Altitude Polycythemia Research Articles

Elevated pentose phosphate pathway is involved in the recovery of hypoxia‑induced erythrocytosis.

As a typical model of hypoxia-induced excessive erythrocytosis, high altitude polycythemia (HAPC) results in microcirculation disturbance, aggravates tissue hypoxia and results in a severe clinical outcome, without any effective intervention methods except for returning to an oxygen-rich environment. The present study aimed to explore potential therapeutic targets which may participate in the recovery of HAPC by studying the mechanisms of reducing the hemoglobin (HB) concentration during re-oxygenation. A total of 14 and 13 subjects were recruited over a 5,300 m distance and 5,170 m area. The patients were classified into HAPC or control groups based on their HB value. Plasma samples were collected on the day when they finished their stay in plateau for a year, and on the 180th day following their reaching in plain. Metabolic profiling was conducted by UPLC-QTOF/MS. MetaboAnalyst platform was performed to explore the most perturbed metabolic pathways. A panel of differential metabolites were obtained in the recovery phase of HAPC and control groups. The present study identified the uniquely upregulated pentose phosphate pathway in HAPC subjects, along with a significantly decreased HB level. The findings were verified via a direct comparison between HAPC and control subjects at a high altitude. An increased pentose phosphate pathway was identified in control groups compared with HAPC subjects. An elevated pentose phosphate pathway may therefore participate in the recovery of HAPC, whereas a downregulated pentose phosphate pathway may contribute to hypoxia-induced erythrocytosis. The results of the present study provide potential therapeutic strategies and novel insights into the pathogenesis of hypoxia-induced polycythemia.

GW28-e0446 Traditional Tibetan medicine Corydalis hendersonii exerts anti-myocardial ischemia effect by attenuating inflammation and fibrosis in acute myocardial infarction mice

Corydalis hendersonii Hemsl. (CH) has been used for centuries in China largely for the treatment of high altitude polycythemia, hypertension, hepatitis, edema, gastritis, and other infectious diseases, but never employed for coronary heart diseases. The current study is to investigate the

Associations of high altitude polycythemia with polymorphisms in EPAS1, ITGA6 and ERBB4 in Chinese Han and Tibetan populations.

High altitude polycythemia (HAPC) is a common chronic disease at high altitude, which is characterized by excessive erythrocytosis (females, hemoglobin ≥ 190 g/L; males, hemoglobin ≥ 210 g/L). It is the most common disease in chronic mountain sickness casued primarily by persistent arterial hypoxia and ventilatory impairment. However, the disease is still unmanageable and related molecular mechanisms remain largely unclear. This study aims to explore the genetic basis of HAPC in the Chinese Han and Tibetan populations. Subjects were screened for HAPC using the latest approved diagnostic criteria. To explore the hereditary basis of HAPC and investigate the association between three genes (EPAS1, ITGA6, ERBB4) and HAPC in Chinese Han and Tibetan populations. We enrolled 100 patients (70 Han, 30 Tibetan) with HAPC and 100 healthy control subjects (30 Han, 70 Tibetan). Subjects were screened for HAPC using the latest approved diagnostic criteria combined with excessive erythrocytosis and clinical symptoms. Analysis of variance was used to evaluate the impact of polymorphism on HAPC based on genetic variation. The Chi-squared test and analyses of genetic models, rs75591953 and rs75984373 in EPAS1, rs6744873 in ITGA6, rs17335043 in ERBB4 showed associations with reduced HAPC susceptibility in Han populations. Additionally, in Tibetan populations, rs3749148 in ITGA6, rs934607 and rs141267844 in ERBB4 showed a reduced risk of HAPC, whereas rs6710946 in ERBB4 increased the risk of HAPC. Our study suggest that the polymorphisms in the EPAS1, ITGA6 and ERBB4 correlate with susceptibility to HAPC.

