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Sample records for growth restriction pulmonary

  1. Intrauterine growth restriction decreases pulmonary alveolar and vessel growth and causes pulmonary artery endothelial cell dysfunction in vitro in fetal sheep.

    PubMed

    Rozance, Paul J; Seedorf, Gregory J; Brown, Alicia; Roe, Gates; O'Meara, Meghan C; Gien, Jason; Tang, Jen-Ruey; Abman, Steven H

    2011-12-01

    Intrauterine growth restriction (IUGR) increases the risk for bronchopulmonary dysplasia (BPD). Abnormal lung structure has been noted in animal models of IUGR, but whether IUGR adversely impacts fetal pulmonary vascular development and pulmonary artery endothelial cell (PAEC) function is unknown. We hypothesized that IUGR would decrease fetal pulmonary alveolarization, vascular growth, and in vitro PAEC function. Studies were performed in an established model of severe placental insufficiency and IUGR induced by exposing pregnant sheep to elevated temperatures. Alveolarization, quantified by radial alveolar counts, was decreased 20% (P < 0.005) in IUGR fetuses. Pulmonary vessel density was decreased 44% (P < 0.01) in IUGR fetuses. In vitro, insulin increased control PAEC migration, tube formation, and nitric oxide (NO) production. This response was absent in IUGR PAECs. VEGFA stimulated tube formation, and NO production also was absent. In control PAECs, insulin increased cell growth by 68% (P < 0.0001). Cell growth was reduced in IUGR PAECs by 29% at baseline (P < 0.01), and the response to insulin was attenuated (P < 0.005). Despite increased basal and insulin-stimulated Akt phosphorylation in IUGR PAECs, endothelial NO synthase (eNOS) protein expression as well as basal and insulin-stimulated eNOS phosphorylation were decreased in IUGR PAECs. Both VEGFA and VEGFR2 also were decreased in IUGR PAECs. We conclude that fetuses with IUGR are characterized by decreased alveolar and vascular growth and PAEC dysfunction in vitro. This may contribute to the increased risk for adverse respiratory outcomes and BPD in infants with IUGR. PMID:21873446

  2. Placental Adaptations in Growth Restriction

    PubMed Central

    Zhang, Song; Regnault, Timothy R.H.; Barker, Paige L.; Botting, Kimberley J.; McMillen, Isabella C.; McMillan, Christine M.; Roberts, Claire T.; Morrison, Janna L.

    2015-01-01

    The placenta is the primary interface between the fetus and mother and plays an important role in maintaining fetal development and growth by facilitating the transfer of substrates and participating in modulating the maternal immune response to prevent immunological rejection of the conceptus. The major substrates required for fetal growth include oxygen, glucose, amino acids and fatty acids, and their transport processes depend on morphological characteristics of the placenta, such as placental size, morphology, blood flow and vascularity. Other factors including insulin-like growth factors, apoptosis, autophagy and glucocorticoid exposure also affect placental growth and substrate transport capacity. Intrauterine growth restriction (IUGR) is often a consequence of insufficiency, and is associated with a high incidence of perinatal morbidity and mortality, as well as increased risk of cardiovascular and metabolic diseases in later life. Several different experimental methods have been used to induce placental insufficiency and IUGR in animal models and a range of factors that regulate placental growth and substrate transport capacity have been demonstrated. While no model system completely recapitulates human IUGR, these animal models allow us to carefully dissect cellular and molecular mechanisms to improve our understanding and facilitate development of therapeutic interventions. PMID:25580812

  3. Prenatal Depression Restricts Fetal Growth

    PubMed Central

    Diego, Miguel A.; Field, Tiffany; Hernandez-Reif, Maria; Schanberg, Saul; Kuhn, Cynthia; Gonzalez-Quintero, Victor Hugo

    2009-01-01

    Objective To identify whether prenatal depression is a risk factor for fetal growth restriction. Methods Midgestation (18-20 weeks GA) estimated fetal weight and urine cortisol and birth weight and gestational age at birth data were collected on a sample of 40 depressed and 40 non-depressed women. Estimated fetal weight and birthweight data were then used to compute fetal growth rates. Results Depressed women had a 13% greater incidence of premature delivery (Odds Ratio (OR) = 2.61) and 15% greater incidence of low birthweight (OR = 4.75) than non-depressed women. Depressed women also had elevated prenatal cortisol levels (p = .006) and fetuses who were smaller (p = .001) and who showed slower fetal growth rates (p = .011) and lower birthweights (p = .008). Mediation analyses further revealed that prenatal maternal cortisol levels were a potential mediator for the relationship between maternal symptoms of depression and both gestational age at birth and the rate of fetal growth. After controlling for maternal demographic variables, prenatal maternal cortisol levels were associated with 30% of the variance in gestational age at birth and 14% of the variance in the rate of fetal growth. Conclusion Prenatal depression was associated with adverse perinatal outcomes, including premature delivery and slower fetal growth rates. Prenatal maternal cortisol levels appear to play a role in mediating these outcomes. PMID:18723301

  4. Placental Nutrient Transport and Intrauterine Growth Restriction

    PubMed Central

    Gaccioli, Francesca; Lager, Susanne

    2016-01-01

    Intrauterine growth restriction refers to the inability of the fetus to reach its genetically determined potential size. Fetal growth restriction affects approximately 5–15% of all pregnancies in the United States and Europe. In developing countries the occurrence varies widely between 10 and 55%, impacting about 30 million newborns per year. Besides having high perinatal mortality rates these infants are at greater risk for severe adverse outcomes, such as hypoxic ischemic encephalopathy and cerebral palsy. Moreover, reduced fetal growth has lifelong health consequences, including higher risks of developing metabolic and cardiovascular diseases in adulthood. Numerous reports indicate placental insufficiency as one of the underlying causes leading to altered fetal growth and impaired placental capacity of delivering nutrients to the fetus has been shown to contribute to the etiology of intrauterine growth restriction. Indeed, reduced expression and/or activity of placental nutrient transporters have been demonstrated in several conditions associated with an increased risk of delivering a small or growth restricted infant. This review focuses on human pregnancies and summarizes the changes in placental amino acid, fatty acid, and glucose transport reported in conditions associated with intrauterine growth restriction, such as maternal undernutrition, pre-eclampsia, young maternal age, high altitude and infection. PMID:26909042

  5. Predictive factors for intrauterine growth restriction

    PubMed Central

    Albu, AR; Anca, AF; Horhoianu, VV; Horhoianu, IA

    2014-01-01

    Abstract Reduced fetal growth is seen in about 10% of the pregnancies but only a minority has a pathological background and is known as intrauterine growth restriction or fetal growth restriction (IUGR / FGR). Increased fetal and neonatal mortality and morbidity as well as adult pathologic conditions are often associated to IUGR. Risk factors for IUGR are easy to assess but have poor predictive value. For the diagnostic purpose, biochemical serum markers, ultrasound and Doppler study of uterine and spiral arteries, placental volume and vascularization, first trimester growth pattern are object of assessment today. Modern evaluations propose combined algorithms using these strategies, all with the goal of a better prediction of risk pregnancies. Abbreviations: SGA = small for gestational age; IUGR = intrauterine growth restriction; FGR = fetal growth restriction; IUFD = intrauterine fetal demise; HIV = human immunodeficiency virus; PAPP-A = pregnancy associated plasmatic protein A; β-hCG = beta human chorionic gonadotropin; MoM = multiple of median; ADAM-12 = A-disintegrin and metalloprotease 12; PP-13 = placental protein 13; VEGF = vascular endothelial growth factor; PlGF = placental growth factor; sFlt-1 = soluble fms-like tyrosine kinase-1; UAD = uterine arteries Doppler ultrasound; RI = resistence index; PI = pulsatility index; VOCAL = Virtual Organ Computer–Aided Analysis software; VI = vascularization index; FI = flow index; VFI = vascularization flow index; PQ = placental quotient PMID:25408721

  6. [Intrauterine growth restriction--diagnosis and treatment].

    PubMed

    Radoń-Pokracka, Małgorzata; Huras, Hubert; Jach, Robert

    2015-01-01

    The prevalence of low birth weight affects approximately 3-10% of live-born newborns in developed countries and in developing countries it affects 15-20% of newborns. The most common cause of low birth weight is considered to intrauterine fetal growth resctriction. Low birth weight is responsible for 69.6% of stillbirths and for 66.4% of neonatal deaths. The purpose of this paper is to review reliable scientific data in order to summarize the current guidelines on intrauterine fetal growth restriction, addressed to obstetricians. The present review is based on guidelines of the American College of Obstetricians and Gynecologists (ACOG), the Royal College of Obstetricians and Gynaecologists (RCOG), the Society of Obstetricians and Gynaecologists of Canada (SOGC), the results of DIGITAT- (ang. The Disproportionate Growth intrauterine Intervention Trial At Term) PORTO Study- (ang. Prospective Observational Trial is the Opitimize Pedriatric Health in intrauterine Growth Restriction), TRUFFLE- (ang. Randomized Trial of Fetal and Umbilical Flow in Europe), and the available literature. PMID:26817352

  7. Intrauterine Growth Restriction: Antenatal and Postnatal Aspects.

    PubMed

    Sharma, Deepak; Shastri, Sweta; Sharma, Pradeep

    2016-01-01

    Intrauterine growth restriction (IUGR), a condition that occurs due to various reasons, is an important cause of fetal and neonatal morbidity and mortality. It has been defined as a rate of fetal growth that is less than normal in light of the growth potential of that specific infant. Usually, IUGR and small for gestational age (SGA) are used interchangeably in literature, even though there exist minute differences between them. SGA has been defined as having birth weight less than two standard deviations below the mean or less than the 10th percentile of a population-specific birth weight for specific gestational age. These infants have many acute neonatal problems that include perinatal asphyxia, hypothermia, hypoglycemia, and polycythemia. The likely long-term complications that are prone to develop when IUGR infants grow up includes growth retardation, major and subtle neurodevelopmental handicaps, and developmental origin of health and disease. In this review, we have covered various antenatal and postnatal aspects of IUGR. PMID:27441006

  8. Intrauterine Growth Restriction: Antenatal and Postnatal Aspects

    PubMed Central

    Sharma, Deepak; Shastri, Sweta; Sharma, Pradeep

    2016-01-01

    Intrauterine growth restriction (IUGR), a condition that occurs due to various reasons, is an important cause of fetal and neonatal morbidity and mortality. It has been defined as a rate of fetal growth that is less than normal in light of the growth potential of that specific infant. Usually, IUGR and small for gestational age (SGA) are used interchangeably in literature, even though there exist minute differences between them. SGA has been defined as having birth weight less than two standard deviations below the mean or less than the 10th percentile of a population-specific birth weight for specific gestational age. These infants have many acute neonatal problems that include perinatal asphyxia, hypothermia, hypoglycemia, and polycythemia. The likely long-term complications that are prone to develop when IUGR infants grow up includes growth retardation, major and subtle neurodevelopmental handicaps, and developmental origin of health and disease. In this review, we have covered various antenatal and postnatal aspects of IUGR. PMID:27441006

  9. Consequences in Infants That Were Intrauterine Growth Restricted

    PubMed Central

    Cosmi, Erich; Fanelli, Tiziana; Visentin, Silvia; Trevisanuto, Daniele; Zanardo, Vincenzo

    2011-01-01

    Intrauterine growth restriction is a condition fetus does not reach its growth potential and associated with perinatal mobility and mortality. Intrauterine growth restriction is caused by placental insufficiency, which determines cardiovascular abnormalities in the fetus. This condition, moreover, should prompt intensive antenatal surveillance of the fetus as well as follow-up of infants that had intrauterine growth restriction as short and long-term sequele should be considered. PMID:21547088

  10. Postnatal nutritional restriction affects growth and immune function of piglets with intra-uterine growth restriction.

    PubMed

    Hu, Liang; Liu, Yan; Yan, Chuan; Peng, Xie; Xu, Qin; Xuan, Yue; Han, Fei; Tian, Gang; Fang, Zhengfeng; Lin, Yan; Xu, Shengyu; Zhang, Keying; Chen, Daiwen; Wu, De; Che, Lianqiang

    2015-07-14

    Postnatal rapid growth by excess intake of nutrients has been associated with an increased susceptibility to diseases in neonates with intra-uterine growth restricted (IUGR). The aim of the present study was to determine whether postnatal nutritional restriction could improve intestinal development and immune function of neonates with IUGR using piglets as model. A total of twelve pairs of normal-birth weight (NBW) and IUGR piglets (7 d old) were randomly assigned to receive adequate nutrient intake or restricted nutrient intake (RNI) by artificially liquid feeding for a period of 21 d. Blood samples and intestinal tissues were collected at necropsy and were analysed for morphology, digestive enzyme activities, immune cells and expression of innate immunity-related genes. The results indicated that both IUGR and postnatal nutritional restriction delayed the growth rate during the sucking period. Irrespective of nutrient intake, piglets with IUGR had a significantly lower villous height and crypt depth in the ileum than the NBW piglets. Moreover, IUGR decreased alkaline phosphatase activity while enhanced lactase activity in the jejunum and mRNA expressions of Toll-like receptor 9 (TLR-9) and DNA methyltransferase 1 (DNMT1) in the ileum of piglets. Irrespective of body weight, RNI significantly decreased the number and/or percentage of peripheral leucocytes, lymphocytes and monocytes of piglets, whereas the percentage of neutrophils and the ratio of CD4+ to CD8+ were increased. Furthermore, RNI markedly enhanced the mRNA expression of TLR-9 and DNMT1, but decreased the expression of NOD2 and TRAF-6 in the ileum of piglets. In summary, postnatal nutritional restriction led to abnormal cellular and innate immune response, as well as delayed the growth and intestinal development of IUGR piglets. PMID:26059215

  11. Intrauterine Growth Restriction and Cerebral Palsy

    PubMed Central

    Kurjak, Asim; Predojevic, Maja; Stanojevic, Milan; Kadic, Aida Salihagic-; Miskovic, Berivoj; Badreldeen, Ahmed; Talic, Amira; Zaputovic, Sanja; Honemeyer, Ulrich

    2010-01-01

    Intrauterine growth restriction (IUGR) can be described as condition in which fetus fails to reach his potential growth. It is common diagnosis in obstetrics, and carries an increased risk of perinatal mortality and morbidity. Moreover, IUGR has lifelong implications on health, especially on neurological outcome. There is a need for additional neurological assessment during monitoring of fetal well-being, in order to better predict antenatally which fetuses are at risk for adverse neurological outcome. Studies have revealed that the behavior of the fetus reflects the maturational processes of the central nervous system (CNS). Hence, ultrasound investigation of the fetal behavior can give us insight into the integrity and functioning of the fetal CNS. Furthermore, investigations carried out using modern method, four-dimensional (4D) sonography, have produced invaluable details of fetal behavior and its development, opening the door to a better understanding of the prenatal functional development of the CNS. Based on previous observations and several years of investigation, our reaserch group has proposed a new scoring system for the assessment of fetal neurological status by 4D sonography named Kurjak antenatal neurodevelopmental test (KANET). The value of KANET in distinguishing fetal brain and neurodevelopmental alterations due to the early brain impairment in utero is yet to be assessed in large population studies. However, preliminary results are very encouraging. PMID:25473145

  12. Obstetric management of intrauterine growth restriction.

    PubMed

    Marsál, Karel

    2009-12-01

    The aim of obstetric management is to identify growth-restricted foetuses at risk of severe intrauterine hypoxia, to monitor their health and to deliver when the adverse outcome is imminent. After 30-32 gestational weeks, a Doppler finding of absent or reverse end-diastolic flow in the umbilical artery of a small-for-gestational age foetus is in itself an indication for delivery. In very preterm foetuses, the intrauterine risks have to be balanced against the risk of prematurity. All available diagnostic information (e.g., Doppler velocimetry of umbilical artery, foetal central arteries and veins and of maternal uterine arteries; foetal heart rate with computerised analysis of short-term variability; amniotic fluid amount; and foetal gestational age-related weight) should be collected to support the timing of delivery. If possible, the delivery should optimally take place before the onset of late signs of foetal hypoxia (pathological foetal heart rate pattern, severely abnormal ductus venosus blood velocity waveform, pulsations in the umbilical vein). PMID:19854682

  13. Plexogenic pulmonary arteriopathy in a cat with non-restrictive ventricular septal defect and chronic pulmonary hypertension.

    PubMed

    Russell, D S; Scansen, B A; Himmel, L

    2015-08-01

    A 10-week-old, male, domestic long-hair cat was medically managed for congenital heart disease over a period of 8 years. Regular clinical examinations, including sequential echocardiography, documented a non-restrictive paramembranous ventricular septal defect, secundum-type atrial septal defect and aortic dextroposition. Pulmonary arterial hypertension was diagnosed by the presence of high-velocity tricuspid regurgitation, bidirectional low velocity flow across the ventricular septal defect, pulmonary arterial dilation and severe right ventricular hypertrophy without evidence of pulmonary outflow tract obstruction. The cat remained clinically stable until it died suddenly at 8 years of age. Histopathology of the lungs found evidence of plexogenic pulmonary arteriopathy. Despite severe pulmonary vascular lesions, other post-mortem evidence of right heart failure was lacking and death was attributed to a fatal cardiac arrhythmia. In this case report of a cat with chronic pulmonary hypertension over 8 years, plexogenic lesions were found on histopathology. The microscopic findings resemble those previously reported in dogs. PMID:25728380

  14. Paternally Inherited IGF2 Mutation and Growth Restriction.

    PubMed

    Begemann, Matthias; Zirn, Birgit; Santen, Gijs; Wirthgen, Elisa; Soellner, Lukas; Büttel, Hans-Martin; Schweizer, Roland; van Workum, Wilbert; Binder, Gerhard; Eggermann, Thomas

    2015-07-23

    In humans, mutations in IGF1 or IGF1R cause intrauterine and postnatal growth restriction; however, data on mutations in IGF2, encoding insulin-like growth factor (IGF) II, are lacking. We report an IGF2 variant (c.191C→A, p.Ser64Ter) with evidence of pathogenicity in a multigenerational family with four members who have growth restriction. The phenotype affects only family members who have inherited the variant through paternal transmission, a finding that is consistent with the maternal imprinting status of IGF2. The severe growth restriction in affected family members suggests that IGF-II affects postnatal growth in addition to prenatal growth. Furthermore, the dysmorphic features of affected family members are consistent with a role of deficient IGF-II levels in the cause of the Silver-Russell syndrome. (Funded by Bundesministerium für Bildung und Forschung and the European Union.). PMID:26154720

  15. Intrauterine Growth Restriction Associated with Excessively Long Umbilical Cord

    PubMed Central

    Schmid, Ann; Jacquemyn, Yves; Loor, Jeannette De

    2013-01-01

    We present a 37-week female baby, known with intrauterine growth restriction since 25 weeks of pregnancy, born with a placenta with an excessive long umbilical cord (ELUC), without any other abnormalities. ELUC is mostly an incidental finding after delivery, but represents a potentially detectable intrauterine cause of growth restriction. A system that allows ultrasound measurement of the length of the umbilical cord could highly increase antenatal diagnosis of ELUC. PMID:24765511

  16. Individual Pulmonary Veins Outgrow Somatic Growth After Primary Sutureless Repair for Total Anomalous Pulmonary Venous Drainage.

    PubMed

    Jung, Hyun-Jin; Bang, Ji Hyun; Park, Chun-Soo; Park, Jeong-Jun; Im, Yu-Mi; Yun, Tae-Jin

    2016-02-01

    Indications of sutureless repair (SR) for pulmonary vein anomalies have evolved from re-operational SR for pulmonary vein stenosis after the repair of total anomalous pulmonary venous drainage (TAPVD) to primary SR for TAPVD associated with right atrial isomerism or isolated TAPVD with small individual pulmonary veins (IPVs) and an unfavorable pulmonary vein anatomy. We sought to determine whether small IPVs outgrow somatic growth after primary SR. Between 2004 and 2013, 21 children underwent primary SR for TAPVD: 13 with a functionally single ventricle, 11 with right atrial isomerism, six with isolated TAPVD, and 13 with a pulmonary venous obstruction. TAPVD types were supracardiac in nine, infracardiac in 10, and mixed in two. Utilizing cardiac computed tomography (CT), the maximal diameter of each IPV was measured, and pulmonary vein index (PVI, summation of cross-sectional areas of all four IPVs divided by body surface area) was calculated. There were five early deaths after SR. Among survivors, 10 had both preoperative and postoperative cardiac CT at a 3.6-month median interval. On postoperative cardiac CT, IPVs were patent in all patients except one who developed a left lower pulmonary vein obstruction. There was a 71 ± 48 % postoperative increase in the actual diameter of all four IPVs, and PVI increased significantly from 215 ± 55 to 402 ± 117 mm(2)/m(2) (P value = 0.005). IPVs outgrew somatic growth after primary SR of TAPVD. Primary SR may be a useful measure in TAPVD patients whose IPVs are small. PMID:26433938

  17. Prevalence of Sodium and Fluid Restriction Recommendations for Patients with Pulmonary Hypertension

    PubMed Central

    Zeiger, Tonya; Cueva Cobo, Giovanna; Dillingham, Christine; Burger, Charles D.

    2015-01-01

    Background: Patients with pulmonary hypertension (PH) are often afflicted with the consequences of right heart failure including volume overload. Counseling to assist the patient in the dietary restriction of sodium and fluid may be underutilized. Methods: Consecutive patients seen in the PH Clinic at Mayo Clinic in Florida from June to November 2013. Results: 100 patients were included; 70 were women and most had group 1 PH (n = 69). Patient characteristics using mean (±SD) were: Age 63 ± 13 years, functional class 3 ± 1, brain natriuretic peptide 302 ± 696 pg/mL, 6-min walk 337 ± 116 m, right atrial pressure 8 ± 5 mmHg, and mean pulmonary artery pressure 42 ± 13 mmHg. Overall, 79 had had complete (32) or partial instruction (47) and 21 had no prior counseling to restrict sodium or fluid. Of the 47 with partial instruction, 42 received complete education during the PH Clinic visit. Of the 21 without prior instruction, 19 received complete education during the PH visit. Seven patients with the opportunity to have their education enhanced or provided did not receive any additional counseling during the PH visit. Conclusion: Sodium and fluid restriction is an important but perhaps underutilized strategy to manage volume overload in patients with right heart failure. Focused questioning and education may permit an increase in the patients receiving instruction in this regard.

  18. Control of Francisella tularensis Intracellular Growth by Pulmonary Epithelial Cells

    PubMed Central

    Maggio, Savannah; Takeda, Kazuyo; Stark, Felicity; Meierovics, Anda I.; Yabe, Idalia; Cowley, Siobhan C.

    2015-01-01

    The virulence of F. tularensis is often associated with its ability to grow in macrophages, although recent studies show that Francisella proliferates in multiple host cell types, including pulmonary epithelial cells. Thus far little is known about the requirements for killing of F. tularensis in the non-macrophage host cell types that support replication of this organism. Here we sought to address this question through the use of a murine lung epithelial cell line (TC-1 cells). Our data show that combinations of the cytokines IFN-γ, TNF, and IL-17A activated murine pulmonary epithelial cells to inhibit the intracellular growth of the F. tularensis Live Vaccine Strain (LVS) and the highly virulent F. tularensis Schu S4 strain. Although paired combinations of IFN-γ, TNF, and IL-17A all significantly controlled LVS growth, simultaneous treatment with all three cytokines had the greatest effect on LVS growth inhibition. In contrast, Schu S4 was more resistant to cytokine-induced growth effects, exhibiting significant growth inhibition only in response to all three cytokines. Since one of the main antimicrobial mechanisms of activated macrophages is the release of reactive nitrogen intermediates (RNI) via the activity of iNOS, we investigated the role of RNI and iNOS in Francisella growth control by pulmonary epithelial cells. NOS2 gene expression was significantly up-regulated in infected, cytokine-treated pulmonary epithelial cells in a manner that correlated with LVS and Schu S4 growth control. Treatment of LVS-infected cells with an iNOS inhibitor significantly reversed LVS killing in cytokine-treated cultures. Further, we found that mouse pulmonary epithelial cells produced iNOS during in vivo respiratory LVS infection. Overall, these data demonstrate that lung epithelial cells produce iNOS both in vitro and in vivo, and can inhibit Francisella intracellular growth via reactive nitrogen intermediates. PMID:26379269

  19. Biomass growth restriction in a packed bed reactor

    DOEpatents

    Griffith, William L.; Compere, Alicia L.

    1978-01-01

    When carrying out continuous biologically catalyzed reactions with anaerobic microorganisms attached to a support in an upflow packed bed column, growth of the microorganisms is restricted to prevent the microorganisms from plugging the column by limiting the availability of an essential nutrient and/or by the presence of predatory protozoa which consume the anaerobic microorganisms. A membrane disruptive detergent may be provided in the column to lyse dead microorganisms to make them available as nutrients for live microorganisms.

  20. Reduced placental volume and flow in severe growth restricted fetuses

    PubMed Central

    Abulé, Renata Montes Dourado; Bernardes, Lisandra Stein; Doro, Giovana Farina; Miyadahira, Seizo; Francisco, Rossana Pulcinelli Vieira

    2016-01-01

    OBJECTIVES: To evaluate placental volume and vascular indices in pregnancies with severe fetal growth restriction and determine their correlations to normal reference ranges and Doppler velocimetry results of uterine and umbilical arteries. METHODS: Twenty-seven fetuses with estimated weights below the 3rd percentile for gestational age were evaluated. Placental volume and vascular indices, including vascularization, flow, and vascularization flow indices, were measured by three-dimensional ultrasound using a rotational technique and compared to a previously described nomogram. The observed-to-expected placental volume ratio for gestational age and observed-to-expected placental volume ratio for fetal weight were calculated. Placental parameters correlated with the Doppler velocimetry results of uterine and umbilical arteries. RESULTS: The mean uterine artery pulsatility index was negatively correlated with the observed-to-expected placental volume ratio for gestational age, vascularization index and vascularization flow index. The observed-to-expected placental volume ratio for gestational age and observed-to-expected placental volume ratio for fetal weight and vascularization index were significantly lower in the group with a bilateral protodiastolic notch. No placental parameter correlated with the umbilical artery pulsatility index. CONCLUSIONS: Pregnancies complicated by severe fetal growth restriction are associated with reduced placental volume and vascularization. These findings are related to changes in uterine artery Doppler velocimetry. Future studies on managing severe fetal growth restriction should focus on combined results of placental three-dimensional ultrasound and Doppler studies of uterine arteries. PMID:27438567

  1. Extrinsic Factors Influencing Fetal Deformations and Intrauterine Growth Restriction

    PubMed Central

    Moh, Wendy; Graham, John M.; Wadhawan, Isha; Sanchez-Lara, Pedro A.

    2012-01-01

    The causes of intrauterine growth restriction (IUGR) are multifactorial with both intrinsic and extrinsic influences. While many studies focus on the intrinsic pathological causes, the possible long-term consequences resulting from extrinsic intrauterine physiological constraints merit additional consideration and further investigation. Infants with IUGR can exhibit early symmetric or late asymmetric growth abnormality patterns depending on the fetal stage of development, of which the latter is most common occurring in 70–80% of growth-restricted infants. Deformation is the consequence of extrinsic biomechanical factors interfering with normal growth, functioning, or positioning of the fetus in utero, typically arising during late gestation. Biomechanical forces play a critical role in the normal morphogenesis of most tissues. The magnitude and direction of force impact the form of the developing fetus, with a specific tissue response depending on its pliability and stage of development. Major uterine constraining factors include primigravida, small maternal size, uterine malformation, uterine fibromata, early pelvic engagement of the fetal head, aberrant fetal position, oligohydramnios, and multifetal gestation. Corrective mechanical forces similar to those that gave rise to the deformation to reshape the deformed structures are often used and should take advantage of the rapid postnatal growth to correct form. PMID:22888434

  2. A serum component mediates food restriction-induced growth attenuation.

    PubMed

    Pando, Rakefet; Shtaif, Biana; Phillip, Moshe; Gat-Yablonski, Galia

    2014-03-01

    Proper nutrition in terms of calories and essential food components is required to maximize longitudinal growth in children. Our previous study showed that prepubertal male rats subjected to 10 days of 40% food restriction (RES) exhibited a dramatic reduction in weight and epiphyseal growth plate height, as well as changes in gene expression and microRNAs (miRNAs) in the epiphyseal growth plate. These findings reversed rapidly after renewal of the regular food supply (catch-up [CU]). To further elucidate the mechanisms underlying the nutrition-growth association, serum collected from the RES and CU rats and control rats fed ad libitum (AL) was added to the culture medium of the chondrocyte cell line ATDC5 (instead of fetal calf serum). Serum from the RES group induced a reduction in cell viability (25%, P < .05) concomitant with an increase in cell differentiation compared with that for the AL group serum. The most interesting observation, in our opinion, was the significant reduction in the expression of specific miRNAs, including the chondro-specific miR-140. These effects were not observed for serum from refed (CU) rats. Serum levels of IGF-I, leptin, and fibroblast growth factor 21 were reduced by food restriction. The addition of IGF-I and leptin to the culture increased cell viability, whereas fibroblast growth factor 21 reduced it, suggesting the involvement of IGF-I, leptin, and possibly other still unidentified serum factors in chondrocyte cell growth. In conclusion, specific miRNAs respond to nutritional cues, and these effects are mediated by serum-borne factors. These results may promote the development of superior interventions for children with malnutrition and growth abnormalities. PMID:24456162

  3. Calorie Restriction Attenuates Monocrotaline-induced Pulmonary Arterial Hypertension in Rats

    PubMed Central

    Ding, Mingge; Lei, Jingyi; Qu, Yinxian; Zhang, Huan; Xin, Weichuan; Ma, Feng; Liu, Shuwen; Li, Zhichao; Jin, Faguang

    2015-01-01

    Abstract: Calorie restriction (CR) is one of the most effective nonpharmacological interventions protecting against cardiovascular disease, such as hypertension in the systemic circulation. However, whether CR could attenuate pulmonary arterial hypertension (PAH) is largely unknown. The PAH model was developed by subjecting the rats to a single subcutaneous injection of monocrotaline. CR lowered mean pulmonary arterial pressure (mPAP) and reduced vascular remodeling and right ventricular hypertrophy in PAH rats. Meanwhile, CR attenuated endothelial dysfunction as evidenced by increased relaxation in response to acetylcholine. The beneficial effects of CR were associated with restored sirtuin-1 (SIRT1) expression and endothelial nitric oxide synthase (eNOS) phosphorylation and reduced eNOS acetylation in pulmonary arteries of PAH rats. To further clarify the role of SIRT1 in the protective effects of CR, adenoviral vectors for overexpression of SIRT1 were administered intratracheally at 1 day before monocrotaline injection. Overexpression of SIRT1 exhibited similar beneficial effects on mPAP and endothelial function, and increased eNOS phosphorylation and reduced eNOS acetylation in the absence of CR. Moreover, SIRT1 overexpression attenuated the increase in mPAP in hypoxia-induced PAH animals. Overall, the present data demonstrate that CR may serve as an effective treatment of PAH, and targeting the SIRT1/eNOS pathway may improve treatment of PAH. PMID:25636073

  4. Cyclic Stretch Affects Pulmonary Endothelial Cell Control of Pulmonary Smooth Muscle Cell Growth

    PubMed Central

    Ochoa, Cristhiaan D.; Baker, Haven; Hasak, Stephen; Matyal, Robina; Salam, Aleya; Hales, Charles A.; Hancock, William; Quinn, Deborah A.

    2008-01-01

    Endothelial cells are subjected to mechanical forces in the form of cyclic stretch resulting from blood pulsatility. Pulmonary artery endothelial cells (PAECs) produce factors that stimulate and inhibit pulmonary artery smooth muscle cell (PASMC) growth. We hypothesized that PAECs exposed to cyclic stretch secrete proteins that inhibit PASMC growth. Media from PAECs exposed to cyclic stretch significantly inhibited PASMC growth in a time-dependent manner. Lyophilized material isolated from stretched PAEC-conditioned media significantly inhibited PASMC growth in a dose-dependent manner. This inhibition was reversed by trypsin inactivation, which is consistent with the relevant factor being a protein(s). To identify proteins that inhibited cell growth in conditioned media from stretched PAECs, we used proteomic techniques and found that thrombospondin (TSP)-1, a natural antiangiogenic factor, was up-regulated by stretch. In vitro, exogenous TSP-1 inhibited PASMC growth. TSP-1–blocking antibodies reversed conditioned media–induced inhibition of PASMC growth. Cyclic stretched PAECs secrete protein(s) that inhibit PASMC proliferation. TSP-1 may be, at least in part, responsible for this inhibition. The complete identification and understanding of the secreted proteome of stretched PAECs may lead to new insights into the pathophysiology of pulmonary vascular remodeling. PMID:18314539

  5. INDOOR AIR POLLUTION AND PULMONARY FUNCTION GROWTH IN PREADOLESCENT CHILDREN

    EPA Science Inventory

    Results are reported from a study of the association between exposure to sidestream cigarette smoke or gas stove emissions and pulmonary function level and growth rate of 7,834 children seen at 2-5 annual visits between the ages of 6-10 years. Children whose mothers smoked one pa...

  6. Aspirin for the Prevention of Preeclampsia and Intrauterine Growth Restriction.

    PubMed

    Roberge, Stephanie; Odibo, Anthony O; Bujold, Emmanuel

    2016-06-01

    Low-dose aspirin (LDA) has been used for several years for the prevention of preeclampsia (PE). LDA started in early pregnancy is associated with improvement of placental implantation. The best evidence suggest that LDA can prevent more than half of PE cases in high-risk women when started before 16 weeks of gestation. Moreover, LDA started in early pregnancy reduces the risk of other placenta-mediated complications such as intrauterine growth restriction (IUGR) and perinatal death. The efficacy of LDA has been demonstrated in women with abnormal first-trimester uterine artery Doppler or with prior history of chronic hypertension or preeclampsia. PMID:27235915

  7. Aberrant Pulmonary Vascular Growth and Remodeling in Bronchopulmonary Dysplasia

    PubMed Central

    Alvira, Cristina M.

    2016-01-01

    In contrast to many other organs, a significant portion of lung development occurs after birth during alveolarization, thus rendering the lung highly susceptible to injuries that may disrupt this developmental process. Premature birth heightens this susceptibility, with many premature infants developing the chronic lung disease, bronchopulmonary dysplasia (BPD), a disease characterized by arrested alveolarization. Over the past decade, tremendous progress has been made in the elucidation of mechanisms that promote postnatal lung development, including extensive data suggesting that impaired pulmonary angiogenesis contributes to the pathogenesis of BPD. Moreover, in addition to impaired vascular growth, patients with BPD also frequently demonstrate alterations in pulmonary vascular remodeling and tone, increasing the risk for persistent hypoxemia and the development of pulmonary hypertension. In this review, an overview of normal lung development will be presented, and the pathologic features of arrested development observed in BPD will be described, with a specific emphasis on the pulmonary vascular abnormalities. Key pathways that promote normal pulmonary vascular development will be reviewed, and the experimental and clinical evidence demonstrating alterations of these essential pathways in BPD summarized. PMID:27243014

  8. Glucose metabolism in pregnant sheep when placental growth is restricted

    SciTech Connect

    Owens, J.A.; Falconer, J.; Robinson, J.S. )

    1989-08-01

    The effect of restricting placental growth on glucose metabolism in pregnant sheep in late gestation was determined by primed constant infusions of D-(U-{sup 14}C)- and D-(2-{sup 3}H)glucose and antipyrine into fetuses of six control sheep and six sheep from which endometrial caruncles had been removed before pregnancy (caruncle sheep). In the latter, placental and fetal weights were reduced, as was the concentration of glucose in fetal arterial blood. Fetal glucose turnover in caruncle sheep was only 52-59% of that in controls, largely because of lower umbilical loss of glucose back to the placenta (38-39% of control) and lower fetal glucose utilization (61-74% of control). However, fetal glucose utilization on a weight-specific basis was similar in control and caruncle sheep. Significant endogenous glucose production occurred in control and caruncle fetal sheep. Maternal glucose production and partition of glucose between the gravid uterus and other maternal tissues were similar in control and caruncle sheep. In conclusion, when placental and fetal growth are restricted, fetal glucose utilization is maintained by reduced loss of glucose back to the placenta and mother and by maintaining endogenous glucose production.

  9. Adaptation to statins restricts human tumour growth in Nude mice

    PubMed Central

    2011-01-01

    Background Statins have long been used as anti-hypercholesterolemia drugs, but numerous lines of evidence suggest that they may also bear anti-tumour potential. We have recently demonstrated that it was possible to isolate cancer cells adapted to growth in the continuous presence of lovastatin. These cells grew more slowly than the statin-sensitive cells of origin. In the present study, we compared the ability of both statin-sensitive and statin-resistant cells to give rise to tumours in Nude mice. Methods HGT-1 human gastric cancer cells and L50 statin-resistant derivatives were injected subcutaneously into Nude mice and tumour growth was recorded. At the end of the experiment, tumours were recovered and marker proteins were analyzed by western blotting, RT-PCR and immunohistochemistry. Results L50 tumours grew more slowly, showed a strong decrease in cyclin B1, over-expressed collagen IV, and had reduced laminin 332, VEGF and CD34 levels, which, collectively, may have restricted cell division, cell adhesion and neoangiogenesis. Conclusions Taken together, these results showed that statin-resistant cells developed into smaller tumours than statin-sensitive cells. This may be reflective of the cancer restricting activity of statins in humans, as suggested from several retrospective studies with subjects undergoing statin therapy for several years. PMID:22107808

  10. Pulmonary (cardio) diagnostic system for combat casualty care capable of extracting embedded characteristics of obstructive or restrictive flow

    NASA Astrophysics Data System (ADS)

    Allgood, Glenn O.; Treece, Dale A.; Pearce, Fred J.; Bentley, Timothy B.

    2000-08-01

    Walter Reed Army Institute of Research and Oak Ridge National Laboratory have developed a prototype pulmonary diagnostic system capable of extracting signatures from adventitious lung sounds that characterize obstructive and/or restrictive flow. Examples of disorders that have been detailed include emphysema, asthma, pulmonary fibrosis, and pneumothorax. The system is based on the premise that acoustic signals associated with pulmonary disorders can be characterized by a set of embedded signatures unique to the disease. The concept is being extended to include cardio signals correlated with pulmonary data to provide an accurate and timely diagnoses of pulmonary function and distress in critically injured soldiers that will allow medical personnel to anticipate the need for accurate therapeutic intervention as well as monitor soldiers whose injuries may lead to pulmonary compromise later. The basic operation of the diagnostic system is as follows: (1) create an image from the acoustic signature based on higher order statistics, (2) deconstruct the image based on a predefined map, (3) compare the deconstructed image with stored images of pulmonary symptoms, and (4) classify the disorder based on a clustering of known symptoms and provide a statistical measure of confidence. The system has produced conformity between adults and infants and provided effective measures of physiology in the presence of noise.

  11. [Placental epigenetic programming in intrauterine growth restriction (IUGR)].

