High-Altitude Andean H194R HIF2A Allele Is a Hypomorphic Allele.

For over 10,000 years, Andeans have resided at high altitude where the partial pressure of oxygen challenges human survival. Recent studies have provided evidence for positive selection acting in Andeans on the HIF2A (also known as EPAS1) locus, which encodes for a central transcription factor of the hypoxia-inducible factor pathway. However, the precise mechanism by which this allele might lead to altitude-adaptive phenotypes, if any, is unknown. By analyzing whole genome sequencing data from 46 high-coverage Peruvian Andean genomes, we confirm evidence for positive selection acting on HIF2A and a unique pattern of variation surrounding the Andean-specific single nucleotide variant (SNV), rs570553380, which encodes for an H194R amino acid substitution in HIF-2α. Genotyping the Andean-associated SNV rs570553380 in a group of 299 Peruvian Andeans from Cerro de Pasco, Peru (4,338 m), reveals a positive association with increased fraction of exhaled nitric oxide, a marker of nitric oxide biosynthesis. In vitro assays show that the H194R mutation impairs binding of HIF-2α to its heterodimeric partner, aryl hydrocarbon receptor nuclear translocator. A knockin mouse model bearing the H194R mutation in the Hif2a gene displays decreased levels of hypoxia-induced pulmonary Endothelin-1 transcripts and protection against hypoxia-induced pulmonary hypertension. We conclude the Andean H194R HIF2A allele is a hypomorphic (partial loss of function) allele.

High-Altitude Erythrocytosis: Mechanisms of Adaptive and Maladaptive Responses.

Erythrocytosis, or increased production of red blood cells, is one of the most well-documented physiological traits that varies within and among in high-altitude populations. Although a modest increase in blood O2-carrying capacity may be beneficial for life in highland environments, erythrocytosis can also become excessive and lead to maladaptive syndromes such as chronic mountain sickness (CMS).

Association of EGLN1 gene with high aerobic capacity of Peruvian Quechua at high altitude.

Highland native Andeans have resided at altitude for millennia. They display high aerobic capacity (VO2max) at altitude, which may be a reflection of genetic adaptation to hypoxia. Previous genomewide (GW) scans for natural selection have nominated Egl-9 homolog 1 gene (EGLN1) as a candidate gene. The encoded protein, EGLN1/PHD2, is an O2 sensor that controls levels of the Hypoxia Inducible Factor-α (HIF-α), which regulates the cellular response to hypoxia. From GW association and analysis of covariance performed on a total sample of 429 Peruvian Quechua and 94 US lowland referents, we identified 5 EGLN1 SNPs associated with higher VO2max (L⋅min-1 and mL⋅min-1⋅kg-1) in hypoxia (rs1769793, rs2064766, rs2437150, rs2491403, rs479200). For 4 of these SNPs, Quechua had the highest frequency of the advantageous (high VO2max) allele compared with 25 diverse lowland comparison populations from the 1000 Genomes Project. Genotype effects were substantial, with high versus low VO2max genotype categories differing by ∼11% (e.g., for rs1769793 SNP genotype TT = 34.2 mL⋅min-1⋅kg-1 vs. CC = 30.5 mL⋅min-1⋅kg-1). To guard against spurious association, we controlled for population stratification. Findings were replicated for EGLN1 SNP rs1769793 in an independent Andean sample collected in 2002. These findings contextualize previous reports of natural selection at EGLN1 in Andeans, and support the hypothesis that natural selection has increased the frequency of an EGLN1 causal variant that enhances O2 delivery or use during exercise at altitude in Peruvian Quechua.

Nox2 Upregulation and p38α MAPK Activation in Right Ventricular Hypertrophy of Rats Exposed to Long-Term Chronic Intermittent Hypobaric Hypoxia.

