RESUMO
Este estudio se realizó con el objetivo de desarrollar y validar un método para la determinación de 30 medicamentos veterinarios en muestras de trucha y langostino. El método utiliza extracción en fase sólida dispersiva (dSPE) con C18 y detección por cromatografía líquida acoplada a espectrometría de masas. Se determinó linealidad, veracidad (porcentaje de recuperación), repetitividad y reproducibilidad intralaboratorio (porcentaje de desviación estándar relativa (% RSD)), límites de detección (LoD), límites de cuantificación (LoQ), selectividad e incertidumbre. La recuperación varió de 70 a 120% y la repetibilidad y la reproducibilidad fueron menores de 20% de la desviación estándar relativa. La selectividad fue adecuada, sin picos interferentes. Las relaciones iónicas cumplieron con los criterios de confirmación. Los coeficientes de determinación (R2) fueron mayores de 0,99, con excepción de la sulfaquinoxalina en langostino (R2 = 0,97). Los LoD y los LoQ variaron entre 0,6 µg/kg y 12,8 µg /kg y los valores de incertidumbre entre 6 µg/kg y 49 µg/ kg. Se analizaron adicionalmente 6 muestras de diferentes mercados de Lima y se detectaron trazas de algunos medicamentos incluidos en el ensayo. El método es adecuado para el análisis de residuos de medicamentos veterinarios y se recomienda su aplicación en los programas nacionales de monitoreo de la inocuidad de truchas y langostinos provenientes de acuicultura.
The study was aimed at developing and validate an analysis method to determine residues of 30 veterinary drugs in rainbow trout and shrimp specimens. The method involves extraction in dispersive solid phase with C18 and the subsequent detection through liquid chromatography coupled to mass spectrometry. Validation was done through determination of linearity, trueness (% of recovery), repeatability and intralaboratory reproducibility, limits of detection (LoD), limits of quantification (LoQ) selectivity and uncertainty. Recovery ranged from 70 to 120% and repeatability and intralaboratory reproducibility were lower than 20%. Selectivity was adequate, without interference peaks. Likewise, the ionic relationships met the confirmation criteria. The linearity was adequate, with determination coefficients (R2) above 0.99, except for sulfaquinolaxin in shrimp specimens (R2 = 0,97). LoD and LoQ varied from 0,6 µg /kg to 12,8 µg / kg. Limits of uncertainty ranged from 6 µg /kg to 49 µg /kg. The method was used to analyze 6 samples from different markets in Lima (Peru), identifying traces of some drugs included in the study. Our results show that the method is adequate for the analysis of veterinary drug residues and allow us to recommend its application in national monitoring programs, to assess the safety of rainbow trout and shrimp specimens from aquaculture.
O estudo foi realizado com o objetivo de desenvolver e validar um método para a determinação de 30 medicamentos veterinários, em amostras de truta e camarão. O método utiliza extração dispersiva em fase sólida com C18 e detecção por cromatografia líquida acoplada à espectrometria de massas. Foram determinados a linearidade, a veracidade (recuperação percentual), a repetibilidade, a reprodutibilidade intra-laboratorial, os limites de detecção (LoD) e de quantificação (LoQ), a linearidade, a selectividade e a incerteza. A recuperação variou de 70 a 120%, a repetibilidade e reprodutibilidade estiveram abaixo do 20% do desvio padrão relativo. A selectividade fio adequada, sem picos de interferentes. As proporções de íons atenderam aos critérios de confirmação. Os coeficientes de determinação (R2) foram superiores a 0,99, com excepção da sulfanoxalina em camarão (R2 = 0,97). LoD e LoQ variavam entre 0,6 µg /kg e 12,8 µg /kg e valores de incerteza entre 6 µg /kg e 49 µg / kg. Seis amostras de mercados do Lima foram adicionalmente analisadas e foram detectados vestígios de alguns medicamentos incluídos no estudo. O método é adequado para o análise de resíduos de medicamentos veterinários e sua aplicação é recomendada em programas nacionais de controlo da segurança da truta e do camarão provenientes da aquicultura.
RESUMO
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.