    PubMed

    Casanello, Paola; Castro-Rodríguez, José A; Uauy, Ricardo; Krause, Bernardo J

    2016-01-01

    Intrauterine growth restriction (IUGR) is a perinatal condition affecting foetal growth, with under the 10th percentile of the weight curve expected for gestational age. This condition has been associated with higher cardiovascular and metabolic risk and post-natal obesity. There are also major changes in placental function, and particularly in a key molecule in this regulation, nitric oxide. The synthesis of nitric oxide has numerous control mechanisms and competition with arginase for their common substrate, the amino acid L-arginine. This competition is reflected in various vascular diseases and particularly in the endothelium of the umbilical vessels of babies with IUGR. Along with this, there is regulation at the epigenetic level, where methylation in specific regions of some gene promoters, such as the nitric oxide synthase, regulating their expression. It is currently of great interest to understand the mechanisms by which diseases such as IUGR may be conditioned, particularly by maternal nutritional and metabolic conditions, and epigenetic mechanisms that could eventually be modifiable, and thus a focus of interest for health interventions. PMID:27209119

  12. Restrictive Fluid Resuscitation Leads to Better Oxygenation than Non-Restrictive Fluid Resuscitation in Piglets with Pulmonary or Extrapulmonary Acute Respiratory Distress Syndrome

    PubMed Central

    Ye, Shunan; Li, Qiujie; Yuan, Shiying; Shu, Huaqing; Yuan, Yin

    2015-01-01

    Background Early goal-directed therapy (EGDT) is used to reduce mortality from septic shock and could be used in early fluid resuscitation of acute respiratory distress syndrome (ARDS). The aim of the present study was to assess the effects of restrictive (RFR) and nonrestrictive fluid resuscitation (NRFR) on hemodynamics, oxygenation, pulmonary function, tissue perfusion, and inflammation in piglets with pulmonary or extrapulmonary ARDS (ARDSp and ARDSexp). Material/Methods Chinese miniature piglets (6–8 weeks; 15±1 kg) were randomly divided into 2 groups (n=12/group) for establishing ARDSp and ARDSexp models, and were further divided into 2 subgroups (n=6/subgroup) for performing RFR and NRFR. Piglets were anesthetized and hemodynamic, pulmonary, and oxygenation indicators were collected at different time points for 6 hours. The goal of EGDT was set for PiCCO parameters (mean arterial pressure (MAP), urine output and cardiac index (CI), and central venous oxygen saturation (ScvO2). Results Piglets under RFR had lower urine output compared with NRFR, as well as lower total fluid volume (P<0.05). EVLW was decreased in ARDSp+RFR and NRFR, as well as in ARDSexp+RFR, but EVLW increased in ARDSexp+NRFR (P<0.05). PaO2/FiO2 decreased in ARDSp using both methods, but was higher with RFR (P<0.05), and was increased in ARDSexp+RFR. Other pulmonary indicators were comparable. The anti-inflammatory cytokines IL-10 and LXA4 were increased in ARDSexp after RFR (P<0.05), but not in the other groups. Conclusions RFR led to better oxygenation in ARDSp and ARDSexp compared with NRFR, but fluid restriction improved oxygenation in ARDSexp only. PMID:26166324

  13. Intrauterine growth restriction programs an accelerated age-related increase in cardiovascular risk in male offspring.

    PubMed

    Dasinger, John Henry; Intapad, Suttira; Backstrom, Miles A; Carter, Anthony J; Alexander, Barbara T

    2016-08-01

    Placental insufficiency programs an increase in blood pressure associated with a twofold increase in serum testosterone in male growth-restricted offspring at 4 mo of age. Population studies indicate that the inverse relationship between birth weight and blood pressure is amplified with age. Thus, we tested the hypothesis that intrauterine growth restriction programs an age-related increase in blood pressure in male offspring. Growth-restricted offspring retained a significantly higher blood pressure at 12 but not at 18 mo of age compared with age-matched controls. Blood pressure was significantly increased in control offspring at 18 mo of age relative to control counterparts at 12 mo; however, blood pressure was not increased in growth-restricted at 18 mo relative to growth-restricted counterparts at 12 mo. Serum testosterone levels were not elevated in growth-restricted offspring relative to control at 12 mo of age. Thus, male growth-restricted offspring no longer exhibited a positive association between blood pressure and testosterone at 12 mo of age. Unlike hypertension in male growth-restricted offspring at 4 mo of age, inhibition of the renin-angiotensin system with enalapril (250 mg/l for 2 wk) did not abolish the difference in blood pressure in growth-restricted offspring relative to control counterparts at 12 mo of age. Therefore, these data suggest that intrauterine growth restriction programs an accelerated age-related increase in blood pressure in growth-restricted offspring. Furthermore, this study suggests that the etiology of increased blood pressure in male growth-restricted offspring at 12 mo of age differs from that at 4 mo of age. PMID:27147668

  14. Indoor air pollution and pulmonary function growth in preadolescent children

    SciTech Connect

    Berkey, C.S.; Ware, J.H.; Dockery, D.W.; Ferris, B.G. Jr.; Speizer, F.E.

    1986-02-01

    Results are reported from a study of the association between exposure to sidestream cigarette smoke or gas stove emissions and pulmonary function level and growth rate of 7834 children seen at 2-5 annual visits between the ages of 6-10 years. Children whose mothers smoked one pack of cigarettes per day had levels of forced expiratory volume in one second (FEV1) at age eight that were 0.81% lower than children of nonsmoking mothers (p less than 0.0001), and FEV1 growth rates approximately 0.17% per year lower (p = 0.05). For a child of age eight with an FEV1 of 1.62 liters, this corresponds to a deficit in rate of change of FEV1 of approximately 3 ml/annum and a deficit of 13 ml at age eight. Children whose mothers smoked one pack per day had levels of forced vital capacity (FVC) at age eight that were 0.33% higher than children of nonsmokers (p = 0.12); however, their growth rates of FVC were 0.17% per year lower (p = 0.04). Because few mothers changed their smoking habits during the course of the study, it was not possible to determine whether the difference in rate of growth was due to current exposure or to an effect of prenatal and early childhood exposure on the course of development. The magnitude of the effect on FEV1 is consistent with deficits in FEV1 of up to 3% in early adult life due to childhood exposure to sidestream cigarette smoke. The importance of this relatively small effect will be evaluated further through follow-up of these children as they are exposed to other risk factors such as personal active smoking. The data provide some evidence for an association between gas stove exposure and pulmonary function level, especially at younger ages, but no evidence for an effect of gas stove exposure on growth rate.

  15. Intrauterine Growth Restriction Alters Mouse Intestinal Architecture during Development.

    PubMed

    Fung, Camille M; White, Jessica R; Brown, Ashley S; Gong, Huiyu; Weitkamp, Jörn-Hendrik; Frey, Mark R; McElroy, Steven J

    2016-01-01

    Infants with intrauterine growth restriction (IUGR) are at increased risk for neonatal and lifelong morbidities affecting multiple organ systems including the intestinal tract. The underlying mechanisms for the risk to the intestine remain poorly understood. In this study, we tested the hypothesis that IUGR affects the development of goblet and Paneth cell lineages, thus compromising the innate immunity and barrier functions of the epithelium. Using a mouse model of maternal thromboxane A2-analog infusion to elicit maternal hypertension and resultant IUGR, we tested whether IUGR alters ileal maturation and specifically disrupts mucus-producing goblet and antimicrobial-secreting Paneth cell development. We measured body weights, ileal weights and ileal lengths from birth to postnatal day (P) 56. We also determined the abundance of goblet and Paneth cells and their mRNA products, localization of cellular tight junctions, cell proliferation, and apoptosis to interrogate cellular homeostasis. Comparison of the murine findings with human IUGR ileum allowed us to verify observed changes in the mouse were relevant to clinical IUGR. At P14 IUGR mice had decreased ileal lengths, fewer goblet and Paneth cells, reductions in Paneth cell specific mRNAs, and decreased cell proliferation. These findings positively correlated with severity of IUGR. Furthermore, the decrease in murine Paneth cells was also seen in human IUGR ileum. IUGR disrupts the normal trajectory of ileal development, particularly affecting the composition and secretory products of the epithelial surface of the intestine. We speculate that this abnormal intestinal development may constitute an inherent "first hit", rendering IUGR intestine susceptible to further injury, infection, or inflammation. PMID:26745886

  16. Intrauterine Growth Restriction Alters Mouse Intestinal Architecture during Development

    PubMed Central

    Brown, Ashley S.; Gong, Huiyu; Weitkamp, Jörn-Hendrik; Frey, Mark R.; McElroy, Steven J.

    2016-01-01

    Infants with intrauterine growth restriction (IUGR) are at increased risk for neonatal and lifelong morbidities affecting multiple organ systems including the intestinal tract. The underlying mechanisms for the risk to the intestine remain poorly understood. In this study, we tested the hypothesis that IUGR affects the development of goblet and Paneth cell lineages, thus compromising the innate immunity and barrier functions of the epithelium. Using a mouse model of maternal thromboxane A2-analog infusion to elicit maternal hypertension and resultant IUGR, we tested whether IUGR alters ileal maturation and specifically disrupts mucus-producing goblet and antimicrobial-secreting Paneth cell development. We measured body weights, ileal weights and ileal lengths from birth to postnatal day (P) 56. We also determined the abundance of goblet and Paneth cells and their mRNA products, localization of cellular tight junctions, cell proliferation, and apoptosis to interrogate cellular homeostasis. Comparison of the murine findings with human IUGR ileum allowed us to verify observed changes in the mouse were relevant to clinical IUGR. At P14 IUGR mice had decreased ileal lengths, fewer goblet and Paneth cells, reductions in Paneth cell specific mRNAs, and decreased cell proliferation. These findings positively correlated with severity of IUGR. Furthermore, the decrease in murine Paneth cells was also seen in human IUGR ileum. IUGR disrupts the normal trajectory of ileal development, particularly affecting the composition and secretory products of the epithelial surface of the intestine. We speculate that this abnormal intestinal development may constitute an inherent “first hit”, rendering IUGR intestine susceptible to further injury, infection, or inflammation. PMID:26745886

  17. Indoor air pollution and pulmonary function growth in preadolescent children

    SciTech Connect

    Berkey, C.S.; Ware, J.H.; Dockery, D.W.; Ferris, B.G.; Speizer, F.E.

    1986-01-01

    Results are reported from a study of the association between exposure to sidestream cigarette smoke or gas-stove emissions and pulmonary-function level and growth rate of 7,834 children seen at 2-5 annual visits between the ages of 6-10 years. Children whose mothers smoked one pack of cigarettes per day had levels of forced expiratory volume in one second (FEV1) at age eight that were 0.81% lower than children of nonsmoking mothers (p<0.0001), and FEV1 growth rates approximately 0.17% per year lower (p=0.05). For a child of age eight with an FEV1 of 1.62 liters, this corresponds to a deficit in rate of change of FEV1 of approximately 3 ml/annum and a deficit of 13 ml at age eight. Children whose mothers smoked one pack per day had levels of forced vital capacity (FVC) at age eight that were 0.33% higher than children of nonsmokers (p=0.12); however, their growth rates of FVC were 0.17% per year lower (p=0.04). Because few mothers changed their smoking habits during the course of the study, it was not possible to determine whether the difference in rate of growth was due to current exposure or to an effect of prenatal and early childhood exposure on the course of development.

  18. The hepatic transcriptome of young suckling and aging intrauterine growth restricted male rats.

    PubMed

    Freije, William A; Thamotharan, Shanthie; Lee, Regina; Shin, Bo-Chul; Devaskar, Sherin U

    2015-04-01

    Intrauterine growth restriction leads to the development of adult onset obesity/metabolic syndrome, diabetes mellitus, cardiovascular disease, hypertension, stroke, dyslipidemia, and non-alcoholic fatty liver disease/steatohepatitis. Continued postnatal growth restriction has been shown to ameliorate many of these sequelae. To further our understanding of the mechanism of how intrauterine and early postnatal growth affects adult health we have employed Affymetrix microarray-based expression profiling to characterize hepatic gene expression of male offspring in a rat model of maternal nutrient restriction in early and late life. At day 21 of life (p21) combined intrauterine and postnatal calorie restriction treatment led to expression changes in circadian, metabolic, and insulin-like growth factor genes as part of a larger transcriptional response that encompasses 144 genes. Independent and controlled experiments at p21 confirm the early life circadian, metabolic, and growth factor perturbations. In contrast to the p21 transcriptional response, at day 450 of life (d450) only seven genes, largely uncharacterized, were differentially expressed. This lack of a transcriptional response identifies non-transcriptional mechanisms mediating the adult sequelae of intrauterine growth restriction. Independent experiments at d450 identify a circadian defect as well as validate expression changes to four of the genes identified by the microarray screen which have a novel association with growth restriction. Emerging from this rich dataset is a portrait of how the liver responds to growth restriction through circadian dysregulation, energy/substrate management, and growth factor modulation. PMID:25371150

  19. Ventilation-induced lung injury is not exacerbated by growth restriction in preterm lambs.

    PubMed

    Allison, Beth J; Hooper, Stuart B; Coia, Elise; Zahra, Valerie A; Jenkin, Graham; Malhotra, Atul; Sehgal, Arvind; Kluckow, Martin; Gill, Andrew W; Sozo, Foula; Miller, Suzanne L; Polglase, Graeme R

    2016-02-01

    Intrauterine growth restriction (IUGR) and preterm birth are frequent comorbidities and, combined, increase the risk of adverse respiratory outcomes compared with that in appropriately grown (AG) infants. Potential underlying reasons for this increased respiratory morbidity in IUGR infants compared with AG infants include altered fetal lung development, fetal lung inflammation, increased respiratory requirements, and/or increased ventilation-induced lung injury. IUGR was surgically induced in preterm fetal sheep (0.7 gestation) by ligation of a single umbilical artery. Four weeks later, preterm lambs were euthanized at delivery or delivered and ventilated for 2 h before euthanasia. Ventilator requirements, lung inflammation, early markers of lung injury, and morphological changes in lung parenchymal and vascular structure and surfactant composition were analyzed. IUGR preterm lambs weighed 30% less than AG preterm lambs, with increased brain-to-body weight ratio, indicating brain sparing. IUGR did not induce lung inflammation or injury or alter lung parenchymal and vascular structure compared with AG fetuses. IUGR and AG lambs had similar oxygenation and respiratory requirements after birth and had significant, but similar, increases in proinflammatory cytokine expression, lung injury markers, gene expression, and surfactant phosphatidylcholine species compared with unventilated controls. IUGR does not induce pulmonary structural changes in our model. Furthermore, IUGR and AG preterm lambs have similar ventilator requirements in the immediate postnatal period. This study suggests that increased morbidity and mortality in IUGR infants is not due to altered lung tissue or vascular structure, or to an altered response to early ventilation. PMID:26608532

  20. OXIDATIVE STRESS CONTRIBUTES TO SEX DIFFERENCES IN BLOOD PRESSURE IN ADULT GROWTH RESTRICTED OFFSPRING

    PubMed Central

    Ojeda, Norma B.; Hennington, Bettye Sue; Williamson, Danielle T.; Hill, Melanie L.; Betson, Nicole E.E.; Sartori-Valinotti, Julio C.; Reckelhoff, Jane F.; Royals, Thomas P.; Alexander, Barbara T.

    2013-01-01

    Numerous experimental studies suggest that oxidative stress contributes to the pathophysiology of hypertension and importantly, that oxidative stress plays a more definitive role in mediating hypertension in males than in females. Intrauterine growth-restriction induced by reduced uterine perfusion initiated at day 14 of gestation in the rat programs hypertension in adult male growth-restricted offspring; yet, female growth-restricted offspring are normotensive. The mechanisms mediating sex differences in blood pressure in adult growth-restricted offspring are not clear. Thus, this study tested the hypothesis that sex specific differences in renal oxidative stress contribute to the regulation of blood pressure in adult growth-restricted offspring. A significant increase in blood pressure measured by telemetry in male growth-restricted offspring (P<0.05) was associated with a marked increase in renal markers of oxidative stress (P<0.05). Chronic treatment with the antioxidant tempol had no effect on blood pressure in male control offspring, but it normalized blood pressure (P<0.05) and renal markers of oxidative stress (P<0.05) in male growth-restricted relative to male control. Renal markers of oxidative stress were not elevated in female growth-restricted offspring; however, renal activity of the antioxidant catalase was significantly elevated relative to female control (P<0.05). Chronic treatment with tempol did not significantly alter oxidative stress or blood pressure measured by telemetry in female offspring. Thus, these data suggest that sex differences in renal oxidative stress and antioxidant activity are present in adult growth-restricted offspring, and that oxidative stress may play a more important role in modulating blood pressure in male, but not female growth-restricted offspring. PMID:22585945

  1. Metabolomic Research on Newborn Infants With Intrauterine Growth Restriction.

    PubMed

    Liu, Jing; Chen, Xin-Xin; Li, Xiang-Wen; Fu, Wei; Zhang, Wan-Qiao

    2016-04-01

    To compare differences in metabolites between newborns with intrauterine growth restriction (IUGR) and those who are appropriate for gestational age (AGA) in order to understand the changes in metabolites of newborns with IUGR and to explore the possible metabolic mechanism of tissue and organ damages in patients with IUGR, with the ultimate goal of providing the basis for clinical intervention.A total of 60 newborns with IUGR and 60 AGA newborns who were hospitalized in the neonatal intensive care unit of our hospital between January 2011 and December 2015 and who underwent metabolic disease screening were enrolled in this study. The differences in 21 amino acids and 55 carnitines in peripheral blood, as well as changes in the ratios of free carnitine and acylcarnitine to total carnitine, were compared.Metabolites, particularly alanine, homocysteine, leucine, methionine, ornithine, serine, tyrosine, isovaleryl carnitine, and eicosenoyl carnitine, differed according to newborns' birth weight (<3rd percentile, 3rd-5th percentiles, 5th-10th percentiles, and 10th-90th percentiles), with those with lower birth weight showing the greater difference (P < 0.05). Metabolites also differed by gestational age, and the differences observed were mainly as follows: preterm and full-term newborns showed differences in metabolites, mainly in alanine, proline, cerotoyl carnitine, and tetradecanedioyl carnitine (P < 0.05); preterm and full-term AGA newborns showed differences in metabolites, mainly in alanine, glutamine, homocysteine, pipecolic acid, proline, heptanoyl carnitine, and sebacoyl carnitine (P < 0.05); and preterm and full-term newborns with IUGR showed differences in metabolites, mainly in arginine, glutamic acid, homocysteine, histidine, leucine, isoleucine, ornithine, serine, threonine, tryptophan, valine, heptanoyl carnitine, decanoyl carnitine, linoleyl carnitine, methylmalonyl carnitine, glutarylcarnitine, sebacoyl carnitine, hydroxyacetyl carnitine

  2. Metabolomic Research on Newborn Infants With Intrauterine Growth Restriction

    PubMed Central

    Liu, Jing; Chen, Xin-Xin; Li, Xiang-Wen; Fu, Wei; Zhang, Wan-Qiao

    2016-01-01

    Abstract To compare differences in metabolites between newborns with intrauterine growth restriction (IUGR) and those who are appropriate for gestational age (AGA) in order to understand the changes in metabolites of newborns with IUGR and to explore the possible metabolic mechanism of tissue and organ damages in patients with IUGR, with the ultimate goal of providing the basis for clinical intervention. A total of 60 newborns with IUGR and 60 AGA newborns who were hospitalized in the neonatal intensive care unit of our hospital between January 2011 and December 2015 and who underwent metabolic disease screening were enrolled in this study. The differences in 21 amino acids and 55 carnitines in peripheral blood, as well as changes in the ratios of free carnitine and acylcarnitine to total carnitine, were compared. Metabolites, particularly alanine, homocysteine, leucine, methionine, ornithine, serine, tyrosine, isovaleryl carnitine, and eicosenoyl carnitine, differed according to newborns’ birth weight (<3rd percentile, 3rd–5th percentiles, 5th–10th percentiles, and 10th–90th percentiles), with those with lower birth weight showing the greater difference (P < 0.05). Metabolites also differed by gestational age, and the differences observed were mainly as follows: preterm and full-term newborns showed differences in metabolites, mainly in alanine, proline, cerotoyl carnitine, and tetradecanedioyl carnitine (P < 0.05); preterm and full-term AGA newborns showed differences in metabolites, mainly in alanine, glutamine, homocysteine, pipecolic acid, proline, heptanoyl carnitine, and sebacoyl carnitine (P < 0.05); and preterm and full-term newborns with IUGR showed differences in metabolites, mainly in arginine, glutamic acid, homocysteine, histidine, leucine, isoleucine, ornithine, serine, threonine, tryptophan, valine, heptanoyl carnitine, decanoyl carnitine, linoleyl carnitine, methylmalonyl carnitine, glutarylcarnitine, sebacoyl carnitine

  3. Pulmonary and systemic hepatocyte and keratinocyte growth factors in patients with chronic obstructive pulmonary disease

    PubMed Central

    Sauleda, Jaume; Noguera, Aina; Blanquer, David; Pons, Jaume; López, Meritxell; Villena, Cristina; Agustí, Alvar GN

    2008-01-01

    Background The potential role of growth factors in chronic obstructive pulmonary disease (COPD) has begun to be addressed only recently and is still poorly understood. For this study, we investigated potential abnormalities of hepatocyte growth factor (HGF) and keratinocyte growth factor (KGF) in patients with COPD. Methods To this end, we compared the levels of HGF and KGF, measured by enzyme-linked immunosorbent assay (ELISA), in bronchoalveolar lavage (BAL) fluid and in serum in 18 patients with COPD (62 ± 9 yrs, forced expiratory volume in one second [FEV1] 57 ± 12% ref, X ± standard deviation of mean), 18 smokers with normal lung function (58 ± 8 yrs, FEV1 90 ± 6% ref) and 8 never smokers (67 ± 9 yrs, 94 ± 14% ref). Results We found that in BAL, HGF levels were higher in patients with COPD than in the other two groups whereas, in serum, HGF concentration was highest in smokers with normal lung function (p < 0.01). KGF levels were not significantly different between groups, neither in blood nor in BAL (most values were below the detection limit). Conclusions These results highlight a different response of HGF in BAL and serum in smokers with and without COPD that may be relevant for tissue repair in COPD. PMID:19281086

  4. Perforin-2 restricts growth of Chlamydia trachomatis in macrophages.

    PubMed

    Fields, K A; McCormack, R; de Armas, L R; Podack, E R

    2013-08-01

    Chlamydia trachomatis is a Gram-negative obligate intracellular bacterium that preferentially infects epithelial cells. Professional phagocytes provide C. trachomatis only a limited ability to survive and are proficient killers of chlamydiae. We present evidence herein that identifies a novel host defense protein, perforin-2, that plays a significant role in the eradication of C. trachomatis during the infection of macrophages. Knockdown of perforin-2 in macrophages did not alter the invasion of host cells but did result in chlamydial growth that closely mirrored that detected in HeLa cells. C trachomatis L2, serovar B, and serovar D and C. muridarum were all equally susceptible to perforin-2-mediated killing. Interestingly, induction of perforin-2 expression in epithelial cells is blocked during productive chlamydial growth, thereby protecting chlamydiae from bactericidal attack. Ectopic expression of perforin-2 in HeLa cells, however, does result in killing. Overall, our data implicate a new innate resistance protein in the control of chlamydial infection and may help explain why the macrophage environment is hostile to chlamydial growth. PMID:23753625

  5. Intrauterine growth restriction: impact on cardiovascular development and function throughout infancy.

    PubMed

    Cohen, Emily; Wong, Flora Y; Horne, Rosemary S C; Yiallourou, Stephanie R

    2016-06-01

    Intrauterine growth restriction (IUGR) refers to the situation where a fetus does not grow according to its genetic growth potential. One of the main causes of IUGR is uteroplacental vascular insufficiency. Under these circumstances of chronic oxygen and nutrient deprivation, the growth-restricted fetus often displays typical circulatory changes, which in part represent adaptations to the suboptimal intrauterine environment. These fetal adaptations aim to preserve oxygen and nutrient supply to vital organs such as the brain, the heart, and the adrenals. These prenatal circulatory adaptations are thought to lead to an altered development of the cardiovascular system and "program" the fetus for life long cardiovascular morbidities. In this review, we discuss the alterations to cardiovascular structure, function, and control that have been observed in growth-restricted fetuses, neonates, and infants following uteroplacental vascular insufficiency. We also discuss the current knowledge on early life surveillance and interventions to prevent progression into chronic disease. PMID:26866903

  6. Uteroplacental Adenovirus Vascular Endothelial Growth Factor Gene Therapy Increases Fetal Growth Velocity in Growth-Restricted Sheep Pregnancies

    PubMed Central

    Wallace, Jacqueline M.; Aitken, Raymond P.; Milne, John S.; Mehta, Vedanta; Martin, John F.; Zachary, Ian C.; Peebles, Donald M.; David, Anna L.

    2014-01-01

    Abstract Fetal growth restriction (FGR) occurs in ∼8% of pregnancies and is a major cause of perinatal mortality and morbidity. There is no effective treatment. FGR is characterized by reduced uterine blood flow (UBF). In normal sheep pregnancies, local uterine artery (UtA) adenovirus (Ad)-mediated overexpression of vascular endothelial growth factor (VEGF) increases UBF. Herein we evaluated Ad.VEGF therapy in the overnourished adolescent ewe, an experimental paradigm in which reduced UBF from midgestation correlates with reduced lamb birthweight near term. Singleton pregnancies were established using embryo transfer in adolescent ewes subsequently offered a high intake (n=45) or control intake (n=12) of a complete diet to generate FGR or normal fetoplacental growth, respectively. High-intake ewes were randomized midgestation to receive bilateral UtA injections of 5×1011 particles Ad.VEGF-A165 (n=18), control vector Ad.LacZ (n=14), or control saline (n=13). Fetal growth/well-being were evaluated using serial ultrasound. UBF was monitored using indwelling flowprobes until necropsy at 0.9 gestation. Vasorelaxation, neovascularization within the perivascular adventitia, and placental mRNA expression of angiogenic factors/receptors were examined using organ bath analysis, anti-vWF immunohistochemistry, and qRT-PCR, respectively. Ad.VEGF significantly increased ultrasonographic fetal growth velocity at 3–4 weeks postinjection (p=0.016–0.047). At 0.9 gestation fewer fetuses were markedly growth-restricted (birthweight >2SD below contemporaneous control-intake mean) after Ad.VEGF therapy. There was also evidence of mitigated fetal brain sparing (lower biparietal diameter-to-abdominal circumference and brain-to-liver weight ratios). No effects were observed on UBF or neovascularization; however, Ad.VEGF-transduced vessels demonstrated strikingly enhanced vasorelaxation. Placental efficiency (fetal-to-placental weight ratio) and FLT1/KDR mRNA expression were

  7. Midterm results of “treat and repair” for adults with non-restrictive ventricular septal defect and severe pulmonary hypertension

    PubMed Central

    Hu, Zhenlei; Xie, Bo; Zhai, Xinming; Liu, Jidong; Gu, Jianmin; Wang, Xudong; Zheng, Hui

    2015-01-01

    Background A non-restrictive ventricular septal defect (VSD) can cause intracardiac left to right shunt, which leads to increased pulmonary vascular resistance (PVR) and pulmonary hypertension causes bi-directional or even right-left shunt, namely the Eisenmenger’s syndrome. For patients with non-restrictive VSD with severe pulmonary hypertension at stage of near or to be Eisenmenger’s syndrome, traditional VSD repair carries high mortality and poor prognosis. Recently, targeted drug therapy was used to decrease pulmonary circulation resistance in these patients before they receive defect repair surgery, namely “treat and repair” strategy, however, there is few reports about the midterm result of this strategy in adults with non-restrictive VSD with severe pulmonary hypertension at stage of near or to be Eisenmenger’s syndrome. Methods In this study, we used this strategy to treat 41 adult VSD patients who received bosentan as the targeted therapy to decrease their PVR before and after repair surgery. Results A total of 39 patients were followed up for an average of 37 months. None of the patients died during follow-up. Among them, 36 cases continued targeted drug therapy, whose mean pulmonary artery pressure (mPAP) was significantly reduced, including 31 cases with mPAP <50 mmHg, and the valve of tap hole was closed. Besides, the SpO2 was significantly elevated. Conclusions These results demonstrated that “treat-and-repair” strategy may be a viable approach for the adults with non-restrictive VSD with severe pulmonary hypertension at stage of near or to be Eisenmenger’s syndrome. PMID:26380732

  8. Sulfolipid-1 biosynthesis restricts Mycobacterium tuberculosis growth in human macrophages.

    PubMed

    Gilmore, Sarah A; Schelle, Michael W; Holsclaw, Cynthia M; Leigh, Clifton D; Jain, Madhulika; Cox, Jeffery S; Leary, Julie A; Bertozzi, Carolyn R

    2012-05-18

    Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis, is a highly evolved human pathogen characterized by its formidable cell wall. Many unique lipids and glycolipids from the Mtb cell wall are thought to be virulence factors that mediate host-pathogen interactions. An intriguing example is Sulfolipid-1 (SL-1), a sulfated glycolipid that has been implicated in Mtb pathogenesis, although no direct role for SL-1 in virulence has been established. Previously, we described the biochemical activity of the sulfotransferase Stf0 that initiates SL-1 biosynthesis. Here we show that a stf0-deletion mutant exhibits augmented survival in human but not murine macrophages, suggesting that SL-1 negatively regulates the intracellular growth of Mtb in a species-specific manner. Furthermore, we demonstrate that SL-1 plays a role in mediating the susceptibility of Mtb to a human cationic antimicrobial peptide in vitro, despite being dispensable for maintaining overall cell envelope integrity. Thus, we hypothesize that the species-specific phenotype of the stf0 mutant is reflective of differences in antimycobacterial effector mechanisms of macrophages. PMID:22360425

  9. Intrauterine Growth Restriction Associated with Hematologic Abnormalities: Probable Manifestations of Placental Mesenchymal Dysplasia.

    PubMed

    Martinez-Payo, Cristina; Bernabeu, Rocio Alvarez; Villar, Isabel Salas; Goy, Enrique Iglesias

    2015-10-01

    Introduction Placental mesenchymal dysplasia is a rare vascular disease associated with intrauterine growth restriction, fetal demise as well as Beckwith-Wiedemann syndrome. Some neonates present hematologic abnormalities possibly related to consumptive coagulopathy and hemolytic anemia in the placental circulation. Case report We present a case of placental mesenchymal dysplasia in a fetus with intrauterine growth restriction and cerebellar hemorrhagic injury diagnosed in the 20th week of pregnancy. During 26th week, our patient had an intrauterine fetal demise in the context of gestational hypertension. We have detailed the ultrasound findings that made us suspect the presence of hematologic disorders during 20th week. Discussion We believe that the cerebellar hematoma could be the consequence of thrombocytopenia accompanied by anemia. If hemorrhagic damage during fetal life is found, above all associates with an anomalous placental appearance and with intrauterine growth restriction, PMD should be suspected along other etiologies. PMID:26495159

  10. Food restriction alters energy allocation strategy during growth in tobacco hornworms (Manduca sexta larvae).

    PubMed

    Jiao, Lihong; Amunugama, Kaushalya; Hayes, Matthew B; Jennings, Michael; Domingo, Azriel; Hou, Chen

    2015-08-01

    Growing animals must alter their energy budget in the face of environmental changes and prioritize the energy allocation to metabolism for life-sustaining requirements and energy deposition in new biomass growth. We hypothesize that when food availability is low, larvae of holometabolic insects with a short development stage (relative to the low food availability period) prioritize biomass growth at the expense of metabolism. Driven by this hypothesis, we develop a simple theoretical model, based on conservation of energy and allometric scaling laws, for understanding the dynamic energy budget of growing larvae under food restriction. We test the hypothesis by manipulative experiments on fifth instar hornworms at three temperatures. At each temperature, food restriction increases the scaling power of growth rate but decreases that of metabolic rate, as predicted by the hypothesis. During the fifth instar, the energy budgets of larvae change dynamically. The free-feeding larvae slightly decrease the energy allocated to growth as body mass increases and increase the energy allocated to life sustaining. The opposite trends were observed in food restricted larvae, indicating the predicted prioritization in the energy budget under food restriction. We compare the energy budgets of a few endothermic and ectothermic species and discuss how different life histories lead to the differences in the energy budgets under food restriction. PMID:26105046

  11. Food restriction alters energy allocation strategy during growth in tobacco hornworms ( Manduca sexta larvae)

    NASA Astrophysics Data System (ADS)

    Jiao, Lihong; Amunugama, Kaushalya; Hayes, Matthew B.; Jennings, Michael; Domingo, Azriel; Hou, Chen

    2015-08-01

    Growing animals must alter their energy budget in the face of environmental changes and prioritize the energy allocation to metabolism for life-sustaining requirements and energy deposition in new biomass growth. We hypothesize that when food availability is low, larvae of holometabolic insects with a short development stage (relative to the low food availability period) prioritize biomass growth at the expense of metabolism. Driven by this hypothesis, we develop a simple theoretical model, based on conservation of energy and allometric scaling laws, for understanding the dynamic energy budget of growing larvae under food restriction. We test the hypothesis by manipulative experiments on fifth instar hornworms at three temperatures. At each temperature, food restriction increases the scaling power of growth rate but decreases that of metabolic rate, as predicted by the hypothesis. During the fifth instar, the energy budgets of larvae change dynamically. The free-feeding larvae slightly decrease the energy allocated to growth as body mass increases and increase the energy allocated to life sustaining. The opposite trends were observed in food restricted larvae, indicating the predicted prioritization in the energy budget under food restriction. We compare the energy budgets of a few endothermic and ectothermic species and discuss how different life histories lead to the differences in the energy budgets under food restriction.

  12. Evaluation of pulmonary alveolar epithelial integrity by the detection of restriction to diffusion of hydrophilic solutes of different molecular sizes.

    PubMed

    Mason, G R; Peters, A M; Bagdades, E; Myers, M J; Snook, D; Hughes, J M

    2001-03-01

    The rate of transfer of a hydrophilic solute from the alveoli to pulmonary blood following inhalation as an aerosol depends on the molecular size of the solute and the permeability of the alveolar epithelium. The value of this measurement for assessing damage to the epithelium in lung disease is compromised by cigarette smoking, which accelerates clearance by unknown mechanisms. The rates of clearance of (99m)Tc-labelled diethylenetriaminepenta-acetic acid (DTPA) (molecular mass 492 Da) and (113m)In-labelled biotinylated DTPA (B-DTPA) (molecular mass 1215 Da) were monitored simultaneously by dynamic gamma-radiation camera imaging following simultaneous inhalation, and compared between eight normal non-smoking subjects and nine habitual cigarette smokers. The clearance rates of DTPA were 0.95 (S.D. 0.39)%/min in non-smokers and 4.13 (1.06) %/min in smokers. These were about twice the clearance rates of B-DTPA, which in the corresponding groups were 0.41 (0.26) and 2.12 (0.72)%/min respectively. The ratio of the B-DTPA/DTPA clearance rates was, in all subjects, less than the ratio (0.74) of the cube roots of the molecular masses of the solutes, assumed to correspond to the ratio of their free diffusion coefficients in water, and was not significantly different between smokers and non-smokers. As alveolar permeability increased, the ratio of clearance rates in the entire population showed a significant trend to increase in a non-linear fashion towards the value corresponding to the ratio of the free diffusion coefficients. We conclude that the diffusion of at least the larger of these two solutes through the pulmonary alveolar epithelium is restricted (i.e. associated with a reflection coefficient greater than zero). Cigarette smoking, however, does not appear to cause a loss of this restriction, and may increase solute clearance by other mechanisms, such as reducing fluid volume within the alveolus, thereby raising the local radiotracer concentration, or increasing

  13. Role of the fetoplacental endothelium in fetal growth restriction with abnormal umbilical artery Doppler velocimetry.

    PubMed

    Su, Emily J

    2015-10-01

    Growth-restricted fetuses with absent or reversed end-diastolic velocities in the umbilical artery are at substantially increased risk for adverse perinatal and long-term outcome, even in comparison to growth-restricted fetuses with preserved end-diastolic velocities. Translational studies show that this Doppler velocimetry correlates with fetoplacental blood flow, with absent or reversed end-diastolic velocities signifying abnormally elevated resistance within the placental vasculature. The fetoplacental vasculature is unique in that it is not subject to autonomic regulation, unlike other vascular beds. Instead, humoral mediators, many of which are synthesized by local endothelial cells, regulate placental vascular resistance. Existing data demonstrate that in growth-restricted pregnancies complicated by absent or reversed umbilical artery end-diastolic velocities, an imbalance in production of these vasoactive substances occurs, favoring vasoconstriction. Morphologically, placentas from these pregnancies also demonstrate impaired angiogenesis, whereby vessels within the terminal villi are sparsely branched, abnormally thin, and elongated. This structural deviation from normal placental angiogenesis restricts blood flow and further contributes to elevated fetoplacental vascular resistance. Although considerable work has been done in the field of fetoplacental vascular development and function, much remains unknown about the mechanisms underlying impaired development and function of the human fetoplacental vasculature, especially in the context of severe fetal growth restriction with absent or reversed umbilical artery end-diastolic velocities. Fetoplacental endothelial cells are key regulators of angiogenesis and vasomotor tone. A thorough understanding of their role in placental vascular biology carries the significant potential of discovering clinically relevant and innovative approaches to prevention and treatment of fetal growth restriction with compromised

  14. Compensatory Feto-Placental Upregulation of the Nitric Oxide System during Fetal Growth Restriction

    PubMed Central

    Pisaneschi, Silvia; Strigini, Francesca A. L.; Sanchez, Angel M.; Begliuomini, Silvia; Casarosa, Elena; Ripoli, Andrea; Ghirri, Paolo; Boldrini, Antonio; Fink, Bruno; Genazzani, Andrea R.; Coceani, Flavio; Simoncini, Tommaso

    2012-01-01

    Background Fetal Growth Restriction is often associated with a feto-placental vascular dysfunction conceivably involving endothelial cells. Our study aimed to verify this pathogenic role for feto-placental endothelial cells and, coincidentally, demonstrate any abnormality in the nitric oxide system. Methods Prenatal assessment of feto-placental vascular function was combined with measurement of nitric oxide (in the form of S-nitrosohemoglobin) and its nitrite byproduct, and of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine. Umbilical vein endothelial cells were also harvested to determine their gene profile. The study comprised term pregnancies with normal (n = 40) or small-for-gestational-age (n = 20) newborns, small-for-gestational-age preterm pregnancies (n = 15), and bi-chorial, bi-amniotic twin pregnancies with discordant fetal growth (n = 12). Results Umbilical blood nitrite (p<0.001) and S-nitrosohemoglobin (p = 0.02) rose with fetal growth restriction while asymmetric dimethylarginine decreased (p = 0.003). Nitrite rise coincided with an abnormal Doppler profile from umbilical arteries. Fetal growth restriction umbilical vein endothelial cells produced more nitrite and also exhibited reciprocal changes in vasodilator (upwards) and vasoconstrictor (downwards) transcripts. Elevation in blood nitrite and S-nitrosohemoglobin persisted postnatally in the fetal growth restriction offspring. Conclusion Fetal growth restriction is typified by increased nitric oxide production during pregnancy and after birth. This response is viewed as an adaptative event to sustain placental blood flow. However, its occurrence may modify the endothelial phenotype and may ultimately represent an element of risk for cardiovascular disease in adult life. PMID:23028913

  15. Restrictive pulmonary deficit is associated with inflammation in sub-optimally controlled obese diabetics

    PubMed Central

    Seemungal, Terence A. R.; Teelucksingh, Surujpal; Nayak, B. Shivananda

    2013-01-01

    Caribbean data linking inflammation, pulmonary dysfunction and diabetes is unavailable. Spirometry, acanthosis nigricans, hs-CRP were assessed in 109 type 2 diabetics (43% males) mean age=55.6 years, BMI=29.29 kg/m2, waist circumference=103.86 cm. Residual FEV1/FVC increased with age (P=0.005), BMI (P=0.011) and waist circumference (P=0.003). Residual FVC related inversely to hs-CRP (–0.178), P<0.06) systolic (–0.028, P<0.031), diastolic (–0.247, P<0.010) pressure and weight (–0.25, P<0.009). Residual FEV1 related inversely to diastolic pressure (–0.219, P<0.023), hs-CRP (–0.234, P<0.015), acanthosis nigricans (–0.029, P<0.029). HbA1C and residual FEV1 predict high hs-CRP (P=0.011, P=0.046). Low FVC with inflammation presents in poorly controlled obese diabetics. PMID:23825761

  16. Proteome Differences in Placenta and Endometrium between Normal and Intrauterine Growth Restricted Pig Fetuses

    PubMed Central

    Chen, Fang; Wang, Taiji; Feng, Cuiping; Lin, Gang; Zhu, Yuhua; Wu, Guoyao; Johnson, Gregory; Wang, Junjun

    2015-01-01

    Uteroplacental tissue plays a key role in substance exchanges between maternal and fetal circulation, and, therefore, in the growth and development of fetuses. In this study, proteomics and western blotting were applied to investigate the changes of proteome in the placenta and endometrium of normal and intrauterine growth restriction (IUGR) porcine fetuses during mid to late pregnancy (D60, 90, and 110 of gestation). Our results showed that proteins participating in cell structure, energy metabolism, stress response, cell turnover, as well as transport and metabolism of nutrients were differentially expressed in placenta and endometrium between normal and IUGR fetuses. Analysis of functions of these proteins suggests reductions in ATP production and nutrients transport, increases in oxidative stress and apoptosis, and impairment of cell metabolism in IUGR fetuses. Collectively, our findings aid in understanding of the mechanisms responsible for uteroplacental dysfunction in IUGR fetus, and are expected to provide new strategies to reduce fetal growth restriction in pigs and other mammals. PMID:26554841

  17. Dietary -carbamylglutamate and rumen-protected -arginine supplementation ameliorate fetal growth restriction in undernourished ewes.