One of the consequences of high altitude (hypobaric hypoxia) exposure is the development of right ventricular hypertrophy (RVH). One particular type of exposure is long-term chronic intermittent hypobaric hypoxia (CIH); the molecular alterations in RVH in this particular condition are less known. Studies show an important role of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase complex-induced oxidative stress and protein kinase activation in different models of cardiac hypertrophy. The aim was to determine the oxidative level, NADPH oxidase expression and MAPK activation in rats with RVH induced by CIH. Male Wistar rats were randomly subjected to CIH (2 days hypoxia/2 days normoxia; n = 10) and normoxia (NX; n = 10) for 30 days. Hypoxia was simulated with a hypobaric chamber. Measurements in the RV included the following: hypertrophy, Nox2, Nox4, p22phox, LOX-1 and HIF-1α expression, lipid peroxidation and H2O2 concentration, and p38α and Akt activation. All CIH rats developed RVH and showed an upregulation of LOX-1, Nox2 and p22phox and an increase in lipid peroxidation, HIF-1α stabilization and p38α activation. Rats with long-term CIH-induced RVH clearly showed Nox2, p22phox and LOX-1 upregulation and increased lipid peroxidation, HIF-1α stabilization and p38α activation. Therefore, these molecules may be considered new targets in CIH-induced RVH.

Exhaled nitric oxide in ethnically diverse high-altitude native populations: A comparative study.

OBJECTIVES: Andean and Tibetan high-altitude natives exhibit a high concentration of nitric oxide (NO) in the lungs, suggesting that NO plays an adaptive role in offsetting hypobaric hypoxia. We examined the exhaled NO concentration as well as partial pressure of several additional high-altitude native populations in order to examine the possibility that this putative adaptive trait, that is, high exhaled NO, is universal. METHODS: We recruited two geographically diverse highland native populations, Tawang Monpa (TM), a Tibetan derived population in North-Eastern India (n = 95, sampled at an altitude of ~3,200 m), and Peruvian Quechua from the highland Andes (n = 412). The latter included three distinct subgroups defined as those residing at altitude (Q-HAR, n = 110, sampled at 4,338 m), those born and residing at sea-level (Q-BSL, n = 152), and those born at altitude but migrant to sea-level (Q-M, n = 150). In addition, we recruited a referent sample of lowland natives of European ancestry from Syracuse, New York. Fraction of exhaled NO concentrations were measured using a NIOX NIMO following the protocol of the manufacturer. RESULTS: Partial pressure of exhaled nitric oxide (PENO) was significantly lower (p < .05) in both high-altitude resident groups (TM = 6.2 ± 0.5 nmHg and Q-HAR = 5.8 ± 0.5 nmHg), as compared to the groups measured at sea level (USA = 14.6 ± 0.7 nmHg, Q-BSL = 18.9 ± 1.6 nmHg, and Q-M = 19.2 ± 1.7 nmHg). PENO was not significantly different between TM and Q-HAR (p < .05). CONCLUSION: In contrast to previous work, we found lower PENO in populations at altitude (compared to sea-level) and no difference in PENO between Tibetan and Andean highland native populations. These results do not support the hypothesis that high nitric oxide in human lungs is a universal adaptive mechanism of highland native populations to offset hypobaric hypoxia.

Towards sustainable partnerships in global health: the case of the CRONICAS Centre of Excellence in Chronic Diseases in Peru.

Human capital requires opportunities to develop and capacity to overcome challenges, together with an enabling environment that fosters critical and disruptive innovation. Exploring such features is necessary to establish the foundation of solid long-term partnerships. In this paper we describe the experience of the CRONICAS Centre of Excellence in Chronic Diseases, based at Universidad Peruana Cayetano Heredia in Lima, Peru, as a case study for fostering meaningful and sustainable partnerships for international collaborative research. The CRONICAS Centre of Excellence in Chronic Diseases was established in 2009 with the following Mission: "We support the development of young researchers and collaboration with national and international institutions. Our motivation is to improve population's health through high quality research." The Centre's identity is embedded in its core values - generosity, innovation, integrity, and quality- and its trajectory is a result of various interactions between multiple individuals, collaborators, teams, and institutions, which together with the challenges confronted, enables us to make an objective assessment of the partnership we would like to pursue, nurture and support. We do not intend to provide a single example of a successful partnership, but in contrast, to highlight what can be translated into opportunities to be faced by research groups based in low- and middle-income countries, and how these encounters can provide a strong platform for fruitful and sustainable partnerships. In defiant contexts, partnerships require to be nurtured and sustained. Acknowledging that all partnerships are not and should not be the same, we also need to learn from the evolution of such relationships, its key successes, hurdles and failures to contribute to the promotion of a culture of global solidarity where mutual goals, mutual gains, as well as mutual responsibilities are the norm. In so doing, we will all contribute to instil a new culture where expectations, roles and interactions among individuals and their teams are horizontal, the true nature of partnerships.

