Browsing by Autor "Julian, Colleen Glyde"

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Augmented uterine artery blood flow and oxygen delivery protect andeans from altitude-associated reductions in fetal growth
(Facultad de Medicina, Enfermería, Nutrición y Tecnología Médica, 2009) Julian, Colleen Glyde
Abstract. The effect of high altitude on reducing birth weight is markedly less in populations of high- (e.g., Andeans) relative to low-altitude origin (e.g., Europeans). Uterine artery (UA) blood flow is greater during pregnancy in Andeans than Europeans at high altitude; however, it is not clear whether such blood flow differences play a causal role in ancestry-associated variations in fetal growth. We tested the hypothesis that greater UA blood flow contributes to the protection of fetal growth afforded by Andean ancestry by comparing UA blood flow and fetal growth throughout pregnancy in 137 Andean or European residents of low (400 m; European n 28, Andean n 23) or high (3,100–4,100 m; European n 51, Andean n 35) altitude in Bolivia. Blood flow and fetal biometry were assessed by Doppler ultrasound, and maternal ancestry was confirmed, using a panel of 100 ancestry-informative genetic markers (AIMs). At low altitude, there were no ancestry-related differences in the pregnancy-associated rise in UA blood flow, fetal biometry, or birth weight. At high altitude, Andean infants weighed 253 g more than European infants after controlling for gestational age and other known influences. UA blood flow and O2 delivery were twofold greater at 20 wk in Andean than European women at high altitude, and were paralleled by greater fetal size. Moreover, variation in the proportion of Indigenous American ancestry among individual women was positively associated with UA diameter, blood flow, O2 delivery, and fetal head circumference. We concluded that greater UA blood flow protects against hypoxiaassociated reductions in fetal growth, consistent with the hypothesis that genetic factors enabled Andeans to achieve a greater pregnancyassociated rise in UA blood flow and O2 delivery than European women at high altitude.
High-altitude ancestry protects against hypoxia-associated reductions in fetal growth
(Facultad de Medicina, Enfermería, Nutrición y Tecnología Médica, 2007) Julian, Colleen Glyde
Objective: The chronic hypoxia of high-altitude (>2500 m) residence has been shown to decrease birth weight in all populations studied to date. However, multigenerational high-altitude populations appear protected relative to newcomer groups. This study aimed to determine whether such protection exists independently of other factors known to influence fetal growth and whether admixed populations (ie, people having both high- and low-altitude ancestry) show an intermediate level of protection. Design: 3551 medical records from consecutive deliveries to Andean, European or Mestizo (ie, admixed) women at low, intermediate or high altitudes in Bolivia were evaluated for maternal characteristics influencing fetal growth as measured by birth weight and the frequency of small for gestational age births (SGA or (10th percentile birth weight for gestational age and sex). Two-way analysis of variance and x2 tests were used to compare maternal and infant characteristics. The effects of ancestry or altitude on SGA and birth weight were assessed using logistic or linear regression models, respectively. Results: Altitude decreased birth weight and increased SGA in all ancestry groups. Andean infants weighed more and were less often SGA than Mestizo or European infants at high altitude (13%, 16% and 33% respectively, p,0.01). After accounting for the influences of maternal hypertensive complications of pregnancy, parity, body weight, and number of prenatal visits, European relative to Andean ancestry increased the frequency of SGA at high altitude nearly fivefold. Conclusions: Andean relative to European ancestry protects against altitude-associated reductions in fetal growth. The intermediate protection seen in the admixed (Mestizo) group is consistent with the influence of genetic or other Andean-specific protective characteristics.