    PubMed

    Zhang, H; Sun, L W; Wang, Z Y; Deng, M T; Zhang, G M; Guo, R H; Ma, T W; Wang, F

    2016-05-01

    This study was conducted with an ovine intrauterine growth restriction (IUGR) model to test the hypothesis that dietary -carbamylglutamate (NCG) and rumen-protected -Arg (RP-Arg) supplementation are effective in ameliorating fetal growth restriction in undernourished ewes. Beginning on d 35 of gestation, ewes were fed a diet providing 100% of NRC-recommended nutrient requirements, 50% of NRC recommendations (50% NRC), 50% of NRC recommendations supplemented with 20 g/d RP-Arg (providing 10 g/d of Arg), and 50% of NRC recommendations supplemented with 5 g/d NCG product (providing 2.5 g/d of NCG). On d 110, maternal, fetal, and placental tissues and fluids were collected and weighed. Ewe weights were lower ( < 0.05) in nutrient-restricted ewes compared with adequately fed ewes. Maternal RP-Arg or NCG supplementation did not alter ( = 0.26) maternal BW in nutrient-restricted ewes. Weights of most fetal organs were increased ( < 0.05) in RP-Arg-treated and NCG-treated underfed ewes compared with 50% NRC-fed ewes. Supplementation of RP-Arg or NCG reduced ( < 0.05) concentrations of β-hydroxybutyrate, triglycerides, and ammonia in serum of underfed ewes but had no effect on concentrations of lactate and GH. Maternal RP-Arg or NCG supplementation markedly improved ( < 0.05) concentrations of AA (particularly arginine-family AA and branched-chain AA) and polyamines in maternal and fetal plasma and in fetal allantoic and amniotic fluids within nutrient-restricted ewes. These novel results indicate that dietary NCG and RP-Arg supplementation to underfed ewes ameliorated fetal growth restriction, at least in part, by increasing the availability of AA in the conceptus and provide support for its clinical use to ameliorate IUGR in humans and sheep industry production. PMID:27285704

  18. Caloric Restriction Normalizes Obesity-Induced Alterations on Regulators of Skeletal Muscle Growth Signaling.

    PubMed

    Dungan, Cory M; Li, Ji; Williamson, David L

    2016-08-01

    The objective of this study was to establish the impact of caloric restriction on high fat diet-induced alterations on regulators of skeletal muscle growth. We hypothesized that caloric restriction would reverse the negative effects of high fat diet-induced obesity on REDD1 and mTOR-related signaling. Following an initial 8 week period of HF diet-induced obesity, caloric restriction (CR ~30 %) was employed while mice continued to consume either a low (LF) or high fat (HF) diet for 8 weeks. Western analysis of skeletal muscle showed that CR reduced (p < 0.05) the obesity-related effects on the lipogenic protein, SREBP1. Likewise, CR reduced (p < 0.05) the obesity-related effects on the hyperactivation of mTORC1 and ERK1/2 signaling to levels comparable to the LF mice. CR also reduced (p < 0.05) obesity-induced expression of negative regulators of growth, REDD1 and cleaved caspase 3. These findings have implications for on the reversibility of dysregulated growth signaling in obese skeletal muscle, using short-term caloric restriction. PMID:27289530

  19. Effects of early feed restriction and cold temperature on lipid peroxidation, pulmonary vascular remodelling and ascites morbidity in broilers under normal and cold temperature.

    PubMed

    Pan, J Q; Tan, X; Li, J C; Sun, W D; Wang, X L

    2005-06-01

    Two experiments were conducted to evaluate the effects of early feed restriction on lipid peroxidation, pulmonary vascular remodelling and ascites incidence in broilers under normal and low ambient temperature. In experiment 1, the restricted birds were fed 8h per day either from 7 to 14 d or from 7 to 21 d, while the controlled birds were fed ad libitum. In experiment 2, the restricted birds were fed 80 or 60% of the previous 24-h feed consumption of full-fed controls for 7 d from 7 to 14 d. On d 14, half of the birds in each treatment both in experiment 1 and experiment 2 were exposed to low ambient temperature to induce ascites. Body weight and feed conversion ratio were measured weekly. The incidences of ascites and other disease were recorded to determine ascites morbidity and total mortality. Blood samples were taken on d 14, 21, 28, 35 and 42 to measure the plasma malondialdehyde (MDA), superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). On d 42, samples were taken to determine the right/total ventricular weight ratio (RV/TV), vessel wall area/vessel total area ratio (WA/TA) and mean media thickness in pulmonary arterioles (mMTPA). Low-temperature treatment increased plasma MDA concentration. When broilers were exposed to a cool environment for 3 weeks, plasma SOD and GSH-Px activity were decreased compared with normal-temperature chicks. RV/TV, WA/TA and mMTPA on d 42 were increased in birds exposed to cold, consistent with the increased pulmonary hypertension and ascites morbidity. Early feed restriction markedly decreased plasma MDA concentration. The plasma SOD and GSH-Px activity of feed-restricted birds were markedly higher than those fed ad libitum on d 35 and d 42. All early feed restriction treatments reduced ascites morbidity and total mortality. On d 42, the RV/TV, WA/TA and mMTPA of feed-restricted broilers were lower than that of the ad libitum-fed broilers. The results suggested that early feed restriction alleviated the lipid

  20. Chronic Blockade of the Androgen Receptor Abolishes Age-Dependent Increases in Blood Pressure in Female Growth-Restricted Rats.

    PubMed

    Dasinger, John Henry; Intapad, Suttira; Rudsenske, Benjamin R; Davis, Gwendolyn K; Newsome, Ashley D; Alexander, Barbara T

    2016-06-01

    Intrauterine growth restriction induced via placental insufficiency programs a significant increase in blood pressure at 12 months of age in female growth-restricted rats that is associated with early cessation of estrous cyclicity, indicative of premature reproductive senescence. In addition, female growth-restricted rats at 12 months of age exhibit a significant increase in circulating testosterone with no change in circulating estradiol. Testosterone is positively associated with blood pressure after menopause in women. Thus, we tested the hypothesis that androgen receptor blockade would abolish the significant increase in blood pressure that develops with age in female growth-restricted rats. Mean arterial pressure was measured in animals pretreated with and without the androgen receptor antagonist, flutamide (8 mg/kg/day, SC for 2 weeks). Flutamide abolished the significant increase in blood pressure in growth-restricted rats relative to control at 12 months of age. To examine the mechanism(s) by which androgens contribute to increased blood pressure in growth-restricted rats, blood pressure was assessed in rats untreated or treated with enalapril (250 mg/L for 2 weeks). Enalapril eliminated the increase in blood pressure in growth-restricted relative to vehicle- and flutamide-treated controls. Furthermore, the increase in medullary angiotensin type 1 receptor mRNA expression was abolished in flutamide-treated growth-restricted relative to untreated counterparts and controls; cortical angiotensin-converting enzyme mRNA expression was reduced in flutamide-treated growth-restricted versus untreated counterparts. Thus, these data indicate that androgens, via activation of the renin-angiotensin system, are important mediators of increased blood pressure that develops by 12 months of age in female growth-restricted rats. PMID:27113045

  1. Birth weight- and fetal weight-growth restriction: impact on neurodevelopment

    PubMed Central

    Streimish, Iris G.; Ehrenkranz, Richard A.; Allred, Elizabeth N.; O’Shea, T. Michael; Kuban, Karl C.K.; Paneth, Nigel; Leviton, Alan

    2013-01-01

    Background The newborn classified as growth-restricted on birth weight curves, but not on fetal weight curves, is classified prenatally as small for gestational age (SGA), but postnatally as appropriate for gestational age (AGA). Aims To see (1) to what extent the neurodevelopmental outcomes at 24 months corrected age differed among three groups of infants (those identified as SGA based on birth weight curves (B-SGA), those identified as SGA based on fetal weight curves only (F-SGA), and the referent group of infants considered AGA, (2) if girls and boys were equally affected by growth restriction, and (3) to what extent neurosensory limitations influenced what we found. Study design Observational cohort of births before the 28 week of gestation. Outcome measures: Mental Development Index (MDI) and Psychomotor Development Index (PDI) of the Bayley Scales of Infant Development II. Results B-SGA, but not F-SGA girls were at an increased risk of a PDI < 70 (OR=2.8; 95% CI: 1.5, 5.3) compared to AGA girls. B-SGA and F-SGA boys were not at greater risk of low developmental indices than AGA boys. Neurosensory limitations diminished associations among girls of B-SGA with low MDI, and among boys B-SGA and F-SGA with PDI < 70. Conclusions Only girls with the most severe growth restriction were at increased risk of neurodevelopmental impairment at 24 months corrected age in the total sample. Neurosensory limitations appear to interfere with assessing growth restriction effects in both girls and boys born preterm. PMID:22732241

  2. Equilibrium-restricted solid-on-solid growth model on fractal substrates.

    PubMed

    Lee, Sang Bub; Kim, Jin Min

    2009-08-01

    The equilibrium-restricted solid-on-solid growth model on fractal substrates is studied by introducing a fractional Langevin equation. The growth exponent beta and the roughness exponent alpha defined, respectively, by the surface width via W approximately t(beta) and the saturated width via W(sat) approximately L(alpha), L being the system size, were obtained by a power-counting analysis, and the scaling relation 2alpha+d(f)=z(RW) was found to hold. The numerical simulation data on Sierpinski gasket, checkerboard fractal, and critical percolation cluster were found to agree well with the analytical predictions of the fractional Langevin equation. PMID:19792071

  3. Shining light in dark corners: diagnosis and management of late-onset fetal growth restriction.

    PubMed

    MacDonald, Teresa M; McCarthy, Elizabeth A; Walker, Susan P

    2015-02-01

    Fetal growth restriction (FGR) is the single biggest risk factor for stillbirth. In the absence of any effective treatment for fetal growth restriction, the mainstay of management is close surveillance and timely delivery. While such statements are almost self-evident, the daily clinical challenge of late-onset fetal growth restriction remains; the competing priorities of minimising stillbirth risk, while avoiding excessive obstetric intervention and the neonatal sequelae of iatrogenic preterm birth. This dilemma is made harder because the tools for late-onset FGR diagnosis and surveillance compare poorly to those used in early-onset FGR; screening tests in early pregnancy have limited predictive value; most cases escape clinical detection, a phenomenon set to worsen given the obesity epidemic; there is a failure of consensus on the definition of small for gestational age, and ancillary tools, such as umbilical artery Doppler--of value in identification of preterm FGR--are less useful in the late-preterm period and at term. Most importantly, the problem is common; 96% of all births occur after 32 weeks. This means a poor noise/signal ratio of any test or management algorithm will inevitably have large clinical consequences. Into such a dark corner, we cast some light; a summary on diagnostic criteria, new developments to improve the diagnosis of late-onset FGR and a suggested approach to management. PMID:25557743

  4. Syncytiotrophoblast Functions and Fetal Growth Restriction during Placental Malaria: Updates and Implication for Future Interventions

    PubMed Central

    Kidima, Winifrida B.

    2015-01-01

    Syncytiotrophoblast lines the intervillous space of the placenta and plays important roles in fetus growth throughout gestation. However, perturbations at the maternal-fetal interface during placental malaria may possibly alter the physiological functions of syncytiotrophoblast and therefore growth and development of the embryo in utero. An understanding of the influence of placental malaria on syncytiotrophoblast function is paramount in developing novel interventions for the control of placental pathology associated with placental malaria. In this review, we discuss how malaria changes syncytiotrophoblast function as evidenced from human, animal, and in vitro studies and, further, how dysregulation of syncytiotrophoblast function may impact fetal growth in utero. We also formulate a hypothesis, stemming from epidemiological observations, that nutrition may override pathogenesis of placental malaria-associated-fetal growth restriction. We therefore recommend studies on nutrition-based-interventional approaches for high placental malaria-risk women in endemic areas. More investigations on the role of nutrition on placental malaria pathogenesis are needed. PMID:26587536

  5. Severe dietary lysine restriction affects growth and body composition and hepatic gene expression for nitrogen metabolism in growing rats.

    PubMed

    Kim, J; Lee, K S; Kwon, D-H; Bong, J J; Jeong, J Y; Nam, Y S; Lee, M S; Liu, X; Baik, M

    2014-02-01

    Dietary lysine restriction may differentially affect body growth and lipid and nitrogen metabolism, depending on the degree of lysine restriction. This study was conducted to examine the effect of dietary lysine restriction on growth and lipid and nitrogen metabolism with two different degree of lysine restriction. Isocaloric amino acid-defined diets containing 1.4% lysine (adequate), 0.70% lysine (50% moderate lysine restriction) and 0.35% lysine (75% severe lysine restriction) were fed from the age of 52 to 77 days for 25 days in male Sprague-Dawley rats. The 75% severe lysine restriction increased (p < 0.05) food intake, but retarded (p < 0.05) growth, increased (p < 0.05) liver and muscle lipid contents and abdominal fat accumulation, increased (p < 0.05) blood urea nitrogen levels and mRNA levels of the serine-synthesizing 3-phosphoglycerate dehydrogenase gene, but decreased (p < 0.05) urea cycle arginase gene mRNA levels. In contrast, the 50% lysine restriction did not significantly (p > 0.05) affect body growth and lipid and nitrogen metabolism. Our results demonstrate that severe 75% lysine restriction has detrimental effects on body growth and deregulate lipid and nitrogen metabolism. PMID:23441935

  6. The dose–response association of urinary metals with altered pulmonary function and risks of restrictive and obstructive lung diseases: a population-based study in China

    PubMed Central

    Feng, Wei; Huang, Xiji; Zhang, Ce; Liu, Chuanyao; Cui, Xiuqing; Zhou, Yun; Sun, Huizhen; Qiu, Gaokun; Guo, Huan; He, Meian; Zhang, Xiaomin; Yuan, Jing; Chen, Weihong; Wu, Tangchun

    2015-01-01

    Objective Reduced pulmonary function is an important predictor of environment-related pulmonary diseases; however, evidence of an association between exposures to various metals from all possible routes and altered pulmonary function is limited. We aimed to investigate the association of various metals in urine with pulmonary function, restrictive lung disease (RLD) and obstructive lung disease (OLD) risks in the general Chinese population. Design A cross-sectional investigation in the Wuhan cohort population. Setting A heavily polluted Chinese city. Participants A total of 2460 community-living Chinese adults from the Wuhan cohort were included in our analysis. Main outcome measures Spirometric parameters (FVC, forced vital capacity; FEV1, forced expiratory volumes in 1 s; FEV1/FVC ratio), RLD and OLD. Results The dose–response associations of pulmonary function, and RLD and OLD, with 23 urinary metals were assessed using regression analysis after adjusting for potential confounders. The false discovery rate (FDR) method was used to correct for multiple hypothesis tests. Our results indicated that there were positive dose–response associations of urinary iron with FEV1 and FEV1/FVC ratio, vanadium with FEV1, and copper and selenium with FEV1/FVC ratio, while a negative dose–response association was observed between urinary lead and FEV1/FVC ratio (all p<0.05). After additional adjusting for multiple comparisons, only iron was dose dependently related to FEV1/FVC ratio (FDR adjusted p<0.05). The dose–response association of iron and lead, with decreased and increased chronic obstructive pulmonary disease risk, respectively, was also observed (both p<0.05). Additionally, we found significant association of urinary zinc with RLD and interaction effects of smoking status with lead on FEV1/FVC, and with cadmium on FVC and FEV1. Conclusions These results suggest that multiple urinary metals are associated with altered pulmonary function, and RLD and OLD

  7. Fetal production of growth factors and inflammatory mediators predicts pulmonary hypertension in congenital diaphragmatic hernia

    PubMed Central

    Fleck, Shannon; Bautista, Geoanna; Keating, Sheila M.; Lee, Tzong-Hae; Keller, Roberta L.; Moon-Grady, Anita J.; Gonzales, Kelly; Norris, Philip J.; Busch, Michael P.; Kim, CJ; Romero, Roberto; Lee, Hanmin; Miniati, Doug; MacKenzie, Tippi C.

    2014-01-01

    Background Congenital diaphragmatic hernia (CDH) represents a spectrum of lung hypoplasia and consequent pulmonary hypertension is an important cause of postnatal morbidity and mortality. We studied biomarkers at the maternal-fetal interface to understand factors associated with the persistence of pulmonary hypertension. Methods Maternal and cord blood samples from fetuses with CDH and unaffected controls were analyzed using a human 39plex immunoassay kit. Cellular trafficking between the mother and the fetu was quantified using quantitative real-time PCR for non-shared alleles. Biomarker profiles were then correlated with CDH severity based on the degree of pulmonary hypertension. Results Cord blood levels of epidermal growth factor, platelet-derived growth factor, and several inflammatory mediators increased significantly as the severity of CDH increased, while maternal levels growth factors and mediators decreased significantly with CDH severity. Maternal cells were increased in fetuses with severe CDH compared to controls, with elevated levels of the chemokine CXCL-10 in patients with the highest trafficking. Conclusion Patients with CDH demonstrate pro-inflammatory and chemotactic signals in fetal blood at the time of birth. Since some of these molecules have been implicated in the development of pulmonary hypertension, prenatal strategies targeting specific molecular pathways may be useful adjuncts to current fetal therapies. PMID:23770923

  8. Surface growth on diluted lattices by a restricted solid-on-solid model.

    PubMed

    Lee, Changhan; Lee, Sang Bub

    2009-08-01

    An influence of diluted sites on surface growth has been investigated, using the restricted solid-on-solid model. It was found that, with respect to equilibrium growth, the surface width and the saturated width exhibited universal power-law behaviors, i.e., W approximately t(beta) and W(sat) approximately L(zeta), regarding all cases with respect to the concentration of diluted sites x=1-p , with p being the occupation probability on each lattice site. For x < x(c) (=1-p(c), p(c) being the percolation threshold), the growth appeared to be similar to that of a regular lattice, both in two and three dimensions. For x=x(c), the growth yielded nontrivial exponents which were different from those on a regular lattice. In nonequilibrium growth, a considerable amount of diluted sites (x < or = x(c)) appeared to yield nonuniversal growth, unlike the case of a regular lattice. The cause of nonuniversal growth dynamics has been investigated, considering the growth on a backbone cluster and on lattices constructed with periodically and randomly diluted subcells. PMID:19792104

  9. Identification of Host-Targeted Small Molecules That Restrict Intracellular Mycobacterium tuberculosis Growth

    PubMed Central

    Silvis, Melanie R.; Luo, Samantha S.; Sogi, Kimberly; Vokes, Martha; Bray, Mark-Anthony; Carpenter, Anne E.; Moore, Christopher B.; Siddiqi, Noman; Rubin, Eric J.; Hung, Deborah T.

    2014-01-01

    Mycobacterium tuberculosis remains a significant threat to global health. Macrophages are the host cell for M. tuberculosis infection, and although bacteria are able to replicate intracellularly under certain conditions, it is also clear that macrophages are capable of killing M. tuberculosis if appropriately activated. The outcome of infection is determined at least in part by the host-pathogen interaction within the macrophage; however, we lack a complete understanding of which host pathways are critical for bacterial survival and replication. To add to our understanding of the molecular processes involved in intracellular infection, we performed a chemical screen using a high-content microscopic assay to identify small molecules that restrict mycobacterial growth in macrophages by targeting host functions and pathways. The identified host-targeted inhibitors restrict bacterial growth exclusively in the context of macrophage infection and predominantly fall into five categories: G-protein coupled receptor modulators, ion channel inhibitors, membrane transport proteins, anti-inflammatories, and kinase modulators. We found that fluoxetine, a selective serotonin reuptake inhibitor, enhances secretion of pro-inflammatory cytokine TNF-α and induces autophagy in infected macrophages, and gefitinib, an inhibitor of the Epidermal Growth Factor Receptor (EGFR), also activates autophagy and restricts growth. We demonstrate that during infection signaling through EGFR activates a p38 MAPK signaling pathway that prevents macrophages from effectively responding to infection. Inhibition of this pathway using gefitinib during in vivo infection reduces growth of M. tuberculosis in the lungs of infected mice. Our results support the concept that screening for inhibitors using intracellular models results in the identification of tool compounds for probing pathways during in vivo infection and may also result in the identification of new anti-tuberculosis agents that work by

  10. Altered immune proteome of Staphylococcus aureus under iron-restricted growth conditions.

    PubMed

    Stentzel, Sebastian; Vu, Hai Chi; Weyrich, Anna Maria; Jehmlich, Nico; Schmidt, Frank; Salazar, Manuela Gesell; Steil, Leif; Völker, Uwe; Bröker, Barbara M

    2014-08-01

    Staphylococcus aureus is one of the major causative agents of severe infections, and is responsible for a high burden of morbidity and mortality. Strains of increased virulence have emerged (e.g. USA300) that can infect healthy individuals in the community and are difficult to treat. To add to the knowledge about the pathophysiology of S. aureus, the adaption to iron restriction, an important in vivo stressor, was studied and the corresponding immune response of the human host characterized. Using a combination of 1D and 2D immune proteomics, the human antibody response to the exoproteomes of S. aureus USA300Δspa grown under iron restriction or with excess iron was compared. Human antibody binding to the altered exoproteome under iron restriction showed a 2.7- to 6.2-fold increase in overall signal intensity, and new antibody specificities appeared. Quantification of the secreted bacterial proteins by gel-free proteomics showed the expected strong increase in level of proteins involved in iron acquisition during iron-restricted growth compared to iron access. This was accompanied by decreased levels of superantigens and hemolysins. The latter was corroborated by functional peripheral blood mononuclear cell proliferation assays. The present data provide a comprehensive view of S. aureus exoproteome adaptation to iron restriction. Adults have high concentrations of serum antibodies specific for some of the newly induced proteins. We conclude that iron restriction is a common feature of the microenvironment, where S. aureus interacts with the immune system of its human host. PMID:24888718

  11. Placental restriction of fetal growth reduces cutaneous responses to antigen after sensitization in sheep.

    PubMed

    Wooldridge, Amy L; Bischof, Robert J; Meeusen, Els N; Liu, Hong; Heinemann, Gary K; Hunter, Damien S; Giles, Lynne C; Kind, Karen L; Owens, Julie A; Clifton, Vicki L; Gatford, Kathryn L

    2014-04-01

    Prenatal and early childhood exposures are implicated as causes of allergy, but the effects of intrauterine growth restriction on immune function and allergy are poorly defined. We therefore evaluated effects of experimental restriction of fetal growth on immune function and allergic sensitization in adolescent sheep. Immune function (circulating total red and white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, and basophils, and the antibody response to Clostridial vaccination) and responses to house dust mite (HDM) allergen and ovalbumin (OVA) antigen sensitization (specific total Ig, IgG1, and IgE antibodies, and cutaneous hypersensitivity) were investigated in adolescent sheep from placentally restricted (PR, n = 23) and control (n = 40) pregnancies. Increases in circulating HDM-specific IgE (P = 0.007) and OVA-specific IgE (P = 0.038) were greater in PR than control progeny. PR did not alter total Ig, IgG1, or IgM responses to either antigen. PR increased OVA-specific but not HDM-specific IgA responses in females only (P = 0.023). Multiple birth increased Ig responses to OVA in a sex-specific manner. PR decreased the proportion of positive cutaneous hypersensitivity responders to OVA at 24 h (P = 0.030) but had no effect on cutaneous responses to HDM. Acute wheal responses to intradermal histamine correlated positively with birth weight in singletons (P = 0.023). Intrauterine growth restriction may suppress inflammatory responses in skin downstream of IgE induction, without impairment in antibody responses to a nonpolysaccharide vaccine. Discord between cutaneous and IgE responses following sensitization suggests new mechanisms for prenatal allergy programming. PMID:24500430

  12. Placental restriction of fetal growth reduces cutaneous responses to antigen after sensitization in sheep

    PubMed Central

    Wooldridge, Amy L.; Bischof, Robert J.; Meeusen, Els N.; Liu, Hong; Heinemann, Gary K.; Hunter, Damien S.; Giles, Lynne C.; Kind, Karen L.; Owens, Julie A.; Clifton, Vicki L.

    2014-01-01

    Prenatal and early childhood exposures are implicated as causes of allergy, but the effects of intrauterine growth restriction on immune function and allergy are poorly defined. We therefore evaluated effects of experimental restriction of fetal growth on immune function and allergic sensitization in adolescent sheep. Immune function (circulating total red and white blood cells, neutrophils, lymphocytes, monocytes, eosinophils, and basophils, and the antibody response to Clostridial vaccination) and responses to house dust mite (HDM) allergen and ovalbumin (OVA) antigen sensitization (specific total Ig, IgG1, and IgE antibodies, and cutaneous hypersensitivity) were investigated in adolescent sheep from placentally restricted (PR, n = 23) and control (n = 40) pregnancies. Increases in circulating HDM-specific IgE (P = 0.007) and OVA-specific IgE (P = 0.038) were greater in PR than control progeny. PR did not alter total Ig, IgG1, or IgM responses to either antigen. PR increased OVA-specific but not HDM-specific IgA responses in females only (P = 0.023). Multiple birth increased Ig responses to OVA in a sex-specific manner. PR decreased the proportion of positive cutaneous hypersensitivity responders to OVA at 24 h (P = 0.030) but had no effect on cutaneous responses to HDM. Acute wheal responses to intradermal histamine correlated positively with birth weight in singletons (P = 0.023). Intrauterine growth restriction may suppress inflammatory responses in skin downstream of IgE induction, without impairment in antibody responses to a nonpolysaccharide vaccine. Discord between cutaneous and IgE responses following sensitization suggests new mechanisms for prenatal allergy programming. PMID:24500430

  13. Micro-environmentally restricted hybridoma cell growth within polysaccharide hydrogel microbeads.

    PubMed

    Pajic-Lijakovic, Ivana

    2013-01-01

    The mechanism of micro-environmentally restricted hybridoma cell growth caused by action of local mechanical compression stress generated within various polysaccharide hydrogel matrixes is estimated by comparing the growth of hybridoma cells within (1) 1.5% Ca-alginate microbeads from Bugarski et al. [in: Fundamentals of Animal Cells Immobilization and Microencapsulation, M.F.A. Goosen, ed., CRC Press, Boca Raton, FL, 1993, p. 267] and (2) 1.3% alginate-agarose microbeads from Shen et al. [Animal Cell Technology: Basic & Applied Aspects, H. Murakami ed., Kluwer Academic Publishers, The Netherlands, 1992, p. 173].Consideration of restricted cell growth dynamics based on developed kinetic model and kinetic 3D Monte Carlo simulation include: (1) changes the fraction of active proliferating cells in the exponential phase and (2) changes of non-proliferating cell concentration in the plateau phase.Higher value of the specific decrease of active fraction of proliferating cells κ is obtained for 1.3% alginate-agarose compared to 1.5% alginate microbeads. It corresponds to higher compression stress generated within hydrogel matrix during cell growth obtained for 1.3% alginate-agarose microbeads. PMID:23988708

  14. Mechanical perturbation-induced ethylene releases apical dominance in Pharbitis nil by restricting shoot growth

    NASA Technical Reports Server (NTRS)

    Prasad, T. K.; Cline, M. G.

    1985-01-01

    Mechanical perturbation (MP, rubbing) or internodes of Pharbitis nil shoots initiates release of lateral buds (LB) from apical dominance within 48 h. Evidence is presented which suggests that MP promotion of LB outgrowth is mediated by ethylene-induced restriction of main shoot growth. Ethylene production in the internodes is stimulated by MP within 2 h. Effects of MP are mimicked by treatments with 1-aminocyclopropane-1-carboxylic acid (ACC) and are negated by the inhibitors of ethylene production or action, aminoethoxy vinylglycine (AVG) and AgNO3. The fact that effects of MP, ACC, and ethylene inhibitors are observed to occur on main shoot growth at least 24 h before they are observed to occur on LB growth suggests a possible cause and effect relationship. MP also causes an increase in internode diameter. MP stimulation of ethylene production appears to be mediated by ACC synthase. The results of this study and our previous studies suggest that apical dominance may be released by any mechanism which induces ethylene restriction of main shoot growth.

  15. Keratinocyte growth factor protects against elastase-induced pulmonary emphysema in mice.

    PubMed

    Plantier, Laurent; Marchand-Adam, Sylvain; Antico Arciuch, Valeria G; Antico, Valeria G; Boyer, Laurent; De Coster, Cécile; Marchal, Joëlle; Bachoual, Rafik; Mailleux, Arnaud; Boczkowski, Jorge; Crestani, Bruno

    2007-11-01

    Pulmonary emphysema is characterized by persistent inflammation and progressive alveolar destruction. The keratinocyte growth factor (KGF) favorably influences alveolar maintenance and repair and possesses anti-inflammatory properties. We aimed to determine whether exogenous KGF prevented or corrected elastase-induced pulmonary emphysema in vivo. Treatment with 5 mg x kg(-1) x day(-1) KGF before elastase instillation prevented pulmonary emphysema. This effect was associated with 1) a sharp reduction in bronchoalveolar lavage fluid total protein and inflammatory cell recruitment, 2) a reduction in the pulmonary expression of the chemokines CCL2 (or monocyte chemoattractant protein-1) and CXCL2 (or macrophage inflammatory protein-2alpha) and of the adhesion molecules ICAM-1 and VCAM-1, 3) a reduction in matrix metalloproteinase (MMP)-2 and MMP-9 activity at day 3, and 4) a major reduction in DNA damage detected by terminal deoxynucleotidyltransferase-mediated dUTP nick end labeling (TUNEL) in alveolar cells at day 7. Treatment with KGF after elastase instillation had no effect on elastase-induced emphysema despite the conserved expression of the KGF receptor in the lungs of elastase-instilled animals as determined by immunohistochemistry. In vitro, KGF abolished the elastase-induced increase in CCL2, CXCL2, and ICAM-1 mRNA in the MLE-12 murine alveolar epithelial cell line. We conclude that KGF pretreatment protected against elastase-induced pulmonary inflammation, activation of MMPs, alveolar cell DNA damage, and subsequent emphysema in mice. PMID:17766584

  16. Tissue localization of transforming growth factor-beta1 in pulmonary eosinophilic granuloma.

    PubMed

    Asakura, S; Colby, T V; Limper, A H

    1996-11-01

    Pulmonary eosinophilic granuloma is characterized by infiltration of the lungs with fibronodular lesions containing specialized Langerhans' cells. In some patients, progressive pulmonary fibrosis leads to significant respiratory impairment. Transforming growth factor-beta1 (TGF-beta1) promotes fibrosis by enhancing the synthesis of extracellular matrix components. The role of TGF-beta1 in promoting fibrosis in the setting of pulmonary eosinophilic granuloma is currently unknown. We used immunohistochemistry to evaluate the extent and distribution of TGF-beta1 and the extracellular matrix components type I collagen and decorin, a TGF-beta1-binding proteoglycan. Lung biopsies from 11 patients with pulmonary eosinophilic granuloma were evaluated. In biopsies with active inflammatory lesions containing Langerhans' cells, hyperplastic type 2 pneumocytes and alveolar macrophages within and surrounding the fibronodular lesions contained abundant TGF-beta1. Langerhans' cells were consistently devoid of immunoreactive TGF-beta1. Active inflammatory lesions also exhibited staining for decorin, in a loosely organized distribution. Advanced fibrotic lesions of eosinophilic granuloma, containing minimal inflammatory cells and few or no Langerhans' cells, exhibited weak or absent staining for TGF-beta1 within either hyperplastic type 2 pneumocytes or alveolar macrophages. The fibroconnective tissues of these advanced fibrotic lesions consistently revealed dense staining for decorin. Through their actions on extracellular matrix protein accumulation, TGF-beta1 and the TGF-beta1-binding proteoglycan decorin may modulate fibrotic repair accompanying pulmonary eosinophilic granuloma. PMID:8912775

  17. Metyrapone alleviates deleterious effects of maternal food restriction on lung development and growth of rat offspring.

    PubMed

    Paek, David S; Sakurai, Reiko; Saraswat, Aditi; Li, Yishi; Khorram, Omid; Torday, John S; Rehan, Virender K

    2015-02-01

    Maternal food restriction (MFR) causes intrauterine growth restriction, a known risk factor for developing chronic lung disease. However, it is unknown whether this negative outcome is gender specific or preventable by blocking the MFR-induced hyperglucocorticoidism. Using a well-established rat model, we used metyrapone (MTP), an inhibitor of glucocorticoid synthesis, to study the MFR-induced lung changes on postnatal day (p) 21 in a gender-specific manner. From embryonic day 10 until delivery, pregnant dams were fed either an ad libitum diet or a 50% caloric restricted diet with or without MTP supplementation. Postnatally, the offspring were fed ad libitum from healthy dams until p21. Morphometric, Western blot, and immunohistochemical analysis of the lungs demonstrated that MTP mitigated the MFR-mediated decrease in alveolar count, decrease in adipogenic protein peroxisome proliferator-activated receptor γ, increase in myogenic proteins (fibronectin, α-smooth muscle actin, and calponin), increase in Wnt signaling intermediates (lymphoid enhancer-binding factor 1 and β-catenin), and increase in glucocorticoid receptor (GR) levels. The MFR-induced lung phenotype and the effects of MTP were similar in both genders. To elucidate the mechanism of MFR-induced shift of the adipogenic-to-myogenic phenotype, lung fibroblasts were used to independently study the effects of (1) nutrient restriction and (2) excess steroid exposure. Nutrient deprivation increased myogenic proteins, Wnt signaling intermediates, and GR, all changes blocked by protein supplementation. MTP also blocked, likely by normalizing nicotinamide adenine dinucleotide phosphate levels, the corticosterone-induced increase in myogenic proteins, but had no effect on GR levels. In summary, protein restriction and increased glucocorticoid levels appear to be the key players in MFR-induced lung disease, affecting both genders. PMID:24916330

  18. Prenatal maternal mental health and fetal growth restriction: a systematic review.

    PubMed

    Lewis, A J; Austin, E; Galbally, M

    2016-08-01

    Maternal mental disorders during pregnancy are associated with a range of adverse health outcomes for offspring. This systematic review examines studies reporting on the relationship between maternal depression, anxiety or stress during pregnancy and fetal growth measured during pregnancy using ultrasound biometry. A systematic search of PsycINFO, Medline, Scopus, Web of Science and Embase was conducted and 1575 records were identified, with nine studies meeting inclusion criteria gathering data from over 7000 participants. All studies measured depression, six examined anxiety and depression, and five examined all three exposures. The majority measured symptoms rather than clinically diagnosable disorder. Studies consistently reported significant associations between maternal mental health, particularly anxiety symptoms, and reduced fetal head growth. Other fetal growth parameters showed inconsistent findings. A number of studies suggest that cortisol dysregulation associated with maternal mental health may play a role in fetal growth restriction. However, heterogeneity in the timing of growth measurement, assessment measures used for mental health and inconsistencies in adjustment for confounders, limits the synthesis and interpretation of findings. Future studies should consider differences in the timing, intensity and duration of mental health symptoms over pregnancy and should employ diagnostic assessment of mental disorders. Fetal growth should be repeatedly measured and further work is needed to establish the biological mechanisms involved. PMID:26983652

  19. Depletion of Ascorbic Acid Restricts Angiogenesis and Retards Tumor Growth in a Mouse Model

    PubMed Central

    Telang, Sucheta; Clem, Amy L; Eaton, John W; Chesney, Jason

    2007-01-01

    Abstract Angiogenesis requires the deposition of type IV collagen by endothelial cells into the basement membrane of new blood vessels. Stabilization of type IV collagen triple helix depends on the hydroxylation of proline, which is catalyzed by the iron-containing enzyme prolyl hydroxylase. This enzyme, in turn, requires ascorbic acid to maintain the enzyme-bound iron in its reduced state. We hypothesized that dietary ascorbic acid might be required for tumor angiogenesis and, therefore, tumor growth. Here, we show that, not surprisingly, ascorbic acid is necessary for the synthesis of collagen type IV by human endothelial cells and for their effective migration and tube formation on a basement membrane matrix. Furthermore, ascorbic acid depletion in mice incapable of synthesizing ascorbic acid (Gulo-/-) dramatically restricts the in vivo growth of implanted Lewis lung carcinoma tumors. Histopathological analyses of these tumors reveal poorly formed blood vessels, extensive hemorrhagic foci, and decreased collagen and von Willebrand factor expression. Our data indicate that ascorbic acid plays an essential role in tumor angiogenesis and growth, and that restriction of ascorbic acid or pharmacological inhibition of prolyl hydroxylase may prove to be novel therapeutic approaches to the treatment of cancer. PMID:17325743

  20. Metformin prevents aggressive ovarian cancer growth driven by high-energy diet: similarity with calorie restriction.

    PubMed

    Al-Wahab, Zaid; Mert, Ismail; Tebbe, Calvin; Chhina, Jasdeep; Hijaz, Miriana; Morris, Robert T; Ali-Fehmi, Rouba; Giri, Shailendra; Munkarah, Adnan R; Rattan, Ramandeep

    2015-05-10

    Caloric restriction (CR) was recently demonstrated by us to restrict ovarian cancer growth in vivo. CR resulted in activation of energy regulating enzymes adenosine monophosphate activated kinase (AMPK) and sirtuin 1 (SIRT1) followed by downstream inhibition of Akt-mTOR. In the present study, we investigated the effects of metformin on ovarian cancer growth in mice fed a high energy diet (HED) and regular diet (RD) and compared them to those seen with CR in an immunocompetent isogeneic mouse model of ovarian cancer. Mice either on RD or HED diet bearing ovarian tumors were treated with 200 mg/kg metformin in drinking water. Metformin treatment in RD and HED mice resulted in a significant reduction in tumor burden in the peritoneum, liver, kidney, spleen and bowel accompanied by decreased levels of growth factors (IGF-1, insulin and leptin), inflammatory cytokines (MCP-1, IL-6) and VEGF in plasma and ascitic fluid, akin to the CR diet mice. Metformin resulted in activation of AMPK and SIRT1 and inhibition of pAkt and pmTOR, similar to CR. Thus metformin can closely mimic CR's tumor suppressing effects by inducing similar metabolic changes, providing further evidence of its potential not only as a therapeutic drug but also as a preventive agent. PMID:25895126

  1. Maternal Serum Analytes as Predictors of Fetal Growth Restriction with Different Degrees of Placental Vascular Dysfunction.

    PubMed

    Blitz, Matthew J; Rochelson, Burton; Vohra, Nidhi

    2016-06-01

    Abnormal levels of maternal serum analytes have been associated with fetal growth restriction (FGR) and preeclampsia secondary to placental vascular dysfunction. Accurately identifying the FGR fetuses at highest risk for adverse outcomes remains challenging. Placental function can be assessed by Doppler analysis of the maternal and fetal circulation. Although the combination of multiple abnormal maternal serum analytes and abnormal Doppler findings is strongly associated with adverse outcomes, the predictive value remains too low to be used as a screening test in a low-risk population. Stratification of cases based on the severity of Doppler abnormalities may improve predictive models. PMID:27235917

  2. Surface growth on percolation networks by a conserved-noise restricted solid-on-solid growth model

    NASA Astrophysics Data System (ADS)

    Lee, Sang Bub

    2016-02-01

    Surface growth by the conserved-noise restricted solid-on-solid model is investigated on diluted lattices, i.e., on percolation networks that are embedded in two spatial dimensions. The growth exponent β and the roughness exponent α are defined, respectively, by the mean-square surface width via W2(t ) ˜t2 β and the mean-square saturated width via Wsat2(L ) ˜L2 α , where L is the system size. These are measured on both an infinite network and a backbone network and the results are compared with power-counting predictions obtained using the fractional Langevin equation. While the Monte Carlo results on deterministic fractal substrates show excellent agreement with the predictions [D. H. Kim and J. M. Kim, Phys. Rev. E 84, 011105 (2011), 10.1103/PhysRevE.84.011105], the results on critical percolation networks deviate by 8%-12% from these predictions.