Development of a panel of genome-wide ancestry informative markers to study admixture throughout the Americas.

Most individuals throughout the Americas are admixed descendants of Native American, European, and African ancestors. Complex historical factors have resulted in varying proportions of ancestral contributions between individuals within and among ethnic groups. We developed a panel of 446 ancestry informative markers (AIMs) optimized to estimate ancestral proportions in individuals and populations throughout Latin America. We used genome-wide data from 953 individuals from diverse African, European, and Native American populations to select AIMs optimized for each of the three main continental populations that form the basis of modern Latin American populations. We selected markers on the basis of locus-specific branch length to be informative, well distributed throughout the genome, capable of being genotyped on widely available commercial platforms, and applicable throughout the Americas by minimizing within-continent heterogeneity. We then validated the panel in samples from four admixed populations by comparing ancestry estimates based on the AIMs panel to estimates based on genome-wide association study (GWAS) data. The panel provided balanced discriminatory power among the three ancestral populations and accurate estimates of individual ancestry proportions (R² > 0.9 for ancestral components with significant between-subject variance). Finally, we genotyped samples from 18 populations from Latin America using the AIMs panel and estimated variability in ancestry within and between these populations. This panel and its reference genotype information will be useful resources to explore population history of admixture in Latin America and to correct for the potential effects of population stratification in admixed samples in the region.

Regulation of hepcidin expression at high altitude.

Enhanced erythropoietic drive and iron deficiency both influence iron homeostasis through the suppression of the iron regulatory hormone hepcidin. Hypoxia also suppresses hepcidin through a mechanism that is unknown. We measured iron indices and plasma hepcidin levels in healthy volunteers during a 7-day sojourn to high altitude (4340 m above sea level), with and without prior intravenous iron loading. Without prior iron loading, a rapid reduction in plasma hepcidin was observed that was almost complete by the second day at altitude. This occurred before any index of iron availability had changed. Prior iron loading delayed the decrease in hepcidin until after the transferrin saturation, but not the ferritin concentration, had normalized. We conclude that hepcidin suppression by the hypoxia of high altitude is not driven by a reduction in iron stores.

Andean and Tibetan patterns of adaptation to high altitude.

OBJECTIVES: 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). METHODS: To measure for the effects of EGLN1 and EPAS1 altitude genotypes on hemoglobin concentration among Andean highlanders, we performed a multiple linear regression analysis of 10 candidate SNPs in or near these two genes. RESULTS: Our analysis did not identify significant associations between EPAS1 or EGLN1 SNP genotypes and hemoglobin concentration in Andeans. CONCLUSIONS: These results contribute to our understanding of the unique set of adaptations developed in different highland groups to the hypoxia of high altitude. Overall, the results provide key insights into the patterns of genetic adaptation to high altitude in Andean and Tibetan populations.

Developmental and genetic components explain enhanced pulmonary volumes of female Peruvian Quechua.

High altitude natives have enlarged vital capacities and residual volumes (RV). Because pulmonary volumes are an indication of functionally relevant traits, such as diffusion capacity, the understanding of the factors (genetic/developmental) that influence lung volumes provides insight into the adaptive responses of highlanders. In order to test for the effect of growth and development at high altitude on lung volumes, we obtained forced vital capacities (FVC), RV, and total lung capacities (TLC) for a sample of 65 Peruvian females of mostly Quechua origins (18-34 years) who were sub-divided into two well-matched groups: 1) sea-level born and raised females (BSL, n = 34) from Lima, Peru (150 m), and 2) high-altitude born and raised females (BHA, n = 31) from Cerro de Pasco, Peru (4,338 m). To determine Quechua origins, Native American ancestry proportion (NAAP) for each individual was assessed using a panel of 70 ancestry informative markers. NAAP was similar between groups (BSL = 91.71%; BHA = 89.93%; P = 0.240), and the analysis confirmed predominantly Quechua origins. After adjusting for body size and NAAP, BHA females had significantly higher FVC (3.79 ± 0.06 l; P < 0.001), RV (0.98 ± 0.03 l; P < 0.001) and TLC (4.80 ± 0.07 l; P < 0.001) compared to BSL females (FVC = 3.33 ± 0.05 l; RV = 0.69 ± 0.03 l; TLC = 4.02 ± 0.06 l). NAAP was not associated with FVC (P = 0.352) or TLC (P = 0.506). However, NAAP was positively associated with RV (P = 0.004). In summary, results indicate that developmental exposure to high altitude in females constitutes an important factor for all lung volumes, whereas both genetic and developmental factors seem to be important for RV.