High-altitude ancestry protects against IUGR and reductions in birth weight associated with high altitude and preeclampsia
(Facultad de Medicina, Enfermería, Nutrición y Tecnología Médica, 2005) Julian, Colleen Glyde
Background. Observations consistently demonstrate diminished birth weight [BW] with ascending altitude; however population comparisons reveal the extent of BW reduction depends, in part, upon high-altitude ancestry. Objective(s): To examine the influence of variable HA ancestry [Andean, European and Mestizo (admixed)] on BW, IUGR and hypertensive complications across a range of altitudes. Methods: Maternal and infant characteristics were collected from medical records of 3538 consecutive deliveries to women having 2 prenatal visits at public or private hospitals in Santa Cruz [300m, LA], Cochabamba [2500m, MA] and La Paz or Orurro [3600- 3800m, HA], Bolivia. Population ancestry was determined using parental surnames. IUGR was defined as birth weights 10th percentile for gestational age and sex using sea-level criteria. Hypertension during pregnancy was defined as two or more BP readings at least six hours apart 140/90 mmHg, or a 30/15 mmHg rise above values recorded at the first prenatal visit in a woman whose BP was 140/90 mmHg before week 20 or postpartum. Severe preeclampsia [PE] was defined BP 160/110 mmHg in late pregnancy and all other cases of PE, gestational hypertension [GH] or PE/GH were considered mild. Results: BW declined with ascending altitude [HA: 3365 18; MA: 3306 16 and LA: 3101 12; p 0.0001], however gestational age was equivalent [p NS]. BW diminished 70g, 56g and 39g per 1000m increase in elevation for Europeans, Mestizoes and Andeans, respectively. IUGR prevalence increased with altitude among Mestizo and European babies; Andeans were unaffected. Likewise, at HA, Andean BW was unaffected by mild or severe PE, whereas severe PE diminished Mestizo and European birth weight [ 346g, 1608g, respectively]; mild PE tended to increase European BW at HA [ 301.4g]. Conclusions: High-altitude ancestry protects infants from IUGR and reductions in birth weight associated with high-altitude and hypertensive complications during pregnancy.
Inhibition of peroxisome proliferator gamma (PPARɣ) : a potential link between chronic maternal hypoxia and impaired fetal growth
(Facultad de Medicina, Enfermería, Nutrición y Tecnología Médica, 2013) Julian, Colleen Glyde
Background and Objective: Chronic maternal hypoxia impairs fetal growth and increases the incidence of intrauterine growth restriction (IUGR). To identify the mechanisms underlying these hypoxia-related effects, we evaluated whether exposure to chronic hypoxia during pregnancy alters maternal gene-expression patterns relative to normoxic pregnancy and, if so, to define the dominant genes and pathways involved. Methods: Gene expression profiles were generated using NimbleGen Human Gene Expression microarrays for 79 peripheral blood mononuclear cell samples collected from 43 women residing at high (n = 25, 3600–4300m) or low (n = 18, 300m) altitude in the nonpregnant state or during pregnancy (20 or 36 weeks). Transcriptional differences between altitudes were detected using Limma, Lme4, and Car packages in R; the relationship of such differences to biological processes and pathways was assessed in IPA. Results: Gene expression differed at high versus low altitude in the non-pregnant state(43 genes), at 20 weeks of pregnancy (59 genes) and at 36 weeks of pregnancy (985 genes). Several genes of known pathologic significance for IUGR varied between altitudes during pregnancy but not in the non-pregnant state. Among the pathways enriched by these genes was the peroxisome proliferator-activated receptor gamma (PPARc) signaling pathway. Transcriptional changes were consistent with the negative regulation of PPARc at high versus low altitude during pregnancy, but not in the non-pregnant state. Conclusions: Pregnancy magnifies the influence of environmental hypoxia on gene expression in ways that may be related to fetal growth. Given its involvement in the regulation of inflammation, vascular function, and glucose metabolism, we consider PPARc to be an important candidate for future study.