Corydalis hendersonii Hemsl. protects against myocardial injury by attenuating inflammation and fibrosis via NF-κB and JAK2-STAT3 signaling pathways

Ethnopharmacological relevanceCorydalis hendersonii Hemsl. (CH) with heat clearing and detoxifying effects are well described in Tibetan folk medicine. It has been used for centuries in China largely for the treatment of high altitude polycythemia, a pathophysiological condition referred to “plethora” in Tibetan medicine, hypertension, hepatitis, edema, gastritis, and other infectious diseases. Aim of the studyTo investigate the cardioprotective effects of Corydalis hendersonii extract in an ICR mouse model of myocardial ischemic injury. Materials and methodsEthanol [85% (v/v)] extract of CH whole plant was prepared, and their chemical profile was analyzed with use of HPLC-DAD and IT-TOF-ESI-MS. A mouse model of AMI was established by ligation of the left ventricular dysfunction (LAD) coronary artery. Mice were randomly divided into six groups (n = 12 per group): sham group, model group, CH groups treated with three doses of CH (100, 200, and 400mg/kg, intragastric), and a positive control group (captopril, 16.67mg/kg, intragastric). Heart function was evaluated by measurement of ejection fraction (EF) and fractional shortening (FS) by echocardiography. Serum levels of creatine kinase-MB (CK-MB) and lactate dehydrogenase (LDH), plasma levels of angiotensin II (AngII), tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), interleukin-1ß (IL-1ß) and expressions of matrix metalloproteinase-2 (MMP-2) and MMP-9 in the cardiac tissue homogenate, protein expressions of signal-transduction proteins, p65, IκBα, JAK2, and STAT3 in heart tissues were measured by ELISA and Western blot analyses. Inflammatory cell infiltration and changes in collagen deposition in the myocardial ischemic heart tissues were observed by histopathological examination. Platelet aggregation in vitro was also assessed. ResultsCH treatment showed a dose-dependent cardioprotective effect. It significantly reduced left ventricular end-diastolic diameter (LVEDd) and left ventricular end-diastolic diameter (LVEDs), improved EF and FS as compared to those in the model group; attenuated the increase levels of CK-MB and LDH in serum; reduced expressions of AngII, TNF-α, IL-6 and IL-1ß in plasma, MMP-2 and MMP-9 expressions in the cardiac tissue homogenate; and down-regulated myocardial expressions of p-p65, p-IκBα, p-JAK2, p-STAT3, MMP-2, and MMP-9 in AMI mice. Also, an obvious reduction in inflammatory cell infiltration in the myocardial infarct was found in all CH treated groups. Besides, CH also inhibited platelet aggregation induced by THR, ADP, and AA. ConclusionCH extract exerted a protective effect against myocardial ischemic injury via inhibition of inflammation, myocardial fibrosis, and platelet aggregation. This study demonstrates such protection for the first time and provides a basis for development of CH-based drugs for treatment of ischemic heart disease in clinical settings.

Associations of high altitude polycythemia with polymorphisms in EPHA2 and AGT in Chinese Han and Tibetan populations.

High altitude polycythemia (HAPC) refers to the long-term living in the plateau of the hypoxia environment is not accustomed to cause red blood cell hyperplasia. The pathological changes are mainly the various organs and tissue congestion, blood stasis and hypoxia damage. Although chronic hypoxia is the main cause of HAPC, the related molecular mechanisms remain largely unclear. This study aims to explore the genetic basis of HAPC in the Chinese Han and Tibetan populations. We enrolled 100 patients (70 Han, 30 Tibetan) with HAPC and 100 healthy control subjects (30 Han, 70 Tibetan). To explore the hereditary basis of HAPC and investigate the association between EPHA2 with AGT and HAPC in Chinese Han and Tibetan populations. Using the Chi-squared test and analyses of genetic models, rs2291804, rs2291805, rs3768294, rs3754334, rs6603856, rs6669624, rs11260742, rs13375644 and rs10907223 in EPHA2, and rs699, rs4762 and rs5051 in AGT showed associations with reduced HAPC susceptibility in Han populations. Additionally, in Tibetan populations, rs2478523 in AGT showed an increased the risk of HAPC. Our study suggest that polymorphisms in the EPHA2 and AGT correlate with susceptibility to HAPC in Chinese Han and Tibetan populations.