Insufficient yet improving involvement of the global south in top sustainability science publications.

The creation of global research partnerships is critical to produce shared knowledge for the implementation of the UN 2030 Agenda for Sustainable Development. Sustainability science promotes the coproduction of inter- and transdisciplinary knowledge, with the expectation that studies will be carried out through groups and truly collaborative networks. As a consequence, sustainability research, in particular that published in high impact journals, should lead the way in terms of ethical partnership in scientific collaboration. Here, we examined this issue through a quantitative analysis of the articles published in Nature Sustainability (300 papers by 2135 authors) and Nature (2994 papers by 46,817 authors) from January 2018 to February 2021. Focusing on these journals allowed us to test whether research published under the banner of sustainability science favoured a more equitable involvement of authors from countries belonging to different income categories, by using the journal Nature as a control. While the findings provide evidence of still insufficient involvement of Low-and-Low-Middle-Income-Countries (LLMICs) in Nature Sustainability publications, they also point to promising improvements in the involvement of such authors. Proportionally, there were 4.6 times more authors from LLMICs in Nature Sustainability than in Nature articles, and 68.8-100% of local Global South studies were conducted with host country scientists (reflecting the discouragement of parachute research practices), with local scientists participating in key research steps. We therefore provide evidence of the promising, yet still insufficient, involvement of low-income countries in top sustainability science publications and discuss ongoing initiatives to improve this.

Peru - Progress in health and sciences in 200 years of independence.

Peru celebrates 200 years of independence in 2021. Over this period of independent life, and despite the turbulent socio-political scenarios, from internal armed conflict to economic crisis to political instability over the last 40 years, Peru has experienced major changes on its epidemiological and population health profile. Major advancements in maternal and child health as well as in communicable diseases have been achieved in recent decades, and today Peru faces an increasing burden of non-communicable diseases including mental health conditions. In terms of the configuration of the public health system, Peru has also strived to secure country-wide optimal health care, struggling in particular to improve primary health care and intercultural services. The science and technology infrastructure has also evolved, although the need for substantial investments remains if advancing science is to be a national priority. Climate change will also bring significant challenges to population health given Peru's geographical and microclimates diversity. Looking back over the 200-years of independence, we present a summary of key advances in selected health-related fields, thus serving as the basis for reflections on pending agendas and future challenges, in order to look forward to ensuring the future health and wellbeing of the Peruvian population. Resumen translated abstract: El Perú cumple 200 años de independencia en 2021. Durante estos dos siglos de vida independiente, junto con periodos sociales y políticos turbulentos, incluyendo un conflicto armado interno, hiperinflación y la inestabilidad política de los últimos 40 años, el Perú ha experimentado importantes cambios en su perfil epidemiológico con repercusiones directas en la salud de la población. En las últimas décadas, los indicadores de salud materno-infantil y de las enfermedades transmisibles muestran mejoría importante, pero el país se enfrenta de manera simultánea a una carga cada vez mayor de enfermedades no transmisibles y de salud mental. En cuanto a los sistemas de salud pública, se han realizado esfuerzos por aumentar la cobertura y calidad de la atención de salud en todo el país, apostándose en particular por mejorar la atención primaria. La ciencia y tecnología relacionadas con la salud también han mejorado, aunque si se quiere que la ciencia sea una prioridad nacional, son necesarias inversiones sustanciales. El cambio climático traerá importantes desafíos para la salud de la población, dada la diversidad geográfica y de microclimas del país. Para conmemorar los 200 años de vida independiente del Perú, presentamos un resumen de avances clave en diversas áreas y temas relacionados con la salud. Este repaso sirve como base para reflexionar sobre agendas y desafíos pendientes y futuros, con el fin de asegurar la salud y el bienestar de la población peruana en las próximas décadas.