Assuntos
Metilação de DNA , Chumbo , Adulto , Epigênese Genética , Epigenoma , Feminino , Hispânico ou Latino , Histona Desmetilases , Humanos , Chumbo/toxicidade , Masculino , Peru , Fatores de Transcrição SOXFRESUMO
BACKGROUND: Childhood diarrhoea mortality has declined substantially in Peru in recent decades. We documented trends in childhood diarrhoea mortality from 1980 to 2015, along with trends in coverage of diarrhoea-related interventions and risk factors, to identify the main drivers of mortality reduction. METHODS: We conducted desk reviews on social determinants, policies and programmes, and diarrhoea-related interventions implemented during the study period. We reviewed different datasets on child mortality, and on coverage of diarrhoea-related interventions. We received input from individuals familiar with implementation of diarrhoea-related policies and programmes. We used the Lives Saved Tool (LiST) to help explain the reasons for the decline in diarrhoea mortality from 1980 to 2015 and to predict additional reduction with further scale up of diarrhoea-related interventions by 2030. RESULTS: In Peru under-five diarrhoea mortality declined from 23.3 in 1980 to 0.8 per 1000 livebirths in 2015. The percentage of under-five diarrhoea deaths as related to total under-five deaths was reduced from 17.8% in 1980 to 4.9% in 2015. Gross domestic product increased and poverty declined from 1990 to 2015. Access to improved water increased from 56% in 1986 to 79.3% in 2015. Oral rehydrating salts (ORS) use during an episode of diarrhoea increased from 3.6% in 1986 to 32% in 2015. Vertical programmes focused on diarrhoea management with ORS were implemented successfully in the 1980s and 1990s, and were replaced by integrated crosscutting interventions since the early 2000s. LiST analyses showed that about half (53.9%) of the reduction in diarrhoea mortality could be attributed to improved water, sanitation and hygiene, 25.0% to direct diarrhoea interventions and 21.1% to nutrition. The remaining mortality could be reduced by three-quarters by 2030 with improved diarrhoea treatment and further with enhanced breastfeeding practices and reduction in stunting. LiST does not take into account the role of social determinants. CONCLUSIONS: The reduction of diarrhoeal under-five mortality in Peru can be explained by a combination of factors, including improvement of social determinants, child nutrition, diarrhoea treatment with ORS and prevention with rotavirus vaccine and increased access to water and sanitation. The already low rate of diarrhoea mortality could be further reduced by a number of interventions, especially additional use of ORS and zinc for diarrhoea treatment. Peru is a remarkable example of a country that was able to reduce childhood diarrhoea mortality by implementing interventions through vertical programmes initially, and afterwards through implementation of integrated multisectoral packages targeting prevalent illnesses and multi-causal problems like stunting.
Assuntos
Mortalidade da Criança/tendências , Diarreia/mortalidade , Mortalidade Infantil/tendências , Pré-Escolar , Diarreia/prevenção & controle , Humanos , Lactente , Recém-Nascido , Peru/epidemiologia , Fatores de RiscoRESUMO
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 (Lâ min-1 and mLâ min-1â 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 â¼11% (e.g., for rs1769793 SNP genotype TT = 34.2 mLâ min-1â kg-1 vs. CC = 30.5 mLâ min-1â 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.
Assuntos
Altitude , Prolina Dioxigenases do Fator Induzível por Hipóxia/fisiologia , Hipóxia/genética , Oxigênio/metabolismo , Polimorfismo de Nucleotídeo Único , Aclimatação , Adaptação Fisiológica , Feminino , Frequência do Gene , Genótipo , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia/genética , Prolina Dioxigenases do Fator Induzível por Hipóxia/metabolismo , Povos Indígenas , Masculino , Peru , Seleção Genética , Estresse FisiológicoRESUMO
We compared expenditure trends for reproductive, maternal, neonatal and child health (RMNCH) with trends in RMNCH service coverage in Peru. We used National Health Accounts data to report on total health expenditure by source; the Countdown database for trends in external funding to RMNCH, and Ministry of Finance data for trends in domestic funding to RMNCH. We undertook over 170 interviews and group discussions to explore factors explaining expenditure trends. We describe trends in total health expenditure and RMNCH expenditure in constant 2012 US$ between 1995 and 2012. We estimated expenditure to coverage ratios. There was a substantial increase in domestic health expenditure over the period. However, domestic health expenditure as share of total government spending and GDP remained stable. Out-of-pocket health spending (OOPS) as a share of total health expenditure remained above 35%, and increased in real terms. Expenditure on reproductive health per woman of reproductive age varied from US$ 1.0 in 2002 to US$ 6.3 in 2012. Expenditure on maternal and neonatal health per pregnant woman increased from US$ 34 in 2000 to US$ 512 in 2012, and per capita expenditure on under-five children increased from US$ 5.6 in 2000 to US$ 148.6 in 2012. Increased expenditure on RMNCH reflects a greater political support for RMNCH, along with greater emphasis on social assistance, family planning, and health reforms targeting poor areas, and a recent emphasis on antipoverty and crosscutting equitable policies and programmes focused on nutrition and maternal and neonatal mortality. Increasing domestic RMNCH expenditure likely enabled Peru to achieve substantial health gains. Peru can provide useful lessons to other countries struggling to achieve sustained gains in RMNCH by relying on their own health financing.