Effect of PD98059 on Proliferation and Apoptosis of CD71(+),CD235a(+) Nucleated Erythrocytes in the Patients with High Altitude Polycythemia

Objective： To study the effect of PD98059, a specific inhibitor of Ras/Raf/MEK/ERK signaling pathway, on the proliferation and apoptisis of bone marrow CD71(+), CD235a(+) nucleated erythrocytes in patients with high altitude polycythemia (HAPC) and the pathogenesis of HAPC. The CD71(+) and CD235a(+) nucleated erythrocytes in HAPC patients and controls (patients with simple obsolete stracture) were sorted by using the immunemagnetic beads, then were added with 5, 10, 20 µmol/L of PD98059 and DMSO (as control) and were cultured for 72 h under hypoxia. The cell apoptosis was detected by flow cytometry with Annexin V and PI double staining, the cell proliferation was detected by CCK8 method, at same time the erythroid colong-formation ability of bone marrow mononuclear cells (BMMNC) treated with 5, 10, 20 µmol/L of PD98059 and DMSO was observed. With the increase of PD98059 concentration, the apoptosis rate of bone marrow CD71(+) and CD235a(+) nucleated erythrocytes in HAPC patients was enhanced (r=0.807,P<0.01), while the proliferation rate of CD71(+) and CD235a(+) nucleated erythrocytes in HAPC patients dereased (r=0.502,P<0.01). The erythroid colong-formation ability of BMMNC in HAPC patients decreased with the increase of PD98059 concentration (r=0.504,P<0.01). There were statistic differences among different groups at 7 and 14 d. The MEK specific inhibitor PD98059 can inhibit the proliferation and promote the apoptosis of CD71(+) and CD235a(+) nucleated erythrocytes in HAPC patients, then inhibit the excessive accumulation of erythrocytes.

Influence of HIF- 2α on the expression of GATA- 1 in bone marrow CD71(+) cell of high altitude polycythemia rat model

目的探讨低氧诱导因子-2α（HIF-2α）对高原红细胞增多症（HAPC）模型大鼠骨髓CD71+细胞红系特异性转录因子GATA-1表达的影响。方法选用雄性SD大鼠48只，随机分为低海拔对照组（海拔2 250 m饲养）和HAPC模型组（海拔4 300 m饲养）。在海拔4 300 m自然环境下复制HAPC大鼠模型并采用骨髓细胞分类计数、血液学参数和血清红细胞生成素（EPO）检测进行验证。应用密度梯度离心和免疫磁珠分选相结合的方法分选大鼠骨髓CD71+细胞，Q-PCR和Western blot法检测其HIF-2α、GATA-1 mRNA和蛋白的表达。低氧培养CD71+细胞，以最佳干扰序列HIF-2α shRNAi3转染96 h, Q-PCR和Western blot检测HIF-2α、GATA-1 mRNA和蛋白的表达水平。结果骨髓细胞分类计数、血液学参数和血清EPO含量测定结果提示HAPC大鼠模型复制成功。HAPC模型组骨髓CD71+细胞HIF-2α、GATA-1 mRNA和蛋白的表达高于低海拔对照组，且HIF-2α与GATA-1在mRNA和蛋白表达均呈正相关（r＝0.923，P<0.01；r＝0.838，P<0.01）。HIF-2α shRNAi3干扰HAPC模型组骨髓CD71+细胞96 h后，HIF-2α、GATA-1 mRNA和蛋白的表达均低于空白对照组和阴性对照组。结论HIF-2α对GATA-1表达的影响可能与HAPC的发生发展相关。

Influence of GATA-1 on Expression of EpoR in Bone Marrow CD71+ Cells of Rat Model with High Altitude Polycythemia