Genome-Wide Epigenetic Signatures of Adaptive Developmental Plasticity in the Andes.

High-altitude adaptation is a classic example of natural selection operating on the human genome. Physiological and genetic adaptations have been documented in populations with a history of living at high altitude. However, the role of epigenetic gene regulation, including DNA methylation, in high-altitude adaptation is not well understood. We performed an epigenome-wide DNA methylation association study based on whole blood from 113 Peruvian Quechua with differential lifetime exposures to high altitude (>2,500) and recruited based on a migrant study design. We identified two significant differentially methylated positions (DMPs) and 62 differentially methylated regions (DMRs) associated with high-altitude developmental and lifelong exposure statuses. DMPs and DMRs were found in genes associated with hypoxia-inducible factor pathway, red blood cell production, blood pressure, and others. DMPs and DMRs associated with fractional exhaled nitric oxide also were identified. We found a significant association between EPAS1 methylation and EPAS1 SNP genotypes, suggesting that local genetic variation influences patterns of methylation. Our findings demonstrate that DNA methylation is associated with early developmental and lifelong high-altitude exposures among Peruvian Quechua as well as altitude-adaptive phenotypes. Together these findings suggest that epigenetic mechanisms might be involved in adaptive developmental plasticity to high altitude. Moreover, we show that local genetic variation is associated with DNA methylation levels, suggesting that methylation associated SNPs could be a potential avenue for research on genetic adaptation to hypoxia in Andeans.

Blood lead levels in Peruvian adults are associated with proximity to mining and DNA methylation.

BACKGROUND: Inorganic lead (Pb) is common in the environment, and is toxic to neurological, renal, and cardiovascular systems. Pb exposure influences the epigenome with documented effects on DNA methylation (DNAm). We assessed the impact of low levels of Pb exposure on DNAm among non-miner individuals from two locations in Peru: Lima, the capital, and Cerro de Pasco, a highland mining town, to study the effects of Pb exposure on physiological outcomes and DNAm. METHODS: Pb levels were measured in whole blood (n = 305). Blood leukocyte DNAm was determined for 90 DNA samples using the Illumina MethylationEPIC chip. An epigenome-wide association study was performed to assess the relationship between Pb and DNAm. RESULTS: Individuals from Cerro de Pasco had higher Pb than individuals from Lima (p-value = 2.00E-16). Males had higher Pb than females (p-value = 2.36E-04). Pb was positively associated with hemoglobin (p-value = 8.60E-04). In Cerro de Pasco, blood Pb decreased with the distance from the mine (p-value = 0.04), and association with soil Pb was approaching significance (p-value = 0.08). We identified differentially methylated positions (DMPs) associated with genes SOX18, ZMIZ1, and KDM1A linked to neurological function. We also found 45 differentially methylated regions (DMRs), seven of which were associated with genes involved in metal ion binding and nine to neurological function and development. CONCLUSIONS: Our results demonstrate that even low levels of Pb can have a significant impact on the body including changes to DNAm. We report associations between Pb and hemoglobin, Pb and distance from mining, and between blood and soil Pb. We also report associations between loci- and region-specific DNAm and Pb.

High-Altitude Hypoxia Decreases Plasma Erythropoietin Soluble Receptor Concentration in Lowlanders.

