanding of underlying mechanisms and predisposing events of chronic hypoxic pulmonary hypertension, we have recently initiated a series of studies among high-risk subpopulations (experiments of nature) of high-altitude dwellers. These studies have allowed to identify novel risk factors and underlying mechanisms that may predispose to sustained hypoxic pulmonary hypertension. The aim of this article is to briefly review this new data, and demonstrate that insufficient NO synthesis/bioavailability, possibly related in part to augmented oxidative stress, may represent an important underlying mechanism predisposing to pulmonary hypertension in high-altitude dwellers.

Studies of high-altitude populations, and in particular of maladapted subgroups, may provide important insight into underlying mechanisms involved in the pathogenesis of hypoxemia-related disease states in general. Over the past decade, studies involving short-term hypoxic exposure have greatly advanced our knowledge regarding underlying mechanisms and predisposing events of hypoxic pulmonary hypertension. Studies in high altitude pulmonary edema (HAPE)-prone subjects, a condition characterized by exaggerated hypoxic pulmonary hypertension, have provided evidence for the central role of pulmonary vascular endothelial and respiratory epithelial nitric oxide (NO) for pulmonary artery pressure homeostasis. More recently, it has been shown that pathological events during the perinatal period (possibly by impairing pulmonary NO synthesis), predispose to exaggerated hypoxic pulmonary hypertension later in life. In an attempt to translate some of this new knowledge to the understanding of underlying mechanisms and predisposing events of chronic hypoxic pulmonary hypertension, we have recently initiated a series of studies among high-risk subpopulations (experiments of nature) of high-altitude dwellers. These studies have allowed to identify novel risk factors and underlying mechanisms that may predispose to sustained hypoxic pulmonary hypertension. The aim of this article is to briefly review this new data, and demonstrate that insufficient NO synthesis/bioavailability, possibly related in part to augmented oxidative stress, may represent an important underlying mechanism predisposing to pulmonary hypertension in high-altitude dwellers.

http://www3.interscience.wiley.com/cgi-bin/jissue/112596548; International audience; Moroccan Berbers and the Bolivian Aymara are two unrelated peasant groups living in adverse environments with a still rather traditional agriculture. Precarious life conditions may be responsible for the importance given to male labor and hence for the cultural preference conferred on male descent. This preference, expressed in the social valorization of sons to the detriment of daughters, is more emphasized if the socioeconomic status of the family is lower. Interpreted according to the cost/benefit approach of Fisher ([1958] Genetical Thoery of Natural Selection, New York: Dover) of variations in the sex ratio and to its later developments (Trivers and Willard [1973] Science 179:90–91; Trivers [1985] Social Evolution, Menlo Park: Benjamin/Cummings; Hewlett [1991] J. Anthropol. Res. 47:1–37; Smith [1993] Ethol. Sociobiol. 14:39–44), these cultural characteristics could determine that parents bias the care allocated to their progeny in favor of sons, to the detriment of daughters. This could eventually affect their respective survival and finally modify the offspring tertiary sex ratio. This study compares differences in survival as indicators of parental care according to a child's sex and across three economic strata: poor, medium, and high. The Moroccan data express no other sex differences in survival than an advantage for daughters during the preweaning period in the medium and high strata. Within the same sex and across economic strata, a greater mortality between age 10–20 years is observed for boys of the poorest stratum. The Aymara data do not show sex differences by economic stratum, except for an advantage to daughters between birth and 5 years in the medium group, and no survival differences within the same sex across economic strata. These results suggest either that despite the social valorization of male progeny no differences in parental care according to sex occur, or that their magnitude is not great enough to contrast the survival of sons and daughters