To explore the influence of GATA-1 on expression of EpoR in bone marrow CD71+ cells of rat model with high altitude polycythemia (HAPC). Forty-eight male SD rats were randomly divided into normal control and HAPC model group. HAPC model was established at the altitude of 4 300 meters in the natural environment, and verified by bone marrow cell counts and hematological parameters. Myeloid CD71+ cells were separated by the density gradient centrifugation combined with magnetic activated cell sorting. The expression of EpoR on cell membrane was detected by flow cytometry and cell immunofluorescence. The expression changes of GATA-1 and EpoR mRNA and protein were detected by Q-PCR and Western blot, respectively. CD71+ cells were cultured under normoxia and hypoxia, respectively. After transfection for 96 h, the optimal interference sequence GATA-1 shRNA1 was selected. And the mRNA and protein expression level of GATA-1 and EpoR were detected by Q-PCR and Western blot respectively. The animal model with HAPC was established successfully and comfirmed by the bone marrow cell counting and the hematologic parameters in comparison with that of the normal control. EpoR expression on the myeloid CD71+ cell membrane in HAPC group was significantly higher than that in normal control (P<0.05). The expression of GATA-1 and EpoR in myeloid CD71+ cells of HAPC group was higher than that in control group (P<0.05). The mRNA and protein expression of GATA-1 and EpoR in two groups positively correlated (control group, r=0.929, P<0.01, r=0.802, P<0.05; HAPC group, r=0.822, P<0.05, r=0.839, P<0.01). However, the mRNA and protein expression of EpoR at normoxia and hypoxia was significantly lower than that in negative control group after interfernce with GATA-1 shRNA1 for 96 h (P<0.05). And the expression of GATA-1 and EpoR under hypoxia was higher than that in normoxia. The effect of GATA-1 on EpoR expression may be correlated with the pathogenesis of HAPC.

Protective effects of traditional Tibetan medicine Zuo-Mu-A Decoction () on the blood parameters and myocardium of high altitude polycythemia model rats.

To explore the protective effects of Tibetan medicine Zuo-Mu-A Decoction (, ZMAD) on the blood parameters and myocardium of high altitude polycythemia (HAPC) model rats. Forty male Wistar rats were randomly divided into 4 groups by a random number table, including the normal, model, Rhodiola rosea L. (RRL) and ZMAD groups (10 in each group). Every group was raised in Lhasa to create a HAPC model except the normal group. After modeling, rats in the RRL and the ZMAD groups were administered intragastrically with RRL (20 mL/kg) and ZMAD (7.5 mL/kg) once a day for 2 months, respectively; for the normal and the model groups, 5 mL of distilled water was administered intragastrically instead of decoction. Then routine blood and hematologic rheology parameters were taken, levels of erythropoietin and 8-hydroxy-2'-deoxyguanosine (8-OHdG) were tested, and ultrastructural change in the left ventricular myocardium was observed using transmission electron microscopy. Compared with the model group, ZMAD significantly reduced the red blood cell count, hemoglobin levels, whole blood viscosity at low/middle shear rates, plasma viscosity, erythrocyte electrophoretic time, erythropoietin and 8-OHdG levels, and also increased the erythrocyte deformation index (P<0.05). There was no difference in all results between the RRL and the ZMAD groups. The cardiac muscle fibers were well-protected, mitochondrial matrix swelled mildly and ultrastructure changes were less prominent in the ZMAD group compared with the model group. ZMAD has significant protective effects on the blood parameters against HAPC, and also has the beneficial effect in protecting against myocardial injury.

Interaction of CARD14, SENP1 and VEGFA polymorphisms on susceptibility to high altitude polycythemia in the Han Chinese population at the Qinghai–Tibetan Plateau