Assuntos
Saúde da Criança/economia , Gastos em Saúde/tendências , Saúde Materna/economia , Avaliação de Resultados em Cuidados de Saúde , Saúde Reprodutiva/economia , Feminino , Humanos , Recém-Nascido , Peru , GravidezRESUMO
BACKGROUND: Peru has increased substantially its domestic public expenditure in maternal and child health. Peruvian departments are heterogeneous in contextual and geographic factors, underlining the importance of disaggregated expenditure analysis up to the district level. We aimed to assess possible district level factors influencing public expenditure on reproductive, maternal, neonatal and child health (RMNCH) in Peru. METHODS: We performed an ecological study in 24 departments, with specific RMNCH expenditure indicators as outcomes, and covariates of different hierarchical dimensions as predictors. To account for the influence of variables included in the different dimensions over time and across departments, we chose a stepwise multilevel mixed-effects regression model, with department-year as the unit of analysis. RESULTS: Public expenditure increased in all departments, particularly for maternal-neonatal and child health activities, with a different pace across departments. The multilevel analysis did not reveal consistently influential factors, except for previous year expenditure on reproductive and maternal-neonatal health. Our findings may be explained by a combination of inertial expenditure, a results-based budgeting approach to increase expenditure efficiency and effectiveness, and by a mixed-effects decentralization process. Sample size, interactions and collinearity cannot be ruled out completely. CONCLUSIONS: Public district-level RMNCH expenditure has increased remarkably in Peru. Evidence on underlying factors influencing such trends warrants further research, most likely through a combination of quantitative and qualitative approaches.
Assuntos
Saúde da Criança/economia , Gastos em Saúde/estatística & dados numéricos , Saúde do Lactente/economia , Saúde Materna/economia , Saúde Reprodutiva/economia , Criança , Atenção à Saúde/economia , Atenção à Saúde/tendências , Feminino , Humanos , Peru , Política , Despesas Públicas/estatística & dados numéricosRESUMO
BACKGROUND: Stunting prevalence in children less than 5 years has remained stagnated in Peru from 1992 to 2007, with a rapid reduction thereafter. We aimed to assess the role of different predictors on stunting reduction over time and across departments, from 2000 to 2012. METHODS: We used various secondary data sources to describe time trends of stunting and of possible predictors that included distal to proximal determinants. We determined a ranking of departments by annual change of stunting and of different predictors. To account for variation over time and across departments, we used an ecological hierarchical approach based on a multilevel mixed-effects regression model, considering stunting as the outcome. Our unit of analysis was one department-year. RESULTS: Stunting followed a decreasing trend in all departments, with differing slopes. The reduction pace was higher from 2007-2008 onwards. The departments with the highest annual stunting reduction were Cusco (-2.31%), Amazonas (-1.57%), Puno (-1.54%), Huanuco (-1.52%), and Ancash (-1.44). Those with the lowest reduction were Ica (-0.67%), Ucayali (-0.64%), Tumbes (-0.45%), Lima (-0.37%), and Tacna (-0.31%). Amazon and Andean departments, with the highest baseline poverty rates and concentrating the highest rural populations, showed the highest stunting reduction. In the multilevel analysis, when accounting for confounding, social determinants seemed to be the most important factors influencing annual stunting reduction, with significant variation between departments. CONCLUSIONS: Stunting reduction may be explained by the adoption of anti-poverty policies and sustained implementation of equitable crosscutting interventions, with focus on poorest areas. Inclusion of quality indicators for reproductive, maternal, neonatal and child health interventions may enable further analyses to show the influence of these factors. After a long stagnation period, Peru reduced dramatically its national and departmental stunting prevalence, thanks to a combination of social determinants and crosscutting factors. This experience offers useful lessons to other countries trying to improve their children's nutrition.