“Helpers at the nest,” young adults remaining in their parents home to take care of younger siblings, are known in many species of birds and mammals. Similar behaviors are occasionally observed in human societies but their frequency and significance for parental reproductive success are still not fully appraised. This study was designed to document this issue in a traditional Aymara peasant society of the Bolivian Altiplano, It is based on 359 reproductive life histories of women 45 years of age or older and on a survey of children's workload in 1998 and 1999. The presence of “potential helpers” in the household is significantly associated with higher fertility and with improved survival of siblings to sexual maturity. Caretaking is not particularly assigned to older daughters. The positive relationship between the availability of offspring help and reproductive success does not demonstrate a causal role for child caretaking because, in contrast with nonhuman helpers, workloads of children range from housekeeping to agricultural tasks, instead of being focused on feeding or protecting younger siblings. Correlation and multiple regression analyses, however, suggest that the total amount of care given by the older offspring and the amount of care received by each recipient are, along with offspring contribution to household economy, among the determinants of parental reproductive success. Am. J. Hum. Biol. 14:372–379, 2002. © 2002 Wiley-Liss, Inc.

The conditions and duration of high-altitude residence differ among high-altitude populations. The Tibetan Plateau is larger, more geographically remote, and appears to have been occupied for a longer period of time than the Andean Altiplano and, certainly, the Rocky Mountain region as judged by archaeological, linguistic, genetic and historical data. In addition, the Tibetan gene pool is less likely to have been constricted by small numbers of initial migrants and/or severe population decline, and to have been less subject to genetic admixture with lowland groups. Comparing Tibetans to other high-altitude residents demonstrates that Tibetans have less intrauterine growth retardation better neonatal oxygenation higher ventilation and hypoxic ventilatory response lower pulmonary arterial pressure and resistance lower hemoglobin concentrations and less susceptibility to CMS These findings are consistent with the conclusion that "adaptation" to high altitude increases with time, considering time in generations of high-altitude exposure. Future research is needed to compare the extent of IUGR and neonatal oxygenation in South American high-altitude residents of Andean vs. European ancestry, controlling for gestational age and other characteristics. Another fruitful line of inquiry is likely to be determining whether persons with CMS or other altitude-associated problems experienced exaggerated hypoxia during prenatal or neonatal life. Finally, the comparison of high-altitude populations with respect to the frequencies of genes involved in oxygen sensing and physiologic response to hypoxia will be useful, once candidate genes have been identified.

Populations living at high altitudes have an adaptive mechanism to offset hypoxia. Nitric oxide is synthesized in the lungs to help regulate blood flow, and its levels have been found to drop in species native to low altitudes, including humans, upon acute exposure to reduced oxygen concentration1,2,3. But we show here that exhalation of nitric oxide by chronically hypoxic populations of Tibetans living at 4,200 m and of Bolivian Aymara at 3,900 m is unexpectedly increased compared with a low-altitude reference sample from the United States. This consistent response in two far-removed, high-altitude locales indicates that increasing the concentration of nitric oxide in the lungs may represent a means of offsetting hypoxia.

The tendency toward hypertension or higher blood pressure is more common in blacks than whites. The factors that account for these differences are attributed to both environmental and genetic factors. To clarify this issue, an anthropological study of black and nonblack populations in the lowland village of Chicaloma, northeastern Bolivia at a midaltitude of 1,800 m was conducted. The study included 159 subjects, of which 79 were black and 80 were nonblack, 17-78 years. The study suggests the following: (1) the socioeconomic status of blacks as measured by an ownership index is greater than that of nonblacks, (2) blacks had higher average systolic and diastolic blood pressures than nonblacks and showed an age-associated increase in blood pressures, (3) the prevalence of hypertension was higher for blacks (7-6%) than nonblacks (1.3%), but three times lower than among blacks in the United States, (4) skin reflectance is inversely related to blood pressures so that contrary to what has been suggested the darker the skin color, the higher the blood pressures even at comparable levels of affluence. These findings together suggest that genetic factors predispose black individuals to increased blood pressures, but the expression of clinical hypertension is influenced by adverse unaccounted environmental factors. Am. J. Hum. Biol. 11:489-498, 1999. Copyright 1999 Wiley-Liss, Inc.

Nature 488, 370–374 (2012); doi:10.1038/nature11258 At the time of publication of this Letter, the authors were unaware of a manuscript arriving at broadly similar conclusions based on allotype analysis by Williams et al.1, which appeared in the American Journal of Physical Anthropology.