  3. Surface growth on percolation networks by a conserved-noise restricted solid-on-solid growth model.

    PubMed

    Lee, Sang Bub

    2016-02-01

    Surface growth by the conserved-noise restricted solid-on-solid model is investigated on diluted lattices, i.e., on percolation networks that are embedded in two spatial dimensions. The growth exponent β and the roughness exponent α are defined, respectively, by the mean-square surface width via W(2)(t)∼t(2β) and the mean-square saturated width via W(sat)(2)(L)∼L(2α), where L is the system size. These are measured on both an infinite network and a backbone network and the results are compared with power-counting predictions obtained using the fractional Langevin equation. While the Monte Carlo results on deterministic fractal substrates show excellent agreement with the predictions [D. H. Kim and J. M. Kim, Phys. Rev. E 84, 011105 (2011)], the results on critical percolation networks deviate by 8%-12% from these predictions. PMID:26986299

  4. Fetal growth restriction and intra-uterine growth restriction: guidelines for clinical practice from the French College of Gynaecologists and Obstetricians.

    PubMed

    Vayssière, C; Sentilhes, L; Ego, A; Bernard, C; Cambourieu, D; Flamant, C; Gascoin, G; Gaudineau, A; Grangé, G; Houfflin-Debarge, V; Langer, B; Malan, V; Marcorelles, P; Nizard, J; Perrotin, F; Salomon, L; Senat, M-V; Serry, A; Tessier, V; Truffert, P; Tsatsaris, V; Arnaud, C; Carbonne, B

    2015-10-01

    Small for gestational age (SGA) is defined by weight (in utero estimated fetal weight or birth weight) below the 10th percentile (professional consensus). Severe SGA is SGA below the third percentile (professional consensus). Fetal growth restriction (FGR) or intra-uterine growth restriction (IUGR) usually correspond with SGA associated with evidence indicating abnormal growth (with or without abnormal uterine and/or umbilical Doppler): arrest of growth or a shift in its rate measured longitudinally (at least two measurements, 3 weeks apart) (professional consensus). More rarely, they may correspond with inadequate growth, with weight near the 10th percentile without being SGA (LE2). Birthweight curves are not appropriate for the identification of SGA at early gestational ages because of the disorders associated with preterm delivery. In utero curves represent physiological growth more reliably (LE2). In diagnostic (or reference) ultrasound, the use of growth curves adjusted for maternal height and weight, parity and fetal sex is recommended (professional consensus). In screening, the use of adjusted curves must be assessed in pilot regions to determine the schedule for their subsequent introduction at national level. This choice is based on evidence of feasibility and the absence of any proven benefits for individualized curves for perinatal health in the general population (professional consensus). Children born with FGR or SGA have a higher risk of minor cognitive deficits, school problems and metabolic syndrome in adulthood. The role of preterm delivery in these complications is linked. The measurement of fundal height remains relevant to screening after 22 weeks of gestation (Grade C). The biometric ultrasound indicators recommended are: head circumference (HC), abdominal circumference (AC) and femur length (FL) (professional consensus). They allow calculation of estimated fetal weight (EFW), which, with AC, is the most relevant indicator for screening

  5. Caloric Restriction Effect on Proinflammatory Cytokines, Growth Hormone, and Steroid Hormone Concentrations during Exercise in Judokas.

    PubMed

    Abedelmalek, Salma; Chtourou, Hamdi; Souissi, Nizar; Tabka, Zouhair

    2015-01-01

    The aim of this study was to evaluate the effect of caloric restriction on the immune and hormonal responses during exercise in judo athletes. In a randomised order, 11 male judokas (age: 20.45 ± 0.51; height: 1.71 ± 0.3 m; and body weight: 75.9 ± 3.1 kg) participate in this study during a period of weight maintenance (baseline) and after 7 days of caloric restriction (CR). All subjects performed the Special Judo Fitness Test (SJFT) during the two conditions. Values for nutrient intakes were obtained from a 7 d food record kept during a period of weight maintenance and after a 7-day food restriction (-5~6 MJ/day). Our results showed that CR resulted in significant decreases in body weight (P < 0.05) and performance (P < 0.05). However, heart rate and SJFT index (P < 0.05) increase significantly during CR in comparison to baseline. Moreover, exercise leads to a significant increase in testosterone, cortisol, growth hormone (GH), leukocytes, neutrophils, TNF-α, and IL-6, in both CR and baseline conditions. Compared to baseline, TNF-α and IL-6 were significantly higher during CR condition (P < 0.05). Additionally, CR leads to an increase in cortisol and GH (P < 0.05) and a decrease in testosterone concentrations (P < 0.05). PMID:26075039

  6. Caloric Restriction Effect on Proinflammatory Cytokines, Growth Hormone, and Steroid Hormone Concentrations during Exercise in Judokas

    PubMed Central

    Abedelmalek, Salma; Chtourou, Hamdi; Souissi, Nizar; Tabka, Zouhair

    2015-01-01

    The aim of this study was to evaluate the effect of caloric restriction on the immune and hormonal responses during exercise in judo athletes. In a randomised order, 11 male judokas (age: 20.45 ± 0.51; height: 1.71 ± 0.3 m; and body weight: 75.9 ± 3.1 kg) participate in this study during a period of weight maintenance (baseline) and after 7 days of caloric restriction (CR). All subjects performed the Special Judo Fitness Test (SJFT) during the two conditions. Values for nutrient intakes were obtained from a 7 d food record kept during a period of weight maintenance and after a 7-day food restriction (−5~6 MJ/day). Our results showed that CR resulted in significant decreases in body weight (P < 0.05) and performance (P < 0.05). However, heart rate and SJFT index (P < 0.05) increase significantly during CR in comparison to baseline. Moreover, exercise leads to a significant increase in testosterone, cortisol, growth hormone (GH), leukocytes, neutrophils, TNF-α, and IL-6, in both CR and baseline conditions. Compared to baseline, TNF-α and IL-6 were significantly higher during CR condition (P < 0.05). Additionally, CR leads to an increase in cortisol and GH (P < 0.05) and a decrease in testosterone concentrations (P < 0.05). PMID:26075039

  7. The Arabidopsis EIN2 restricts organ growth by retarding cell expansion

    PubMed Central

    Feng, Guanping; Liu, Gang; Xiao, Jianhua

    2015-01-01

    The growth of plant organ to its characteristic size is a fundamental developmental process, but the mechanism is still poorly understood. Plant hormones play a great role in organ size control by modulating cell division and/or cell expansion. ETHYLENE INSENSITVE 2 (EIN2) was first identified by a genetic screen for ethylene insensitivity and is regarded as a central component of ethylene signaling, but its role in cell growth has not been reported. Here we demonstrate that changed expression of EIN2 led to abnormity of cell expansion by morphological and cytological analyses of EIN2 loss-of-function mutants and the overexpressing transgenic plant. Our findings suggest that EIN2 controls final organ size by restricting cell expansion. PMID:26039475

  8. Sequestration of Vascular Endothelial Growth Factor (VEGF) Induces Late Restrictive Lung Disease

    PubMed Central

    Wieck, Minna M.; Spurrier, Ryan G.; Levin, Daniel E.; Mojica, Salvador Garcia; Hiatt, Michael J.; Reddy, Raghava; Hou, Xiaogang; Navarro, Sonia; Lee, Jooeun; Lundin, Amber; Driscoll, Barbara; Grikscheit, Tracy C.

    2016-01-01

    Rationale Neonatal respiratory distress syndrome is a restrictive lung disease characterized by surfactant deficiency. Decreased vascular endothelial growth factor (VEGF), which demonstrates important roles in angiogenesis and vasculogenesis, has been implicated in the pathogenesis of restrictive lung diseases. Current animal models investigating VEGF in the etiology and outcomes of RDS require premature delivery, hypoxia, anatomically or temporally limited inhibition, or other supplemental interventions. Consequently, little is known about the isolated effects of chronic VEGF inhibition, started at birth, on subsequent developing lung structure and function. Objectives To determine whether inducible, mesenchyme-specific VEGF inhibition in the neonatal mouse lung results in long-term modulation of AECII and whole lung function. Methods Triple transgenic mice expressing the soluble VEGF receptor sFlt-1 specifically in the mesenchyme (Dermo-1/rtTA/sFlt-1) were generated and compared to littermate controls at 3 months to determine the impact of neonatal downregulation of mesenchymal VEGF expression on lung structure, cell composition and function. Reduced tissue VEGF bioavailability has previously been demonstrated with this model. Measurements and Main Results Triple transgenic mice demonstrated restrictive lung pathology. No differences in gross vascular development or protein levels of vascular endothelial markers was noted, but there was a significant decrease in perivascular smooth muscle and type I collagen. Mutants had decreased expression levels of surfactant protein C and hypoxia inducible factor 1-alpha without a difference in number of type II pneumocytes. Conclusions These data show that mesenchyme-specific inhibition of VEGF in neonatal mice results in late restrictive disease, making this transgenic mouse a novel model for future investigations on the consequences of neonatal RDS and potential interventions. PMID:26863115

  9. Role of vascular endothelial growth factor signaling in Schistosoma-induced experimental pulmonary hypertension

    PubMed Central

    2014-01-01

    Abstract There is significant evidence that Th2 (T helper 2)-mediated inflammation supports the pathogenesis of both human and experimental animal models of pulmonary hypertension (PH). A key immune regulator is vascular endothelial growth factor (VEGF), which is produced by Th2 inflammation and can itself contribute to Th2 pulmonary responses. In this study, we interrogated the role of VEGF signaling in a murine model of schistosomiasis-induced PH with a phenotype of significant intrapulmonary Th2 inflammation, vascular remodeling, and elevated right ventricular pressures. We found that VEGF receptor blockade partially suppressed the levels of the Th2 inflammatory cytokines interleukin (IL)-4 and IL-13 in both the lung and the liver after Schistosoma mansoni exposure and suppressed pulmonary vascular remodeling. These findings suggest that VEGF positively contributes to schistosomiasis-induced vascular inflammation and remodeling, and they also provide evidence for a VEGF-dependent signaling pathway necessary for pulmonary vascular remodeling and inflammation in this model. PMID:25006448

  10. Human mast cell basic fibroblast growth factor in pulmonary fibrotic disorders.

    PubMed Central

    Inoue, Y.; King, T. E.; Tinkle, S. S.; Dockstader, K.; Newman, L. S.

    1996-01-01

    Mast cells (MCs) are abundant in fibrotic tissue, although their role in fibrogenesis remains obscure. Recent studies suggest MCs may produce basic fibroblast growth factor (bFGF). To evaluate the hypothesis that MC bFGF contributes to the fibrotic response in human interstitial lung disease, we studied lung tissue, bronchoalveolar lavage fluid and serum in 1) idiopathic pulmonary fibrosis, 2) chronic beryllium disease and sarcoidosis, 3) control subjects with no disease or who were beryllium sensitized with normal lung histology. Diseased subjects underwent clinical assessments to stage disease severity. We determined that most bFGF+ cells in lung interstitium are MCs and are most abundant in idiopathic pulmonary fibrosis. Distribution of bFGF+ MCs matched that of extracellular matrix deposition and correlated with the extent of fibrosis morphometrically. Only one bFGF isoform (17.8 kd) was found in idiopathic pulmonary fibrosis and chronic beryllium disease lung tissues and interacted with heparin-like molecules in the lung. Using a human MC line, we verified that MCs express bFGF mRNA and protein that localizes to cytoplasmic granules. Clinically, bFGF concentrations in bronchoalveolar lavage fluid and serum were highest in disease states and correlated with bronchoalveolar lavage cellularity and severity of gas exchange abnormalities, supporting a role for MC bFGF in the pulmonary fibrotic response and its clinical consequence. Images Figure 1 Figure 2 Figure 7 Figure 10 Figure 11 Figure 12 PMID:8952537

  11. Bone quality is affected by food restriction and by nutrition-induced catch-up growth.

    PubMed

    Pando, Rakefet; Masarwi, Majdi; Shtaif, Biana; Idelevich, Anna; Monsonego-Ornan, Efrat; Shahar, Ron; Phillip, Moshe; Gat-Yablonski, Galia

    2014-12-01

    Growth stunting constitutes the most common effect of malnutrition. When the primary cause of malnutrition is resolved, catch-up (CU) growth usually occurs. In this study, we have explored the effect of food restriction (RES) and refeeding on bone structure and mechanical properties. Sprague-Dawley male rats aged 24 days were subjected to 10 days of 40% RES, followed by refeeding for 1 (CU) or 26 days long-term CU (LTCU). The rats fed ad libitum served as controls. The growth plates were measured, osteoclasts were identified using tartrate-resistant acid phosphatase staining, and micro-computed tomography (CT) scanning and mechanical testing were used to study structure and mechanical properties. Micro-CT analysis showed that RES led to a significant reduction in trabecular BV/TV and trabecular number (Tb.N), concomitant with an increase in trabecular separation (Tb.Sp). Trabecular BV/TV and Tb.N were significantly greater in the CU group than in the RES in both short- and long-term experiments. Mechanical testing showed that RES led to weaker and less compliant bones; interestingly, bones of the CU group were also more fragile after 1 day of CU. Longer term of refeeding enabled correction of the bone parameters; however, LTCU did not achieve full recovery. These results suggest that RES in young rats attenuated growth and reduced trabecular bone parameters. While nutrition-induced CU growth led to an immediate increase in epiphyseal growth plate height and active bone modeling, it was also associated with a transient reduction in bone quality. This should be taken into consideration when treating children undergoing CU growth. PMID:25248555

  12. S6K1 controls pancreatic β cell size independently of intrauterine growth restriction.

    PubMed

    Um, Sung Hee; Sticker-Jantscheff, Melanie; Chau, Gia Cac; Vintersten, Kristina; Mueller, Matthias; Gangloff, Yann-Gael; Adams, Ralf H; Spetz, Jean-Francois; Elghazi, Lynda; Pfluger, Paul T; Pende, Mario; Bernal-Mizrachi, Ernesto; Tauler, Albert; Tschöp, Matthias H; Thomas, George; Kozma, Sara C

    2015-07-01

    Type 2 diabetes mellitus (T2DM) is a worldwide heath problem that is characterized by insulin resistance and the eventual loss of β cell function. As recent studies have shown that loss of ribosomal protein (RP) S6 kinase 1 (S6K1) increases systemic insulin sensitivity, S6K1 inhibitors are being pursued as potential agents for improving insulin resistance. Here we found that S6K1 deficiency in mice also leads to decreased β cell growth, intrauterine growth restriction (IUGR), and impaired placental development. IUGR is a common complication of human pregnancy that limits the supply of oxygen and nutrients to the developing fetus, leading to diminished embryonic β cell growth and the onset of T2DM later in life. However, restoration of placental development and the rescue of IUGR by tetraploid embryo complementation did not restore β cell size or insulin levels in S6K1-/- embryos, suggesting that loss of S6K1 leads to an intrinsic β cell lesion. Consistent with this hypothesis, reexpression of S6K1 in β cells of S6K1-/- mice restored embryonic β cell size, insulin levels, glucose tolerance, and RPS6 phosphorylation, without rescuing IUGR. Together, these data suggest that a nutrient-mediated reduction in intrinsic β cell S6K1 signaling, rather than IUGR, during fetal development may underlie reduced β cell growth and eventual development of T2DM later in life. PMID:26075820

  13. S6K1 controls pancreatic β cell size independently of intrauterine growth restriction

    PubMed Central

    Um, Sung Hee; Sticker-Jantscheff, Melanie; Chau, Gia Cac; Vintersten, Kristina; Mueller, Matthias; Gangloff, Yann-Gael; Adams, Ralf H.; Spetz, Jean-Francois; Elghazi, Lynda; Pfluger, Paul T.; Pende, Mario; Bernal-Mizrachi, Ernesto; Tauler, Albert; Tschöp, Matthias H.; Thomas, George; Kozma, Sara C.

    2015-01-01

    Type 2 diabetes mellitus (T2DM) is a worldwide heath problem that is characterized by insulin resistance and the eventual loss of β cell function. As recent studies have shown that loss of ribosomal protein (RP) S6 kinase 1 (S6K1) increases systemic insulin sensitivity, S6K1 inhibitors are being pursued as potential agents for improving insulin resistance. Here we found that S6K1 deficiency in mice also leads to decreased β cell growth, intrauterine growth restriction (IUGR), and impaired placental development. IUGR is a common complication of human pregnancy that limits the supply of oxygen and nutrients to the developing fetus, leading to diminished embryonic β cell growth and the onset of T2DM later in life. However, restoration of placental development and the rescue of IUGR by tetraploid embryo complementation did not restore β cell size or insulin levels in S6K1–/– embryos, suggesting that loss of S6K1 leads to an intrinsic β cell lesion. Consistent with this hypothesis, reexpression of S6K1 in β cells of S6K1–/– mice restored embryonic β cell size, insulin levels, glucose tolerance, and RPS6 phosphorylation, without rescuing IUGR. Together, these data suggest that a nutrient-mediated reduction in intrinsic β cell S6K1 signaling, rather than IUGR, during fetal development may underlie reduced β cell growth and eventual development of T2DM later in life. PMID:26075820

  14. Occurrence of respiratory symptoms in persons with restrictive ventilatory impairment compared with persons with chronic obstructive pulmonary disease: The PLATINO study.

    PubMed

    Nonato, Nívia L; Nascimento, Oliver A; Padilla, Rogelio P; de Oca, Maria M; Tálamo, Carlos; Valdivia, Gonzalo; Lisboa, Carmen; López, Maria V; Celli, Bartolomé; Menezes, Ana Maria B; Jardim, José R

    2015-08-01

    Patients with chronic obstructive pulmonary disease (COPD) usually complain of symptoms such as cough, sputum, wheezing, and dyspnea. Little is known about clinical symptoms in individuals with restrictive ventilatory impairment. The aim of this study was to compare the prevalence and type of respiratory symptoms in patients with COPD to those reported by individuals with restrictive ventilatory impairment in the Proyecto Latinoamericano de Investigacion en Obstruccion Pulmonar study. Between 2002 and 2004, individuals ≥40 years of age from five cities in Latin America performed pre and post-bronchodilator spirometry and had their respiratory symptoms recorded in a standardized questionnaire. Among the 5315 individuals evaluated, 260 (5.1%) had a restrictive spirometric diagnosis (forced vital capacity (FVC) < lower limit of normal (LLN) with forced expiratory volume in the first second to forced vital capacity ratio (FEV1/FVC) ≥ LLN; American Thoracic Society (ATS)/European Respiratory Society (ERS) 2005) and 610 (11.9%) were diagnosed with an obstructive pattern (FEV1/FVC < LLN; ATS/ERS 2005). Patients with mild restriction wheezed more ((30.8%) vs. (17.8%); p < 0.028). No difference was seen in dyspnea, cough, and sputum between the two groups after adjusting for severity stage. The health status scores for the short form 12 questionnaire were similar in restricted and obstructed patients for both physical (48.4 ± 9.4 vs. 48.3 ± 9.8) and mental (50.8 ± 10.6 vs. 50.0 ± 11.5) domains. Overall, respiratory symptoms are not frequently reported by patients with restricted and obstructed patterns as defined by spirometry. Wheezing was more frequent in patients with restricted pattern compared with those with obstructive ventilatory defect. However, the prevalence of cough, sputum production, and dyspnea are not different between the two groups when adjusted by the same severity stage. PMID:26041119

  15. The alteration in placental volume and placental mean grey value in growth-restricted pregnancies assessed by 3D ultrasound (Growth Restriction & 3D Ultrasonography).

    PubMed

    Artunc Ulkumen, B; Pala, H G; Uyar, Y; Koyuncu, F M; Bulbul Baytur, Y

    2015-01-01

    We aimed to evaluate the volumetric and echogenic alterations in placentas between the intrauterine growth restriction (IUGR) and normal pregnancies using three-dimensional ultrasound and virtual organ computer-aided analysis (VOCAL) software. This case-control prospective study consisted of 48 singleton pregnancies complicated by IUGR and 60 healthy singleton pregnancies matched for maternal age, gestational age and parity. Placental volume (PV) and placental volumetric mean grey values (MGV) were evaluated. PV (cm(3)) was analysed using the VOCAL imaging analysis program, and 3D histogram was used to calculate the volumetric MGV (%). PV was 278.50 ± 63.68 and 370.98 ± 97.82 cm(3) in IUGR and control groups, respectively (p = 0.004). MGV of the placenta was 38.24 ± 8.41 and 38.24 ± 8.41 in IUGR and control groups, respectively (p = 0.30). receiver operator curve (ROC) curve analysis revealed that area under curve was 0.731 for PV. Correlation analysis revealed that PV was significantly associated with estimated fetal weight (r = 0.319, p = 0.003), biparietal diameter (r = 0.346, p = 0.002), head circumference (r = 0.269, p = 0.019), abdominal circumference (r = 0.344, p = 0.002) and femur length (r = 0.328, p = 0.004). PV was inversely related to the umbilical artery pulsatility index (r = - 0.244, p = 0.017). To the best of our knowledge, this is the first study evaluating volumetric MGV in IUGR placentas by comparing them with healthy pregnancies. Our study showed that PV diminishes significantly in IUGR pregnancies, whereas volumetric MGV does not alter significantly. PMID:25409488

  16. Elevated circulating insulin-like growth factor binding protein-1 is sufficient to cause fetal growth restriction.

    PubMed

    Watson, Carole S; Bialek, Peter; Anzo, Makoto; Khosravi, Javad; Yee, Siu-Pok; Han, Victor K M

    2006-03-01

    IGF binding protein-1 (IGFBP-1) inhibits the mitogenic actions of the IGFs. Circulating IGFBP-1 is elevated in newborns and experimental animals with fetal growth restriction (FGR). To establish a causal relationship between high circulating IGFBP-1 and FGR, we have generated transgenic mice using the mouse alpha-fetoprotein gene promoter to target overexpression of human IGFBP-1 (hIGFBP-1) in the fetal liver. These transgenic mice (AFP-BP1) expressed hIGFBP-1 mainly in the fetal hepatocytes, starting at embryonic d 14.5 (E14.5), with lower levels in the gut. The expression peaked at 1 wk postnatally (plasma concentration, 474 +/- 34 ng/ml). At birth, AFP-BP1 pups were 18% smaller [weighed 1.34 +/- 0.02 g compared with 1.62 +/- 0.04 g for wild type (WT); P < 0.05], and they did not demonstrate any postnatal catch-up growth. The placentas of the AFP-BP1 mice were larger than WT from E16.5 onwards (150 +/- 12 for AFP-BP1 vs. 100 +/- 5 mg for WT at E16.5; P < 0.05). Thus, this model of FGR is associated with a larger placenta, but without postnatal catch-up growth. Overall, these data clearly demonstrate that high concentrations of circulating IGFBP-1 are sufficient to cause FGR. PMID:16293667

  17. Increased fetal myocardial sensitivity to insulin-stimulated glucose metabolism during ovine fetal growth restriction.

    PubMed

    Barry, James S; Rozance, Paul J; Brown, Laura D; Anthony, Russell V; Thornburg, Kent L; Hay, William W

    2016-04-01

    Unlike other visceral organs, myocardial weight is maintained in relation to fetal body weight in intrauterine growth restriction (IUGR) fetal sheep despite hypoinsulinemia and global nutrient restriction. We designed experiments in fetal sheep with placental insufficiency and restricted growth to determine basal and insulin-stimulated myocardial glucose and oxygen metabolism and test the hypothesis that myocardial insulin sensitivity would be increased in the IUGR heart. IUGR was induced by maternal hyperthermia during gestation. Control (C) and IUGR fetal myocardial metabolism were measured at baseline and under acute hyperinsulinemic/euglycemic clamp conditions at 128-132 days gestation using fluorescent microspheres to determine myocardial blood flow. Fetal body and heart weights were reduced by 33% (P = 0.008) and 30% (P = 0.027), respectively. Heart weight to body weight ratios were not different. Basal left ventricular (LV) myocardial blood flow per gram of LV tissue was maintained in IUGR fetuses compared to controls. Insulin increased LV myocardial blood flow by ∼38% (P < 0.01), but insulin-stimulated LV myocardial blood flow in IUGR fetuses was 73% greater than controls. Similar to previous reports testing acute hypoxia, LV blood flow was inversely related to arterial oxygen concentration (r(2 )= 0.71) in both control and IUGR animals. Basal LV myocardial glucose delivery and uptake rates were not different between IUGR and control fetuses. Insulin increased LV myocardial glucose delivery (by 40%) and uptake (by 78%) (P < 0.01), but to a greater extent in the IUGR fetuses compared to controls. During basal and hyperinsulinemic-euglycemic clamp conditions LV myocardial oxygen delivery, oxygen uptake, and oxygen extraction efficiency were not different between groups. These novel results demonstrate that the fetal heart exposed to nutrient and oxygen deprivation from placental insufficiency appears to maintain myocardial energy supply

  18. Altered Platelet Function in Intrauterine Growth Restriction: A Cause or a Consequence of Uteroplacental Disease?

    PubMed

    Müllers, Sieglinde M; Burke, Naomi; Flood, Karen; Cowman, Jonathan; O'connor, Hugh; Cotter, Brian; Kearney, Morgan; Dempsey, Mark; Dicker, Patrick; Tully, Elizabeth; Geary, Michael P; Kenny, Dermot; Malone, Fergal D

    2016-07-01

    Objective A limited number of platelet function studies in intrauterine growth restriction (IUGR) have yielded conflicting results. We sought to evaluate platelet reactivity in IUGR using a novel platelet aggregation assay. Study Design Pregnancies with IUGR were recruited from 24 weeks' gestation (estimated fetal weight < 10th centile) and had platelet function testing performed after diagnosis. A modification of light transmission aggregometry created dose-response curves of platelet reactivity in response to multiple agonists at differing concentrations. Findings were compared with healthy third trimester controls. IUGR cases with a subsequent normal birth weight were analyzed separately. Results In this study, 33 pregnancies retained their IUGR diagnosis at birth, demonstrating significantly reduced platelet reactivity in response to all agonists (arachidonic acid, adenosine diphosphate, collagen, thrombin receptor-activating peptide, and epinephrine) when compared with 36 healthy pregnancy controls (p < 0.0001). Similar results were obtained for cases demonstrating an increasing in utero growth trajectory. When IUGR preceded preeclampsia or gestational hypertension, platelet function was significantly reduced compared with normotensive IUGR. Conclusion Using this comprehensive platelet assay, we have demonstrated a functional impairment of platelets in IUGR. This may reflect platelet-derived placental growth factor release. Further evaluation of platelet function may aid in the development of future platelet-targeted therapies for uteroplacental disease. PMID:26906182

  19. Extrauterine growth restriction in preterm infants: importance of optimizing nutrition in neonatal intensive care units.

    PubMed

    Yu, Victor Y H

    2005-10-01

    Extrauterine growth restriction in preterm infants secondary to suboptimal nutrition is a major problem in neonatal intensive care units. Evidence is emerging that early growth deficits have long-term adverse effects, including short stature and poor neurodevelopmental outcomes. The parenteral route of feeding is essential to maintain nutritional integrity before successful transition to the enteral route of feeding is achieved. Nevertheless, early initiation of enteral feeding in sub-nutritional trophic quantity is vital for promoting gut motility and bile secretion, inducing lactase activity, and reducing sepsis and cholestatic jaundice. Results emerging from over sixty randomized clinical trials are available for providing a template on which feeding protocols can be based. Preterm breast milk expressed from the infant's own mother is the milk of choice. Supplementation with a human milk fortifier is necessary to optimize nutritional intake. Preterm formulas are an appropriate substitute for preterm human milk when the latter is unavailable. There are over ten systematic reviews of randomized controlled trials published by the Cochrane Library that addressed feeding strategies, but most do not address long-term outcome measures of clinical importance. There is an urgent need for large-scale, long-term randomized controlled trials to help evaluate metabolic, growth, and neurodevelopmental responses of preterm infants to earlier and more aggressive nutritional management. PMID:16158465

  20. Growth and Flowering Responses of Cut Chrysanthemum Grown under Restricted Root Volume to Irrigation Frequency

    PubMed Central

    Taweesak, Viyachai; Lee Abdullah, Thohirah; Hassan, Siti Aishah; Kamarulzaman, Nitty Hirawaty; Wan Yusoff, Wan Abdullah

    2014-01-01

    Influences of irrigation frequency on the growth and flowering of chrysanthemum grown under restricted root volume were tested. Chrysanthemum cuttings (Chrysanthemum morifolium “Reagan White”) were grown in seedling tray which contained coconut peat in volumes of 73 and 140 cm3. Plants were irrigated with drip irrigation at irrigation frequencies of 4 (266 mL), 6 (400 mL), and 8 (533 mL) times/day to observe their growth and flowering performances. There was interaction between irrigation frequency and substrate volume on plant height of chrysanthemum. Plants grown in 140 cm3 substrates and irrigated 6 times/day produced the tallest plant of 109.25 cm. Plants irrigated 6 and 8 times/day had significantly higher level of phosphorus content in their leaves than those plants irrigated 4 times/day. The total leaf area, number of internodes, leaf length, and leaf width of chrysanthemums grown in 140 cm3 substrate were significantly higher than those grown in 73 cm3 substrate. The numbers of flowers were affected by both irrigation frequencies and substrate volumes. Chrysanthemums irrigated 8 times/day had an average of 19.56 flowers while those irrigated 4 times/day had an average of 16.63 flowers. Increasing irrigation frequency can improve the growth and flowering of chrysanthemums in small substrate volumes. PMID:25478586

  1. Growth and flowering responses of cut chrysanthemum grown under restricted root volume to irrigation frequency.

    PubMed

    Taweesak, Viyachai; Lee Abdullah, Thohirah; Hassan, Siti Aishah; Kamarulzaman, Nitty Hirawaty; Wan Yusoff, Wan Abdullah

    2014-01-01

    Influences of irrigation frequency on the growth and flowering of chrysanthemum grown under restricted root volume were tested. Chrysanthemum cuttings (Chrysanthemum morifolium "Reagan White") were grown in seedling tray which contained coconut peat in volumes of 73 and 140 cm(3). Plants were irrigated with drip irrigation at irrigation frequencies of 4 (266 mL), 6 (400 mL), and 8 (533 mL) times/day to observe their growth and flowering performances. There was interaction between irrigation frequency and substrate volume on plant height of chrysanthemum. Plants grown in 140 cm(3) substrates and irrigated 6 times/day produced the tallest plant of 109.25 cm. Plants irrigated 6 and 8 times/day had significantly higher level of phosphorus content in their leaves than those plants irrigated 4 times/day. The total leaf area, number of internodes, leaf length, and leaf width of chrysanthemums grown in 140 cm(3) substrate were significantly higher than those grown in 73 cm(3) substrate. The numbers of flowers were affected by both irrigation frequencies and substrate volumes. Chrysanthemums irrigated 8 times/day had an average of 19.56 flowers while those irrigated 4 times/day had an average of 16.63 flowers. Increasing irrigation frequency can improve the growth and flowering of chrysanthemums in small substrate volumes. PMID:25478586

  2. Peri- and Postnatal Effects of Prenatal Adenoviral VEGF Gene Therapy in Growth-Restricted Sheep.

    PubMed

    Carr, David J; Wallace, Jacqueline M; Aitken, Raymond P; Milne, John S; Martin, John F; Zachary, Ian C; Peebles, Donald M; David, Anna L

    2016-06-01

    Uterine artery (UtA) adenovirus (Ad) vector-mediated overexpression of vascular endothelial growth factor (VEGF) enhances uterine blood flow in normal sheep pregnancy and increases fetal growth in the overnourished adolescent sheep model of fetal growth restriction (FGR). Herein, we examined its impact on gestation length, neonatal survival, early postnatal growth and metabolism. Singleton-bearing ewes were evenly allocated to receive Ad.VEGF-A165 (5 × 10(10) particles/ml, 10 ml, n = 17) or saline (10 ml, n = 16) injected into each UtA at laparotomy (0.6 gestation). Fetal growth was serially monitored (blind) by ultrasound until delivery. Lambs were weighed and blood was sampled weekly and a glucose tolerance test performed (68-day postnatal age). Hepatic DNA/RNA was extracted at necropsy (83-day postnatal age) to examine methylation status of eight somatotropic axis genes. IGF1 mRNA and protein expression were measured by RT-PCR and radioimmunoassay, respectively. All pregnancies remained viable following Ad.VEGF-A165 treatment. Fetal abdominal circumference and renal volume were greater in the Ad.VEGF-A165 group compared with the saline group at 21/28 days (P ≤ 0.04) postinjection. At delivery, gestation length (P = 0.07), lamb birthweight (P = 0.08), umbilical girth (P = 0.06), and plasma glucose (P = 0.09) tended to be greater in Ad.VEGF-A165-treated lambs. Levels of neonatal intervention required to ensure survival was equivalent between groups. Absolute postnatal growth rate (P = 0.02), insulin area under the curve (P = 0.04) and carcass weight at necropsy (P = 0.04) were increased by Ad.VEGF-A165 treatment. There was no impact on markers of insulin sensitivity or methylation/expression of key genes involved in somatic growth. Ad.VEGF-A165 gene therapy increased fetal growth in a sheep FGR model, and lambs continued to thrive during the neonatal and early postnatal period. PMID:27103444

  3. Estimated in vivo postnatal surface growth patterns of the ovine main pulmonary artery and ascending aorta.

    PubMed

    Fata, Bahar; Gottlieb, Danielle; Mayer, John E; Sacks, Michael S

    2013-07-01

    Delineating the normal postnatal development of the pulmonary artery (PA) and ascending aorta (AA) can inform our understanding of congenital abnormalities, as well as pulmonary and systolic hypertension. We thus conducted the following study to delineate the PA and AA postnatal growth deformation characteristics in an ovine model. MR images were obtained from endoluminal surfaces of 11 animals whose ages ranged from 1.5 months/15.3 kg mass (very young) to 12 months/56.6 kg mass (adult). A bicubic Hermite finite element surface representation was developed for the each artery from each animal. Under the assumption that the relative locations of surface points were retained during growth, the individual animal surface fits were subsequently used to develop a method to estimate the time-evolving local effective surface growth (relative to the youngest measured animal) in the end-diastolic state. Results indicated that the spatial and temporal surface growth deformation patterns of both arteries, especially in the circumferential direction, were heterogeneous, leading to an increase in taper and increase in cross-sectional ellipticity of the PA. The longitudinal PA growth stretch of a large segment on the posterior wall reached 2.57 ± 0.078 (mean ± SD) at the adult stage. In contrast, the longitudinal growth of the AA was smaller and more uniform (1.80 ± 0.047). Interestingly, a region of the medial wall of both arteries where both arteries are in contact showed smaller circumferential growth stretches-specifically 1.12 ± 0.012 in the PA and 1.43 ± 0.071 in the AA at the adult stage. Overall, our results indicated that contact between the PA and AA resulted in increasing spatial heterogeneity in postnatal growth, with the PA demonstrating the greatest changes. Parametric studies using simplified geometric models of curved arteries during growth suggest that heterogeneous effective surface growth deformations must occur to account for the

  4. Isolated placental vessel response to vascular endothelial growth factor and placenta growth factor in normal and growth-restricted pregnancy.

    PubMed

    Szukiewicz, Dariusz; Szewczyk, Grzegorz; Watroba, Mateusz; Kurowska, Ewa; Maslinski, Slawomir

    2005-01-01

    Vascular endothelial growth factor (VEGF) and placenta growth factor (PlGF) cause vasodilation. We examined the vasomotor response of isolated placental vessels to VEGF and PlGF in normal (group I) and intrauterine growth retardation (IUGR)-complicated pregnancy (group II). Rings of vessels were prepared in vitro and mounted on the vessel myograph plunged in tissue bath. The magnitude of dilation to increased doses of VEGF and PlGF has been studied. VEGF is a more potent vasodilator than PlGF. Both, VEGF- and PlGF-induced vasorelaxation was diminished in the IUGR (group II) nearly by half, compared to control (group I). Relative placental nitric oxide deficiency, or decreased sensitivity to VEGF and PlGF may contribute to the development of high impedance fetoplacental circulation. PMID:15591804

  5. PEG3 domain gene expression in maternal and foetal placenta in intrauterine growth restricted bovine foetuses.

    PubMed

    Li, Shun; Pausch, Hubert; Venhoranta, Heli; Adamowicz, Krzysztof; Andersson, Magnus; Zwierzchowski, Lech; Kind, Alexander; Schnieke, Angelika; Flisikowski, Krzysztof

    2016-02-01

    We used a genetic (MIMT1(Del)) model of intrauterine growth restriction to investigate dysregulation of PEG3 domain gene expression in bovine foetal and maternal placenta. ZIM2, APEG3 and PEG3 expressions were similarly reduced in MIMT1(Del/) (WT) foetal placenta, suggesting coordinated regulation. Methylation of DNA CpG sites associated with these genes showed no differences, but differences in the levels of MIMT1 RNA methylation at three CpG sites were found in foetal placenta. Our data are consistent with the presence of a bidirectional promoter 5' of MIMT1 and suggest a regulatory role for the MIMT1 non-coding transcript. PEG3 domain expression on the maternal placenta side was not affected by the foetal mutation. PMID:26537866

  6. Essential nutrient supplementation prevents heritable metabolic disease in multigenerational intrauterine growth-restricted rats

    PubMed Central

    Goodspeed, Danielle; Seferovic, Maxim D.; Holland, William; Mcknight, Robert A.; Summers, Scott A.; Branch, D. Ware; Lane, Robert H.; Aagaard, Kjersti M.