Assuntos
Desenvolvimento Econômico , Transtornos do Crescimento/prevenção & controle , Política de Saúde , Pobreza/prevenção & controle , Saúde da População Rural , Determinantes Sociais da Saúde , Pré-Escolar , Feminino , Transtornos do Crescimento/economia , Transtornos do Crescimento/epidemiologia , Disparidades nos Níveis de Saúde , Humanos , Lactente , Recém-Nascido , Masculino , Modelos Estatísticos , Peru/epidemiologia , Prevalência , Fatores de ProteçãoRESUMO
BACKGROUND: Peru has impressively reduced its neonatal mortality rate (NMR). We aimed, for the period 2000-2013, to: (a) describe national and district NMR variations over time; (b) assess NMR trends by wealth quintile and place of residence; (c) describe evolution of mortality causes; (d) assess completeness of registered mortality; (e) assess coverage and equity of NMR-related interventions; and (f) explore underlying driving factors. METHODS: We compared national NMR time trends from different sources. To describe NMR trends by wealth quintiles, place of residence and districts, we pooled data on births and deaths by calendar year for neonates born to women interviewed in multiple surveys. We disaggregated coverage of NMR-related interventions by wealth quintiles and place of residence. To identify success factors, we ran regression analyses and combined desk reviews with qualitative interviews and group discussions. RESULTS: NMR fell by 51 % from 2000 to 2013, second only to Brazil in Latin America. Reduction was higher in rural and poorest segments (52 and 58 %). District NMR change varied by source. Regarding cause-specific NMRs, prematurity decreased from 7.0 to 3.2 per 1,000 live births, intra-partum related events from 2.9 to 1.2, congenital abnormalities from 2.4 to 1.8, sepsis from 1.9 to 0.8, pneumonia from 0.9 to 0.4, and other conditions from 1.2 to 0.7. Under-registration of neonatal deaths decreased recently, more in districts with higher development index and lower rural population. Coverage of family planning, antenatal care and skilled birth attendance increased more in rural areas and in the poorest quintile. Regressions did not show consistent associations between mortality and predictors. During the study period social determinants improved substantially, and dramatic out-of-health-sector and health-sector changes occurred. Rural areas and the poorest quintile experienced greater NMR reduction. This progress was driven, within a context of economic growth and poverty reduction, by a combination of strong societal advocacy and political will, which translated into pro-poor implementation of evidence-based interventions with a rights-based approach. CONCLUSIONS: Although progress in Peru for reducing NMR has been remarkable, future challenges include closing remaining gaps for urban and rural populations and improving newborn health with qualified staff and intermediate- and intensive-level health facilities.
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Saúde do Lactente/estatística & dados numéricos , Características de Residência/estatística & dados numéricos , Adulto , Serviços de Planejamento Familiar/estatística & dados numéricos , Feminino , Habitação , Humanos , Lactente , Mortalidade Infantil/tendências , Recém-Nascido , Recém-Nascido Prematuro , Peru/epidemiologia , Gravidez , Cuidado Pré-Natal/estatística & dados numéricos , População RuralRESUMO
The developing human fetus is able to cope with the physiological reduction in oxygen supply occurring in utero. However, it is not known if microvascularization of the fetus is augmented when pregnancy occurs at high altitude. Fifty-three healthy term newborns in Puno, Peru (3,840 m) were compared with sea-level controls. Pre- and postductal arterial oxygen saturation (SpO2) was determined. Cerebral and calf muscle regional tissue oxygenation was measured using near infrared spectroscopy (NIRS). Skin microcirculation was noninvasively measured using incident dark field imaging. Pre- and postductal SpO2 in Peruvian babies was 88.1 and 88.4%, respectively, which was 10.4 and 9.7% lower than in newborns at sea level (P < 0.001). Cerebral and regional oxygen saturation was significantly lower in the Peruvian newborns (cerebral: 71.0 vs. 74.9%; regional: 68.5 vs. 76.0%, P < 0.001). Transcutaneously measured total vessel density in the Peruvian newborns was 14% higher than that in the newborns born at sea level (29.7 vs. 26.0 mm/mm(2); P ≤ 0.001). This study demonstrates that microvascular vessel density in neonates born to mothers living at high altitude is higher than that in neonates born at sea level.