High altitude polycythemia (HAPC) is a serious public health problem among Han Chinese immigrants to the Qinghai–Tibetan Plateau. This study aims to explore the genetic basis of HAPC in the Han Chinese population. 484 male subjects (234 patients and 250 controls) were enrolled in this study. Genotyping was performed for polymorphisms of I/D in ACE, C1772T and G1790A in exon 12 of HIF-1α, rs2567206 in CYP1B1, rs726354 in SENP1, rs3025033 in VEGFA, rs7251432 in HAMP, rs2075800 in HSPA1L and rs8065364 in CARD14. Gene–gene interaction was assessed by multifactor dimensionality reduction. A significant association was seen between CARD14 polymorphism rs8065364 and risk of HAPC development in male Han Chinese, and the C allele of rs8065364 was a risk factor (odds ratio (OR)=1.59, 95% confidence interval (95% CI)=1.21–2.08). Gene–gene interaction analysis indicated that a synergistic relationship existed between rs3025033 and rs8065364 (1.00%), rs3025033 and rs726354 (0.18%), and rs726354 and rs8065364 (0.17%). The combination of rs8065364 in CARD14, rs3025033 in VEGFA and rs726354 in SENP1 was the best model to predict HAPC development in this study (testing accuracy=0.6183, p=0.0010, cross-validated consistency=10/10). Genetic interactions of SNPs in CARD14, SENP1 and VEGFA might represent a functional mechanism in the pathogenesis of HAPC.

CYP17A1 and CYP2E1 variants associated with high altitude polycythemia in Tibetans at the Qinghai-Tibetan Plateau

Tibetans adapt to high altitude environments through low blood hemoglobin concentrations. Previous work has identified that CYP17A1 and CYP2E1 genes exhibit evidence of local positive selection for this Tibetan high-altitude adaptation. Nevertheless, despite this apparent genetic advantage, some Tibetans still develop high altitude polycythemia (HAPC) yet the reasons for this remain unknown. We sought to determine if polymorphisms in CYP17A1 and CYP2E1 genes were associated with susceptibility to HAPC in Tibetans at the Qinghai-Tibetan Plateau in China. We enrolled 63 Tibetan HAPC patients and 131 healthy, age- and gender-matched control Tibetans. All subjects are from the Yushu area of Qinghai where the altitude is over 3500m. Three SNPs of the CYP17A1 including rs3781287, rs11191548 and rs1004467, and four SNPs of CYP2E1 gene, including rs1536836, rs3813865, rs3813867 and rs743535, were genotyped by the Sequenom MassARRAY SNP assays. We discovered that SNP rs1004467 of the CYP17A1 gene and SNP rs3813865 of the CYP2E1 gene were significantly associated with HAPC risk. Furthermore, we identified a positive correlation between these two SNPs and plasma hemoglobin levels. Thus, taken together, our study is the first to our knowledge to show that polymorphisms in the rs1004467 SNP of CYP17A1 and rs3813865 SNP of CYP2E1 correlate with susceptibility to HAPC.

EPAS1 Gene Polymorphisms Are Associated With High Altitude Polycythemia in Tibetans at the Qinghai-Tibetan Plateau

To test the hypothesis that the polymorphisms in the EPAS1 gene are associated with the susceptibility to high altitude polycythemia (HAPC) in Tibetans at the Qinghai-Tibetan Plateau. We enrolled 63 Tibetan HAPC patients and 131 matched healthy Tibetans as a control group, from the Yushu area in Qinghai where the altitude is greater than 3500 m. Eight single-nucleotide polymorphisms (SNPs) of the EPAS1 gene, including rs12619696, rs13420857, rs2881504, rs4953388, rs13419896, rs4953354, rs10187368, and rs7587138, were genotyped by the Sequenom MassARRAY SNP assay. The frequencies of the G allele of EPAS1 SNP rs13419896 were significantly higher in the HAPC group than in the control group (P < .05). Moreover, the A alleles of rs12619696 and rs4953354 were prevalent in the HAPC group, and their counterpart homozygotes were prevalent in the normal Tibetan group (P < .05). Compared with normal Tibetans, Tibetans with HAPC are maladapted and have a different haplotype in EPAS1 SNPs rs12619696, rs13419896, and rs4953354.