    2015-01-01

    Intrauterine growth restriction (IUGR) confers heritable alterations in DNA methylation, rendering risk of adult metabolic syndrome (MetS). Because CpG methylation is coupled to intake of essential nutrients along the one-carbon pathway, we reasoned that essential nutrient supplementation (ENS) may abrogate IUGR-conferred multigenerational MetS. Pregnant Sprague-Dawley rats underwent bilateral uterine artery ligation causing IUGR in F1. Among the F2 generation, IUGR lineage rats were underweight at birth (6.7 vs. 8.0 g, P < 0.0001) and obese by adulthood (p160: 613 vs. 510 g; P < 0.0001). Dual energy X-ray absorptiometry studies revealed increased central fat mass (Δ+40 g), accompanied by dyslipidemic (>30% elevated, P < 0.05) serum triglycerides (139 mg/dl), very-LDLs (27.8 mg/dl), and fatty acids (632 µM). Hyperglycemic-euglycemic clamp studies and glucose tolerance testing revealed insulin resistance. Conversely, IUGR lineage ENS-fed rats did not manifest MetS, with significantly lower body weight (p160: 410 g), >5-fold less central fat mass, normal hepatic glucose efflux, and >70% reduced circulating triglycerides and very-LDLs compared with IUGR control-fed F2 offspring (P < 0.01). Moreover, increased methylation of the IGF-1 P2 transcriptional start site among IUGR lineage F2 offspring was reversed in ENS (P < 0.04). This is an initial demonstration that supplementation along the one-carbon pathway abrogates adult morbidity and associated epigenomic modifications of IGF-1 in a rodent model of multigenerational MetS.—Goodspeed, D., Seferovic, M. D., Holland, W., Mcknight, R. A., Summers, S. A., Branch, D. W., Lane, R. H., Aagaard, K. M. Essential nutrient supplementation prevents heritable metabolic disease in multigenerational intrauterine growth-restricted rats. PMID:25395450

  7. The Effect of Subclinical Maternal Thyroid Dysfunction and Autoimmunity on Intrauterine Growth Restriction

    PubMed Central

    Tong, Zhao; Xiaowen, Zhang; Baomin, Chen; Aihua, Liu; Yingying, Zhou; Weiping, Teng; Zhongyan, Shan

    2016-01-01

    Abstract The objective of this study was to evaluate the association between maternal subclinical thyroid dysfunction and autoimmunity with the risk for intrauterine growth restriction (IUGR). Design is a systematic review and meta-analysis. A literature search was conducted using PubMed, Embase, and Cochrane database. A combination of 2 key words was used to search for the eligible studies: one indexed thyroid dysfunction or antithyroid antibodies; and the other one indexed the adverse neonatal outcomes of pregnancy, such as IUGR, small for gestational age, fetal growth restriction, or low birth weight. Two reviewers selected the studies, and eligible studies met the following criteria: prospective cohort studies or case control studies, studies of maternal thyroid dysfunction and positive antithyroid antibodies as the exposure of interest, and studies of IUGR or small for gestational age as the outcome of interest. Data were recorded, including data from maternal thyroid disorders and IUGR, and compared with a reference group. There were 22 individual data from the 13 cohort articles. Among these, 7 were focused on subclinical hypothyroidism (SCH), 4 on subclinical hyperthyroidism, 7 on positivity for thyroid peroxidase antibody (TPOAb), and 4 on isolated hypothyroxinemia. Meta-analysis showed that there was no effect of subclinical hyperthyroidism (odds ratio (OR) = 0.98; 95% confidence interval (CI), 0.40–2.41), TPOAb positivity (OR = 1.57; 95% CI, 0.77–3.18), or isolated hypothyroxinemia (OR = 1.05, 95% CI: 0.37–2.92) on IUGR. However, SCH is associated with IUGR (OR = 1.54; 95% CI, 1.06–2.25). SCH is associated with IUGR; however, subclinical hyperthyroidism, TPOAb positivity, or isolated hypothyroxinemia do not affect the risk of IUGR. PMID:27175703

  8. CCL5 Neutralization Restricts Cancer Growth and Potentiates the Targeting of PDGFRβ in Colorectal Carcinoma

    PubMed Central

    Cambien, Béatrice; Richard-Fiardo, Peggy; Karimdjee, Babou F.; Martini, Violette; Ferrua, Bernard; Pitard, Bruno; Schmid-Antomarchi, Heidy; Schmid-Alliana, Annie

    2011-01-01

    Increased CCL5 levels are markers of an unfavourable outcome in patients with melanoma, breast, cervical, prostate, gastric or pancreatic cancer. Here, we have assessed the role played by CCL5/CCR5 interactions in the development of colon cancer. To do so, we have examined a number of human colorectal carcinoma clinical specimens and found CCL5 and its receptors over-expressed within primary as well as liver and pulmonary metastases of patients compared to healthy tissues. In vitro, CCL5 increased the growth and migratory responses of colon cancer cells from both human and mouse origins. In addition, systemic treatment of mice with CCL5-directed antibodies reduced the extent of development of subcutaneous colon tumors, of liver metastases and of peritoneal carcinosis. Consistently, we found increased numbers of CD45-immunoreactive cells within the stroma of the remaining lesions as well as at the interface with the healthy tissue. In contrast, selective targeting of CCR5 through administration of TAK-779, a CCR5 antagonist, only partially compromised colon cancer progression. Furthermore, CCL5 neutralization rendered the tumors more sensitive to a PDGFRβ-directed strategy in mice, this combination regimen offering the greatest protection against liver metastases and suppressing macroscopic peritoneal carcinosis. Collectively, our data demonstrate the involvement of CCL5 in the pathogenesis of colorectal carcinoma and point to its potential value as a therapeutic target. PMID:22205974

  9. A type IV translocated Legionella cysteine phytase counteracts intracellular growth restriction by phytate.

    PubMed

    Weber, Stephen; Stirnimann, Christian U; Wieser, Mara; Frey, Daniel; Meier, Roger; Engelhardt, Sabrina; Li, Xiaodan; Capitani, Guido; Kammerer, Richard A; Hilbi, Hubert

    2014-12-01

    The causative agent of Legionnaires' pneumonia, Legionella pneumophila, colonizes diverse environmental niches, including biofilms, plant material, and protozoa. In these habitats, myo-inositol hexakisphosphate (phytate) is prevalent and used as a phosphate storage compound or as a siderophore. L. pneumophila replicates in protozoa and mammalian phagocytes within a unique "Legionella-containing vacuole." The bacteria govern host cell interactions through the Icm/Dot type IV secretion system (T4SS) and ∼300 different "effector" proteins. Here we characterize a hitherto unrecognized Icm/Dot substrate, LppA, as a phytate phosphatase (phytase). Phytase activity of recombinant LppA required catalytically essential cysteine (Cys(231)) and arginine (Arg(237)) residues. The structure of LppA at 1.4 Å resolution revealed a mainly α-helical globular protein stabilized by four antiparallel β-sheets that binds two phosphate moieties. The phosphates localize to a P-loop active site characteristic of dual specificity phosphatases or to a non-catalytic site, respectively. Phytate reversibly abolished growth of L. pneumophila in broth, and growth inhibition was relieved by overproduction of LppA or by metal ion titration. L. pneumophila lacking lppA replicated less efficiently in phytate-loaded Acanthamoeba castellanii or Dictyostelium discoideum, and the intracellular growth defect was complemented by the phytase gene. These findings identify the chelator phytate as an intracellular bacteriostatic component of cell-autonomous host immunity and reveal a T4SS-translocated L. pneumophila phytase that counteracts intracellular bacterial growth restriction by phytate. Thus, bacterial phytases might represent therapeutic targets to combat intracellular pathogens. PMID:25339170

  10. A Type IV Translocated Legionella Cysteine Phytase Counteracts Intracellular Growth Restriction by Phytate

    PubMed Central

    Weber, Stephen; Stirnimann, Christian U.; Wieser, Mara; Frey, Daniel; Meier, Roger; Engelhardt, Sabrina; Li, Xiaodan; Capitani, Guido; Kammerer, Richard A.; Hilbi, Hubert

    2014-01-01

    The causative agent of Legionnaires' pneumonia, Legionella pneumophila, colonizes diverse environmental niches, including biofilms, plant material, and protozoa. In these habitats, myo-inositol hexakisphosphate (phytate) is prevalent and used as a phosphate storage compound or as a siderophore. L. pneumophila replicates in protozoa and mammalian phagocytes within a unique “Legionella-containing vacuole.” The bacteria govern host cell interactions through the Icm/Dot type IV secretion system (T4SS) and ∼300 different “effector” proteins. Here we characterize a hitherto unrecognized Icm/Dot substrate, LppA, as a phytate phosphatase (phytase). Phytase activity of recombinant LppA required catalytically essential cysteine (Cys231) and arginine (Arg237) residues. The structure of LppA at 1.4 Å resolution revealed a mainly α-helical globular protein stabilized by four antiparallel β-sheets that binds two phosphate moieties. The phosphates localize to a P-loop active site characteristic of dual specificity phosphatases or to a non-catalytic site, respectively. Phytate reversibly abolished growth of L. pneumophila in broth, and growth inhibition was relieved by overproduction of LppA or by metal ion titration. L. pneumophila lacking lppA replicated less efficiently in phytate-loaded Acanthamoeba castellanii or Dictyostelium discoideum, and the intracellular growth defect was complemented by the phytase gene. These findings identify the chelator phytate as an intracellular bacteriostatic component of cell-autonomous host immunity and reveal a T4SS-translocated L. pneumophila phytase that counteracts intracellular bacterial growth restriction by phytate. Thus, bacterial phytases might represent therapeutic targets to combat intracellular pathogens. PMID:25339170

  11. Intrauterine growth restriction perturbs nucleosome depletion at a growth hormone-responsive element in the mouse IGF-1 gene.

    PubMed

    McKnight, Robert A; Yost, Christian C; Yu, Xing; Wiedmeier, Julia E; Callaway, Christopher W; Brown, Ashley S; Lane, Robert H; Fung, Camille M

    2015-12-01

    Intrauterine growth restriction (IUGR) is a common human pregnancy complication. IUGR offspring carry significant postnatal risk for early-onset metabolic syndrome, which is associated with persistent reduction in IGF-1 protein expression. We have previously shown that preadolescent IUGR male mice have decreased hepatic IGF-1 mRNA and circulating IGF-1 protein at postnatal day 21, the age when growth hormone (GH) normally upregulates hepatic IGF-1 expression. Here we studied nucleosome occupancy and CpG methylation at a putative growth hormone-responsive element in intron 2 (in2GHRE) of the hepatic IGF-1 gene in normal, sham-operated, and IUGR mice. Nucleosome occupancy and CpG methylation were determined in embryonic stem cells (ESCs) and in liver at postnatal days 14, 21, and 42. For CpG methylation, additional time points out to 2 yr were analyzed. We confirmed the putative mouse in2GHRE was GH-responsive, and in normal mice, a single nucleosome was displaced from the hepatic in2GHRE by postnatal day 21, which exposed two STAT5b DNA binding sites. Nucleosome displacement correlated with developmentally programmed CpG demethylation. Finally, IUGR significantly altered the nucleosome-depleted region (NDR) at the in2GHRE of IGF-1 on postnatal day 21, with either complete absence of the NDR or with a shifted NDR exposing only one of two STAT5b DNA binding sites. An NDR shift was also seen in offspring of sham-operated mothers. We conclude that prenatal insult such as IUGR or anesthesia/surgery could perturb the proper formation of a well-positioned NDR at the mouse hepatic IGF-1 in2GHRE necessary for transitioning to an open chromatin state. PMID:26487705

  12. Effect of Prenatal Hypoxia in Transgenic Mouse Models of Preeclampsia and Fetal Growth Restriction

    PubMed Central

    Rueda-Clausen, C. F.; Thambiraj, D. F.; Poudel, R.; Davidge, S. T.; Baker, P. N.

    2014-01-01

    Mice lacking endothelial nitric oxide synthase (eNOS− /−) or catechol-O-methyl transferase (COMT−/−) exhibit a preeclampsia-like phenotype and fetal growth restriction. We hypothesized that a hypoxic insult would result in a more severe phenotype. Pregnant eNOS−/−, COMT−/− and control (C57BL/6J) mice were randomized to hypoxic (10.5% O2) or normal conditions (20.9% O2) from gestational day 10.5 to 18.5. Hypoxia increased the blood pressure in all genotypes and proteinuria in C57BL/6J and eNOS−/− mice. Fetal survival was significantly reduced following hypoxia, particularly in eNOS−/− mice. Birth weight was decreased in both C57BL/6J and COMT−/− mice. Placentas from COMT−/− mice demonstrated increased peroxynitrite. Despite similar hypoxia-induced effects on maternal blood pressure and proteinuria, eNOS−/− embryos have a decreased tolerance to hypoxia. Compared to C57BL/6J, COMT−/− mice exhibited less severe changes in proteinuria and fetal growth when exposed to prenatal hypoxia. This relative resistance to prenatal hypoxia was associated with a significant increase in placental levels of peroxynitrite. PMID:24084523

  13. Intrauterine Growth Restricted Rats Exercised at Pregnancy: Maternal-Fetal Repercussions.

    PubMed

    Corvino, S B; Netto, A O; Sinzato, Y K; Campos, K E; Calderon, I M P; Rudge, M V C; Volpato, G T; Zambrano, E; Damasceno, D C

    2015-08-01

    To evaluate the effect of swimming in pregnant rats born with intrauterine growth restriction (IUGR) and their offspring, IUGR rats were obtained using the streptozotocin-induced severe diabetic (SD) rats. In this study, the nondiabetic parental generation presented 10 rats and diabetic parental generation presented 116 rats. Of these, the mated nondiabetic female rats were 10 and the number of diabetic rats was 45. In relation to term pregnancy, there were 10 animals in the nondiabetic group and 15 rats in the diabetic group. In the offspring of SD rats (IUGR group), 43 females were classified as small for pregnancy age, 19 rats were classified as appropriate for pregnancy age, and 0 female was classified as large for pregnancy age. The nondiabetic and SD pregnant rats generated offspring with appropriate (control [C]) and small (IUGR) weight for pregnancy age, respectively. At adult life, the C group was maintained as nonexercised C group and IUGR rats were distributed into 2 subgroups, namely, nonexercised (IUGR) and exercised (IUGRex). The rate of mated rats in the IUGR group was reduced compared to the C group. During pregnancy, the IUGR rats presented hyperinsulinemia, impaired reproductive outcomes, decreased body weight, hypertriglyceridemia, and hyperlactacidemia. The IUGRex presented reduced insulin and triglyceride levels. Thus, swimming improved lipid metabolism and increased insulin sensitivity. However, the offspring showed retarded growth, reinforcing the need to stimulate the exercise practice in women under supervision with different professional expertise to promote appropriate gestational conditions and improve perinatal outcomes. PMID:25761405

  14. Activation of Nod1 Signaling Induces Fetal Growth Restriction and Death through Fetal and Maternal Vasculopathy

    PubMed Central

    Nishio, Hisanori; Takada, Hidetoshi; Sakai, Yasunari; Nanishi, Etsuro; Ochiai, Masayuki; Onimaru, Mitsuho; Chen, Si Jing; Matsui, Toshiro; Hara, Toshiro

    2016-01-01

    Intrauterine fetal growth restriction (IUGR) and death (IUFD) are both serious problems in the perinatal medicine. Fetal vasculopathy is currently considered to account for a pathogenic mechanism of IUGR and IUFD. We previously demonstrated that an innate immune receptor, the nucleotide-binding oligomerization domain-1 (Nod1), contributed to the development of vascular inflammations in mice at postnatal stages. However, little is known about the deleterious effects of activated Nod1 signaling on embryonic growth and development. We report that administration of FK565, one of the Nod1 ligands, to pregnant C57BL/6 mice induced IUGR and IUFD. Mass spectrometry analysis revealed that maternally injected FK565 was distributed to the fetal tissues across placenta. In addition, maternal injection of FK565 induced robust increases in the amounts of CCL2, IL-6, and TNF proteins as well as NO in maternal, placental and fetal tissues. Nod1 was highly expressed in fetal vascular tissues, where significantly higher levels of CCL2 and IL-6 mRNAs were induced with maternal injection of FK565 than those in other tissues. Using Nod1-knockout mice, we verified that both maternal and fetal tissues were involved in the development of IUGR and IUFD. Furthermore, FK565 induced upregulation of genes associated with immune response, inflammation, and apoptosis in fetal vascular tissues. Our data thus provided new evidence for the pathogenic role of Nod1 in the development of IUGR and IUFD at the maternal-fetal interface. PMID:26880761

  15. Fibroblast Growth Factor 2 Is Required for Epithelial Recovery, but Not for Pulmonary Fibrosis, in Response to Bleomycin

    PubMed Central

    Guzy, Robert D.; Stoilov, Ivan; Elton, Timothy J.; Mecham, Robert P.

    2015-01-01

    The pathogenesis of pulmonary fibrosis involves lung epithelial injury and aberrant proliferation of fibroblasts, and results in progressive pulmonary scarring and declining lung function. In vitro, fibroblast growth factor (FGF) 2 promotes myofibroblast differentiation and proliferation in cooperation with the profibrotic growth factor, transforming growth factor-β1, but the in vivo requirement for FGF2 in the development of pulmonary fibrosis is not known. The bleomycin model of lung injury and pulmonary fibrosis was applied to Fgf2 knockout (Fgf2−/−) and littermate control mice. Weight loss, mortality, pulmonary fibrosis, and histology were analyzed after a single intranasal dose of bleomycin. Inflammation was evaluated in bronchoalveolar lavage (BAL) fluid, and epithelial barrier integrity was assessed by measuring BAL protein and Evans Blue dye permeability. Fgf2 is expressed in mouse and human lung epithelial and inflammatory cells, and, in response to bleomycin, Fgf2−/− mice have significantly increased mortality and weight loss. Analysis of BAL fluid and histology show that pulmonary fibrosis is unaltered, but Fgf2−/− mice fail to efficiently resolve inflammation, have increased BAL cellularity, and, importantly, deficient recovery of epithelial integrity. Fgf2−/− mice similarly have deficient recovery of club cell secretory protein+ bronchial epithelium in response to naphthalene. We conclude that FGF2 is not required for bleomycin-induced pulmonary fibrosis, but rather is essential for epithelial repair and maintaining epithelial integrity after bleomycin-induced lung injury in mice. These data identify that FGF2 acts as a protective growth factor after lung epithelial injury, and call into question the role of FGF2 as a profibrotic growth factor in vivo. PMID:24988442

  16. Epigenetic Characterization of CDKN1C in Placenta Samples from Non-syndromic Intrauterine Growth Restriction.

    PubMed

    López-Abad, Miriam; Iglesias-Platas, Isabel; Monk, David

    2016-01-01

    The cyclin-dependent kinase (CDK)-inhibitor 1C (CDKN1C) gene is expressed from the maternal allele and is located within the centromeric imprinted domain at chromosome 11p15. It is a negative regulator of proliferation, with loss-of-function mutations associated with the overgrowth disorder Beckwith-Wiedemann syndrome. Recently, gain-of-function mutations within the PCNA domain have been described in two disorders characterized by growth failure, namely IMAGe (intra-uterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital abnormalities) syndrome and Silver-Russell syndrome (SRS). Over-expression of CDKN1C by maternally inherited microduplications also results in SRS, suggesting that in addition to activating mutations this gene may regulate growth by changes in dosage. To determine if CDKN1C is involved in non-syndromic IUGR we compared the expression and DNA methylation levels in a large cohort of placental biopsies from IUGR and uneventful pregnancies. We observe higher levels of expression of CDKN1C in IUGR placentas compared to those of controls. All placenta biopsies heterozygous for the PAPA repeat sequence in exon 2 showed appropriate monoallelic expression and no mutations in the PCNA domain were observed. The expression profile was independent of both genetic or methylation variation in the minimal CDKN1C promoter interval and of methylation of the cis-acting maternally methylated region associated with the neighboring KCNQ1OT1 non-coding RNA. Chromatin immunoprecipitation revealed binding sites for CTCF within the unmethylated CDKN1C gene body CpG island and putative enhancer regions, associated with the canonical enhancer histone signature, H3K4me1 and H3K27ac, located ∼58 and 360 kb away. Using 3C-PCR we identify constitutive higher-order chromatin loops that occur between one of these putative enhancer regions and CDKN1C in human placenta tissues, which we propose facilitates expression. PMID:27200075

  17. Epigenetic Characterization of CDKN1C in Placenta Samples from Non-syndromic Intrauterine Growth Restriction

    PubMed Central

    López-Abad, Miriam; Iglesias-Platas, Isabel; Monk, David

    2016-01-01

    The cyclin-dependent kinase (CDK)-inhibitor 1C (CDKN1C) gene is expressed from the maternal allele and is located within the centromeric imprinted domain at chromosome 11p15. It is a negative regulator of proliferation, with loss-of-function mutations associated with the overgrowth disorder Beckwith–Wiedemann syndrome. Recently, gain-of-function mutations within the PCNA domain have been described in two disorders characterized by growth failure, namely IMAGe (intra-uterine growth restriction, metaphyseal dysplasia, adrenal hypoplasia congenita and genital abnormalities) syndrome and Silver–Russell syndrome (SRS). Over-expression of CDKN1C by maternally inherited microduplications also results in SRS, suggesting that in addition to activating mutations this gene may regulate growth by changes in dosage. To determine if CDKN1C is involved in non-syndromic IUGR we compared the expression and DNA methylation levels in a large cohort of placental biopsies from IUGR and uneventful pregnancies. We observe higher levels of expression of CDKN1C in IUGR placentas compared to those of controls. All placenta biopsies heterozygous for the PAPA repeat sequence in exon 2 showed appropriate monoallelic expression and no mutations in the PCNA domain were observed. The expression profile was independent of both genetic or methylation variation in the minimal CDKN1C promoter interval and of methylation of the cis-acting maternally methylated region associated with the neighboring KCNQ1OT1 non-coding RNA. Chromatin immunoprecipitation revealed binding sites for CTCF within the unmethylated CDKN1C gene body CpG island and putative enhancer regions, associated with the canonical enhancer histone signature, H3K4me1 and H3K27ac, located ∼58 and 360 kb away. Using 3C-PCR we identify constitutive higher-order chromatin loops that occur between one of these putative enhancer regions and CDKN1C in human placenta tissues, which we propose facilitates expression. PMID:27200075

  18. Chronic Protein Restriction in Mice Impacts Placental Function and Maternal Body Weight before Fetal Growth

    PubMed Central

    Barbeito-Andrés, Jimena; Klenin, Natasha; Cross, James C.; Hallgrímsson, Benedikt

    2016-01-01

    Mechanisms of resource allocation are essential for maternal and fetal survival, particularly when the availability of nutrients is limited. We investigated the responses of feto-placental development to maternal chronic protein malnutrition to test the hypothesis that maternal low protein diet produces differential growth restriction of placental and fetal tissues, and adaptive changes in the placenta that may mitigate impacts on fetal growth. C57BL/6J female mice were fed either a low-protein diet (6% protein) or control isocaloric diet (20% protein). On embryonic days E10.5, 17.5 and 18.5 tissue samples were prepared for morphometric, histological and quantitative RT-PCR analyses, which included markers of trophoblast cell subtypes. Potential endocrine adaptations were assessed by the expression of Prolactin-related hormone genes. In the low protein group, placenta weight was significantly lower at E10.5, followed by reduction of maternal weight at E17.5, while the fetuses became significantly lighter no earlier than at E18.5. Fetal head at E18.5 in the low protein group, though smaller than controls, was larger than expected for body size. The relative size and shape of the cranial vault and the flexion of the cranial base was affected by E17.5 and more severely by E18.5. The junctional zone, a placenta layer rich in endocrine and energy storing glycogen cells, was smaller in low protein placentas as well as the expression of Pcdh12, a marker of glycogen trophoblast cells. Placental hormone gene Prl3a1 was altered in response to low protein diet: expression was elevated at E17.5 when fetuses were still growing normally, but dropped sharply by E18.5 in parallel with the slowing of fetal growth. This model suggests that nutrients are preferentially allocated to sustain fetal and brain growth and suggests the placenta as a nutrient sensor in early gestation with a role in mitigating impacts of poor maternal nutrition on fetal growth. PMID:27018791

  19. Chronic Protein Restriction in Mice Impacts Placental Function and Maternal Body Weight before Fetal Growth.

    PubMed

    Gonzalez, Paula N; Gasperowicz, Malgorzata; Barbeito-Andrés, Jimena; Klenin, Natasha; Cross, James C; Hallgrímsson, Benedikt

    2016-01-01

    Mechanisms of resource allocation are essential for maternal and fetal survival, particularly when the availability of nutrients is limited. We investigated the responses of feto-placental development to maternal chronic protein malnutrition to test the hypothesis that maternal low protein diet produces differential growth restriction of placental and fetal tissues, and adaptive changes in the placenta that may mitigate impacts on fetal growth. C57BL/6J female mice were fed either a low-protein diet (6% protein) or control isocaloric diet (20% protein). On embryonic days E10.5, 17.5 and 18.5 tissue samples were prepared for morphometric, histological and quantitative RT-PCR analyses, which included markers of trophoblast cell subtypes. Potential endocrine adaptations were assessed by the expression of Prolactin-related hormone genes. In the low protein group, placenta weight was significantly lower at E10.5, followed by reduction of maternal weight at E17.5, while the fetuses became significantly lighter no earlier than at E18.5. Fetal head at E18.5 in the low protein group, though smaller than controls, was larger than expected for body size. The relative size and shape of the cranial vault and the flexion of the cranial base was affected by E17.5 and more severely by E18.5. The junctional zone, a placenta layer rich in endocrine and energy storing glycogen cells, was smaller in low protein placentas as well as the expression of Pcdh12, a marker of glycogen trophoblast cells. Placental hormone gene Prl3a1 was altered in response to low protein diet: expression was elevated at E17.5 when fetuses were still growing normally, but dropped sharply by E18.5 in parallel with the slowing of fetal growth. This model suggests that nutrients are preferentially allocated to sustain fetal and brain growth and suggests the placenta as a nutrient sensor in early gestation with a role in mitigating impacts of poor maternal nutrition on fetal growth. PMID:27018791

  20. Redox regulation of epidermal growth factor receptor signaling during the development of pulmonary hypertension.

    PubMed

    Rafikova, Olga; Rafikov, Ruslan; Kangath, Archana; Qu, Ning; Aggarwal, Saurabh; Sharma, Shruti; Desai, Julin; Fields, Taylor; Ludewig, Britta; Yuan, Jason X-Y; Jonigk, Danny; Black, Stephen M

    2016-06-01

    The development of pulmonary hypertension (PH) involves the uncontrolled proliferation of pulmonary smooth muscle cells via increased growth factor receptor signaling. However, the role of epidermal growth factor receptor (EGFR) signaling is controversial, as humans with advanced PH exhibit no changes in EGFR protein levels and purpose of the present study was to determine whether there are post-translational mechanisms that enhance EGFR signaling in PH. The EGFR inhibitor, gefinitib, significantly attenuated EGFR signaling and prevented the development of PH in monocrotaline (MCT)-exposed rats, confirming the contribution of EGFR activation in MCT induced PH. There was an early MCT-mediated increase in hydrogen peroxide, which correlated with the binding of the active metabolite of MCT, monocrotaline pyrrole, to catalase Cys377, disrupting its multimeric structure. This early oxidative stress was responsible for the oxidation of EGFR and the formation of sodium dodecyl sulfate (SDS) stable EGFR dimers through dityrosine cross-linking. These cross-linked dimers exhibited increased EGFR autophosphorylation and signaling. The activation of EGFR signaling did not correlate with pp60(src) dependent Y845 phosphorylation or EGFR ligand expression. Importantly, the analysis of patients with advanced PH revealed the same enhancement of EGFR autophosphorylation and covalent dimer formation in pulmonary arteries, while total EGFR protein levels were unchanged. As in the MCT exposed rat model, the activation of EGFR in human samples was independent of pp60(src) phosphorylation site and ligand expression. This study provides a novel molecular mechanism of oxidative stress stimulated covalent EGFR dimerization via tyrosine dimerization that contributes into development of PH. PMID:26928584

  1. MEK-ERK Pathway Modulation Ameliorates Pulmonary Fibrosis Associated with Epidermal Growth Factor Receptor Activation

    PubMed Central

    Madala, Satish K.; Schmidt, Stephanie; Davidson, Cynthia; Ikegami, Machiko; Wert, Susan

    2012-01-01

    Pulmonary fibrosis remains a significant public health burden with no proven therapies. The mitogen-activated protein kinase (MAPK)/MAPK kinase (MEK)/extracellular signal–regulated kinase (ERK) signaling cascade is a major pathway controlling cellular processes associated with fibrogenesis, including growth, proliferation, and survival. Activation of the MAPK/ERK pathway is detected in the lungs of human fibrosis samples; however, the effect of modulating the pathway in vivo is unknown. Overexpression of transforming growth factor (TGF)-α in the lung epithelium of transgenic mice causes a progressive pulmonary fibrosis associated with increased MEK/ERK activation localized primarily in mesenchymal cells. To determine the role of the MEK pathway in the induction of TGF-α–induced lung fibrosis, TGF-α was overexpressed for 4 weeks while mice were simultaneously treated with the specific MEK inhibitor, ARRY-142886 (ARRY). Treatment with ARRY prevented increases in lung cell proliferation and total lung collagen, attenuated production of extracellular matrix genes, and protected mice from changes in lung function. ARRY administered as a rescue treatment after fibrosis was already established inhibited fibrosis progression, as assessed by lung histology, changes in body weights, extracellular matrix gene expression, and lung mechanics. These findings demonstrate that MEK inhibition prevents progression of established fibrosis in the TGF-α model, and provides proof of concept of targeting the MEK pathway in fibrotic lung disease. PMID:22021337

  2. Dysregulated flow-mediated vasodilatation in the human placenta in fetal growth restriction

    PubMed Central

    Jones, Sarah; Bischof, Helen; Lang, Ingrid; Desoye, Gernot; Greenwood, Sue L; Johnstone, Edward D; Wareing, Mark; Sibley, Colin P; Brownbill, Paul

    2015-01-01

    Increased vascular resistance and reduced fetoplacental blood flow are putative aetiologies in the pathogenesis of fetal growth restriction (FGR); however, the regulating sites and mechanisms remain unclear. We hypothesised that placental vessels dictate fetoplacental resistance and in FGR exhibit endothelial dysfunction and reduced flow-mediated vasodilatation (FMVD). Resistance was measured in normal pregnancies (n = 10) and FGR (n = 10) both in vivo by umbilical artery Doppler velocimetry and ex vivo by dual placental perfusion. Ex vivo FMVD is the reduction in fetal-side inflow hydrostatic pressure (FIHP) following increased flow rate. Results demonstrated a significant correlation between vascular resistance measured in vivo and ex vivo in normal pregnancy, but not in FGR. In perfused FGR placentas, vascular resistance was significantly elevated compared to normal placentas (58 ± 7.7 mmHg and 36.8 ± 4.5 mmHg, respectively; 8 ml min−1; means ± SEM; P < 0.0001) and FMVD was severely reduced (3.9 ± 1.3% and 9.1 ± 1.2%, respectively). In normal pregnancies only, the highest level of ex vivo FMVD was associated with the lowest in vivo resistance. Inhibition of NO synthesis during perfusion (100 μm l-NNA) moderately elevated FIHP in the normal group, but substantially in the FGR group. Human placenta artery endothelial cells from FGR groups exhibited increased shear stress-induced NO generation, iNOS expression and eNOS expression compared with normal groups. In conclusion, fetoplacental resistance is determined by placental vessels, and is increased in FGR. The latter also exhibit reduced FMVD, but with a partial compensatory increased NO generation capacity. The data support our hypothesis, which highlights the importance of FMVD regulation in normal and dysfunctional placentation. Key points A correlation was found between in vivo umbilical artery Doppler velocimetry and resistance to fetal-side flow in the human ex vivo dually

  3. Development and preclinical efficacy of novel transforming growth factor-β1 short interfering RNAs for pulmonary fibrosis.

    PubMed

    D'Alessandro-Gabazza, Corina N; Kobayashi, Tetsu; Boveda-Ruiz, Daniel; Takagi, Takehiro; Toda, Masaaki; Gil-Bernabe, Paloma; Miyake, Yasushi; Yasukawa, Atsushi; Matsuda, Yoshikazu; Suzuki, Noboru; Saito, Hiromitsu; Yano, Yutaka; Fukuda, Ayako; Hasegawa, Tetsuya; Toyobuku, Hidekazu; Rennard, Stephen I; Wagner, Peter D; Morser, John; Takei, Yoshiyuki; Taguchi, Osamu; Gabazza, Esteban C

    2012-03-01

    Idiopathic pulmonary fibrosis is a chronic devastating disease of unknown etiology. No therapy is currently available. A growing body of evidence supports the role of transforming growth factor (TGF)-β1 as the major player in the pathogenesis of the disease. However, attempts to control its expression and to improve the outcome of pulmonary fibrosis have been disappointing. We tested the hypothesis that TGF-β1 is the dominant factor in the acute and chronic phases of pulmonary fibrosis and developed short interfering (si)RNAs directed toward molecules implicated in the disease. This study developed novel sequences of siRNAs targeting the TGF-β1 gene and evaluated their therapeutic efficacy in two models of pulmonary fibrosis: a model induced by bleomycin and a novel model of the disease developed spontaneously in mice overexpressing the full length of human TGF-β1 in the lungs. Intrapulmonary delivery of aerosolized siRNAs of TGF-β1 with sequences common to humans and rodents significantly inhibited bleomycin-induced pulmonary fibrosis in the acute and chronic phases of the disease and in a dose-dependent manner. Aerosolized human-specific siRNA also efficiently inhibited pulmonary fibrosis, improved lung function, and prolonged survival in human TGF-β1 transgenic mice. Mice showed no off-target effects after intratracheal administration of siRNA. These results suggest the applicability of these novel siRNAs as tools for treating pulmonary fibrosis in humans. PMID:22033267

  4. Spontaneous intrauterine umbilical artery thrombosis leading to severe fetal growth restriction.

    PubMed

    Klaritsch, P; Haeusler, M; Karpf, E; Schlembach, D; Lang, U

    2008-04-01

    Intrauterine thrombosis of umbilical cord vessels is a rare event (2.5-4.5/10,000) and usually followed by poor fetal outcome. We present the rare case of spontaneous intrauterine thrombosis of an umbilical artery leading to severe intrauterine growth restriction (IUGR) and provide clinical and pathological findings. A 28-year-old nulliparous third gravida was referred to our institution because of IUGR at 32+4 weeks of gestation. Fetal growth had been appropriate until the 31st week of gestation and had stopped thereafter. There were no signs of abruption of the placenta and no structural abnormalities except an absent paravesical colour Doppler flow in the region of the right umbilical artery. Other Doppler measurements, karyotype and TORCH serology were normal. Intermittent non-reassuring fetal heart rate led to cesarean section at 34+3 weeks of gestation. A healthy girl with measurements on the 3rd centile was born (weight of 1,590 g, length of 41 cm and head circumference of 29 cm). Gross examination displayed an elongated, highly twisted umbilical cord with a length of 70 cm, central insertion and three umbilical vessels. Microscopic examination confirmed the diagnosis of umbilical artery thrombosis along the entire length of the umbilical cord. Calcification within the thrombus and microcalcification in occluded chorionic vessels were observed as well as hemorrhagic endovasculitis and endangiopathia obliterans in the stem villi arteries. This fetal thrombotic vasculopathy (FTV) comprised about 40% of the parenchyma. The coagulation parameters and blood counts of the mother and the infant were normal apart from transient neonatal thrombocytopenia. The reason for thrombosis remained unclear but could be attributed to the elongated and highly twisted umbilical cord. Intrauterine arterial thrombosis may cause severe IUGR. This condition might be detectable by ultrasound in the course of an IUGR workup, especially when no other reasons can be found. PMID:18289672

  5. Intrauterine Growth Restricted Rats Exercised before and during Pregnancy: Maternal and Perinatal Repercussions

    PubMed Central

    Corvino, S. B.; Volpato, G. T.; Rudge, M. V. C.; Damasceno, D. C.

    2015-01-01

    This study aimed at evaluating the effect of swimming before and during pregnancy on rats born with intrauterine growth restriction (IUGR) and their offspring. For this, nondiabetic and streptozotocin-induced severely diabetic (SD) pregnant rats were mated and generated offspring with appropriate (control, C) and small (IUGR) for pregnancy age, respectively. Following that, C and IUGR groups were further distributed into nonexercised control (C), exercised control (Cex), nonexercised IUGR (IUGR), and exercised IUGR (IUGRex). IUGR rats presented lower mating rate than control rats. Regardless of physical exercise IUGR rats presented decreased body weight from birth to lactation. At 90 days of life, IUGR rats presented glucose intolerance. Maternal organ weights were increased and relative adiposity of IUGRex rats was lower than Cex. IUGR and IUGRex offspring presented reduced body weight than C and Cex, respectively. IUGRex dams presented an increased rate of appropriate for pregnancy age newborns. IUGEex male and female offspring relative brain weight was increased compared with Cex. Therefore, swimming before and during pregnancy prevented glucose intolerance, reduced general adiposity, and increased maternal and offspring organ weight in rats, showing the benefit of physical exercise for IUGR rats. PMID:26345406

  6. Neural injury markers to predict neonatal complications in intrauterine growth restriction.

    PubMed

    Velipaşaoğlu, M; Yurdakök, M; Özyüncü, Ö; Portakal, O; Deren, Ö

    2015-01-01

    We assessed the neural injury markers (NIMs) in maternal and umbilical blood in preterm deliveries with and without intrauterine growth restriction (IUGR), and relationship between NIMs and neonatal complications. Deliveries between 24 and 34 weeks' gestation with (study group) and without (control group) IUGR were included to the study. Three NIMs (s100B, neurone-specific enolase [NSE] and alpha-foetoprotein [AFP]) were investigated in umbilical arterial, umbilical venous and maternal venous serum. Thirty-two IUGR and twenty-nine non-IUGR pregnancies with preterm delivery were included. Maternal and umbilical arterial s100B levels were significantly higher in the study group, whereas there was no relationship among IUGR, AFP and NSE levels. In the study group, umbilical venous s100B and NSE levels were associated with perinatal mortality (p = 0.012, 0.005, respectively), necrotising enterocolitis (NEC) (p = 0.001, 0.04, respectively) and need for intubation (p = 0.001, 0.007, respectively). Negative predictive values for perinatal mortality and NEC were 100% and for need for intubation it was 92.8% when both s100B and NSE were below the cutoff line determined by the receiver-operating characteristic curves. Perinatal mortality, NEC and need for intubation can be predicted by assessment of umbilical venous s100B and NSE measurement during birth in IUGR newborns. PMID:25392968

  7. Intrauterine growth restriction inhibits expression of eukaryotic elongation factor 2 kinase, a regulator of protein translation.

    PubMed

    McKnight, Robert A; Yost, Christian C; Zinkhan, Erin K; Fu, Qi; Callaway, Christopher W; Fung, Camille M

    2016-08-01

    Nutrient deprivation suppresses protein synthesis by blocking peptide elongation. Transcriptional upregulation and activation of eukaryotic elongation factor 2 kinase (eEF2K) blocks peptide elongation by phosphorylating eukaryotic elongation factor 2. Previous studies examining placentas from intrauterine growth restricted (IUGR) newborn infants show decreased eEF2K expression and activity despite chronic nutrient deprivation. However, the effect of IUGR on hepatic eEF2K expression in the fetus is unknown. We, therefore, examined the transcriptional regulation of hepatic eEF2K gene expression in a Sprague-Dawley rat model of IUGR. We found decreased hepatic eEF2K mRNA and protein levels in IUGR offspring at birth compared with control, consistent with previous placental observations. Furthermore, the CpG island within the eEF2K promoter demonstrated increased methylation at a critical USF 1/2 transcription factor binding site. In vitro methylation of this binding site caused near complete loss of eEF2K promoter activity, designating this promoter as methylation sensitive. The eEF2K promotor in IUGR offspring also lost the protective histone covalent modifications associated with unmethylated CGIs. In addition, the +1 nucleosome was displaced 3' and RNA polymerase loading was reduced at the IUGR eEF2K promoter. Our findings provide evidence to explain why IUGR-induced chronic nutrient deprivation does not result in the upregulation of eEF2K gene transcription. PMID:27317589

  8. Sildenafil citrate for the management of fetal growth restriction and oligohydramnios

    PubMed Central

    Choudhary, Rana; Desai, Kavita; Parekh, Hetal; Ganla, Kedar

    2016-01-01

    Fetal growth restriction (FGR) and preeclampsia are the major causes of neonatal morbidity and mortality, which affect up to 8% of all pregnancies. The pathogenesis in FGR is an abnormal trophoblastic invasion leading to compromised uteroplacental circulation. However, in spite of this understanding and identification of high-risk patients, the management options are limited. There are some new studies which have demonstrated the role of sildenafil citrate in improving vasodilatation of small myometrial vessels and therefore improvement in amniotic fluid index, fetal weight, and even uterine and umbilical artery Doppler patterns. We report here the case of a 31-year-old female with infertility and preconceptional thin endometrium responding well to sildenafil citrate, followed by conception. However, she presented with an early-onset FGR at 26 weeks of gestation, and again after treatment with sildenafil citrate, showed improvement in amniotic fluid index and fetal weight, finally resulting in delivery of a full-term healthy baby with uneventful neonatal course. PMID:27563258

  9. Nitric Oxide-Mediated Intracellular Growth Restriction of Pathogenic Rhodococcus equi Can Be Prevented by Iron▿

    PubMed Central

    von Bargen, Kristine; Wohlmann, Jens; Taylor, Gregory Alan; Utermöhlen, Olaf; Haas, Albert

    2011-01-01

    Rhodococcus equi is an intracellular pathogen which causes pneumonia in young horses and in immunocompromised humans. R. equi arrests phagosome maturation in macrophages at a prephagolysosome stage and grows inside a privileged compartment. Here, we show that, in murine macrophages activated with gamma interferon and lipopolysaccharide, R. equi does not multiply but stays viable for at least 24 h. Whereas infection control of other intracellular pathogens by activated macrophages is executed by enhanced phagosome acidification or phagolysosome formation, by autophagy or by the interferon-inducible GTPase Irgm1, none of these mechanisms seems to control R. equi infection. Growth control by macrophage activation is fully mimicked by treatment of resting macrophages with nitric oxide donors, and inhibition of bacterial multiplication by either activation or nitric oxide donors is annihilated by cotreatment of infected macrophages with ferrous sulfate. Transcriptional analysis of the R. equi iron-regulated gene iupT demonstrates that intracellular R. equi encounters iron stress in activated, but not in resting, macrophages and that this stress is relieved by extracellular addition of ferrous sulfate. Our results suggest that nitric oxide is central to the restriction of bacterial access to iron in activated macrophages. PMID:21383050

  10. Measuring aging rates of mice subjected to caloric restriction and genetic disruption of growth hormone signaling

    PubMed Central

    Koopman, Jacob J.E.; van Heemst, Diana; van Bodegom, David; Bonkowski, Michael S.; Sun, Liou Y.; Bartke, Andrzej

    2016-01-01

    Caloric restriction and genetic disruption of growth hormone signaling have been shown to counteract aging in mice. The effects of these interventions on aging are examined through age-dependent survival or through the increase in age-dependent mortality rates on a logarithmic scale fitted to the Gompertz model. However, these methods have limitations that impede a fully comprehensive disclosure of these effects. Here we examine the effects of these interventions on murine aging through the increase in age-dependent mortality rates on a linear scale without fitting them to a model like the Gompertz model. Whereas these interventions negligibly and non-consistently affected the aging rates when examined through the age-dependent mortality rates on a logarithmic scale, they caused the aging rates to increase at higher ages and to higher levels when examined through the age-dependent mortality rates on a linear scale. These results add to the debate whether these interventions postpone or slow aging and to the understanding of the mechanisms by which they affect aging. Since different methods yield different results, it is worthwhile to compare their results in future research to obtain further insights into the effects of dietary, genetic, and other interventions on the aging of mice and other species. PMID:26959761

  11. Neonatal short-term outcomes in infants with intrauterine growth restriction

    PubMed Central

    Hasmasanu, Monica G.; Bolboaca, Sorana D.; Baizat, Melinda I.; Drugan, Tudor C.; Zaharie, Gabriela C.