Assuntos
Aclimatação/fisiologia , Altitude , Recém-Nascido/fisiologia , Microcirculação/fisiologia , Microvasos/anatomia & histologia , Microvasos/fisiologia , Gravidez/fisiologia , Adulto , Feminino , Humanos , Masculino , Peru , Estudos Prospectivos , Adulto JovemRESUMO
A study of chronic mountain sickness (CMS) with a candidate gene--vascular endothelial growth factor A (VEGFA)--was carried out in a Peruvian population living at high altitude in Cerro de Pasco (4380 m). The study was performed by genotyping of 11 tag SNPs encompassing 2.2 kb of region of VEGFA gene in patients with a diagnosis of CMS (n = 131; 49.1 ± 12.7 years old) and unrelated healthy controls (n = 84; 47.2 ± 13.4 years old). The VEGFA tag SNP rs3025033 was found associated with CMS (p < 0.05), individuals with AG genotype have 2.5 more risk of CMS compared to those with GG genotype (p < 0.02; OR, 2.54; 95% CI: 1.10-5.88). Pairwise Fst and Nei's distance indicate genetic differentiation between Cerro de Pasco population and HapMap3 population (Fst > 0.36, p < 0.01), suggesting selection is operating on the VEGF gene. Our results suggest that VEGFA is associated with CMS in long-term residents at high altitude in the Peruvian Andes.
Assuntos
Doença da Altitude/genética , Polimorfismo de Nucleotídeo Único , Fator A de Crescimento do Endotélio Vascular/genética , Adulto , Idoso , Altitude , Estudos de Casos e Controles , Doença Crônica , Feminino , Marcadores Genéticos , Genótipo , Técnicas de Genotipagem , Humanos , Masculino , Pessoa de Meia-Idade , PeruRESUMO
BACKGROUND: Excessive erythrocytosis (EE) is a prevalent condition in populations living at high altitudes (> 2,500 m above sea level). Few large population-based studies have explored the association between EE and multiple subject-specific traits including oxygen saturation, iron status indicators, and pulmonary function. METHODS: We enrolled a sex-stratified and age-stratified sample of 1,065 high-altitude residents aged ≥ 35 years from Puno, Peru (3,825 m above sea level) and conducted a standardized questionnaire and physical examination that included spirometry, pulse oximetry, and a blood sample for multiple clinical markers. Our primary objectives were to estimate the prevalence of EE, characterize the clinical profile and iron status indicators of subjects with EE, and describe subject-specific traits associated with EE. RESULTS: Overall prevalence of EE was 4.5% (95% CI, 3.3%-6.0%). Oxygen saturation was significantly lower among EE than non-EE group subjects (85.3% vs 90.1%, P < .001) but no difference was found in iron status indicators between both groups (P > .09 for all values). In multivariable logistic regression, we found that age ≥ 65 years (OR = 2.45, 95% CI, 1.16-5.09), male sex (3.86, 1.78-9.08), having metabolic syndrome (2.66, 1.27-5.75) or being overweight (5.20, 1.95-16.77), pulse oximetry < 85% (14.90, 6.43-34.90), and % predicted FVC < 80% (13.62, 4.40-41.80) were strongly associated with EE. Attributable fractions for EE were greatest for being overweight (26.7%), followed by male sex (21.5%), pulse oximetry < 85% (16.4%), having metabolic syndrome (14.4%), and % predicted FVC < 80% (9.3%). CONCLUSIONS: We found a lower prevalence of EE than in previous reports in the Peruvian Andes. Although the presence of hypoxemia and decreased vital capacity were strongly associated with excessive erythrocytosis, being overweight or having metabolic syndrome were associated with an important fraction of cases in our study population.
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Altitude , Etnicidade , Ferro/sangue , Policitemia/etnologia , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Oximetria , Peru/epidemiologia , Policitemia/sangue , Prevalência , Valores de ReferênciaRESUMO
BACKGROUND: Life at altitude depends on adaptation to ambient hypoxia. In the Andes, susceptibility to chronic mountain sickness (CMS), a clinical condition that occurs to native highlanders or to sea level natives with prolonged residence at high altitude, remains poorly understood. We hypothesized that hypoxia-associated gene expression in children of men with CMS might identify markers that predict the development of CMS in adults. We assessed distinct patterns of gene expression of hypoxia-responsive genes in children of highland Andean men, with and without CMS. METHODS: We compared molecular signatures in children of highland (HA) men with CMS (n = 10), without CMS (n = 10) and in sea level (SL) children (n = 20). Haemoglobin, haematocrit, and oxygen saturation were measured. Gene expression in white cells was assessed at HA and then, in the same subjects, within one hour of arrival at sea level. RESULTS: HA children showed higher expression levels of genes regulated by HIF (hypoxia inducible factor) and lower levels of those involved in glycolysis and in the tricarboxylic acid (TCA) cycle. Pyruvate dehydrogenase kinase 1(PDK1) and HIF prolyl hydroxylase 3 (HPH3) mRNA expressions were lowest in children of CMS fathers at altitude. At sea level the pattern of gene expression in the 3 children's groups was indistinguishable. CONCLUSION: The molecular signatures of children of CMS patients show impaired adaptation to hypoxia. At altitude children of CMS fathers had defective coupling between glycolysis and mitochondria TCA cycle, which may be a key mechanism/biomarker for adult CMS. Early biologic markers of disease susceptibility in Andeans might impact health services and social planning.