An EPAS1 Haplotype Is Associated With High Altitude Polycythemia in Male Han Chinese at the Qinghai-Tibetan Plateau

Hemoglobin concentration at high altitude is considered an important marker of high altitude adaptation, and native Tibetans in the Qinghai-Tibetan plateau show lower hemoglobin concentrations than Han people who have emigrated from plains areas. Genetic studies revealed that EPAS1 plays a key role in high altitude adaptation and is associated with the low hemoglobin concentration in Tibetans. Three single nucleotide polymorphisms (rs13419896, rs4953354, rs1868092) of noncoding regions in EPAS1 exhibited significantly different allele frequencies in the Tibetan and Han populations and were associated with low hemoglobin concentrations in Tibetans. To explore the hereditary basis of high altitude polycythemia (HAPC) and investigate the association between EPAS1 and HAPC in the Han population, these 3 single nucleotide polymorphisms were assessed in 318 male Han Chinese HAPC patients and 316 control subjects. Genotyping was performed by high resolution melting curve analysis. The G-G-G haplotype of rs13419896, rs4953354, and rs1868092 was significantly more frequent in HAPC patients than in control subjects, whereas no differences in the allele or genotype frequencies of the 3 single nucleotide polymorphisms were found between HAPC patients and control subjects. Moreover, genotypes of rs1868092 (AA) and rs4953354 (GG) that were not observed in the Chinese Han in the Beijing population were found at frequencies of 1.6% and 0.9%, respectively, in our study population of HAPC patients and control subjects. Carriers of this EPAS1 haplotype (G-G-G, rs13419896, rs4953354, and rs1868092) may have a higher risk for HAPC. These results may contribute to a better understanding of the pathogenesis of HAPC in the Han population.

Th2 lymphocytes migrating to the bone marrow under high-altitude hypoxia promote erythropoiesis via activin A and interleukin-9

The mechanism of accelerated erythropoiesis under the hypoxic conditions of high altitude (HA) remains largely obscure. Here, we investigated the potential role of bone marrow (BM) T cells in the increased production of erythrocytes at HA. We found that mice exposed to a simulated altitude of 6,000 m for 1-3 weeks exhibited a significant expansion of BM CD4+ cells, mainly caused by increasing T helper 2 (Th2) cells. Using a coculture model of BM T cells and hematopoietic stem/progenitor cells, we observed that BM CD4+ cells from hypoxic mice induced erythroid output more easily, in agreement with the erythroid-enhancing effect observed for Th2-condition-cultured BM CD4+ cells. It was further demonstrated that elevated secretion of activin A and interleukin-9 by BM Th2 cells of hypoxic mice promoted erythroid differentiation of hematopoietic stem/progenitor cells and the growth of erythroblasts, respectively. Our study also provided evidence that the CXCL12-CXCR4 interaction played an important role in Th2 cell trafficking to the BM under HA conditions. These results collectively suggest that Th2 cells migrating to the BM during HA exposure have a regulatory role in erythropoiesis, which provides new insight into the mechanism of high altitude polycythemia.

Mitochondrial DNA 10609T Promotes Hypoxia-Induced Increase of Intracellular ROS and Is a Risk Factor of High Altitude Polycythemia

Hypobaric hypoxia is the primary cause of high altitude polycythemia (HAPC). Mitochondria are critical organelles that consume high levels of oxygen and generate ATP. We hypothesize that the mitochondrion may be at the center of HAPC, and mitochondrial DNA (mtDNA) SNPs may be involved in its development. First, we conducted a case-control study to investigate the association of mtDNA variants with HAPC in Han Chinese migrating to the Qinghai-Tibetan Plateau. Pearson’s chi-square tests revealed that mtDNA 8414T (MU) frequency (19.5%) in the HAPC group was significantly higher than that of the control (13.0%, P = 0.04, OR = 1.615, 95%CI: 1.020–2.555). The multivariate logistic regression analysis, after adjustment for environmental factors, revealed that mtDNA 10609T (WT) was significantly associated with an increased risk of HAPC (P<0.01, OR = 2.558, 95%CI: 1.250–5.236). Second, to verify the association, in vitro experiments of transmitochondrial cybrids was performed and revealed that the mtDNA 10609 variant promoted hypoxia-induced increase of intracellular ROS, but the mtDNA 8414 variant did not. Our findings provide evidence that, in Han Chinese, mtDNA 10609T promotes hypoxia-induced increase of intracellular ROS and is a HAPC risk factor.