Background: The soluble form of the erythropoietin (Epo) receptor (sEpoR) is an endogenous antagonist of Epo. Decreasing plasma sEpoR increases free Epo, thereby increasing the availability of the hormone. In humans, short-term intermittent normobaric hypoxia exposure reduces sEpoR concentration in plasma. However, whether similar changes occur during continuous hypoxia, such as during high-altitude exposure with ongoing acclimatization, is yet unknown. Therefore, this study aimed to characterize the time-course concentration profile of sEpoR, and also of Epo, reticulocyte count (RC), and hematocrit in healthy lowlanders during 4 days at high altitude. Methods: Twenty-two men residents at sea level traveled by road (∼7 hours) from Lima to Cerro de Pasco (4340 m) for 72 hours. Oxygen saturation as measured by pulse oximetry (SpO2), heart rate, systolic and diastolic blood pressure, Lake Louise Score, sEpoR, Epo, RC, and hematocrit were evaluated every 12 hours, starting 12 hours before the ascent. Results: Plasma sEpoR decreased by 19% and remained below baseline values throughout high-altitude exposure. In parallel, Epo levels increased during the first hours, reaching a peak at 48 hours, and then progressively decreased until 72 hours. As a result, the Epo-to-sEpoR ratio (Epo/sEpoR) remained significantly elevated compared with baseline values. RC increased linearly until the end of the protocol, and hematocrit only showed a marginal increase. Conclusion: Our results show that high-altitude hypoxia causes a significant and stable reduction of plasma sEpoR concentration within the first 24 hours, whereas plasma Epo constantly decreases after having reached a maximum by 48 hours. This simultaneous change leads to a relatively high Epo/sEpoR after 72 hours at high altitude. The early increase in hematocrit likely relates to hemoconcentration, but the steady increase in RC reflects a sustained erythropoietic drive that will lead to elevate hematocrit to a new steady state after acclimatization.

Lower Body Weight in Rats Under Hypobaric Hypoxia Exposure Would Lead to Reduced Right Ventricular Hypertrophy and Increased AMPK Activation.

BACKGROUND: Both chronic hypoxia (CH) and long-term chronic intermittent hypoxia (CIH) exposure lead to right ventricular hypertrophy (RVH). Weight loss is an effective intervention to improve cardiac function and energy metabolism in cardiac hypertrophy. Likewise, caloric restriction (CR) also plays an important role in this cardioprotection through AMPK activation. We aimed to determine the influence of body weight (BW) on RVH, AMPK and related variables by comparing rats exposed to both hypoxic conditions. METHODS: Sixty male adult rats were separated into two groups (n = 30 per group) according to their previous diet: a caloric restriction (CR) group and an ad libitum (AL) group. Rats in both groups were randomly assigned to 3 groups: a normoxic group (NX, n = 10), a CIH group (2 days hypoxia/2 days normoxia; n = 10) and a CH group (n = 10). The CR group was previously fed 10 g daily, and the other was fed ad libitum. Rats were exposed to simulated hypobaric hypoxia in a hypobaric chamber set to 428 Torr (the equivalent pressure to that at an altitude of 4,600 m above sea level) for 30 days. Measurements included body weight; hematocrit; serum insulin; glycemia; the degree of RVH (Fulton's index and histology); and AMPK, mTOR, and PP2C expression levels in the right ventricle determined by western blotting. RESULTS: A lower degree of RVH, higher AMPK activation, and no activation of mTOR were found in the CR groups exposed to hypobaric hypoxia compared to the AL groups (p < 0.05). Additionally, decreased glycemia and serum insulin levels were observed. Interestingly, PP2C expression showed an increase in the AL groups but not in the CR groups (p < 0.05). CONCLUSION: Maintaining a low weight before and during exposure to high-altitude hypoxia, during either CH or CIH, could prevent a major degree of RVH. This cardioprotection would likely be due to the activation of AMPK. Thus, body weight is a factor that might contribute to RVH at high altitudes.

Developing capacity in health informatics in a resource poor setting: lessons from Peru.

The public sectors of developing countries require strengthened capacity in health informatics. In Peru, where formal university graduate degrees in biomedical and health informatics were lacking until recently, the AMAUTA Global Informatics Research and Training Program has provided research and training for health professionals in the region since 1999. The Fogarty International Center supports the program as a collaborative partnership between Universidad Peruana Cayetano Heredia in Peru and the University of Washington in the United States of America. The program aims to train core professionals in health informatics and to strengthen the health information resource capabilities and accessibility in Peru. The program has achieved considerable success in the development and institutionalization of informatics research and training programs in Peru. Projects supported by this program are leading to the development of sustainable training opportunities for informatics and eight of ten Peruvian fellows trained at the University of Washington are now developing informatics programs and an information infrastructure in Peru. In 2007, Universidad Peruana Cayetano Heredia started offering the first graduate diploma program in biomedical informatics in Peru.

Acetazolamide for Monge's disease: efficiency and tolerance of 6-month treatment.