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Doença da Altitude/fisiopatologia , Altitude , Metabolismo Energético/fisiologia , Hipóxia/fisiopatologia , Adaptação Fisiológica/genética , Adaptação Fisiológica/fisiologia , Adolescente , Adulto , Doença da Altitude/genética , Doença da Altitude/metabolismo , Criança , Pré-Escolar , Doença Crônica , Ciclo do Ácido Cítrico/fisiologia , Estudos Transversais , Dioxigenases/genética , Metabolismo Energético/genética , Expressão Gênica , Glicólise/fisiologia , Hematócrito , Hemoglobina A/análise , Humanos , Prolina Dioxigenases do Fator Induzível por Hipóxia , Masculino , Valor Preditivo dos Testes , Proteínas Serina-Treonina Quinases/genética , Piruvato Desidrogenase Quinase de Transferência de Acetil , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase ReversaRESUMO
Although the effects of acetazolamide (ACZ) on ventilation during acute mountain sickness are well known, there are no studies assessing its effect on ventilatory response in chronic hypoxia. We studied this effect in patients with chronic mountain sickness (CMS). Subjects with CMS, living permanently at 4300 m, were assigned in a randomized, double-blind study to 250 mg/day (n=9) or to 500 mg/day (n=9) of ACZ. Resting end-tidal PET(O2) and end-tidal PET(CO2) were measured before and after 3 weeks of acetazolamide. Ventilatory responses were evaluated by the determination of sensitivity to hypoxia and to CO2. After treatment ventilatory response to hypoxia increased, resting PET(CO2) decreased, and ACZ caused a leftward shift in the position, but not a change in the slope of the ventilation (VE) versus PET(CO2) relationship. There were no differences between the two doses used. ACZ administration provides a beneficial effect on respiratory function of high altitude natives with CMS and thus it can be an effective therapy for the disease.
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Acetazolamida/uso terapêutico , Doença da Altitude/tratamento farmacológico , Doença da Altitude/fisiopatologia , Anticonvulsivantes/uso terapêutico , Mecânica Respiratória/efeitos dos fármacos , Adulto , Análise de Variância , Dióxido de Carbono/farmacologia , Doença Crônica , Relação Dose-Resposta a Droga , Método Duplo-Cego , Humanos , Hipóxia/fisiopatologia , Masculino , Pessoa de Meia-Idade , Oxigênio , Mecânica Respiratória/fisiologiaRESUMO
The study of the biology of evolution has been confined to laboratories and model organisms. However, controlled laboratory conditions are unlikely to model variations in environments that influence selection in wild populations. Thus, the study of "fitness" for survival and the genetics that influence this are best carried out in the field and in matching environments. Therefore, we studied highland populations in their native environments, to learn how they cope with ambient hypoxia. The Andeans, African highlanders and Himalayans have adapted differently to their hostile environment. Chronic mountain sickness (CMS), a loss of adaptation to altitude, is common in the Andes, occasionally found in the Himalayas; and absent from the East African altitude plateau. We compared molecular signatures (distinct patterns of gene expression) of hypoxia-related genes, in white blood cells (WBC) from Andeans with (n = 10), without CMS (n = 10) and sea-level controls from Lima (n = 20) with those obtained from CMS (n = 8) and controls (n = 5) Ladakhi subjects from the Tibetan altitude plateau. We further analyzed the expression of a subset of these genes in Ethiopian highlanders (n = 8). In all subjects, we performed the studies at their native altitude and after they were rendered normoxic. We identified a gene that predicted CMS in Andeans and Himalayans (PDP2). After achieving normoxia, WBC gene expression still distinguished Andean and Himalayan CMS subjects. Remarkably, analysis of the small subset of genes (n = 8) studied in all 3 highland populations showed normoxia induced gene expression changes in Andeans, but not in Ethiopians nor Himalayan controls. This is consistent with physiologic studies in which Ethiopians and Himalayans show a lack of responsiveness to hypoxia of the cerebral circulation and of the hypoxic ventilatory drive, and with the absence of CMS on the East African altitude plateau.