Characteristics of Polycythemia in Sana'a, Yemen

Background: High altitude polycythemia is one of the altitude illnesses. Sana'a region is located at high altitudewhich reaches 3600 meters above the sea level. Objectives: To determine the hematological and clinical features of polycythemic patients residingin Sana'a region and to clarify the effect of high altitude in causing polycythemia. Methods: Hematological, clinical and demographic data were obtained from 30 polycythemic patients (26 males, 4 females, aged 26 to 85 years residing Sana'a regionand referred to the National Centre of Public Health aboratories in Sana'a city for the firsttime venesection. Results:All studied samples showed high hemoglobinlevels (mean 18.85 g/dL for both sexes), normal platelet counts (228 and 267 x109/L for males and females, respectively),normal white cell counts in 96.7% of the cases (means 6.01 to 5.98 x109/L). Their clinical features showed predominance of headache, ruddy cyanosis, dyspnea and night sweating by 86.7%, 76.7%, 70% and 60%, respectively. Hypertension, joint pain, renal disease, peptic ulcer were less commonly mentioned by 36.7%, 20%, 13.3%, and10%, respectively. Hemorrhage, pruritus, splenomegaly, heart disease andliver disease ereobserved by only 6.67% each. Conclusions: Findings suggest thatsecondary polycythemia is predominant among polycythemicpatients due to the high altitude of Sana’a region. Findings needs to be confirmed bystudyinga larger sample and extended to investigate the erythropoietin level and JAK2V617F mutation for accurate diagnosis. Keywords: Polycythemia, Sana'a, Yemen

Exercise capacity and oxygen transport in native Tibetan highlanders with high‐ compared to low‐hemoglobin concentration

Evidence suggests elevated [Hb] at high altitude is a non‐advantageous, possibly misguided, response to high‐altitude hypoxia. In support of that, lower [Hb] is often observed in native high‐altitude resident Tibetans. To determine whether [Hb] in Tibetans is associated with peak VO2 and/or changes in particular step(s) of the O2 transport chain, we compared ventilation, lung diffusional conductance, cardiac output and systemic O2 delivery, and muscle O2 diffusional conductance in 21 Tibetan males with [Hb] ranging from 15.2 g/gl to 22.9 g/dl [Hb] by measuring their ventilation, VO2 and VCO2, heart rate, cardiac output, and arterial PO2, PCO2, pH, P50, and O2 saturation at peak exercise on a cycle ergometer. [Hb] showed a significant negative relationship with VO2/kg (r= −0.45, p&lt; 0.05), cardiac output/kg (r= −0.54, p &lt; 0.01), and diffusion capacity in muscle (DM/kg: r= −0.44, p&lt;0.05) but not lung. Furthermore, VO2/kg was highly positively correlated with DM/kg (r=0.84, p&lt; 2×10‐6), QT/kg (r=0.76, p &lt; 7.5×10‐5), and arterial [H+] (r= 0.52, p &lt; 0.02), and DM/kg was related to QT/kg (r=0.43, p &lt; 0.051). These trends suggest that genetic mutations resulting in reduced [Hb] may convey an advantage in exercise capacity, possibly via higher cardiac function, ventilation, and diffusion capacity in the muscle and support the emerging hypothesis that the polycythemia of altitude is a misguided response to low cellular PO2.

Gene expression profiling of high altitude polycythemia in Han Chinese migrating to the Qinghai-Tibetan plateau

Chronic mountain sickness (CMS) is a condition in which the hematocrit is increased above the normal level in residents at high altitude. High altitude polycythemia (HAPC) is the most characteristic sign of CMS. However, the pathogenesis of HAPC is poorly understood. The present study aimed to investigate the gene expression profile of HAPC in Han Chinese migrating to the Qinghai-Tibetan Plateau and to identify the pathogenetic mechanisms. A total of 9 differentially expressed genes were identified in HAPC patients using microarrays: 5 were up-regulated and 4 were down-regulated. Functional analysis of the array data revealed that cell division cycle 42 (CDC42) and the human immune response may be key features underlying the mechanism and development of HAPC.