Inhibition of peroxisome proliferator-activated receptor ɣ : a potential link between chronic maternal hypoxia and impaired fetal growth
(Facultad de Medicina, Enfermería, Nutrición y Tecnología Médica, 2014) Julian, Colleen Glyde
Abstract. Chronic exposure to hypoxia raises the risk of pregnancy disorders characterized by maternal vascular dysfunction and diminished fetal growth. In an effort to identify novel pathways for these hypoxiarelated effects, we assessed gene expression profiles of peripheral blood mononuclear cells (PBMCs) obtained from 43 female, high-altitude or sea-level residents in the nonpregnant state or during pregnancy (20 or 36 wk). Hypoxia-related fetal growth restriction becomes apparent between 25 and 29 wk of gestation and continues until delivery. Our sampling strategy was designed to capture changes occurring before (20 wk) and during (36 wk) the time frame of slowed fetal growth. PBMC gene expression profiles were generated using human gene expression microarrays and compared between altitudes. Biological pathways were identified using pathway analysis. Modest transcriptional differences were observed between altitudes in the nonpregnant state. Of the genes that were differentially expressed at high altitude vs. sea level during pregnancy (20 wk: 59 probes mapped to 41 genes; 36 wk: 985 probes mapped to 700 genes), several are of pathological relevance for fetal growth restriction. In particular, transcriptional changes were consistent with the negative regulation of peroxisome proliferatoractivated receptor (PPAR ) at high altitude; such effects were accompanied by reduced birth weight (P <0.05) and head circumference (P <0.01) at high altitude vs. sea level. Our findings indicate that chronic exposure to hypoxia during pregnancy alters maternal gene expression patterns in general and, in particular, expression of key genes involved in metabolic homeostasis that have been proposed to play a role in the pathophysiology of fetal growth restriction.
Lowland origin women raised at high altitude are not protected against lower uteroplacental O2 delivery during pregnancy or reduced birth weight
(Facultad de Medicina, Enfermería, Nutrición y Tecnología Médica, 2011) Julian, Colleen Glyde
Objective. Maternal physiologic responses to pregnancy promoting fetal oxygen and nutrient delivery are important determinants of reproductive success. Incomplete physiologic compensation for reduced oxygen availability at high altitude ( 2,500 m) compromises fetal growth. Populations of highland (e.g., Andeans, Tibetans) compared with lowland origin groups (e.g., Europeans, Han Chinese) are protected from this altitude-associated decrease in birth weight; here we sought to determine whether maternal development at high altitude—rather than highland ancestry—contributed to the protection of birth weight and uterine artery (UA) blood flow during pregnancy. Methods. In women of lowland ancestry who were either raised at high altitude in La Paz, Bolivia (3,600–4,100 m) (‘‘lifelong,’’ n 5 18) or who had migrated there as adults (‘‘newcomers,’’ n 5 40) we compared maternal O2 transport during pregnancy and their infant’s birth weight. Results. Pregnancy raised maternal ventilation and arterial O2 saturation equally, with the result that arterial O2 content was similarly maintained at nonpregnant levels despite a fall in hemoglobin. UA blood flow and uteroplacental O2 delivery were lower in lifelong than newcomer residents (main effect). Birth weight was similar in lifelong residents versus newcomers (2,948 6 93 vs. 3,090 6 70 gm), with both having values below those of a subset of eight high-altitude residents who descended to deliver at low altitude (3,418 6 133 gm, P < 0.05). Conclusion. Lifelong compared with newcomer high-altitude residents have lower uteroplacental O2 delivery and similar infant birth weights, suggesting that developmental factors are likely not responsible for the protective effect of highland ancestry.
Perinatal hypoxia increases susceptibility to high-altitude polycythemia and attendant pulmonary vascular dysfunction
(Facultad de Medicina, Enfermería, Nutrición y Tecnología Médica, 2015) Julian, Colleen Glyde
Perinatal hypoxia increases susceptibility to high-altitude polycythemia and attendant pulmonary vascular dysfunction. Am J Physiol Heart Circ Physiol 309: H565–H573, 2015. First published June 19, 2015; doi:10.1152/ajpheart.00296.2015.—Perinatal exposures exert a profound influence on physiological function, including developmental processes vital for efficient pulmonary gas transfer throughout the lifespan. We extend the concept of developmental programming to chronic mountain sickness (CMS), a debilitating syndrome marked by polycythemia, ventilatory impairment, and pulmonary hypertension that affects 10% of male high-altitude residents. We hypothesized that adverse perinatal oxygenation caused abnormalities of ventilatory and/or pulmonary vascular function that increased susceptibility to CMS in adulthood. Subjects were 67 male high-altitude (3,600–4,100 m) residents aged 18–25 yr with excessive erythrocytosis (EE, Hb concentration 18.3 g/dl), a preclinical form of CMS, and 66 controls identified from a community-based survey (n 981). EE subjects not only had higher Hb concentrations and erythrocyte counts, but also lower alveolar ventilation, impaired pulmonary diffusion capacity, higher systolic pulmonary artery pressure, lower pulmonary artery acceleration time, and more frequent right ventricular hypertrophy, than controls. Compared with controls, EE subjects were more often born to mothers experiencing hypertensive complications of pregnancy and hypoxia during the perinatal period, with each increasing the risk of developing EE (odds ratio 5.25, P 0.05 and odds ratio 6.44, P 0.04, respectively) after other factors known to influence EE status were taken into account. Adverse perinatal oxygenation is associated with increased susceptibility to EE accompanied by modest abnormalities of the pulmonary circulation that are independent of increased blood viscosity. The association between perinatal hypoxia and EE may be due to disrupted alveolarization and microvascular development, leading to impaired gas exchange and/or pulmonary hypertension.