    2015-01-01

    Objectives: To assess the neonatal outcomes in newborns with intrauterine growth restriction (IUGR) in a Romanian population in a 3 level maternity unit. Methods: A matched case-control design, with one control for each patient was used. The case group comprised neonates with birth weight and birth length below the 10th percentile for the gestational age. Individual matching by gender and age of gestation was used to identify the control group. Both cases and controls were selected from the infants admitted to and discharged from the Neonatal Ward, at the First Gynecology Clinic, of the County Emergency Hospital Cluj-Napoca, Cluj-Napoca, Romania, between January 2012 and June 2014. Results: One hundred and forty-two subjects were included in each group. The cesarean delivery was significantly more frequent in the IUGR group (66.9%) compared with controls (46.5%; p=0.0006). The Apgar score at one minute was ≥7 for most infants in both groups (77.9% IUGR group versus 77.5% control group), with no significant differences between the groups. A significantly higher percentage of infants in the IUGR group had hypoglycemia or intraventricular hemorrhage compared with the controls (p<0.05). Hypoglycemia proved a significant factor for IUGR (odds ratio = 4.763, 95% confidence interval: 1.711-13.255). Conclusion: Hypoglycemia and intraventricular hemorrhage characterized the IUGR newborns. PMID:26219445

  12. Increased aggressive and affiliative display behavior in intrauterine growth restricted (IUGR) baboons

    PubMed Central

    Huber, Hillary F; Ford, Susan M; Bartlett, Thad Q; Nathanielsz, Peter W

    2016-01-01

    Background We hypothesized intrauterine growth restricted offspring (IUGR) demonstrate higher rates of aggression and higher dominance ranks than control (CTR) offspring with normal weight at term; if aggressive behavior is advantageous during resource scarcity, developmental programming may lead to an association between aggression and IUGR. Methods We studied 22 group-housed baboons (ages 3-5 years). CTR (male n=8, female n=5) mothers ate ad libitum. IUGR (male n=4, female n=5) mothers were fed 70% feed eaten by CTR mothers during pregnancy and lactation. Results IUGR showed higher rates of aggressive displays (p<0.01) and friendly displays (p<0.02). Dominance ranks and physical aggression rates did not differ between groups. Conclusions High rates of IUGR aggressive display might reflect developmental programming of behavioral phenotypes enhancing fitness. Friendly displays may reflect reconciliation. Potential mechanisms include neurodevelopment and learning. Exploration of IUGR as a risk factor for behavioral patterns is important for developing diagnostic and therapeutic strategies. PMID:25891005

  13. Altered resting-state whole-brain functional networks of neonates with intrauterine growth restriction.

    PubMed

    Batalle, Dafnis; Muñoz-Moreno, Emma; Tornador, Cristian; Bargallo, Nuria; Deco, Gustavo; Eixarch, Elisenda; Gratacos, Eduard

    2016-04-01

    The feasibility to use functional MRI (fMRI) during natural sleep to assess low-frequency basal brain activity fluctuations in human neonates has been demonstrated, although its potential to characterise pathologies of prenatal origin has not yet been exploited. In the present study, we used intrauterine growth restriction (IUGR) as a model of altered neurodevelopment due to prenatal condition to show the suitability of brain networks to characterise functional brain organisation at neonatal age. Particularly, we analysed resting-state fMRI signal of 20 neonates with IUGR and 13 controls, obtaining whole-brain functional networks based on correlations of blood oxygen level-dependent (BOLD) signal in 90 grey matter regions of an anatomical atlas (AAL). Characterisation of the networks obtained with graph theoretical features showed increased network infrastructure and raw efficiencies but reduced efficiency after normalisation, demonstrating hyper-connected but sub-optimally organised IUGR functional brain networks. Significant association of network features with neurobehavioral scores was also found. Further assessment of spatiotemporal dynamics displayed alterations into features associated to frontal, cingulate and lingual cortices. These findings show the capacity of functional brain networks to characterise brain reorganisation from an early age, and their potential to develop biomarkers of altered neurodevelopment. PMID:26927726

  14. Nitric oxide-mediated intracellular growth restriction of pathogenic Rhodococcus equi can be prevented by iron.

    PubMed

    von Bargen, Kristine; Wohlmann, Jens; Taylor, Gregory Alan; Utermöhlen, Olaf; Haas, Albert

    2011-05-01

    Rhodococcus equi is an intracellular pathogen which causes pneumonia in young horses and in immunocompromised humans. R. equi arrests phagosome maturation in macrophages at a prephagolysosome stage and grows inside a privileged compartment. Here, we show that, in murine macrophages activated with gamma interferon and lipopolysaccharide, R. equi does not multiply but stays viable for at least 24 h. Whereas infection control of other intracellular pathogens by activated macrophages is executed by enhanced phagosome acidification or phagolysosome formation, by autophagy or by the interferon-inducible GTPase Irgm1, none of these mechanisms seems to control R. equi infection. Growth control by macrophage activation is fully mimicked by treatment of resting macrophages with nitric oxide donors, and inhibition of bacterial multiplication by either activation or nitric oxide donors is annihilated by cotreatment of infected macrophages with ferrous sulfate. Transcriptional analysis of the R. equi iron-regulated gene iupT demonstrates that intracellular R. equi encounters iron stress in activated, but not in resting, macrophages and that this stress is relieved by extracellular addition of ferrous sulfate. Our results suggest that nitric oxide is central to the restriction of bacterial access to iron in activated macrophages. PMID:21383050

  15. Sildenafil citrate for the management of fetal growth restriction and oligohydramnios.

    PubMed

    Choudhary, Rana; Desai, Kavita; Parekh, Hetal; Ganla, Kedar

    2016-01-01

    Fetal growth restriction (FGR) and preeclampsia are the major causes of neonatal morbidity and mortality, which affect up to 8% of all pregnancies. The pathogenesis in FGR is an abnormal trophoblastic invasion leading to compromised uteroplacental circulation. However, in spite of this understanding and identification of high-risk patients, the management options are limited. There are some new studies which have demonstrated the role of sildenafil citrate in improving vasodilatation of small myometrial vessels and therefore improvement in amniotic fluid index, fetal weight, and even uterine and umbilical artery Doppler patterns. We report here the case of a 31-year-old female with infertility and preconceptional thin endometrium responding well to sildenafil citrate, followed by conception. However, she presented with an early-onset FGR at 26 weeks of gestation, and again after treatment with sildenafil citrate, showed improvement in amniotic fluid index and fetal weight, finally resulting in delivery of a full-term healthy baby with uneventful neonatal course. PMID:27563258

  16. Permanent Cardiac Sarcomere Changes in a Rabbit Model of Intrauterine Growth Restriction

    PubMed Central

    Torre, Iratxe; González-Tendero, Anna; García-Cañadilla, Patricia; Crispi, Fátima; García-García, Francisco; Bijnens, Bart; Iruretagoyena, Igor; Dopazo, Joaquin; Amat-Roldán, Ivan; Gratacós, Eduard

    2014-01-01

    Background Intrauterine growth restriction (IUGR) induces fetal cardiac remodelling and dysfunction, which persists postnatally and may explain the link between low birth weight and increased cardiovascular mortality in adulthood. However, the cellular and molecular bases for these changes are still not well understood. We tested the hypothesis that IUGR is associated with structural and functional gene expression changes in the fetal sarcomere cytoarchitecture, which remain present in adulthood. Methods and Results IUGR was induced in New Zealand pregnant rabbits by selective ligation of the utero-placental vessels. Fetal echocardiography demonstrated more globular hearts and signs of cardiac dysfunction in IUGR. Second harmonic generation microscopy (SHGM) showed shorter sarcomere length and shorter A-band and thick-thin filament interaction lengths, that were already present in utero and persisted at 70 postnatal days (adulthood). Sarcomeric M-band (GO: 0031430) functional term was over-represented in IUGR fetal hearts. Conclusion The results suggest that IUGR induces cardiac dysfunction and permanent changes on the sarcomere. PMID:25402351

  17. Global health indicators and maternal health futures: The case of Intrauterine Growth Restriction.

    PubMed

    Erikson, Susan L

    2015-01-01

    Public health indicators generally operate in the world as credible, apolitical and authoritative. But indicators are less stable than they appear. Clinical critiques of Intrauterine Growth Restriction (IUGR) criteria have been forthcoming for decades. This article, though, takes up the measuring and calculation gradients of IUGR in the ultrasound machine itself, including the software algorithms that identify IUGR. One hospital where research was conducted incorrectly predicted pathological birth outcomes 14 of 14 times. We are at a historical moment when the global use of prenatal diagnostic ultrasound for the express purpose of assessing IUGR is set to escalate. Medical imaging device corporations like Siemens, Toshiba, General Electric and Phillips are quite literally banking on it, and new forms of ultrasound technology and diagnostic software are increasingly available on smartphones, tablets and laptops. Clinical guidelines for IUGR--assumed to be authoritative and evidence-based--are evolving right along with the installation throughout the world of the technology capable of diagnosing it. Maternal malnutrition remains the single strongest predictive factor for IUGR, regardless of the technological investments currently amassing to identify the indicator, which is cause for a reassessment of priority spending and investment. PMID:26172620

  18. Readiness and Adjustments to School for Children with Intrauterine Growth Restriction (IUGR): An Extreme Test Case Paradigm

    ERIC Educational Resources Information Center

    Geva, Ronny; Yosipof, Rina; Eshel, Rina; Leitner, Yael; Valevski, Aviva Fattal; Harel, Shaul

    2009-01-01

    This long-term, prospective study evaluated repeatedly school readiness and adjustment at kindergarten and first grade of children with extreme intrauterine growth restriction (IUGR; n = 20) in relation to controls (n = 19). Methods included individual testing of cognitive competence, self-perception, motivation, loneliness and academic…

  19. Verbal Short-Term Memory Span in Children: Long-Term Modality Dependent Effects of Intrauterine Growth Restriction

    ERIC Educational Resources Information Center

    Geva, R.; Eshel, R.; Leitner, Y.; Fattal-Valevski, A.; Harel, S.

    2008-01-01

    Background: Recent reports showed that children born with intrauterine growth restriction (IUGR) are at greater risk of experiencing verbal short-term memory span (STM) deficits that may impede their learning capacities at school. It is still unknown whether these deficits are modality dependent. Methods: This long-term, prospective design study…

  20. Connective tissue growth factor stimulates the proliferation, migration and differentiation of lung fibroblasts during paraquat-induced pulmonary fibrosis.

    PubMed

    Yang, Zhizhou; Sun, Zhaorui; Liu, Hongmei; Ren, Yi; Shao, Danbing; Zhang, Wei; Lin, Jinfeng; Wolfram, Joy; Wang, Feng; Nie, Shinan

    2015-07-01

    It is well established that paraquat (PQ) poisoning can cause severe lung injury during the early stages of exposure, finally leading to irreversible pulmonary fibrosis. Connective tissue growth factor (CTGF) is an essential growth factor that is involved in tissue repair and pulmonary fibrogenesis. In the present study, the role of CTGF was examined in a rat model of pulmonary fibrosis induced by PQ poisoning. Histological examination revealed interstitial edema and extensive cellular thickening of interalveolar septa at the early stages of poisoning. At 2 weeks after PQ administration, lung tissue sections exhibited a marked thickening of the alveolar walls with an accumulation of interstitial cells with a fibroblastic appearance. Masson's trichrome staining revealed a patchy distribution of collagen deposition, indicating pulmonary fibrogenesis. Western blot analysis and immunohistochemical staining of tissue samples demonstrated that CTGF expression was significantly upregulated in the PQ-treated group. Similarly, PQ treatment of MRC-5 human lung fibroblast cells caused an increase in CTGF in a dose-dependent manner. Furthermore, the addition of CTGF to MRC-5 cells triggered cellular proliferation and migration. In addition, CTGF induced the differentiation of fibroblasts to myofibroblasts, as was evident from increased expression of α-smooth muscle actin (α-SMA) and collagen. These findings demonstrate that PQ causes increased CTGF expression, which triggers proliferation, migration and differentiation of lung fibroblasts. Therefore, CTGF may be important in PQ-induced pulmonary fibrogenesis, rendering this growth factor a potential pharmacological target for reducing lung injury. PMID:25815693

  1. Follicle-restricted compartmentalization of transforming growth factor beta superfamily ligands in the feline ovary.

    PubMed

    Bristol, Sarah K; Woodruff, Teresa K

    2004-03-01

    Ovarian follicular development, follicle selection, and the process of ovulation remain poorly understood in most species. Throughout reproductive life, follicle fate is balanced between growth and apoptosis. These opposing forces are controlled by numerous endocrine, paracrine, and autocrine factors, including the ligands represented by the transforming growth factor beta (TGFbeta) superfamily. TGFbeta, activin, inhibin, bone morphometric protein (BMP), and growth differentiation factor 9 (GDF-9) are present in the ovary of many animals; however, no comprehensive analysis of the localization of each ligand or its receptors and intracellular signaling molecules during folliculogenesis has been done. The domestic cat is an ideal model for studying ovarian follicle dynamics due to an abundance of all follicle populations, including primordial stage, and the amount of readily available tissue following routine animal spaying. Additionally, knowledge of the factors involved in feline follicular development could make an important impact on in vitro maturation/in vitro fertilization (IVM/IVF) success for endangered feline species. Thus, the presence and position of TGFbeta superfamily members within the feline ovary have been evaluated in all stages of follicular development by immunolocalization. The cat inhibin alpha subunit protein is present in all follicle stages but increases in intensity within the mural granulosa cells in large antral follicles. The inhibin betaA and betaB subunit proteins, in addition to the activin type I (ActRIB) and activin type II receptor (ActRIIB), are produced in primordial and primary follicle granulosa cells. Additionally, inhibin betaA subunit is detected in the theca cells from secondary through large antral follicle size classes. GDF-9 is restricted to the oocyte of preantral and antral follicles, whereas the type II BMP receptor (BMP-RII) protein is predominantly localized to primordial- and primary-stage follicles. TGFbeta1, 2

  2. Inhibition of Neuroblastoma Tumor Growth by Ketogenic Diet and/or Calorie Restriction in a CD1-Nu Mouse Model

    PubMed Central

    Morscher, Raphael Johannes; Aminzadeh-Gohari, Sepideh; Feichtinger, René Gunther; Mayr, Johannes Adalbert; Lang, Roland; Neureiter, Daniel; Sperl, Wolfgang; Kofler, Barbara

    2015-01-01

    Introduction Neuroblastoma is a malignant pediatric cancer derived from neural crest cells. It is characterized by a generalized reduction of mitochondrial oxidative phosphorylation. The goal of the present study was to investigate the effects of calorie restriction and ketogenic diet on neuroblastoma tumor growth and monitor potential adaptive mechanisms of the cancer’s oxidative phosphorylation system. Methods Xenografts were established in CD-1 nude mice by subcutaneous injection of two neuroblastoma cell lines having distinct genetic characteristics and therapeutic sensitivity [SH-SY5Y and SK-N-BE(2)]. Mice were randomized to four treatment groups receiving standard diet, calorie-restricted standard diet, long chain fatty acid based ketogenic diet or calorie-restricted ketogenic diet. Tumor growth, survival, metabolic parameters and weight of the mice were monitored. Cancer tissue was evaluated for diet-induced changes of proliferation indices and multiple oxidative phosphorylation system parameters (respiratory chain enzyme activities, western blot analysis, immunohistochemistry and mitochondrial DNA content). Results Ketogenic diet and/or calorie restriction significantly reduced tumor growth and prolonged survival in the xenograft model. Neuroblastoma growth reduction correlated with decreased blood glucose concentrations and was characterized by a significant decrease in Ki-67 and phospho-histone H3 levels in the diet groups with low tumor growth. As in human tumor tissue, neuroblastoma xenografts showed distinctly low mitochondrial complex II activity in combination with a generalized low level of mitochondrial oxidative phosphorylation, validating the tumor model. Neuroblastoma showed no ability to adapt its mitochondrial oxidative phosphorylation activity to the change in nutrient supply induced by dietary intervention. Conclusions Our data suggest that targeting the metabolic characteristics of neuroblastoma could open a new front in supporting

  3. Comparative Analysis of Normal versus Fetal Growth Restriction in Pregnancy: The Significance of Maternal Body Mass Index, Nutritional Status, Anemia, and Ultrasonography Screening

    PubMed Central

    Sawant, Laxmichaya D.; Venkat, Shirin

    2013-01-01

    Fetal growth restriction or intrauterine growth restriction is one of the leading causes of perinatal mortality and morbidity in newborns. Fetal growth restriction is a complex multifactorial condition resulting from several fetal and maternal disorders. The objective of this study was twofold: first to examine the correlation between maternal parameters such as body mass index (BMI), nutritional status, anemia, and placental weight and diameter, and their effects on fetal growth and then to evaluate the effect of early screening by ultrasonography (USG) on the outcome of growth restricted pregnancies. In this study, 53 cases of fetal growth restriction were compared to 53 normal fetuses delivered in consecutive sequence. Growth restricted fetuses were delivered earlier in gestation, when compared with normal growth fetuses. Maternal anemia and malnutrition have significant association with the fetal growth restriction. Maternal anthropometry, such as low BMI, had effects on placental diameter and weight, which, in turn, adversely affected fetal weight. Thus, early USG screening along with robust screening for maternal BMI, nutritional status, and anemia can assist the obstetric team in providing early diagnosis, prompt intervention, and better outcome in pregnancy with fetal growth restriction. PMID:25763389

  4. Role of GDF15 (growth and differentiation factor 15) in pulmonary oxygen toxicity.

    PubMed

    Tiwari, Kirti Kumar; Moorthy, Bhagavatula; Lingappan, Krithika

    2015-10-01

    GDF15 (growth and differentiation factor 15) is a secreted cytokine, a direct target of p53 and plays a role in cell proliferation and apoptosis. It is induced by oxidative stress and has anti-apoptotic effects. The role of GDF15 in hyperoxic lung injury is unknown. We tested the hypothesis that GDF15 will be induced in vitro, in a model of pulmonary oxygen toxicity, and will play a critical role in decreasing cell death and oxidative stress. BEAS-2B (human bronchial epithelial cells) and human pulmonary vascular endothelial cells (HPMEC) were exposed to hyperoxia, and expression of GDF15 and effect of GDF15 disruption on cell viability and oxidative stress was determined. Furthermore, we studied the effect of p53 knockdown on GDF15 expression. In vitro, both BEAS-2B and HPMEC cells showed a significant increase in GDF15 expression upon exposure to hyperoxia. After GDF15 knockdown, there was a significant decrease in cell viability and increase in oxidative stress compared to control cells transfected with siRNA with a scrambled sequence. Knockdown of p53 significantly decreased the induction of GDF15 by hyperoxia. In conclusion, we show that GDF15 has a pro-survival and anti-oxidant role in hyperoxia and that p53 plays a key role in its induction. PMID:26004619

  5. Growth, Nutritional Status, and Pulmonary Function in Children with Chronic Recurrent Bronchitis.

    PubMed

    Umławska, Wioleta; Lipowicz, Anna

    2016-01-01

    Bronchitis is a common health problem in children. Frequent bronchitis in infancy increases the risk of developing chronic respiratory diseases. The aim of the study was to assess the level of growth and the nutritional status in children and youths with special regard to the level of body fatness assessed by measuring skin-fold thickness. Relationships between somatic development, pulmonary function and the course of the disease were also explored. The study was carried out using anthropometric and spirometric measurements and also information on the severity and course of the disease in 141 children with chronic or recurrent bronchitis. All of the subjects were patients of the Pulmonary Medicine and Allergology Center in Karpacz, Poland. The mean body height did not differ significantly between the children examined and their healthy peers. However, the infection-prone children had excessive body fatness and muscle mass deficiency. The increased level of subcutaneous adipose tissue occurred especially in children with short duration of the disease, i.e. a maximum of 1 year. The functional lung parameters were generally normal. The presence of atopic diseases such as allergic rhinitis or atopic dermatitis did not impair the course of the children's somatic development. Also, long-term disease or the presence of additional allergic diseases did not impair lung function in the examined children. Taking appropriate preventive measures is recommended to achieve and maintain normal body weight in children who receive therapy due to bronchitis. PMID:26801150

  6. Adipokine, adropin and endothelin-1 levels in intrauterine growth restricted neonates and their mothers.

    PubMed

    Aydin, Halil Ibrahim; Eser, Ayla; Kaygusuz, Ikbal; Yildirim, Sevgi; Celik, Tugrul; Gunduz, Suzan; Kalman, Suleyman

    2016-08-01

    Intrauterine growth retardation/restriction (IUGR) is associated with fetal malnutrition. It has consequences for later life including increased incidence of obesity, diabetes mellitus, cardiovascular disease (CVD), and metabolic syndrome. Adipokines (adiponectin and leptin), adropin, and endothelin-1 are associated with obesity and metabolic syndrome regulation. Intrauterine changes in these mediators could affect programming of later adult obesity and metabolic syndrome. Our objectives were to compare the levels of these mediators in both cord and maternal blood between IUGR pregnancies and control, healthy pregnancies, and to study the correlation of adipokines with adropin and endothelin-1 in maternal and cord blood in IUGR pregnancies as well as in healthy control pregnancies. Maternal and cord blood samples were taken from 16 women with IUGR pregnancies and 16 women with healthy pregnancies. Serum levels of leptin, adiponectin, adropin, and endothelin-1 were measured by ELISA. Maternal blood adropin levels were significantly lower in the IUGR group than in the control group; the other mediators did not differ significantly. There was a positive correlation between maternal blood adropin and endothelin levels. (r=0.731, P=0.001) in the control but not the IUGR group. Cord blood adropin and adiponectin levels were significantly lower in the IUGR group compared with the control group, while leptin or endothelin-1 did not differ significantly. There was a negative correlation between adropin and leptin (r=-0.704, P=0.001) in the IUGR but not the control group cord blood. There were also positive correlations between endothelin and adropin for both groups (r=0.594, P=0.006; r=0.560, P=0.010, respectively); to the best of our knowledge, this is the first report of such a correlation. Differences in fetal expression of adropin and adiponectin in IUGR could influence programming of obesity, metabolic syndrome, diabetes, and CVD in later life. PMID:26352058

  7. Limited capacity for glucose oxidation in fetal sheep with intrauterine growth restriction.

    PubMed

    Brown, Laura D; Rozance, Paul J; Bruce, Jennifer L; Friedman, Jacob E; Hay, William W; Wesolowski, Stephanie R

    2015-10-15

    Intrauterine growth-restricted (IUGR) fetal sheep, produced by placental insufficiency, have lower oxygen concentrations, higher lactate concentrations, and increased hepatic glucose production that is resistant to suppression by insulin. We hypothesized that increased lactate production in the IUGR fetus results from reduced glucose oxidation, during basal and maximal insulin-stimulated conditions, and is used to support glucose production. To test this, studies were performed in late-gestation control (CON) and IUGR fetal sheep under basal and hyperinsulinemic-clamp conditions. The basal glucose oxidation rate was similar and increased by 30-40% during insulin clamp in CON and IUGR fetuses (P < 0.005). However, the fraction of glucose oxidized was 15% lower in IUGR fetuses during basal and insulin-clamp periods (P = 0.05). IUGR fetuses also had four-fold higher lactate concentrations (P < 0.001) and lower lactate uptake rates (P < 0.05). In IUGR fetal muscle and liver, mRNA expression of pyruvate dehydrogenase kinase (PDK4), an inhibitor of glucose oxidation, was increased over fourfold. In IUGR fetal liver, but not skeletal muscle, mRNA expression of lactate dehydrogenase A (LDHA) was increased nearly fivefold. Hepatic expression of the gluconeogenic genes, phosphoenolpyruvate carboxykinase (PCK)1, and PCK2, was correlated with expression of PDK4 and LDHA. Collectively, these in vivo and tissue data support limited capacity for glucose oxidation in the IUGR fetus via increased PDK4 in skeletal muscle and liver. We speculate that lactate production also is increased, which may supply carbon for glucose production in the IUGR fetal liver. PMID:26224688

  8. Cauterization of meso-ovarian vessels, a new model of intrauterine growth restriction in rats.

    PubMed

    Camprubí, M; Ortega, A; Balaguer, A; Iglesias, I; Girabent, M; Callejo, J; Figueras, J; Krauel, X

    2009-09-01

    Intrauterine growth restriction (IUGR) remains an important cause of perinatal morbidity and mortality. Both IUGR and low birth weight have been identified as risk factors for increased incidence of cardiovascular disease, dyslipemia, and other diseases in the adulthood. Several animal models have been developed to study the underlying mechanisms of IUGR and its later consequences, with utero-placental ischemia by uterine artery ligation (UAL) being the most frequently used in rats. The relevance of this model lies in the fact that it induces altered placental perfusion, the main cause of IUGR in humans in Western countries. However, there is also controversy over the grade and homogeneity of IUGR obtained. In this study, we propose a new animal model of IUGR related to placental ischemia through the cauterization of meso-ovarian vessels. We aimed to test the feasibility of meso-ovarian vessel cauterization (CMO), and to compare it with uterine artery ligation (UAL). The CMO group had similar incidence of perinatal mortality, percentage of IUGR, and evolution of body weight during early extrauterine life to the UAL group, indicating that both methods are similarly efficient for inducing IUGR. Moreover, both of them affect the ratio of fetal to placental weight, and the weight of vital organs, supporting the hypothesis of a fetal compensatory response or "brain- and heart-sparing effect". Both operative models suffer approximately 50% perinatal mortality, implying that they are both more efficient in the production of IUGR when C-section is performed. On the other hand, CMO was significantly faster to perform than UAL and seemed to produce a more uniform ischemia throughout the uterus than the UAL method, resulting in a more homogeneous group of IUGR pups. PMID:19631378

  9. Lack of Thromboxane Synthase Prevents Hypertension and Fetal Growth Restriction after High Salt Treatment during Pregnancy.

    PubMed

    Pai, Chen-Hsueh; Yen, Ching-Tzu; Chen, Chie-Pein; Yu, I-Shing; Lin, Shu-Wha; Lin, Shu-Rung

    2016-01-01

    Preeclampsia (PE) is a potentially fatal pregnancy-related hypertensive disorder characterized by poor placenta development that can cause fetal growth restriction. PE-associated pathologies, including thrombosis, hypertension, and impaired placental development, may result from imbalances between thromboxane A2 (TXA2) and prostacyclin. Low-dose aspirin, which selectively inhibits TXA2 production, is used to prevent high-risk PE. However, the role of TXA2 in aspirin-mediated protective effects in women with PE is not understood fully. In this study, we examined the role of prostanoids in PE using human samples and an induced PE mouse model. We demonstrated that the administration of salted drinking water (2.7% NaCl) to wild-type mice resulted in elevated placental TXA2 synthase (TXAS) and plasma TXA2, but not prostacyclin, levels, which was also found in our clinical PE placenta samples. The high salt-treated wild-type pregnant mice had shown unchanged maternal body weight, hypertension (MAP increase 15 mmHg), and decreased pup weight (~50%) and size (~24%), but these adverse effects were ameliorated in TXAS knockout (KO) mice. Moreover, increased expression of interleukin-1β and downstream phosphorylated-p38-mitogen-activated protein kinase were concordant with apoptosis induction in the placentas of salt water-treated wild-type mice. These alterations were not observed in TXAS KO mice. Together, our data suggest that TXA2 depletion has anti-PE effects due to the prevention of hypertension and placental damage through downregulation of the interleukin-1β pathway. PMID:26974824

  10. Spiral artery remodeling and trophoblast invasion in preeclampsia and fetal growth restriction: relationship to clinical outcome.

    PubMed

    Lyall, Fiona; Robson, Stephen C; Bulmer, Judith N

    2013-12-01

    Failure to transform uteroplacental spiral arteries is thought to underpin disorders of pregnancy, including preeclampsia and fetal growth restriction (FGR). In this study, spiral artery remodeling and extravillous-cytotrophoblast were examined in placental bed biopsies from normal pregnancy (n = 25), preeclampsia (n = 22), and severe FGR (n = 10) and then compared with clinical parameters. Biopsies were immunostained to determine vessel wall integrity, extravillous-cytotrophoblast location/density, periarterial fibrinoid, and endothelium. Muscle disruption was reduced in myometrial spiral arteries in preeclampsia (P = 0.0001) and FGR (P = 0.0001) compared with controls. Myometrial vessels from cases with birth weight <5th percentile (P<0.001), abnormal uterine Doppler (P<0.01), abnormal umbilical artery Doppler (P<0.001), and preterm delivery (P<0.001) had less muscle destruction compared with >5th percentile. Fewer extravillous-cytotrophoblast surrounded both decidual and myometrial vessels in the normal group and preeclampsia group compared with the FGR group (P = 0.001). For myometrial vessels, the normal group contained more intramural extravillous-cytotrophoblast than in preeclampsia (P = 0.015). Decidual vessels in the FGR group had less fibrinoid deposition compared with controls (P = 0.013). For myometrial vessels, less fibrinoid was deposited in both the preeclampsia group (P = 0.0001) and the FGR group (P = 0.01) when compared with controls, and less fibrinoid was deposited in the preeclampsia group when compared with FGR group (P<0.001). Myometrial vessels obtained from birth weights <5th percentile had less periarterial fibrinoid than those with >5th percentile (P<0.02). A major defect in myometrial spiral artery remodeling occurs in preeclampsia and FGR that is linked to clinical parameters. Interstitial extravillous-cytotrophoblast is not reduced in preeclampsia but is increased in FGR. PMID:24060885

  11. Postnatal Anthropometric and Body Composition Profiles in Infants with Intrauterine Growth Restriction Identified by Prenatal Doppler

    PubMed Central

    Mazarico, E.; Martinez-Cumplido, R.; Díaz, M.; Sebastiani, G.; Ibáñez, L.; Gómez-Roig, M. D.

    2016-01-01

    Introduction Infant anthropometry and body composition have been previously assessed to gauge the impact of intrauterine growth restriction (IUGR) at birth, but the interplay between prenatal Doppler measurements and postnatal development has not been studied in this setting. The present investigation was performed to assess the significance of prenatal Doppler findings relative to postnatal anthropometrics and body composition in IUGR newborns over the first 12 months of life. Patients and Methods Consecutive cases of singleton pregnancies with suspected IUGR were prospectively enrolled over 12 months. Fetal biometry and prenatal Doppler ultrasound examinations were performed. Body composition was assessed by absorptiometry at ages 10 days, and at 4 and12 months. Results A total of 48 pregnancies qualifying as IUGR were studied. Doppler parameters were normal in 26 pregnancies. The remaining 22 deviated from normal, marked by an Umbilical Artery Pulsatility Index (UA-PI) >95th centil or Cerebro-placental ratio (CPR) <5th centile. No significant differences emerged when comparing anthropometry and body composition at each time point, in relation to Doppler findings. Specifically, those IUGR newborns with and without abnormal Doppler findings had similar weight, length, body mass index, lean and fat mass, and bone mineral content throughout the first 12 months of life. In a separate analysis, when comparing IUGR newborns by Doppler (abnormal UA-PI vs. abnormal CPR), anthropometry and body composition did not differ significantly. Conclusions Infants with IUGR maintain a pattern of body composition during the first year of life that is independent of prenatal Doppler findings. Future studies with larger sample sizes and correlating with hormonal status are warranted to further extend the phenotypic characterization of the various conditions now classified under the common label of IUGR. PMID:26938993

  12. Placental TonEBP/NFAT5 osmolyte regulation in an ovine model of intrauterine growth restriction.

    PubMed

    Arroyo, Juan A; Garcia-Jones, Pastora; Graham, Amanda; Teng, Cecilia C; Battaglia, Frederick C; Galan, Henry L

    2012-03-01

    TonEBP/NFAT5 (the tonicity-responsive enhancer binding protein/nuclear factor of activated T cells) modulates cellular response to osmotic changes by accumulating inositol and sorbitol inside the cells. Our objective was to assess placental osmolytes, TonEBP/NFAT5 RNA and protein expression, and signaling molecules across gestation between control and intrauterine growth restriction (IUGR) ovine pregnancies. Pregnant sheep were placed in hyperthermic conditions to induce IUGR. Placental tissues were collected at 55, 95, and 130 days gestational age (dGA) to measure inositol, sorbitol, TonEBP/NFAT5 (NFAT5), sodium-dependent myo-inositol transporter (SMIT; official symbol SLC5A3), aldose reductase (AR), and NADPH (official symbol DE-CR1). Placental weight was reduced in IUGR compared to controls at 95 and 130 dGA. Osmolyte concentrations were similar between control and IUGR placentas, but both groups demonstrated a significant decrease in inositol concentration and an increase in sorbitol concentration with advancing gestation. Cytosolic NFAT5 protein decreased significantly from 55 to 95 dGA in both groups, and nuclear NFAT5 protein increased only at 130 dGA in the IUGR group, but no differences were seen between groups for either cytosolic or nuclear NFAT5 protein concentrations. DE-CR1 concentrations were similar between groups and increased significantly with advancing gestational age. AR was lowest at 55dGA, and SLC5A3 increased with advancing gestational age. We conclude that both placental osmolytes inositol and sorbitol (and their corresponding proteins SLC5A3 and AR) change with gestational age and are regulated, at least in part, by NFAT5 and DE-CR1 (NADPH). The inverse relationship between each osmolyte across gestation (e.g., inositol higher in early gestation and sorbitol higher in late gestation) may reflect nutritional needs that change across gestation. PMID:22190709

  13. Sutural growth restriction and modern human facial evolution: an experimental study in a pig model

    PubMed Central

    Holton, Nathan E; Franciscus, Robert G; Nieves, Mary Ann; Marshall, Steven D; Reimer, Steven B; Southard, Thomas E; Keller, John C; Maddux, Scott D

    2010-01-01

    Facial size reduction and facial retraction are key features that distinguish modern humans from archaic Homo. In order to more fully understand the emergence of modern human craniofacial form, it is necessary to understand the underlying evolutionary basis for these defining characteristics. Although it is well established that the cranial base exerts considerable influence on the evolutionary and ontogenetic development of facial form, less emphasis has been placed on developmental factors intrinsic to the facial skeleton proper. The present analysis was designed to assess anteroposterior facial reduction in a pig model and to examine the potential role that this dynamic has played in the evolution of modern human facial form. Ten female sibship cohorts, each consisting of three individuals, were allocated to one of three groups. In the experimental group (n = 10), microplates were affixed bilaterally across the zygomaticomaxillary and frontonasomaxillary sutures at 2 months of age. The sham group (n = 10) received only screw implantation and the controls (n = 10) underwent no surgery. Following 4 months of post-surgical growth, we assessed variation in facial form using linear measurements and principal components analysis of Procrustes scaled landmarks. There were no differences between the control and sham groups; however, the experimental group exhibited a highly significant reduction in facial projection and overall size. These changes were associated with significant differences in the infraorbital region of the experimental group including the presence of an infraorbital depression and an inferiorly and coronally oriented infraorbital plane in contrast to a flat, superiorly and sagittally infraorbital plane in the control and sham groups. These altered configurations are markedly similar to important additional facial features that differentiate modern humans from archaic Homo, and suggest that facial length restriction via rigid plate fixation is a

  14. Long-term reorganization of structural brain networks in a rabbit model of intrauterine growth restriction.

    PubMed

    Batalle, Dafnis; Muñoz-Moreno, Emma; Arbat-Plana, Ariadna; Illa, Miriam; Figueras, Francesc; Eixarch, Elisenda; Gratacos, Eduard

    2014-10-15

    Characterization of brain changes produced by intrauterine growth restriction (IUGR) is among the main challenges of modern fetal medicine and pediatrics. This condition affects 5-10% of all pregnancies and is associated with a wide range of neurodevelopmental disorders. Better understanding of the brain reorganization produced by IUGR opens a window of opportunity to find potential imaging biomarkers in order to identify the infants with a high risk of having neurodevelopmental problems and apply therapies to improve their outcomes. Structural brain networks obtained from diffusion magnetic resonance imaging (MRI) is a promising tool to study brain reorganization and to be used as a biomarker of neurodevelopmental alterations. In the present study this technique is applied to a rabbit animal model of IUGR, which presents some advantages including a controlled environment and the possibility to obtain high quality MRI with long acquisition times. Using a Q-Ball diffusion model, and a previously published rabbit brain MRI atlas, structural brain networks of 15 IUGR and 14 control rabbits at 70 days of age (equivalent to pre-adolescence human age) were obtained. The analysis of graph theory features showed a decreased network infrastructure (degree and binary global efficiency) associated with IUGR condition and a set of generalized fractional anisotropy (GFA) weighted measures associated with abnormal neurobehavior. Interestingly, when assessing the brain network organization independently of network infrastructure by means of normalized networks, IUGR showed increased global and local efficiencies. We hypothesize that this effect could reflect a compensatory response to reduced infrastructure in IUGR. These results present new evidence on the long-term persistence of the brain reorganization produced by IUGR that could underlie behavioral and developmental alterations previously described. The described changes in network organization have the potential to be used

  15. Lack of Thromboxane Synthase Prevents Hypertension and Fetal Growth Restriction after High Salt Treatment during Pregnancy

    PubMed Central

    Pai, Chen-Hsueh; Yen, Ching-Tzu; Chen, Chie-Pein; Yu, I-Shing

    2016-01-01

    Preeclampsia (PE) is a potentially fatal pregnancy-related hypertensive disorder characterized by poor placenta development that can cause fetal growth restriction. PE-associated pathologies, including thrombosis, hypertension, and impaired placental development, may result from imbalances between thromboxane A2 (TXA2) and prostacyclin. Low-dose aspirin, which selectively inhibits TXA2 production, is used to prevent high-risk PE. However, the role of TXA2 in aspirin-mediated protective effects in women with PE is not understood fully. In this study, we examined the role of prostanoids in PE using human samples and an induced PE mouse model. We demonstrated that the administration of salted drinking water (2.7% NaCl) to wild-type mice resulted in elevated placental TXA2 synthase (TXAS) and plasma TXA2, but not prostacyclin, levels, which was also found in our clinical PE placenta samples. The high salt-treated wild-type pregnant mice had shown unchanged maternal body weight, hypertension (MAP increase 15 mmHg), and decreased pup weight (~50%) and size (~24%), but these adverse effects were ameliorated in TXAS knockout (KO) mice. Moreover, increased expression of interleukin-1β and downstream phosphorylated-p38-mitogen-activated protein kinase were concordant with apoptosis induction in the placentas of salt water-treated wild-type mice. These alterations were not observed in TXAS KO mice. Together, our data suggest that TXA2 depletion has anti-PE effects due to the prevention of hypertension and placental damage through downregulation of the interleukin-1β pathway. PMID:26974824

  16. Impaired alveolarization and intra-uterine growth restriction in rats: a postnatal genome-wide analysis.

    PubMed

    Zana-Taieb, E; Pham, H; Franco-Montoya, M L; Jacques, S; Letourneur, F; Baud, O; Jarreau, P H; Vaiman, D