RATIONALE: Monge's disease is characterized by an excessive erythrocytosis, frequently associated with pulmonary hypertension, in high-altitude dwellers. It has a considerable impact on public health in high-altitude regions. A preliminary study demonstrated the efficiency of acetazolamide (Acz) (250 mg/d for 3 wk) in reducing serum erythropoietin and hematocrit. OBJECTIVES: Evaluate the efficacy and tolerance of a 6-month treatment with 250 mg Acz that could be chronically implemented and its effects on pulmonary artery pressure and cardiac function. METHODS: A two-phase study was performed in patients (hematocrit > or = 63%) from Cerro de Pasco, Peru (4,300 m). First phase: a double-blind, placebo-controlled study in 55 patients who received a single dose of either 250 mg Acz (n = 40) or placebo (n = 15) by daily oral administration for 12 weeks. Second phase (open label): after a 4-week washout period, all patients received 250 mg Acz for 12 weeks. Hematocrit, blood gases, clinical outcome, and pulmonary artery circulation were evaluated. MEASUREMENTS AND MAIN RESULTS: First phase: Acz decreased by 44% the number of polycythemic subjects (P = 0.02), decreased hematocrit from 69 to 64% (P < 0.001), and increased arterial O(2) pressure from 42 to 45 mm Hg (P < 0.001). No severe adverse effect or hypokalemia was recorded. The second phase reproduced the effects observed during the first phase, without cumulative effects on hematocrit. A 4-week washout restored basal hematocrit. Only patients who received Acz for 6 months showed a clear reduction in pulmonary vascular resistance. CONCLUSIONS: Acz reduces erythrocytosis and improves pulmonary circulation in Monge's disease without adverse effects. Its implementation as a chronic treatment for this disease appears efficient and safe.

Effects of iron supplementation and depletion on hypoxic pulmonary hypertension: two randomized controlled trials.

CONTEXT: Hypoxia is a major cause of pulmonary hypertension in respiratory disease and at high altitude. Recent work has established that the effect of hypoxia on pulmonary arterial pressure may depend on iron status, possibly acting through the transcription factor hypoxia-inducible factor, but the pathophysiological and clinical importance of this interaction is unknown. OBJECTIVE: To determine whether increasing or decreasing iron availability modifies altitude-induced hypoxic pulmonary hypertension. DESIGN, SETTING, AND PARTICIPANTS: Two randomized, double-blind, placebo-controlled protocols conducted in October-November 2008. In the first protocol, 22 healthy sea-level resident men (aged 19-60 years) were studied over 1 week of hypoxia at Cerro de Pasco, Peru (altitude 4340 m). In the second protocol, 11 high-altitude resident men (aged 30-59 years) diagnosed with chronic mountain sickness were studied over 1 month of hypoxia at Cerro de Pasco, Peru. INTERVENTION: In the first protocol, participants received intravenous infusions of Fe(III)-hydroxide sucrose (200 mg) or placebo on the third day of hypoxia. In the second protocol, patients underwent staged isovolemic venesection of 2 L of blood. Two weeks later, patients received intravenous infusions of Fe(III)-hydroxide sucrose (400 mg) or placebo, which were subsequently crossed over. MAIN OUTCOME MEASURE: Effect of varying iron availability on pulmonary artery systolic pressure (PASP) assessed by Doppler echocardiography. RESULTS: In the sea-level resident protocol, approximately 40% of the pulmonary hypertensive response to hypoxia was reversed by infusion of iron, which reduced PASP by 6 mm Hg (95% confidence interval [CI], 4-8 mm Hg), from 37 mm Hg (95% CI, 34-40 mm Hg) to 31 mm Hg (95% CI, 29-33 mm Hg; P = .01). In the chronic mountain sickness protocol, progressive iron deficiency induced by venesection was associated with an approximately 25% increase in PASP of 9 mm Hg (95% CI, 4-14 mm Hg), from 37 mm Hg (95% CI, 30-44 mm Hg) to 46 mm Hg (95% CI, 40-52 mm Hg; P = .003). During the subsequent crossover period, no acute effect of iron replacement on PASP was detected. CONCLUSION: Hypoxic pulmonary hypertension may be attenuated by iron supplementation and exacerbated by iron depletion. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00952302.