Potential role for elevated maternal enzymatic antioxidant status in Andean protection against altitude-associated SGA
(Facultad de Medicina, Enfermería, Nutrición y Tecnología Médica, 2012) Julian, Colleen Glyde
Oxidative stress has been implicated in the uteroplacental ischemia characteristic of preeclampsia and small-for-gestational-age (SGA) birth, both of which are more common at high (>2500 m) vs low altitude. Since Andeans are protected relative to Europeans from the altitude-associated rise in SGA, we asked whether alterations in maternal antioxidant status or oxidative stress contributed to their protection. Enzymatic antioxidant (erythrocyte catalase and superoxide dismutase [SOD]) activity and a plasma marker of lipid peroxidation (8-iso-PGF2α) were measured during pregnancy and in the non-pregnant state in Andean or European residents of low (400 m) or high altitude (3600–4100 m). Pregnancy and altitude increased catalase and/ or SOD activity to a greater extent in Andeans than Europeans. 8-iso-PGF2α levels were independent of altitude and pregnancy. SOD was lower in mothers of SGA infants at weeks 20 and 36. Our findings are consistent with the possibility that elevated enzymatic antioxidant activity contributes to Andean protection against altitude-associated SGA.
Reduced endothelin-1 (ET-1) and elevated nitric oxide metabolites (NOX) across pregnancy among andean vs. european women at high (3100-3600 m) altitude
(Facultad de Medicina, Enfermería, Nutrición y Tecnología Médica, 2005) Julian, Colleen Glyde
Background. A consistent reduction in infant birth weight occurs with ascending altitude; however multigenerational high-altitude residents [Andeans] demonstrate a degree of protection from altitude-associated IUGR relative to their European HA counterparts. This difference has been attributed, in part, to greater uterine artery [UA] enlargement during pregnancy among Andeans. Objective: We asked whether maternal circulating levels of vasoactive and angiogenic proteins regulated by the hypoxia inducible factors [HIF] differed between multi-generational Andean HA residents vs. short-term HA and low-altitude [LA] Europeans. Methods: Serum or plasma was collected from women residing at LA (1610m, Denver, Colorado) and HA (3100 and 3600m, Leadville, CO and La Paz, Bolivia) altitude at 20, 30 and 36w gestation and 3 mo post-partum for a nonpregnant measure. ET-1, placental-like growth factor [PLGF], vascular endothelial growth factor [VEGF-free] and soluble Flt-1 [sFlt-1] were assessed via ELISA [R&D, UK]; NOx was measured using chemiluminescence [Sievers, CO]. Effects of pregnancy, altitude and ancestry were quantified using repeated measures and 2-way ANOVA. Results: Circulating levels of the vasoconstrictor ET-1 declined during pregnancy in both Europeans at LA and Andeans at HA; however at HA ET-1 increased during gestation among Europeans but not Andeans [pregnancy: p 0.05; altitude: p 0.05 and ancestry: p 0.05]. NOx declined across pregnancy in all groups [pregnancy: p 0.05]. Altitude decreased circulating NOx levels among Europeans [altitude: p 0.01]. Andeans at HA demonstrated higher NOx levels relative to Europeans at HA [ancestry: p 0.001]. With pregnancy, VEGF declined and sFlt-1and PLGF increased among all groups [p 0.001], but neither altitude nor ancestry influenced their maternal circulating levels. Conclusions: Protection from IUGR and greater UA enlargement during pregnancy among multi-generational HA residents may be due, in part, to reduced production of the vasoconstrictor ET-1 and/or increased production of the vasodilator NO.