    2015-02-01

    Intra-uterine growth restriction (IUGR) dramatically increases the risk of bronchopulmonary dysplasia in preterm babies, a disease characterized by arrested alveolarization and abnormal microvascular angiogenesis. We have previously described a rodent low protein diet (LPD) model of IUGR inducing impaired alveolarization, but failed to demonstrate any modification of the classical factors involved in lung development. We performed a genome-wide microarray analysis in 120 rat pups with LPD-induced IUGR and their controls, at three key time points of the alveolarization process: postnatal day 4 (P4): start of alveolarization; P10: peak of the alveolarization process and P21: end of the alveolarization process. Results were analysed using Arraymining, DAVID and KEGG software and validated by qRT-PCR and western blots. Considering a cut-off of 2:1 as significant, 67 transcripts at P4, 102 transcripts at P10 and 451 transcripts at P21 were up-regulated, and 89 transcripts at P4, 25 transcripts at P10 and 585 transcripts at P21 were down-regulated. Automatic functional classification identified three main modified pathways, 'cell adhesion molecules', 'cardiac muscle contraction' and 'peroxisome proliferator-activated receptor' (PPAR). Protein analysis confirmed involvement of the PPAR pathway, with an increase of FABP4, an activator of this pathway, at P4 and an increase of adiponectin at P21. Other data also suggest involvement of the PPAR pathway in impaired alveolarization. Our results show that deregulation of the PPAR pathway may be an important component of the mechanism inducing impaired alveolarization observed in IUGR. The complete dataset is available as GEO profiles on the Gene Expression Omnibus (GEO) database ( www.ncbi.nih.gov/geo/, GEO Accession No. GSE56956). PMID:25347958

  17. Oral oestrogen reverses ovariectomy-induced morning surge hypertension in growth-restricted mice.

    PubMed

    Haskell, Sarah E; Peotta, Veronica; Reinking, Benjamin E; Zhang, Catherine; Zhu, Vivian; Kenkel, Elizabeth J; Roghair, Robert D

    2016-04-01

    Perinatal growth restriction (GR) is associated with heightened sympathetic tone and hypertension. We have previously shown that naturally occurring neonatal GR programmes hypertension in male but not female mice. We therefore hypothesized that intact ovarian function or post-ovariectomy (OVX) oestrogen administration protects GR female mice from hypertension. Utilizing a non-interventional model that categorizes mice with weanling weights below the tenth percentile as GR, control and GR adult mice were studied at three distinct time points: baseline, post-OVX and post-OVX with oral oestrogen replacement. OVX elicited hypertension in GR mice that was significantly exacerbated by psychomotor arousal (systolic blood pressure at light to dark transition: control 122 ± 2; GR 119 ± 2; control-OVX 116 ± 3; GR-OVX 126 ± 3 mmHg). Oestrogen partially normalized the rising blood pressure surge seen in GR-OVX mice (23 ± 7% reduction). GR mice had left ventricular hypertrophy, and GR-OVX mice in particular had exaggerated bradycardic responses to sympathetic blockade. For GR mice, a baseline increase in baroreceptor reflex sensitivity and high frequency spectral power support a vagal compensatory mechanism, and that compensation was lost following OVX. For GR mice, the OVX-induced parasympathetic withdrawal was partially restored by oestrogen (40 ± 25% increase in high frequency spectral power, P<0.05). In conclusion, GR alters cardiac morphology and cardiovascular regulation. The haemodynamic consequences of GR are attenuated in ovarian-sufficient or oestrogen-replete females. Further investigations are needed to define the role of hormone replacement therapy targeted towards young women with oestrogen deficiency and additional cardiovascular risk factors, including perinatal GR, cardiac hypertrophy and morning surge hypertension. PMID:26795436

  18. Response of wheat restricted-tillering and vigorous growth traits to variables of climate change.

    PubMed

    Dias de Oliveira, Eduardo A; Siddique, Kadambot H M; Bramley, Helen; Stefanova, Katia; Palta, Jairo A

    2015-02-01

    The response of wheat to the variables of climate change includes elevated CO2, high temperature, and drought which vary according to the levels of each variable and genotype. Independently, elevated CO2, high temperature, and terminal drought affect wheat biomass and grain yield, but the interactive effects of these three variables are not well known. The aim of this study was to determine the effects of elevated CO2 when combined with high temperature and terminal drought on the high-yielding traits of restricted-tillering and vigorous growth. It was hypothesized that elevated CO2 alone, rather than combined with high temperature, ameliorates the effects of terminal drought on wheat biomass and grain yield. It was also hypothesized that wheat genotypes with more sink capacity (e.g. high-tillering capacity and leaf area) have more grain yield under combined elevated CO2, high temperature, and terminal drought. Two pairs of sister lines with contrasting tillering and vigorous growth were grown in poly-tunnels in a four-factor completely randomized split-plot design with elevated CO2 (700 µL L(-1)), high day time temperature (3 °C above ambient), and drought (induced from anthesis) in all combinations to test whether elevated CO2 ameliorates the effects of high temperature and terminal drought on biomass accumulation and grain yield. For biomass and grain yield, only main effects for climate change variables were significant. Elevated CO2 significantly increased grain yield by 24-35% in all four lines and terminal drought significantly reduced grain yield by 16-17% in all four lines, while high temperature (3 °C above the ambient) had no significant effect. A trade-off between yield components limited grain yield in lines with greater sink capacity (free-tillering lines). This response suggests that any positive response to predicted changes in climate will not overcome the limitations imposed by the trade-off in yield components. PMID:25330325

  19. Site-specific IGFBP-1 hyper-phosphorylation in fetal growth restriction: clinical and functional relevance.

    PubMed

    Abu Shehab, Majida; Khosravi, Javad; Han, Victor K M; Shilton, Brian H; Gupta, Madhulika B

    2010-04-01

    Phosphorylation enhances IGFBP-1 binding to IGF-I, thereby limiting the bioavailability of IGF-I that may be important in fetal growth. Our goal in this study was to determine whether changes in site-specific IGFBP-1 phosphorylation were unique to fetal growth restriction. To establish a link, we compared IGFBP-1 phosphorylation (sites and degree) in amniotic fluid from FGR (N = 10) and controls (N = 12). The concentration of serine phosphorylated IGFBP-1 showed a negative correlation with birth weight in FGR (P = 0.049). LC-MS/MS analysis revealed all four previously identified phosphorylation sites (Ser98, Ser101, Ser119, and Ser169) to be common to FGR and control groups. Relative phosphopeptide intensities (LC-MS) between FGR and controls demonstrated 4-fold higher intensity for Ser101 (P = 0.026), 7-fold for Ser98/Ser101 (P = 0.02), and 23-fold for Ser169 (P = 0.002) in the FGR group. Preliminary BIAcore data revealed 4-fold higher association and 1.7-fold lower dissociation constants for IGFBP-1/IGF-I in FGR. A structural model of IGFBP-1 bound to IGF-I indicates that all the phosphorylation sites are on relatively mobile regions of the IGFBP-1 sequence. Residues Ser98, Ser101, and Ser169 are close to structured regions that are involved in IGF-I binding and, therefore, could potentially make direct contact with IGF-I. On the other hand, residue Ser119 is in the middle of the unstructured linker that connects the N- and C-terminal domains of IGFBP-1. The model is consistent with the assumption that residues Ser98, Ser101, and Ser169 could directly interact with IGF-I, and therefore phosphorylation at these sites could change IGF-I interactions. We suggest that site-specific increase in IGFBP-1 phosphorylation limits IGF-I bioavailability, which directly contributes to the development of FGR. This study delineates the potential role of higher phosphorylation of IGFBP-1 in FGR and provides the basis to substantiate these findings with larger sample size. PMID

  20. Implication of phagosome-lysosome fusion in restriction of Mycobacterium avium growth in bone marrow macrophages from genetically resistant mice.

    PubMed Central

    de Chastellier, C; Fréhel, C; Offredo, C; Skamene, E

    1993-01-01

    The ability of the host to resist infection to a variety of intracellular pathogens, including mycobacteria, is strongly dependent upon the expression of the Bcg gene. Mouse strains which express the resistance phenotype (Bcgr) restrict bacterial growth, whereas susceptible strains (Bcgs) allow bacterial growth. Expression of the Bcg allele is known to influence the priming of host macrophages (M phi s) for bactericidal function. In the present work, bone marrow-derived M phi s from congenic BALB/c (Bcgs) and C.D2 (BALB/c.Bcgr) mice were infected with the virulent strain Mycobacterium avium TMC 724 to define the mechanism involved in growth restriction of M. avium. By combining CFU measurements and ultrastructural analyses, we show that growth of this bacterium is restricted in marrow M phi s from resistant mice. Using acid phosphatase as a lysosomal marker, we provide evidence that the hydrolytic activity of M phi s, as measured by the capacity of lysosomes to fuse with and transfer active hydrolytic enzymes to phagosomes in which M. avium resides, is an expression of the Bcg gene and that this phenomenon is a key antibacterial activity responsible for growth restriction of M. avium: (i) the percentage of phagosome-lysosome fusions was twice as high in Bcgr M phi s as in Bcgs M phi s, and (ii) the percentage of intact viable bacteria residing in acid phosphatase-negative phagosomes was twice as low in Bcgr M phi s as in the Bcgs counterparts. These differences are not due to a lower activity of the enzyme in Bcgr M phi s. The mechanism by which the Bcg gene exerts control over the phagolysosomal fusion is discussed. Images PMID:8359899

  1. Regional structural and biomechanical alterations of the ovine main pulmonary artery during postnatal growth.

    PubMed

    Fata, Bahar; Carruthers, Christopher A; Gibson, Gregory; Watkins, Simon C; Gottlieb, Danielle; Mayer, John E; Sacks, Michael S

    2013-02-01

    The engineering foundation for novel approaches for the repair of congenital defects that involve the main pulmonary artery (PA) must rest on an understanding of changes in the structure-function relationship that occur during postnatal maturation. In the present study, we quantified the postnatal growth patterns in structural and biomechanical behavior in the ovine PA in the juvenile and adult stages. The biaxial mechanical properties and collagen and elastin fiber architecture were studied in four regions of the PA wall, with the collagen recruitment of the medial region analyzed using a custom biaxial mechanical-multiphoton microscopy system. Circumferential residual strain was also quantified at the sinotubular junction and bifurcation locations, which delimit the PA. The PA wall demonstrated significant mechanical anisotropy, except in the posterior region where it was nearly isotropic. Overall, we observed only moderate changes in regional mechanical properties with growth. We did observe that the medial and lateral locations experience a moderate increase in anisotropy. There was an average of about 24% circumferential residual stain present at the luminal surface in the juvenile stage that decreased to 16% in the adult stage with a significant decrease at the bifurcation, implying that the PA wall remodels toward the bifurcation with growth. There were no measurable changes in collagen and elastin content of the tunica media with growth. On average, the collagen fiber recruited more rapidly with strain in the adult compared to the juvenile. Interestingly, the PA thickness remained constant with growth. When this fact is combined with the observed stable overall mechanical behavior and increase in vessel diameter with growth, a simple Laplace Law wall stress estimate suggests an increase in effective PA wall stress with postnatal maturation. This observation is contrary to the accepted theory of maintenance of homeostatic stress levels in the regulation of

  2. Fetal growth restriction and risk of chronic lung disease among infants born before the 28th week of gestation

    PubMed Central

    Bose, Carl; Van Marter, Linda J.; Laughon, Matthew; O'Shea, T. Michael; Allred, Elizabeth N.; Karna, Padmani; Ehrenkranz, Richard A.; Boggess, Kim; Leviton, Alan

    2009-01-01

    Objective Improvement in survival of extremely premature infants over the past several decades has resulted in an increase in the number infants with chronic lung disease (CLD). Historical neonatal exposures associated with CLD now less frequently precede the disease. There is now increasing interest in exposures and events before delivery that predict CLD. The objective of this study was to identify current antenatal predictors of CLD. Patients and Methods We collected data about antenatal, placental and neonatal characteristics of 1241 newborns delivered before completion of the 28th week of gestation who were enrolled in a 14-center, observational study conducted during the years 2002-2004. Associations between antenatal factors, microbiologic and histologic characteristics of the placenta, and selected neonatal characteristics and CLD risk were first evaluated in univariate analyses. Subsequent multivariate analyses investigated the contribution of antenatal factors, particularly fetal growth restriction (FGR), to CLD risk. Results Among the antenatal factors, birth weight Z-score, used as a marker of FGR, provided the most information about CLD risk. Indicators of placental inflammation and infection were not associated with increased risk of CLD. Within nearly all strata of antenatal, placental and neonatal variables, growth restricted infants were at increased CLD risk compared with infants who were not growth restricted. FGR was the only maternal or antenatal characteristic that was highly predictive of CLD after adjustment for other risk factors. Conclusions FGR is independently associated with the risk of CLD. Thus factors that control fetal somatic growth may have a significant impact on vulnerability to lung injury, and in this way increase CLD risk. Future investigations should focus on the impact of FGR on growth factors that modulate lung growth. PMID:19706590

  3. Antidepressant Use During Pregnancy and the Risk of Preterm Delivery and Fetal Growth Restriction

    PubMed Central

    Toh, Sengwee; Mitchell, Allen A.; Louik, Carol; Werler, Martha M.; Chambers, Christina D.; Hernández-Díaz, Sonia

    2011-01-01

    Objective The associations between prenatal exposure to antidepressants and preterm delivery and fetal growth restriction are controversial and poorly understood. We studied the relation between antidepressant use and these outcomes. Methods Analysis included women with nonmalformed infants interviewed in the Slone Epidemiology Center Birth Defects Study between 1998 and 2008. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) for premature and small-for–gestational age (SGA) offsprings, adjusting for sociodemographic, lifestyle, medical, and reproductive factors. Results The frequencies of preterm delivery were 7.3% among the 5710 nonusers (reference), 8.9% among the 192 selective serotonin reuptake inhibitor (SSRI) users (OR, 1.1; 95% CI, 0.6–2.0), and 15.3% among the 59 non-SSRI antidepressant users (OR, 2.2; 95% CI, 1.0–4.9); the respective frequencies of delivering an SGA offspring were 7.2%, 10.9% (OR, 1.7; 95% CI, 1.0–2.7), and 13.6% (OR, 2.2; 95% CI, 1.0–4.9). Compared with nonusers, the frequencies of preterm delivery (7.6%) and SGA offspring (5.7%) were not increased among the 106 women who discontinued SSRIs before the end of the first trimester. Among women who continued SSRIs beyond the first trimester, 10.5% delivered a preterm infant (OR, 1.3; 95% CI, 0.6–2.8) and 17.4% had an SGA offspring (OR, 3.0; 95% CI, 1.7–5.5). Conclusions Women treated with SSRIs late in pregnancy had a higher frequency of delivering SGA infants, and women receiving non-SSRI antidepressants were more likely to deliver premature and SGA offsprings. The findings suggest an effect of underlying mood disorder or an effect common to both drug classes. In any case, prenatal antidepressant use may help identify women at elevated risks of delivering preterm and SGA infants. PMID:19910720

  4. NFAT5 Is Up-Regulated by Hypoxia: Possible Implications in Preeclampsia and Intrauterine Growth Restriction.

    PubMed

    Dobierzewska, Aneta; Palominos, Macarena; Irarrazabal, Carlos E; Sanchez, Marianela; Lozano, Mauricio; Perez-Sepulveda, Alejandra; Monteiro, Lara J; Burmeister, Yara; Figueroa-Diesel, Horacio; Rice, Gregory E; Illanes, Sebastian E

    2015-07-01

    During gestation, low oxygen environment is a major determinant of early placentation process, while persistent placental hypoxia leads to pregnancy-related complications such as preeclampsia (PE) and intrauterine growth restriction (IUGR). PE affects 5%-8% of all pregnancies worldwide and is a cause of maternal and fetal morbidity and mortality. During placental development, persistent hypoxia due to poor trophoblast invasion and reduced uteroplacental perfusion leads to maternal endothelial dysfunction and clinical manifestation of PE. Here we hypothesized that nuclear factor of activated T cells-5 (NFAT5), a well-known osmosensitive renal factor and recently characterized hypoxia-inducible protein, is also activated in vivo in placentas of PE and IUGR complications as well as in the in vitro model of trophoblast hypoxia. In JAR cells, low oxygen tension (1% O2) induced NFAT5 mRNA and increased its nuclear abundance, peaking at 16 h. This increase did not occur in parallel with the earlier HIF1A induction. Real-time PCR and Western blot analysis confirmed up-regulation of NFAT5 mRNA and NFAT5 nuclear content in human preeclamptic placentas and in rabbit placentas of an experimentally induced IUGR model, as compared with the control groups. In vitro lambda protein phosphatase (lambda PPase) treatment revealed that increased abundance of NFAT5 protein in nuclei of either JAR cells (16 h of hypoxia) or PE and IUGR placentas is at least partially due to NFAT5 phosphorylation. NFAT5 downstream targets aldose reductase (AR) and sodium-myo-inositol cotransporter (SMIT; official symbol SLC5A3) were not significantly up-regulated either in JAR cells exposed to hypoxia or in placentas of PE- and IUGR-complicated pregnancies, suggesting that hypoxia-dependent activation of NFAT5 serves as a separate function to its tonicity-dependent stimulation. In conclusion, we propose that NFAT5 may serve as a novel marker of placental hypoxia and ischemia independently of HIF1A. PMID

  5. Antenatal taurine supplementation increases taurine content in intrauterine growth restricted fetal rat brain tissue.

    PubMed

    Li, Fang; Teng, Hui-Yun; Liu, Jing; Wang, Hua-Wei; Zeng, Li; Zhao, Li-Fang

    2014-09-01

    This study aimed to determine the influence of antenatal taurine supplementation on taurine content in the brains of fetal rats with intrauterine growth restriction (IUGR). Experiments were performed at the Central Laboratory of Bayi Children's Hospital Affiliated to Beijing Military General Hospital in China from January to June 2013. Fifteen pregnant rats were randomly divided into three groups: normal controls, an IUGR group and an IUGR + antenatal taurine supplement group (Taurine group) (n = 5). The IUGR model was induced using a low-protein diet throughout gestation. Rats in the taurine group were fed a diet supplemented with 300 mg/kg/day taurine for 12 days after conception until natural delivery. Two fetal rats were randomly selected in every litter, and taurine levels in the brains of rats were detected using high-performance liquid chromatography-mass spectrometry. Results showed that (1) the mean body weight of the fetal rats in the normal control, IUGR and IUGR + antenatal taurine supplement groups was 6.619 ± 0.4132, 4.509 ± 0.454, and 5.176 ± 0.436 g (F = 429.818, P < 0.01), respectively, and (2) that taurine levels in the brains of the fetal rats in the normal control, IUGR and taurine groups were (2.399 ± 0.134) × 10(5), (1.881 ± 0.166) × 10(5) and (2.170 ± 0.191) × 10(5) μg/g (F = 24.828, P < 0.01), respectively. Overall, our results indicated that taurine levels in IUGR fetal rat brains were lower than in the control animals, and that antenatal taurine supplementation could significantly increase taurine levels in the brains of fetal rats with IUGR. PMID:24676564

  6. The effect of hypoxia-induced intrauterine growth restriction on renal artery function.

    PubMed

    Verschuren, M T C; Morton, J S; Abdalvand, A; Mansour, Y; Rueda-Clausen, C F; Compston, C A; Luyckx, V; Davidge, S T

    2012-10-01

    The risk of developing cardiovascular diseases is known to begin before birth and the impact of the intrauterine environment on subsequent adult health is currently being investigated from many quarters. Following our studies demonstrating the impact of hypoxia in utero and consequent intrauterine growth restriction (IUGR) on the rat cardiovascular system, we hypothesized that changes extend throughout the vasculature and alter function of the renal artery. In addition, we hypothesized that hypoxia induces renal senescence as a potential mediator of altered vascular function. We demonstrated that IUGR females had decreased responses to the adrenergic agonist phenylephrine (PE; pEC50 6.50 ± 0.05 control v. 6.17 ± 0.09 IUGR, P < 0.05) and the endothelium-dependent vasodilator methylcholine (MCh; E max 89.8 ± 7.0% control v. 41.0 ± 6.5% IUGR, P < 0.001). In IUGR females, this was characterised by increased basal nitric oxide (NO) modulation of vasoconstriction (PE pEC50 6.17 ± 0.09 IUGR v. 6.42 ± 0.08 in the presence of the NO synthase inhibitor N-nitro-l-arginine methyl ester hydrochloride (l-NAME; P < 0.01) but decreased activated NO modulation (no change in MCh responses in the presence of l-NAME), respectively. In contrast, IUGR males had no changes in PE or MCh responses but demonstrated increased basal NO (PE pEC50 6.29 ± 0.06 IUGR v. 6.42 ± 0.12 plus l-NAME, P < 0.01) and activated NO (E max 37.8 ± 9.4% control v. -0.8 ± 13.0% plus l-NAME, P < 0.05) modulation. No significant changes were found in gross kidney morphology, proteinuria or markers of cellular senescence in either sex. In summary, renal vascular function was altered by hypoxia in utero in a sex-dependent manner but was unlikely to be mediated by premature renal senescence. PMID:25102262

  7. Intrauterine growth restricted piglets defined by their head shape ingest insufficient amounts of colostrum.

    PubMed

    Amdi, C; Krogh, U; Flummer, C; Oksbjerg, N; Hansen, C F; Theil, P K

    2013-12-01

    The increasing litter sizes of modern pig breeds have led to a significant number of piglets that are born undersized ("small" piglets) and some have been exposed to different degrees of intrauterine growth restriction (IUGR). The aim of this study was to investigate the physiology and capability to ingest colostrum of these small piglets, suffering from various degrees of IUGR, to see if their IUGR score could be a useful tool for easy identification of piglets in need of intervention in the colostrum period. Piglets were classified at birth based on head morphology. Piglets were classified either "normal," "mildly IUGR" (m-IUGR), or "severe IUGR" (s-IUGR), based on head morphology. Blood samples were collected at birth and at 24 h, and colostrum intake during two 12-h periods and blood metabolites at 0 and 24 h were measured. At 24 h, piglets weighing <900 g at birth and the median piglet in birth order were sacrificed, and organ weights and hepatic glycogen were measured. Overall, there was an influence of the piglets' classification on most characteristics, with normal piglets having a greater colostrum intake between 0 and 12 h (P < 0.001) and between 12 and 24 h (P < 0.05), and higher birth weight, crown rump length, body mass index, and ponderal index (P < 0.001), and a tendency toward a higher vitality score (P < 0.069) than s-IUGR piglets. There was a time × IUGR interaction, with plasma glucose levels being lowered (P < 0.001) and lactate levels elevated (P < 0.001) in s-IUGR piglets at 24 h compared with normal and m-IUGR piglets. Some differences were found in electrolytes; sodium plasma concentrations were greatest for normal piglets (P < 0.05) and highest at 0 h (P < 0.05). At 24 h of age, s-IUGR piglets had a higher heart (P < 0.001) and brain percentage (P < 0.001), and a lower liver percentage (P < 0.001) relative to body weight, compared with normal piglets. In addition, s-IUGR piglets had less hepatic glycogen than m-IUGR piglets and normal

  8. Prenatal diagnosis of a placental infarction hematoma associated with fetal growth restriction, preeclampsia and fetal death: clinicopathological correlation

    PubMed Central

    Aurioles-Garibay, Alma; Hernandez-Andrade, Edgar; Romero, Roberto; Qureshi, Faisal; Ahn, Hyunyoung; Jacques, Suzanne M.; Garcia, Maynor; Yeo, Lami; Hassan, Sonia S.

    2014-01-01

    The lesion termed “placental infarction hematoma” is associated with fetal death and adverse perinatal outcome. Such lesion has been associated with a high risk of fetal death and abruption placentae. The fetal and placental hemodynamic changes associated with placental infarction hematoma have not been reported. This communication describes a case of early and severe growth restriction with preeclampsia, and progressive deterioration of the fetal and placental Doppler parameters in the presence of a placental infarction hematoma. PMID:24852332

  9. Modulation of body fluids and angiotensin II receptors in a rat model of intra-uterine growth restriction

    PubMed Central

    Bédard, Sophie; Sicotte, Benoit; St-Louis, Jean; Brochu, Michèle

    2005-01-01

    We previously reported that sodium restriction during pregnancy reduces plasma volume expansion and promotes intra-uterine growth restriction (IUGR) in rats while it activates the renin–angiotensin–aldosterone system (RAAS). In the present study, we proceeded to determine whether expression of the two angiotensin II (ANGII) receptor subtypes (AT1 and AT2) change in relation to maternal water–electrolyte homeostasis and fetal growth. To this end, pregnant (gestation day 15) and non-pregnant Sprague-Dawley rats were randomly assigned to two groups fed either normal, or Na+-restricted diets for 7 days. At the end of the treatment period, plasma aldosterone and renin activity as well as plasma and urine electrolytes were measured. Determinations for AT1 and AT2 mRNA and protein were made by RNase protection assay and photoaffinity labelling, respectively, using a number of tissues implicated in volume regulation and fetal growth. In non-pregnant rats, Na+ restriction decreases Na+ excretion without altering plasma volume, plasma Na+ concentration or the expression of AT1 and AT2 mRNA or protein in the tissues examined. In normally fed pregnant rats when compared to non-pregnant controls, AT1 mRNA increases in the hypothalamus as well as pituitary and declines in uterine arteries, while AT1 protein decreases in the kidney and AT2 mRNA declines in the adrenal cortex. In pregnant rats, Na+ restriction induces a decrease in plasma Na+, an increase in plasma urea, as well as a decline in renal urea and creatinine clearance rates. Protein levels for both AT1 and AT2 in the pituitary and AT2 mRNA in the adrenal cortex are lower in the Na+-restricted pregnant group when compared to normally fed pregnant animals. Na+ restriction also induces a decrease in AT1 protein in the placenta. In conclusion, these results suggest that pregnancy may increase sensitivity to Na+ depletion by the tissue-specific modulation of ANGII receptors. Finally, these receptors may be implicated

  10. Agonist of growth hormone-releasing hormone reduces pneumolysin-induced pulmonary permeability edema

    PubMed Central

    Lucas, Rudolf; Sridhar, Supriya; Rick, Ferenc G.; Gorshkov, Boris; Umapathy, Nagavedi S.; Yang, Guang; Oseghale, Aluya; Verin, Alexander D.; Chakraborty, Trinad; Matthay, Michael A.; Zemskov, Evgeny A.; White, Richard; Block, Norman L.; Schally, Andrew V.

    2012-01-01

    Aggressive treatment with antibiotics in patients infected with Streptococcus pneumoniae induces release of the bacterial virulence factor pneumolysin (PLY). Days after lungs are sterile, this pore-forming toxin can still induce pulmonary permeability edema in patients, characterized by alveolar/capillary barrier dysfunction and impaired alveolar liquid clearance (ALC). ALC is mainly regulated through Na+ transport by the apically expressed epithelial sodium channel (ENaC) and the basolaterally expressed Na+/K+-ATPase in type II alveolar epithelial cells. Because no standard treatment is currently available to treat permeability edema, the search for novel therapeutic candidates is of high priority. We detected mRNA expression for the active receptor splice variant SV1 of the hypothalamic polypeptide growth hormone-releasing hormone (GHRH), as well as for GHRH itself, in human lung microvascular endothelial cells (HL-MVEC). Therefore, we have evaluated the effect of the GHRH agonist JI-34 on PLY-induced barrier and ALC dysfunction. JI-34 blunts PLY-mediated endothelial hyperpermeability in monolayers of HL-MVEC, in a cAMP-dependent manner, by means of reducing the phosphorylation of myosin light chain and vascular endothelial (VE)-cadherin. In human airway epithelial H441 cells, PLY significantly impairs Na+ uptake, but JI-34 restores it to basal levels by means of increasing cAMP levels. Intratracheal instillation of PLY into C57BL6 mice causes pulmonary alveolar epithelial and endothelial hyperpermeability as well as edema formation, all of which are blunted by JI-34. These findings point toward a protective role of the GHRH signaling pathway in PLY-induced permeability edema. PMID:22308467

  11. Cellular localization of transforming growth factor-beta expression in bleomycin-induced pulmonary fibrosis.

    PubMed Central

    Zhang, K.; Flanders, K. C.; Phan, S. H.

    1995-01-01

    Bleomycin-induced pulmonary fibrosis is associated with increased lung transforming growth factor-beta (TGF-beta) gene expression, but cellular localization of the source of this expression has not been unequivocally established. In this study, lung fibrosis was induced in rats by endotracheal bleomycin injection on day 0 and, on selected days afterwards, lungs were harvested for in situ hybridization, immunohistochemical and histochemical analyses for TGF-beta 1 mRNA and protein expression, and cell identification. The results show that control lungs express essentially no detectable TGF-beta 1 mRNA or protein in the parenchyma. Before day 3 after bleomycin treatment, scattered bronchiolar epithelial cells, mononuclear cells, and eosinophils expressed elevated levels of TGF-beta 1. Between days 3 and 14, there was a major increase in the number of eosinophils, myofibroblasts, and fibroblasts strongly expressing TGF-beta 1 mRNA and protein. TGF-beta 1-producing cells were predominantly localized within areas of injury and active fibrosis. After day 14, the intensity and number of TGF-beta 1-expressing cells significantly declined and were predominantly found in fibroblasts in fibrotic areas. The expression of TGF-beta 1 protein was generally coincident with that for mRNA with the exception of bronchiolar epithelial cells in which strong protein expression was unaccompanied by a commensurate increase in mRNA. The study demonstrates that myofibroblasts, fibroblasts, and eosinophils represent the major sources of increased lung TGF-beta 1 expression in this model of pulmonary fibrosis. Images Figure 2 Figure 3 Figure 4 PMID:7543734

  12. Pulmonary hypertension

    MedlinePlus

    Pulmonary arterial hypertension; Sporadic primary pulmonary hypertension; Familial primary pulmonary hypertension; Idiopathic pulmonary arterial hypertension; Primary pulmonary hypertension; PPH; Secondary pulmonary ...

  13. Trajectories of Body Dissatisfaction and Dietary Restriction in Early Adolescent Girls: A Latent Class Growth Analysis.

    PubMed

    Rodgers, Rachel F; McLean, Siân A; Marques, Mathew; Dunstan, Candice J; Paxton, Susan J

    2016-08-01

    Clarifying the trajectories of body image and eating concerns in adolescents is critical. We examined longitudinal patterns of development of body dissatisfaction and dietary restriction among early adolescent girls within a sociocultural framework. A sample of 259 school girls (M age = 12.76 years, SD = 0.44) reported on sociocultural influences, body dissatisfaction and dietary restriction at baseline, 8, and 14 months. A subsample provided height and weight. Analyses identified four trajectories of body dissatisfaction: low, moderate-increasing, moderate-decreasing, and high. Three trajectories of dietary restriction emerged: low, moderate, and high. Baseline and 8-month sociocultural variables and BMI differed between the trajectories. A subgroup of girls displays high levels of body image and eating concerns by early adolescence. Sociocultural variables influence these trajectories. PMID:26386562

  14. Alterations in muscle metabolism and growth during nutritional restrictions and refeeding in rainbow trout.

    Technology Transfer Automated Retrieval System (TEKTRAN)

    Rainbow trout, as well as many other species of fish, demonstrate the ability to survive starvation for long periods of time. During starvation, growth rate is decreased and muscle exhibits signs of wasting. However, upon resumption of feeding, accelerated growth (also known as compensatory growth) ...

  15. Role for the thromboxane A2 receptor β-isoform in the pathogenesis of intrauterine growth restriction

    PubMed Central

    Powell, Katie L.; Stevens, Veronica; Upton, Dannielle H.; McCracken, Sharon A.; Simpson, Ann M.; Cheng, Yan; Tasevski, Vitomir; Morris, Jonathan M.; Ashton, Anthony W.

    2016-01-01

    Intrauterine growth restriction (IUGR) is a pathology of pregnancy that results in failure of the fetus to reach its genetically determined growth potential. In developed nations the most common cause of IUGR is impaired placentation resulting from poor trophoblast function, which reduces blood flow to the fetoplacental unit, promotes hypoxia and enhances production of bioactive lipids (TXA2 and isoprostanes) which act through the thromboxane receptor (TP). TP activation has been implicated as a pathogenic factor in pregnancy complications, including IUGR; however, the role of TP isoforms during pregnancy is poorly defined. We have determined that expression of the human-specific isoform of TP (TPβ) is increased in placentae from IUGR pregnancies, compared to healthy pregnancies. Overexpression of TPα enhanced trophoblast proliferation and syncytialisation. Conversely, TPβ attenuated these functions and inhibited migration. Expression of the TPβ transgene in mice resulted in growth restricted pups and placentae with poor syncytialisation and diminished growth characteristics. Together our data indicate that expression of TPα mediates normal placentation; however, TPβ impairs placentation, and promotes the development of IUGR, and represents an underappreciated pathogenic factor in humans. PMID:27363493

  16. Metabolic alterations due to caloric restriction and every other day feeding in normal and growth hormone receptor knockout mice.

    PubMed

    Westbrook, Reyhan; Bonkowski, Michael S; Arum, Oge; Strader, April D; Bartke, Andrzej

    2014-01-01

    Mutations causing decreased somatotrophic signaling are known to increase insulin sensitivity and extend life span in mammals. Caloric restriction and every other day (EOD) dietary regimens are associated with similar improvements to insulin signaling and longevity in normal mice; however, these interventions fail to increase insulin sensitivity or life span in growth hormone receptor knockout (GHRKO) mice. To investigate the interactions of the GHRKO mutation with caloric restriction and EOD dietary interventions, we measured changes in the metabolic parameters oxygen consumption (VO2) and respiratory quotient produced by either long-term caloric restriction or EOD in male GHRKO and normal mice. GHRKO mice had increased VO2, which was unaltered by diet. In normal mice, EOD diet caused a significant reduction in VO2 compared with ad libitum (AL) mice during fed and fasted conditions. In normal mice, caloric restriction increased both the range of VO2 and the difference in minimum VO2 between fed and fasted states, whereas EOD diet caused a relatively static VO2 pattern under fed and fasted states. No diet significantly altered the range of VO2 of GHRKO mice under fed conditions. This provides further evidence that longevity-conferring diets cause major metabolic changes in normal mice, but not in GHRKO mice. PMID:23833202

  17. Using coagulation to restrict microbial re-growth in tap water by phosphate limitation in water treatment.

    PubMed

    Wen, Gang; Ma, Jun; Huang, Ting-Lin; Egli, Thomas

    2014-09-15

    Extensive microbial re-growth in a drinking water distribution system can deteriorate water quality. The limiting factor for microbial re-growth in a tap water produced by a conventional drinking water treatment plant in China was identified by determining the microbial re-growth potential (MRP) by adding different nutrients to stimulate growth of a natural microbial consortium as inoculum and flow-cytometric enumeration. No obvious change of MRP was found in tap water after addition of carbon, whereas, a 1- to 2-fold increase of MRP was observed after addition of phosphate (P). This clearly demonstrated that microbial re-growth in this tap water was limited by P. Most of the re-grown microbial flora (>85%) consisted of high nucleic acid content cells. A subsequent investigation of the MRP in the actual water treatment plant demonstrated that coagulation was the crucial step for decreasing MRP and producing P-limited water. Therefore, a comparison concerning the control of MRP by three different coagulants was conducted. It showed that all the three coagulants efficiently reduced the MRP and shifted the limitation regime from C to P, but the required dose was different. The study shows that it is feasible to restrict microbial re-growth by P limitation using coagulation in water treatment. PMID:25179107

  18. Maternal Nutrient Restriction During Late Gestation and Early Postnatal Growth in Sheep Differentially Reset the Control of Energy Metabolism in the Gastric Mucosa

    PubMed Central

    Sebert, S. P.; Dellschaft, N. S.; Chan, L. L. Y.; Street, H.; Henry, M.; Francois, C.; Sharma, V.; Fainberg, H. P.; Patel, N.; Roda, J.; Keisler, D.; Budge, H.

    2011-01-01

    Fetal growth restriction followed by accelerated postnatal growth contributes to impaired metabolic function in adulthood. The extent to which these outcomes may be mediated centrally within the hypothalamus, as opposed to in the periphery within the digestive tract, remains unknown. In a sheep model, we achieved intrauterine growth restriction experimentally by maternal nutrient restriction (R) that involved a 40% reduction in food intake through late gestation. R offspring were then either reared singly to accelerate postnatal growth (RA) or as twins and compared with controls also reared singly. From weaning, all offspring were maintained indoors until adulthood. A reduced litter size accelerated postnatal growth for only the first month of lactation. Independently from postnatal weight gain and later fat mass, R animals developed insulin resistance as adults. However, restricted accelerated offspring compared with both the control accelerated and restricted restricted offspring ate less and had higher fasting plasma leptin as adults, an adaptation which was accompanied by changes in energy sensing and cell proliferation within the abomasum. Additionally, although fetal restriction down-regulated gene expression of mammalian target of rapamycin and carnitine palmitoyltransferase 1-dependent pathways in the abomasum, RA offspring compensated for this by exhibiting greater activity of AMP-activated kinase-dependent pathways. This study demonstrates a role for perinatal nutrition in the peripheral control of food intake and in energy sensing in the gastric mucosal and emphasizes the importance of diet in early life in regulating energy metabolism during adulthood. PMID:21558318

  19. Moderate postnatal hyperoxia accelerates lung growth and attenuates pulmonary hypertension in infant rats after exposure to intra-amniotic endotoxin.

    PubMed

    Tang, Jen-Ruey; Seedorf, Gregory J; Muehlethaler, Vincent; Walker, Deandra L; Markham, Neil E; Balasubramaniam, Vivek; Abman, Steven H

    2010-12-01

    To determine the separate and interactive effects of fetal inflammation and neonatal hyperoxia on the developing lung, we hypothesized that: 1) antenatal endotoxin (ETX) causes sustained abnormalities of infant lung structure; and 2) postnatal hyperoxia augments the adverse effects of antenatal ETX on infant lung growth. Escherichia coli ETX or saline (SA) was injected into amniotic sacs in pregnant Sprague-Dawley rats at 20 days of gestation. Pups were delivered 2 days later and raised in room air (RA) or moderate hyperoxia (O₂, 80% O₂ at Denver's altitude, ∼65% O₂ at sea level) from birth through 14 days of age. Heart and lung tissues were harvested for measurements. Intra-amniotic ETX caused right ventricular hypertrophy (RVH) and decreased lung vascular endothelial growth factor (VEGF) and VEGF receptor-2 (VEGFR-2) protein contents at birth. In ETX-exposed rats (ETX-RA), alveolarization and vessel density were decreased, pulmonary vascular wall thickness percentage was increased, and RVH was persistent throughout the study period compared with controls (SA-RA). After antenatal ETX, moderate hyperoxia increased lung VEGF and VEGFR-2 protein contents in ETX-O₂ rats and improved their alveolar and vascular structure and RVH compared with ETX-RA rats. In contrast, severe hyperoxia (≥95% O₂ at Denver's altitude) further reduced lung vessel density after intra-amniotic ETX exposure. We conclude that intra-amniotic ETX induces fetal pulmonary hypertension and causes persistent abnormalities of lung structure with sustained pulmonary hypertension in infant rats. Moreover, moderate postnatal hyperoxia after antenatal ETX restores lung growth and prevents pulmonary hypertension during infancy. PMID:20709730

  20. Role of the Placental Vitamin D Receptor in Modulating Feto-Placental Growth in Fetal Growth Restriction and Preeclampsia-Affected Pregnancies

    PubMed Central

    Murthi, Padma; Yong, Hannah E. J.; Ngyuen, Thy P. H.; Ellery, Stacey; Singh, Harmeet; Rahman, Rahana; Dickinson, Hayley; Walker, David W.; Davies-Tuck, Miranda; Wallace, Euan M.; Ebeling, Peter R.