Assuntos
Adaptação Fisiológica/genética , Doença da Altitude/genética , Altitude , Hipóxia/genética , Doença da Altitude/fisiopatologia , Estudos de Coortes , Etiópia , Hipóxia/fisiopatologia , Nepal , PeruRESUMO
The I-allele of the angiotensin-converting enzyme (ACE) gene insertion/deletion (I/D) polymorphism has been associated with performance benefits at high altitude (HA). In n = 142 young males and females of largely Quechua origins in Peru, we evaluated 3 specific hypotheses with regard to the HA benefits of the I-allele: (1) the I-allele is associated with higher arterial oxygen saturation (Sa(O(2))) at HA, (2) the I-allele effect depends on the acclimatization state of the subjects, and (3) the putative I-allele effect on Sa(O(2)) is mediated by the isocapnic hypoxic ventilatory response (HVR, l/min(1)/% Sa(O(2))(1)). The subject participants comprised two different study groups including BLA subjects (born at low altitude) who were lifelong sea-level residents transiently exposed to hypobaric hypoxia (<24 h) and BHA subjects (born at HA) who were lifelong residents of HA. To control for the possibility of population stratification, Native American ancestry proportion (NAAP) was estimated as a covariate for each individual using a panel of 70 ancestry-informative molecular markers (AIMS). At HA, resting and exercise Sa(O(2)) was strongly associated with the ACE genotype, p = 0.008 with approximately 4% of the total variance in Sa(O(2)) attributed to ACE genotype. Moreover, I/I individuals maintained approximately 2.3 percentage point higher Sa(O(2)) compared to I/D and D/D. This I-allele effect was evident in both BLA and BHA groups, suggesting that acclimatization state has little influence on the phenotypic expression of the ACE gene. Finally, ACE genotype was not associated with the isocapnic HVR, although HVR had a strong independent effect on Sa(O(2)) (p = 0.001). This suggests that the I-allele effect on Sa(O(2)) is not mediated by the peripheral control of breathing, but rather by some other central cardiopulmonary effect of the ACE gene on the renin-angiotensin-aldosterone system (RAAS).
Assuntos
Aclimatação/genética , Indígenas Sul-Americanos/genética , Consumo de Oxigênio/fisiologia , Peptidil Dipeptidase A/genética , Polimorfismo Genético , Adulto , Alelos , Feminino , Deleção de Genes , Humanos , Masculino , Peru , Artéria Pulmonar , Valores de ReferênciaRESUMO
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.
Assuntos
Acetazolamida/uso terapêutico , Doença da Altitude/tratamento farmacológico , Inibidores da Anidrase Carbônica/uso terapêutico , Policitemia/tratamento farmacológico , Acetazolamida/efeitos adversos , Acetazolamida/farmacologia , Doença da Altitude/complicações , Doença da Altitude/diagnóstico por imagem , Análise de Variância , Inibidores da Anidrase Carbônica/efeitos adversos , Inibidores da Anidrase Carbônica/farmacologia , Débito Cardíaco/efeitos dos fármacos , Doença Crônica , Método Duplo-Cego , Ecocardiografia , Humanos , Hipertensão Pulmonar/tratamento farmacológico , Hipóxia/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Peru , Estudos Prospectivos , Insuficiência da Valva Tricúspide/etiologiaRESUMO
A review is made on the different treatment strategies essayed to date in the management of chronic mountain sickness (CMS). After a brief presentation of the epidemiology and of the pathophysiological mechanisms proposed for explaining the disease, the advantages and drawbacks of the different treatment approaches are discussed, along with their pathopysiological rationale. A particular emphasis is dedicated to the scientific foundations underlying the development of acetazolamide and angiotensin-converting enzyme inhibitors as promising therapeutic agents for CMS, as well as the clinical evidence existing so far on their usefulness in the treatment of CMS. Various methodological issues that need to be addressed in future clinical studies on efficacy of therapies for CMS are discussed. There is also a brief discussion on potential treatment options for chronic high altitude pulmonary hypertension. Closing remarks on the need of taking increasingly into account the development and implementation of preventive measures are made.