Sleep-disordered breathing and oxidative stress in preclinical chronic mountain sickness (excessive erythrocytosis)
(Facultad de Medicina, Enfermería, Nutrición y Tecnología Médica, 2013) Julian, Colleen Glyde
Abstract. Chronic mountain sickness (CMS) is considered to be a loss of ventilatory acclimatization to high altitude (>2500 m) resulting in marked arterial hypoxemia and polycythemia. This case-control study explores the possibility that sleep-disordered breathing (SBD) and associated oxidative stress contribute to the etiology of CMS. Nocturnal respiratory and SaO2 patterns were measured using standard polysomnography techniques and compared between male high-altitude residents (aged 18–25) with preclinical CMS ([excessive erythrocytosis (EE)], n=20) and controls (n=19). Measures of oxidative stress and antioxidant status included isoprostanes (8-iso-PGF2 alpha), superoxide dismutase and ascorbic acid. EE cases had a greater apnea-hypopnea index, a higher frequency of apneas (central and obstructive) and hypopneas during REM sleep, and lower nocturnal SaO2 compared to controls. 8-iso-PGF2alpha was greater in EE than controls, negatively associated with nocturnal SaO2, and positively associated with hemoglobin concentration. Mild sleep-disordered breathing and oxidative stress are evident in preclinical CMS, suggesting that the resolution of nocturnal hypoxemia or antioxidant treatment may prevent disease progression.
The relationship between perinatl hypoxia and sleep-disordered breathing in preclinical chronic mountain sickness
(Facultad de Medicina, Enfermería, Nutrición y Tecnología Médica, 2010) Julian, Colleen Glyde
Introduction: Chronic intermittent hypoxia due to sleepdisordered breathing is implicated as a potential etiological factor for chronic mountain sickness (CMS). Whether sleepdisordered breathing precedes or results from CMS is not known. Likewise, factors responsible for sleep-disordered breathing in CMS are not well understood. Based on our preliminary data that perinatal hypoxia increases susceptibility to excessive erythrocytosis (EE, Hb 18.3 g/dL), a preclinical phase of CMS, we sought to determine whether respiratory characteristics during wakefulness or sleep differ between EE subjects and controls and, if so, to determine the relationship of this variation with perinatal hypoxia.
Unique DNA methylation patterns in offspring of hypertensive pregnancy
(Facultad de Medicina, Enfermería, Nutrición y Tecnología Médica, 2015) Julian, Colleen Glyde
Abstract. Epigenomic processes are believed to play a pivotal role for the effect of environmental exposures in early life to modify disease risk throughout the lifespan. Offspring of women with hypertensive complications of pregnancy (HTNPREG) have an increased risk of developing systemic and pulmonary vascular dysfunction in adulthood. In this preliminary report, we sought to determine whether epigenetic modifications of genes involved in the regulation of vascular function were present in HTNPREG offspring. We contrasted DNA methylation and gene expression patterns of peripheral blood mononuclear cells obtained from young male offspring of HTNPREG (n = 5) to those of normotensive controls (n = 19). In HTNPREG offspring we identified six differentially methylated regions (DMRs) including three genes (SMOC2, ARID1B and CTRHC1) relevant to vascular function. The transcriptional activity of ARID1B and CTRCH1 was inversely related to methylation status. HTNPREG offspring had higher systolic pulmonary artery pressure (sPPA) versus controls. Our findings demonstrate that epigenetic marks are altered in offspring of HTNPREG with a modest elevation of sPPA and introduce novel epigenomic targets for further study. On the basis of these findings we speculate that epigenomic mechanisms may be involved in mediating the effect of HTN PREG to raise the risk of vascular disease later in life. Clin Trans Sci 2015; Volume 8: 740–745