Strategies for national health care systems in emerging countries: The case of screening and prevention of renal disease progression in Bolivia

Strategies for national health care systems in emerging countries: The case of screening and prevention of renal disease progression in Bolivia. There are close to 1 million people in the world who are alive simply because they have access to one form or another of renal replacement therapy (RRT). Ninety percent live in high-income countries. Little is known of prevalence and incidence of chronic kidney disease and of end-stage renal disease (ESRD) in middle-income and low-income countries, where the use of RRT is scarce or nonexistent. However, no intervention is undertaken, these people will experience progression to ESRD and death from uremia, because RRT is out of reach for them. These are the individuals for whom efforts should be focused to prevent or delay progression toward ESRD. AbstractIn 1992, the Mario Negri Institute for Pharmacological Research in Bergamo, Italy, with the cooperation of the young doctors of the Ospedale Giovanni XXIII in La Paz (Bolivia), activated a specific project titled “El Proyecto de Enfermedades Renales en Bolivia” (The Project for Renal Diseases in Bolivia). The project sought to demonstrate that in emerging countries the best strategies against renal disease are prevention and early detection. After proper training of local personnel at the Clinical Research Center “Aldo e Cele Dacco” of the Mario Negri Institute in Bergamo, Italy, an educational campaign titled “First Clinical and Epidemiological Program of Renal Diseases”—under the auspices of the Renal Sister Center Program of the International Society of Nephrology—was conducted in 3 selected areas of Bolivia, including tropical, valley, and plains areas. The goal was to define the frequency of asymptomatic renal disease in these areas by screening a large population of patients at relatively low costs. The screening was formally performed at first-level health centers (Unidad de Salud). Participants were instructed to void a clean urine specimen, and a dipstick test was performed. Patients with positive urinalysis were enrolled in a follow-up program with subsequent laboratory and clinical checks. The study was conducted by 21 clinical centers. Apparently healthy patients (14,082) were enrolled over a period of 7 months. Urinary abnormalities were found on first screening in 4261 patients, but only 1019 patients (23.9%) were available for follow-up. At second urinalysis, 35% of patients had no abnormalities. In the remaining positive group of patients, further investigations disclosed the following abnormalities: urinary tract infection (48.4%), isolated hematuria (43.9%), chronic renal failure (1.6%), renal tuberculosis (1.6%), and other diagnoses 4.3% (kidney stones, 1.3%; diabetic nephropathy, 1%; polycystic kidney diseases, 1.9%). AbstractThe experience gained from this initial screening program formed the basis for a second study aimed to prevent renal disease progression in a selected Bolivian population with high altitude polycythemia. AbstractIn conclusion, our studies show that mass screening of the population for renal disease is feasible in developing countries and can provide useful information on frequency of renal diseases. Also, in patients with altitude polycythemia, long-term treatment with low doses of enalapril safely prevents increase in arterial blood pressure and progressively reduces hematocrit and proteinuria. Aside from its scientific value, this last study can be taken as an example of how, by rationalizing resources and investing in research programs, renal disease progression and cardiovascular risk may eventually improve, which ultimately should translate into less demand for dialysis, and thus provide alternatives to costly RRT. The transformation of the Bolivian pilot model into a systematic program applicable to most emerging countries may be seen as a task of national nephrology societies, along with methodologic and economic support of international bodies.

Mössbauer spectroscopy in biomedical physics research

Several applications of Mossbauer spectroscopy (MS) as an analytical tool in research on biomedical physics are reviewed: (1) The evaluation of treatments for some diseases such as thalassemia, iron-overload disease, high altitude polycythemia. (2) Medical research on the effects of environmental factors on the human body, for example, the effects of electromagnetic radiation on human red blood cells (RBCs). Some advantages and weaknesses of MS, a new application of the Mossbauer effect, cancer therapy, and some possible applications such as monitoring the RBCs of the patients before, during, and after surgical operation, are discussed.