Assuntos
Aclimatação/efeitos dos fármacos , Acetazolamida/uso terapêutico , Doença da Altitude/terapia , Altitude , Inibidores da Enzima Conversora de Angiotensina/uso terapêutico , Inibidores da Anidrase Carbônica/uso terapêutico , Aclimatação/fisiologia , Doença da Altitude/fisiopatologia , Doença Crônica , Humanos , Hipertensão Pulmonar/fisiopatologia , Hipertensão Pulmonar/terapia , Flebotomia , Policitemia/terapiaRESUMO
This report is a comparison of orthostatic tolerance and autonomic function in three groups of high-altitude dwellers: Andeans with and without chronic mountain sickness (CMS) and healthy Ethiopians. Results are compared with those from healthy sea-level residents. The aim was to determine whether different high-altitude populations adapted differently to the prevailing hypobaric hypoxia. Orthostatic tolerance was assessed using a test involving head-up tilt (HUT) and graded lower body suction. This was performed at the subjects' resident altitude. Blood pressure (Portapres) and R-R interval (ECG) were recorded during the test, and spectral and cross-spectral analyses of heart period and systolic blood pressure time series were performed using data obtained both while supine and during HUT. The transfer function gain in the low-frequency range (LF, approximately 0.1 Hz) at the point of maximal coherence was used as a measure of cardiac baroreflex sensitivity (BRS). As previously reported, Peruvians displayed an unusually good orthostatic tolerance, while Ethiopians showed an orthostatic tolerance comparable to that of healthy sea-level residents. There were no significant differences between groups in the supine values of the spectral analysis results. Head-up tilt induced the expected changes in Ethiopians (an increase in the LF components and a decrease in the respiratory components) but not in Andeans. Cross-spectral analysis showed abnormal results from all groups of high-altitude dwellers. These results indicate that Ethiopians, but not Peruvians, behave similarly to sea-level residents in terms of orthostatic tolerance and autonomic responses to orthostatic stress, as assessed from spectral analyses, and this indicates good adaptation to their environment. However, in all the high-altitude groups the results of cross-spectral analysis were atypical, suggesting some degree of impairment in baroreflex function.
Assuntos
Aclimatação , Doença da Altitude/fisiopatologia , Altitude , Sistema Nervoso Autônomo/fisiopatologia , Barorreflexo , Tontura/fisiopatologia , Hipóxia/complicações , Estresse Fisiológico/fisiopatologia , Adulto , Doença da Altitude/sangue , Doença da Altitude/etiologia , Pressão Sanguínea , Doença Crônica , Tontura/sangue , Tontura/etiologia , Eletrocardiografia , Etiópia , Frequência Cardíaca , Hematócrito , Humanos , Hipóxia/fisiopatologia , Masculino , Oxigênio/sangue , Peru , Mecânica Respiratória , Processamento de Sinais Assistido por Computador , Estresse Fisiológico/sangue , Estresse Fisiológico/etiologia , Teste da Mesa Inclinada , Fatores de Tempo , Reino UnidoRESUMO
We investigated carotid baroreflex control of vascular resistance in two groups of high-altitude natives: healthy subjects (HA) and a group with chronic mountain sickness (CMS), a maladaptation condition characterized by high haematocrit values and symptoms attributable to chronic hypoxia. Eleven HA controls and 11 CMS patients underwent baroreflex testing, using the neck collar method in which the pressure distending the carotid baroreceptors was changed by applying pressures of -40 to +60 mmHg to the chamber. Responses of forearm vascular resistance were assessed from changes in the quotient of blood pressure divided by brachial artery blood velocity. Stimulus-response curves were defined at high altitude (4338 m) and within 1 day of descent to sea level. We applied a sigmoid function or third-order polynomial to the curves and determined the maximal slope (equivalent to peak gain) and the corresponding carotid pressure (equivalent to 'set point'). The results showed that the peak gains of the reflex were similar in both groups and at both locations. The 'set point' of the reflex, however, was significantly higher in the CMS patients compared to HA controls, indicating that the reflex operates over higher pressures in the patients (94.4 +/- 3.0 versus 79.6 +/- 4.1 mmHg; P < 0.01). This, however, was seen only when subjects were studied at altitude; after descent to sea level the curve reset to a lower pressure with no significant difference between HA and CMS subjects. These results indicate that carotid baroreceptor control of vascular resistance may be abnormal in CMS patients but that descent to sea level rapidly normalizes it. We speculate that this may be explained by CMS patients having greater vasoconstrictor activity at altitude owing to greater hypoxic stimulation of chemoreceptors.