    2016-01-01

    Fetal growth restriction (FGR) is a common pregnancy complication that affects up to 5% of pregnancies worldwide. Recent studies demonstrate that Vitamin D deficiency is implicated in reduced fetal growth, which may be rescued by supplementation of Vitamin D. Despite this, the pathway(s) by which Vitamin D modulate fetal growth remains to be investigated. Our own studies demonstrate that the Vitamin D receptor (VDR) is significantly decreased in placentae from human pregnancies complicated by FGR and contributes to abnormal placental trophoblast apoptosis and differentiation and regulation of cell-cycle genes in vitro. Thus, Vitamin D signaling is important for normal placental function and fetal growth. This review discusses the association of Vitamin D with fetal growth, the function of Vitamin D and its receptor in pregnancy, as well as the functional significance of a placental source of Vitamin D in FGR. Additionally, we propose that for Vitamin D to be clinically effective to prevent and manage FGR, the molecular mechanisms of Vitamin D and its receptor in modulating fetal growth requires further investigation. PMID:26924988

  1. Role of the Placental Vitamin D Receptor in Modulating Feto-Placental Growth in Fetal Growth Restriction and Preeclampsia-Affected Pregnancies.

    PubMed

    Murthi, Padma; Yong, Hannah E J; Ngyuen, Thy P H; Ellery, Stacey; Singh, Harmeet; Rahman, Rahana; Dickinson, Hayley; Walker, David W; Davies-Tuck, Miranda; Wallace, Euan M; Ebeling, Peter R

    2016-01-01

    Fetal growth restriction (FGR) is a common pregnancy complication that affects up to 5% of pregnancies worldwide. Recent studies demonstrate that Vitamin D deficiency is implicated in reduced fetal growth, which may be rescued by supplementation of Vitamin D. Despite this, the pathway(s) by which Vitamin D modulate fetal growth remains to be investigated. Our own studies demonstrate that the Vitamin D receptor (VDR) is significantly decreased in placentae from human pregnancies complicated by FGR and contributes to abnormal placental trophoblast apoptosis and differentiation and regulation of cell-cycle genes in vitro. Thus, Vitamin D signaling is important for normal placental function and fetal growth. This review discusses the association of Vitamin D with fetal growth, the function of Vitamin D and its receptor in pregnancy, as well as the functional significance of a placental source of Vitamin D in FGR. Additionally, we propose that for Vitamin D to be clinically effective to prevent and manage FGR, the molecular mechanisms of Vitamin D and its receptor in modulating fetal growth requires further investigation. PMID:26924988

  2. Salinity Stiffens the Epidermal Cell Walls of Salt-Stressed Maize Leaves: Is the Epidermis Growth-Restricting?

    PubMed Central

    Zörb, Christian; Mühling, Karl H.; Kutschera, Ulrich; Geilfus, Christoph-Martin

    2015-01-01

    As a result of salt (NaCl)-stress, sensitive varieties of maize (Zea mays L.) respond with a strong inhibition of organ growth. The reduction of leaf elongation investigated here has several causes, including a modification of the mechanical properties of the cell wall. Among the various tissues that form the leaf, the epidermis plays a special role in controlling organ growth, because it is thought to form a rigid outer leaf coat that can restrict elongation by interacting with the inner cell layers. This study was designed to determine whether growth-related changes in the leaf epidermis and its cell wall correspond to the overall reduction in cell expansion of maize leaves during an osmotic stress-phase induced by salt treatment. Two different maize varieties contrasting in their degree of salt resistance (i.e., the hybrids Lector vs. SR03) were compared in order to identify physiological features contributing to resistance towards salinity. Wall loosening-related parameters, such as the capacity of the epidermal cell wall to expand, β-expansin abundance and apoplastic pH values, were analysed. Our data demonstrate that, in the salt-tolerant maize hybrid which maintained leaf growth under salinity, the epidermal cell wall was more extensible under salt stress. This was associated with a shift of the epidermal apoplastic pH into a range more favourable for acid growth. The more sensitive hybrid that displayed a pronounced leaf growth-reduction was shown to have stiffer epidermal cell walls under stress. This may be attributable to the reduced abundance of cell wall-loosening β-expansin proteins following a high salinity-treatment in the nutrient solution (100 mM NaCl, 8 days). This study clearly documents that salt stress impairs epidermal wall-loosening in growth-reduced maize leaves. PMID:25760715

  3. Clustering and classical analysis of clinical and placental phenotypes in fetal growth restriction and constitutional fetal smallness.

    PubMed

    Stanek, Jerzy; Biesiada, Jacek

    2016-06-01

    This study aims to determine whether placental examination can be used to distinguish between pathologic fetal growth restriction (FGR) and constitutional fetal smallness. Data were extracted from a clinicoplacental database of high risk pregnancies during the period 1994-2013. These data were used to compare the 590 consecutive cases having birth weights below the 10th percentile with the 5201 remaining cases having gestational ages ≥20 weeks. The authors analyzed 20 clinical and 46 placental phenotypes using classical statistics, clustering analysis, and multidimensional scaling. Of the low-birth-weight babies, the following types of cases were compared: Four categories of placental phenotypes (those with features of poor uteroplacental perfusion, postuterine placental pathology, chronic inflammation, and a mixed category) better defined the presumably true FGR than did the clinical phenotypes. Maternal smoking and oligohydramnios were associated with fewer abnormal placental phenotypes than were maternal hypertensive diseases and abnormal Dopplers. Early-onset cases of fetal smallness clustered with placental features of poor uteroplacental perfusion, whereas late onset cases did not. Placental examination helps to retrospectively distinguish constitutionally small fetuses from those that are pathologically growth restricted. The latter correlate best with the clinical risk for FGR and with early-onset FGR. This correlation may have prognostic significance for the child and for future pregnancies, since hypoxic placental lesions can occur without clinical risk factors but with a tendency to recur in future pregnancies. PMID:27238719

  4. The promoter methylomes of monochorionic twin placentas reveal intrauterine growth restriction-specific variations in the methylation patterns

    PubMed Central

    He, Zhiming; Lu, Hanlin; Luo, Huijuan; Gao, Fei; Wang, Tong; Gao, Yu; Fang, Qun; Wang, Junwen

    2016-01-01

    Intrauterine growth restriction (IUGR) affects the foetus and has a number of pathological consequences throughout life. Recent work has indicated that variations in DNA methylation might cause placental dysfunction, which may be associated with adverse pregnancy complications. Here, we investigated the promoter methylomes of placental shares from seven monochorionic (MC) twins with selective intrauterine growth restriction (sIUGR) using the healthy twin as an ideal control. Our work demonstrated that the IUGR placental shares harboured a distinct DNA hypomethylation pattern and that the methylation variations preferentially occurred in CpG island shores or non-CpG island promoters. The differentially methylated promoters could significantly separate the IUGR placental shares from the healthy ones. Ultra‐performance liquid chromatography/tandem mass spectrometry (UPLC‐MS/MS) further confirmed the genome‐wide DNA hypomethylation and the lower level of hydroxymethylation statuses in the IUGR placental shares. The methylation variations of the LRAT and SLC19A1 promoters, which are involved in vitamin A metabolism and folate transportation, respectively, and the EFS promoter were further validated in an additional 12 pairs of MC twins with sIUGR. Although the expressions of LRAT, SLC19A1 and EFS were not affected, we still speculated that DNA methylation and hydroxymethylation might serve a functional role during in utero foetal development. PMID:26830322

  5. The promoter methylomes of monochorionic twin placentas reveal intrauterine growth restriction-specific variations in the methylation patterns.

    PubMed

    He, Zhiming; Lu, Hanlin; Luo, Huijuan; Gao, Fei; Wang, Tong; Gao, Yu; Fang, Qun; Wang, Junwen

    2016-01-01

    Intrauterine growth restriction (IUGR) affects the foetus and has a number of pathological consequences throughout life. Recent work has indicated that variations in DNA methylation might cause placental dysfunction, which may be associated with adverse pregnancy complications. Here, we investigated the promoter methylomes of placental shares from seven monochorionic (MC) twins with selective intrauterine growth restriction (sIUGR) using the healthy twin as an ideal control. Our work demonstrated that the IUGR placental shares harboured a distinct DNA hypomethylation pattern and that the methylation variations preferentially occurred in CpG island shores or non-CpG island promoters. The differentially methylated promoters could significantly separate the IUGR placental shares from the healthy ones. Ultra-performance liquid chromatography/tandem mass spectrometry (UPLC-MS/MS) further confirmed the genome-wide DNA hypomethylation and the lower level of hydroxymethylation statuses in the IUGR placental shares. The methylation variations of the LRAT and SLC19A1 promoters, which are involved in vitamin A metabolism and folate transportation, respectively, and the EFS promoter were further validated in an additional 12 pairs of MC twins with sIUGR. Although the expressions of LRAT, SLC19A1 and EFS were not affected, we still speculated that DNA methylation and hydroxymethylation might serve a functional role during in utero foetal development. PMID:26830322

  6. Aortic Intima-Media Thickness and Aortic Diameter in Small for Gestational Age and Growth Restricted Fetuses

    PubMed Central

    Gomez-Roig, M. Dolores; Mazarico, Edurne; Valladares, Esther; Guirado, Laura; Fernandez-Arias, Mireia; Vela, Antonio

    2015-01-01

    Objective The objective of this study is to measure aortic intima-media thickness (aIMT) and aortic diameter (AD) in appropriate for gestational age (AGA) fetuses, small for gestational age (SGA) fetuses, and intrauterine growth restricted (IUGR) fetuses. Methods Case-control study performed between June 2011 and June 2012. Forty-nine AGA fetuses, 40 SGA fetuses, and 35 IUGR fetuses underwent concomitant measurement of aIMT and AD at a mean gestational age of 34.4 weeks. Results Median aIMT was higher in fetuses with IUGR (0.504 mm [95%CI: 0.477-0.530 mm]), than in SGA fetuses (0.466 mm [95% CI: 0.447–0.485 mm]), and AGA fetuses (0.471 mm [95% CI: 0.454-0.488 mm]) (p = 0.023). Mean AD was significantly lower in fetuses with IUGR (4.451 mm [95% CI: 4.258–4.655 mm]), than in AGA fetuses (4.74 mm [95% CI: 4.63-4.843 mm]) (p = 0.028). Conclusions Growth restricted fetuses have a thicker aortic wall than AGA and SGA fetuses, which possibly represents preclinical atherosclerosis and a predisposition to later cardiovascular disease. PMID:26017141

  7. The impact of a human IGF-II analog ([Leu27]IGF-II) on fetal growth in a mouse model of fetal growth restriction.

    PubMed

    Charnock, Jayne C; Dilworth, Mark R; Aplin, John D; Sibley, Colin P; Westwood, Melissa; Crocker, Ian P

    2016-01-01

    Enhancing placental insulin-like growth factor (IGF) availability appears to be an attractive strategy for improving outcomes in fetal growth restriction (FGR). Our approach was the novel use of [Leu(27)]IGF-II, a human IGF-II analog that binds the IGF-II clearance receptor IGF-IIR in fetal growth-restricted (FGR) mice. We hypothesized that the impact of [Leu(27)]IGF-II infusion in C57BL/6J (wild-type) and endothelial nitric oxide synthase knockout (eNOS(-/-); FGR) mice would be to enhance fetal growth and investigated this from mid- to late gestation; 1 mg·kg(-1)·day(-1) [Leu(27)]IGF-II was delivered via a subcutaneous miniosmotic pump from E12.5 to E18.5. Fetal and placental weights recorded at E18.5 were used to generate frequency distribution curves; fetuses <5th centile were deemed growth restricted. Placentas were harvested for immunohistochemical analysis of the IGF system, and maternal serum was collected for measurement of exogenously administered IGF-II. In WT pregnancies, [Leu(27)]IGF-II treatment halved the number of FGR fetuses, reduced fetal(P = 0.028) and placental weight variations (P = 0.0032), and increased the numbers of pups close to the mean fetal weight (131 vs. 112 pups within 1 SD). Mixed-model analysis confirmed litter size to be negatively correlated with fetal and placental weight and showed that [Leu(27)]IGF-II preferentially improved fetal weight in the largest litters, as defined by number. Unidirectional (14C)MeAIB transfer per gram placenta (System A amino acid transporter activity) was inversely correlated with fetal weight in [Leu(27)]IGF-II-treated WT animals (P < 0.01). In eNOS(-/-) mice, [Leu(27)]IGF-II reduced the number of FGR fetuses(1 vs. 5 in the untreated group). The observed reduction in FGR pup numbers in both C57 and eNOS(-/-) litters suggests the use of this analog as a means of standardizing and rescuing fetal growth, preferentially in the smallest offspring. PMID:26530156

  8. The impact of a human IGF-II analog ([Leu27]IGF-II) on fetal growth in a mouse model of fetal growth restriction

    PubMed Central

    Charnock, Jayne C.; Dilworth, Mark R.; Aplin, John D.; Sibley, Colin P.; Westwood, Melissa

    2015-01-01

    Enhancing placental insulin-like growth factor (IGF) availability appears to be an attractive strategy for improving outcomes in fetal growth restriction (FGR). Our approach was the novel use of [Leu27]IGF-II, a human IGF-II analog that binds the IGF-II clearance receptor IGF-IIR in fetal growth-restricted (FGR) mice. We hypothesized that the impact of [Leu27]IGF-II infusion in C57BL/6J (wild-type) and endothelial nitric oxide synthase knockout (eNOS−/−; FGR) mice would be to enhance fetal growth and investigated this from mid- to late gestation; 1 mg·kg−1·day−1 [Leu27]IGF-II was delivered via a subcutaneous miniosmotic pump from E12.5 to E18.5. Fetal and placental weights recorded at E18.5 were used to generate frequency distribution curves; fetuses <5th centile were deemed growth restricted. Placentas were harvested for immunohistochemical analysis of the IGF system, and maternal serum was collected for measurement of exogenously administered IGF-II. In WT pregnancies, [Leu27]IGF-II treatment halved the number of FGR fetuses, reduced fetal(P = 0.028) and placental weight variations (P = 0.0032), and increased the numbers of pups close to the mean fetal weight (131 vs. 112 pups within 1 SD). Mixed-model analysis confirmed litter size to be negatively correlated with fetal and placental weight and showed that [Leu27]IGF-II preferentially improved fetal weight in the largest litters, as defined by number. Unidirectional 14CMeAIB transfer per gram placenta (System A amino acid transporter activity) was inversely correlated with fetal weight in [Leu27]IGF-II-treated WT animals (P < 0.01). In eNOS−/− mice, [Leu27]IGF-II reduced the number of FGR fetuses(1 vs. 5 in the untreated group). The observed reduction in FGR pup numbers in both C57 and eNOS−/− litters suggests the use of this analog as a means of standardizing and rescuing fetal growth, preferentially in the smallest offspring. PMID:26530156

  9. The Effect of a Retinoic Acid Derivative on Cell-Growth Inhibition in a Pulmonary Carcinoma Cell Line.

    PubMed

    Akita, Tomomi; Horiguchi, Michiko; Ozawa, Chihiro; Terada, Hiroshi; Yamashita, Chikamasa

    2016-01-01

    Pulmonary carcinoma is a major cause of cancer-related death worldwide. Because the prognosis remains poor, the development of novel therapeutic approaches is highly desirable. In this study, we investigated the effect of Tamibarotene (Am80), a retinoic acid derivative, on the growth of human lung adenocarcinoma cell line A549. Our ultimate goal in this study is to provide pulmonary carcinoma therapy with a new approach. First, we treated A549 cells with Am80 to clarify the effect of cell-growth inhibition. Am80 significantly reduced the viability of A549 cells in a dose- and time-dependent manner. The IC50 value, which was determined using CellTiter-Glo Luminescent Cell Viability assay, of Am80 and all-trans retinoic acid (ATRA) against A549 cells at 6 d was 49.1±8.1 µM and 92.3±8.0 µM, respectively. Furthermore, Am80 reduced the anchorage-independent cell-growth ability of A549 cells. However, it was not an apoptosis-mediated mechanism. These results suggest that Am80 can be used as an effective, novel cell-growth inhibitor in lung adenocarcinoma. PMID:26934924

  10. The synergistic therapeutic effect of hepatocyte growth factor and granulocyte colony-stimulating factor on pulmonary hypertension in rats.

    PubMed

    Guo, Yinghua; Su, Longxiang; Li, Yinghui; Guo, Na; Xie, Lixin; Zhang, Dong; Zhang, Xiaojun; Li, Hongxia; Zhang, Guizhi; Wang, Yajuan; Liu, Changting

    2014-07-01

    Pulmonary arterial hypertension (PAH) is characterized by a progressive increase in pulmonary arterial pressure and vascular resistance. Despite advances in therapy for PAH, its treatment and prognosis remain poor. We aimed to investigate whether the transplantation of bone marrow mesenchymal stem cells (MSCs) overexpressing hepatocyte growth factor (HGF), alone or in combination with granulocyte colony-stimulating factor (G-CSF), attenuates the development of experimental monocrotaline (MCT)-induced PAH. Three weeks after MCT administration, rats were divided into the following groups: (1) untreated (PAH); (2) HGF treated; (3) MSCs administered; (4) HGF-MSCs treated; and (5) HGF-MSCs plus G-CSF treated. After 3 weeks, hemodynamic changes, histomorphology, and angiogenesis were evaluated. To elucidate the molecular mechanisms of vascular remodeling and angiogenesis, serum levels of transforming growth factor (TGF)-β and endothelin-1 (ET-1) were measured, and the gene and protein expression levels of vascular cell adhesion molecule-1 (VCAM-1) and matrix metalloproteinase-9 (MMP-9) were determined. Compared with the PAH, MSC, and G-CSF groups, the HGF and HGF+G-CSF groups exhibited significantly reduced right ventricular hypertrophy and mean pulmonary arterial pressure (P < 0.05). Histologically, vessel muscularization or thickening and collagen deposition were also significantly decreased (P < 0.05). The number of vessels in the HGF+G-CSF group was higher than that in the other groups (P < 0.05). The TGF-β and ET-1 concentrations in the plasma of pulmonary hypertensive rats were markedly lower in the HGF and HGF+G-CSF groups (P < 0.05). Furthermore, HGF induced the expression of VCAM-1, and HGF treatment together with G-CSF synergistically stimulated MMP-9 expression. Transplanted HGF-MSCs combined with G-CSF potentially offer synergistic therapeutic benefit for the treatment of PAH. PMID:23933910

  11. Auxin-mediated lamina growth in tomato leaves is restricted by two parallel mechanisms.

    PubMed

    Ben-Gera, Hadas; Dafna, Asaf; Alvarez, John Paul; Bar, Maya; Mauerer, Mareike; Ori, Naomi

    2016-06-01

    In the development of tomato compound leaves, local auxin maxima points, separated by the expression of the Aux/IAA protein SlIAA9/ENTIRE (E), direct the formation of discrete leaflets along the leaf margin. The local auxin maxima promote leaflet initiation, while E acts between leaflets to inhibit auxin response and lamina growth, enabling leaflet separation. Here, we show that a group of auxin response factors (ARFs), which are targeted by miR160, antagonizes auxin response and lamina growth in conjunction with E. In wild-type leaf primordia, the miR160-targeted ARFs SlARF10A and SlARF17 are expressed in leaflets, and SlmiR160 is expressed in provascular tissues. Leaf overexpression of the miR160-targeted ARFs SlARF10A, SlARF10B or SlARF17, led to reduced lamina and increased leaf complexity, and suppressed auxin response in young leaves. In agreement, leaf overexpression of miR160 resulted in simplified leaves due to ectopic lamina growth between leaflets, reminiscent of e leaves. Genetic interactions suggest that E and miR160-targeted ARFs act partially redundantly but are both required for local inhibition of lamina growth between initiating leaflets. These results show that different types of auxin signal antagonists act cooperatively to ensure leaflet separation in tomato leaf margins. PMID:27121172

  12. Sprouty gain of function disrupts lens cellular processes and growth by restricting RTK signaling.

    PubMed

    Shin, Eun Hae; Zhao, Guannan; Wang, Qian; Lovicu, Frank J

    2015-10-15

    Sprouty proteins function as negative regulators of the receptor tyrosine kinase (RTK)-mediated Ras/Raf/MAPK pathway in many varied physiological and developmental processes, inhibiting growth factor-induced cellular proliferation, migration and differentiation. Like other negative regulators, Sprouty proteins are expressed in various organs during development, including the eye; ubiquitously expressed in the optic vesicle, lens pit, optic cup and lens vesicle. Given the synexpression of different antagonists (e.g, Sprouty, Sef, Spred) in the developing lens, to gain a better understanding of their specific role, in particular, their ability to regulate ocular growth factor signaling in lens cells, we characterized transgenic mice overexpressing Sprouty1 or Sprouty2 in the eye. Overexpression of Sprouty in the lens resulted in reduced lens and eye size during ocular morphogenesis, influenced by changes to the lens epithelium, aberrant fiber cell differentiation and compromised de novo maintenance of the lens capsule. Here we demonstrate an important inhibitory role for Sprouty in the regulation of lens cell proliferation and fiber differentiation in situ, potentially through its ability to modulate FGF- (and even EGF-) mediated MAPK/ERK1/2 signaling in lens cells. Whilst growth factor regulation of lens cell proliferation and fiber differentiation are required for orchestrating lens morphogenesis and growth, in turn, antagonists such as Sprouty are just as important for regulating the intracellular signaling pathways driving lens cellular processes. PMID:26375880

  13. Hepatic IGF1 DNA methylation is influenced by gender but not by intrauterine growth restriction in the young lamb.

    PubMed

    Carr, D J; Milne, J S; Aitken, R P; Adam, C L; Wallace, J M

    2015-12-01

    Intrauterine growth restriction (IUGR) and postnatal catch-up growth confer an increased risk of adult-onset disease. Overnourishment of adolescent ewes generates IUGR in ∼ 50% of lambs, which subsequently exhibit increased fractional growth rates. We investigated putative epigenetic changes underlying this early postnatal phenotype by quantifying gene-specific methylation at cytosine:guanine (CpG) dinucleotides. Hepatic DNA/RNA was extracted from IUGR [eight male (M)/nine female (F)] and normal birth weight (12 M/9 F) lambs. Polymerase chain reaction was performed using primers targeting CpG islands in 10 genes: insulin, growth hormone, insulin-like growth factor (IGF)1, IGF2, H19, insulin receptor, growth hormone receptor, IGF receptors 1 and 2, and the glucocorticoid receptor. Using pyrosequencing, methylation status was determined by quantifying cytosine:thymine ratios at 57 CpG sites. Messenger RNA (mRNA) expression of IGF system genes and plasma IGF1/insulin were determined. DNA methylation was independent of IUGR status but sexual dimorphism in IGF1 methylation was evident (MF (both P<0.001). IGF1 mRNA expression correlated negatively with IGF1 methylation (r=-0.507, P=0.002) and positively with plasma IGF1 (r=0.884, P<0.001). Carcass and empty body weights were greater in males (P=0.002-0.014) and this gender difference in early body conformation was mirrored by sexual dimorphism in hepatic IGF1 DNA methylation, mRNA expression and plasma IGF1 concentrations. PMID:26310177

  14. Restricted Heterochromatin Formation Links NFATc2 Repressor Activity With Growth Promotion in Pancreatic Cancer

    PubMed Central

    BAUMGART, SANDRA; GLESEL, ELISABETH; SINGH, GARIMA; CHEN, NAI-MING; REUTLINGER, KRISTINA; ZHANG, JINSAN; BILLADEAU, DANIEL D.; FERNANDEZ-ZAPICO, MARTIN E.; GRESS, THOMAS M.; SINGH, SHIV K.; ELLENRIEDER, VOLKER

    2012-01-01

    BACKGROUND & AIMS Transcriptional silencing of the p15INK4b tumor suppressor pathway overcomes cellular protection against unrestrained proliferation in cancer. Here we show a novel pathway involving the oncogenic transcription factor nuclear factor of activated T cells (NFAT) c2 targeting a p15INK4b-mediated failsafe mechanism to promote pancreatic cancer tumor growth. METHODS Immunohistochemistry, real-time polymerase chain reaction, immunoblotting, and immunofluorescence microscopy were used for expression studies. Cancer growth was assessed in vitro by [3H]thymidine incorporation, colony formation assays, and in vivo using xenograft tumor models. Protein-protein interactions, promoter regulation, and local histone modifications were analyzed by immunoprecipitation, DNA pull-down, reporter, and chromatin immunoprecipitation assays. RESULTS Our study uncovered induction of NFATc2 in late-stage pancreatic intraepithelial neoplasia lesions with increased expression in tumor cell nuclei of advanced cancers. In the nucleus, NFATc2 targets the p15INK4b promoter for inducible heterochromatin formation and silencing. NFATc2 binding to its cognate promoter site induces stepwise recruitment of the histone methyltransferase Suv39H1, causes local H3K9 trimethylation, and allows docking of heterochromatin protein HP1γ to the repressor complex. Conversely, inactivation of NFATc2 disrupts this repressor complex assembly and local heterochromatin formation, resulting in restoration of p15INK4b expression and inhibition of pancreatic cancer growth in vitro and in vivo. CONCLUSIONS Here we describe a novel mechanism for NFATc2-mediated gene regulation and identify a functional link among its repressor activity, the silencing of the suppressor pathway p15INK4b, and its pancreatic cancer growth regulatory functions. Thus, we provide evidence that inactivation of oncogenic NFATc2 might be an attractive strategy in treatment of pancreatic cancer. PMID:22079596

  15. Insulin-like growth factor-1 receptor immunoreactive cells are selectively maintained in the paraventricular hypothalamus of calorically restricted mice.

    PubMed

    Saeed, O; Yaghmaie, F; Garan, S A; Gouw, A M; Voelker, M A; Sternberg, H; Timiras, P S

    2007-02-01

    The mammalian lifespan is dramatically extended by both caloric restriction (CR) and insulin-like growth factor-1 (IGF-1) suppression. Both interventions involve neuroendocrine alterations directed by the hypothalamus. Yet, it remains unclear whether CR exerts its affects by altering central IGF-1 sensitivity. With this question in mind, we investigated the influence of CR and normal aging on hypothalamic IGF-1 sensitivity, by measuring the changes in IGF-1 receptor (IGF-1R) populations. Taking IGF-1 receptor (IGF-1R) immunoreactivity as an index of sensitivity to IGF-1, we counted IGF-1R immunoreactive and non-immunoreactive cells in the paraventricular nucleus (PVN) of Young-ad libitum fed (Young-Al, 6 weeks old), Old-ad libitum fed (Old-Al, 22 months old), and old calorically restricted (Old-CR, 22 months old) female B6D2F1 mice. An automated imaging microscopy system (AIMS) was used to generate cell counts for each cross-section of PVN hypothalamus. Ad libitum fed mice show a 37% reduction in IGF-1R immunoreactive cells and a 12% reduction in the total cell population of the PVN with aging. In comparison, caloric-restricted mice show a 33% reduction in IGF-1R immunoreactive cells and a notable 24% decrease in the total cell population with aging. This selective maintenance of IGF-1R expressing cells coupled with the simultaneous loss of non-immunoreactive cells, results in a higher percentage of IGF-1R immunoreactive cells in the PVNs of CR mice. Thus, the decline in the percentage of IGF-1 sensitive cells in the PVN with age is attenuated by CR. PMID:17194562

  16. Growth factor restriction impedes progression of wound healing following cataract surgery: identification of VEGF as a putative therapeutic target

    PubMed Central

    Eldred, Julie A.; McDonald, Matthew; Wilkes, Helen S.; Spalton, David J.; Wormstone, I. Michael

    2016-01-01

    Secondary visual loss occurs in millions of patients due to a wound-healing response, known as posterior capsule opacification (PCO), following cataract surgery. An intraocular lens (IOL) is implanted into residual lens tissue, known as the capsular bag, following cataract removal. Standard IOLs allow the anterior and posterior capsules to become physically connected. This places pressure on the IOL and improves contact with the underlying posterior capsule. New open bag IOL designs separate the anterior capsule and posterior capsules and further reduce PCO incidence. It is hypothesised that this results from reduced cytokine availability due to greater irrigation of the bag. We therefore explored the role of growth factor restriction on PCO using human lens cell and tissue culture models. We demonstrate that cytokine dilution, by increasing medium volume, significantly reduced cell coverage in both closed and open capsular bag models. This coincided with reduced cell density and myofibroblast formation. A screen of 27 cytokines identified nine candidates whose expression profile correlated with growth. In particular, VEGF was found to regulate cell survival, growth and myofibroblast formation. VEGF provides a therapeutic target to further manage PCO development and will yield best results when used in conjunction with open bag IOL designs. PMID:27076230

  17. Prevention of Intrauterine Growth Restriction and Preterm Birth with Presumptive Antibiotic Treatment of Pregnant Women: A Literature Review.

    PubMed

    Ashorn, Per; Vanhala, Hanna; Pakarinen, Outi; Ashorn, Ulla; De Costa, Ayesha

    2015-01-01

    Intrauterine growth restriction and preterm birth (PTB) account for a large share of global child mortality, morbidity and developmental loss. Of the numerous risk factors for these conditions, maternal infections have been most consistently identified. Our aim was to study if presumptive antibiotic treatment of pregnant women before any signs of the onset of labor would promote fetal growth and reduce the incidence of PTB or low birthweight (LBW). In a systematic literature search, we identified 14 clinical trials of sufficient quality. Eight trials concluded that there was a positive effect on one or both of the conditions, and others found no such association. The trials reporting an effect were typically conducted in Sub-Saharan Africa (6 trials) and with broadest spectrum antibiotics, whereas data from India (2) suggested no intervention effect and trials in the US (5) or Europe (1) yielded both positive and negative findings. We conclude that appropriately chosen presumptive antimicrobial treatment of pregnant women, targeting infections in the reproductive tract but also other maternal infections such as malaria, other parasitic diseases, skin infections, and periodontitis, can in selected contexts promote fetal growth and reduce the incidence of PTB and LBW. PMID:26111562

  18. Compensatory growth in hybrid tilapia ( Oreochromis mossambicus ×O. niloticus) reared in seawater, following restricted feeding

    NASA Astrophysics Data System (ADS)

    Wang, Yan; Cui, Yibo; Yang, Yunxia; Cai, Fasheng

    2004-12-01

    Hybrid tilapia weighing 7.71 g were reared in seawater at 24.0 29.0°C for 8 weeks. The controls were fed to satiation twice a day throughout the experiment, whereas treatment groups were fed at 0.5%, 1.5% or 3.0% body weight per day for 4 weeks, and then to satiation for the remainder of the experiment. During the first 4-week period, there was a curvilinear relationship between growth rate and ration size. Fish fed 0.5% and 1.5% rations displayed compensatory growth response of 2 weeks duration during realimentation. The weight-adjusted growth rate of fish fed at 3% ration was not significantly different from that of the controls by the end of the experiment, when none of the treatment groups had caught up in body weight with the controls. Hyperphagia was observed for the first 2 weeks of realimenatation in fish previously fed at 3% ration, but persisted for the whole realimentation period in groups previously fed at 0.5% and 1.5% rations. None of the feed restricted groups showed improved digestibility, feed efficiency, or protein and energy retention efficiency.

  19. Transforming growth factor. beta. sub 1 is present at sites of extracellular matrix gene expression in human pulmonary fibrosis

    SciTech Connect

    Broekelmann, T.J.; Limper, A.H.; McDonald, J.A. ); Colby, T.V. )

    1991-08-01

    Idiopathic pulmonary fibrosis is an inexorably fatal disorder characterized by connective tissue deposition within the terminal air spaces resulting in loss of lung function and eventual respiratory failure. Previously, the authors demonstrated that foci of activated fibroblasts expressing high levels of fibronectin, procollagen, and smooth muscle actin and thus resembling those found in healing wounds are responsible for the connective tissue deposition and scarring in idiopathic pulmonary fibrosis. Using in situ hybridization and immunohistochemistry, they now demonstrate the presence of transforming growth factor {beta}{sub 1} (TGF-{beta}{sub 1}), a potent profibrotic cytokine, in the foci containing these activated fibroblasts. These results suggest that matrix-associated TGF-{beta}{sub 1} may serve as a stimulus for the persistent expression of connective tissue genes. One potential source of the TGF-{beta}{sub 1} is the alveolar macrophage, and they demonstrate the expression of abundant TGF-{beta}{sub 1} mRNA in alveolar macrophages in lung tissue from patients with idiopathic pulmonary fibrosis.

  20. Interaction of growth hormone receptor/binding protein gene disruption and caloric restriction for insulin sensitivity and attenuated aging.

    PubMed

    Arum, Oge; Saleh, Jamal; Boparai, Ravneet; Turner, Jeremy; Kopchick, John; Khardori, Romesh; Bartke, Andrzej

    2014-01-01

    The correlation of physiological sensitivity to insulin ( vis-à-vis glycemic regulation) and longevity is extensively established, creating a justifiable gerontological interest on whether insulin sensitivity is causative, or even predictive, of some or all phenotypes of slowed senescence (including longevity). The growth hormone receptor/ binding protein gene-disrupted (GHR-KO) mouse is the most extensively investigated insulin-sensitive, attenuated aging model. It was reported that, in a manner divergent from similar mutants, GHR-KO mice fail to respond to caloric restriction (CR) by altering their insulin sensitivity. We hypothesized that maximized insulin responsiveness is what causes GHR-KO mice to exhibit a suppressed survivorship response to dietary (including caloric) restriction; and attempted to refute this hypothesis by assessing the effects of CR on GHR-KO mice for varied slow-aging-associated phenotypes. In contrast to previous reports, we found GHR-KO mice on CR to be less responsive than their ad libitum (A.L.) counterparts to the hypoglycemia-inducing effects of insulin. Further, CR had negligible effects on the metabolism or cognition of GHR-KO mice. Therefore, our data suggest that the effects of CR on the insulin sensitivity of GHR-KO mice do not concur with the effects of CR on the aging of GHR-KO mice. PMID:25789159

  1. Nerve growth factor and neurotrophin-3 mediate survival of pulmonary plasma cells during the allergic airway inflammation.

    PubMed

    Abram, Melanie; Wegmann, Michael; Fokuhl, Verena; Sonar, Sanchaita; Luger, Elke Olga; Kerzel, Sebastian; Radbruch, Andreas; Renz, Harald; Zemlin, Michael

    2009-04-15

    Allergen-specific Abs play a pivotal role in the induction and maintenance of allergic airway inflammation. During secondary immune responses, plasma cell survival and Ab production is mediated by extrinsic factors provided by the local environment (survival niches). It is unknown whether neurotrophins, a characteristic marker of allergic airway inflammation, influence plasma cell survival in the lung. Using a mouse model of allergic asthma, we found that plasma cells from the lung and spleen are distinct subpopulations exhibiting differential expression patterns of neurotrophins and their receptors (Trks). In vitro, the nerve growth factor (NGF) and neurotrophin-3 (NT3) led to a dose-dependent increase in viability of isolated pulmonary plasma cells due to up-regulation of the antiapoptotic Bcl2 pathway. In parallel, the expression of transcription factors that stimulate the production of immunoglobulins (X-box binding protein 1 and NF-kappaB subunit RelA) was enhanced in plasma cells treated with NGF and NT3. These findings were supported in vivo. When the NGF pathway was blocked by intranasal application of a selective TrkA inhibitor, sensitized mice showed reduced numbers of pulmonary plasma cells and developed lower levels of allergen-specific and total serum IgE in response to OVA inhalation. This suggests that in the allergic airway inflammation, NGF/TrkA-mediated pulmonary IgE production contributes significantly to serum-IgE levels. We conclude that the neurotrophins NGF and NT3 act as survival factors for pulmonary plasma cells and thus are important regulators of the local Ab production in the allergic airway disease. PMID:19342646

  2. The Effect of Subclinical Maternal Thyroid Dysfunction and Autoimmunity on Intrauterine Growth Restriction: A Systematic Review and Meta-Analysis.

    PubMed

    Tong, Zhao; Xiaowen, Zhang; Baomin, Chen; Aihua, Liu; Yingying, Zhou; Weiping, Teng; Zhongyan, Shan

    2016-05-01

    The objective of this study was to evaluate the association between maternal subclinical thyroid dysfunction and autoimmunity with the risk for intrauterine growth restriction (IUGR).Design is a systematic review and meta-analysis.A literature search was conducted using PubMed, Embase, and Cochrane database. A combination of 2 key words was used to search for the eligible studies: one indexed thyroid dysfunction or antithyroid antibodies; and the other one indexed the adverse neonatal outcomes of pregnancy, such as IUGR, small for gestational age, fetal growth restriction, or low birth weight.Two reviewers selected the studies, and eligible studies met the following criteria: prospective cohort studies or case control studies, studies of maternal thyroid dysfunction and positive antithyroid antibodies as the exposure of interest, and studies of IUGR or small for gestational age as the outcome of interest.Data were recorded, including data from maternal thyroid disorders and IUGR, and compared with a reference group.There were 22 individual data from the 13 cohort articles. Among these, 7 were focused on subclinical hypothyroidism (SCH), 4 on subclinical hyperthyroidism, 7 on positivity for thyroid peroxidase antibody (TPOAb), and 4 on isolated hypothyroxinemia. Meta-analysis showed that there was no effect of subclinical hyperthyroidism (odds ratio (OR) = 0.98; 95% confidence interval (CI), 0.40-2.41), TPOAb positivity (OR = 1.57; 95% CI, 0.77-3.18), or isolated hypothyroxinemia (OR = 1.05, 95% CI: 0.37-2.92) on IUGR. However, SCH is associated with IUGR (OR = 1.54; 95% CI, 1.06-2.25).SCH is associated with IUGR; however, subclinical hyperthyroidism, TPOAb positivity, or isolated hypothyroxinemia do not affect the risk of IUGR. PMID:27175703

  3. Imaging of zymogen granules in fully wet cells: evidence for restricted mechanism of granule growth.

    PubMed

    Hammel, Ilan; Anaby, Debbie

    2007-09-01

    The introduction of wet SEM imaging technology permits electron microscopy of wet samples. Samples are placed in sealed specimen capsules and are insulated from the vacuum in the SEM chamber by an impermeable, electron-transparent membrane. The complete insulation of the sample from the vacuum allows direct imaging of fully hydrated, whole-mount tissue. In the current work, we demonstrate direct inspection of thick pancreatic tissue slices (above 400 mum). In the case of scanning of the pancreatic surface, the boundaries of intracellular features are seen directly. Thus no unfolding is required to ascertain the actual particle size distribution based on the sizes of the sections. This method enabled us to investigate the true granule size distribution and confirm early studies of improved conformity to a Poisson-like distribution, suggesting that the homotypic granule growth results from a mechanism, which favors the addition of a single unit granule to mature granules. PMID:17557275

  4. Rapid Growth of Lung Nodules due to Combined Pulmonary Vasculitis, Silicoanthracosis, and Chondrocalcinosis

    PubMed Central

    Distler, Oliver; Kolios, Antonios G. A.; Weder, Walter; Franzen, Daniel

    2016-01-01

    Background. Silicoanthracosis is a pneumoconiosis due to occupational inhalation of silica and carbon dusts. Clinically, it can be associated with vasculitis or rheumatoid arthritis. In association with these diseases, silicoanthracosis can present within the lung with multiple pulmonary nodules which, as a differential diagnosis, can mimic metastatic disease or multiple abscesses. Case Presentation. We present the case of a 62-year old former pit worker with pulmonary nodules, chondrocalcinosis due to calcium pyrophosphate deposition (CPPD), and a history of renal cancer. Within a short period of time, pulmonary nodules grew rapidly. Thoracoscopically, the resected lung specimen revealed silicoanthracosis associated with small-to-medium-size vasculitis in the presence of antineutrophil cytoplasmatic autoantibodies (c-ANCA). Conclusion. Pulmonary silicoanthracotic lesions on the base of ANCA-associated vasculitis and CPPD arthritis can rapidly grow. A mutual correlation between silicoanthracosis, ANCA-associated vasculitis, and CPPD seems possible. Apart from this, consideration of metastatic disease should be obligatory in patients with a history of cancer at the same time being immunosuppressed. PMID:27478398

  5. Sotos syndrome: An unusual presentation with intrauterine growth restriction, generalized lymphedema, and intention tremor.

    PubMed

    McClelland, Jessie; Burgess, Bronwyn; Crock, Patricia; Goel, Himanshu

    2016-04-01

    Sotos syndrome is a childhood overgrowth syndrome characterized clinically by a distinctive facial gestalt, advanced bone age, childhood overgrowth, and non-progressive developmental delay; and genetically by haploinsufficiency of the Nuclear receptor binding SET Domain 1 (NSD1) gene. Generalized lymphedema has not previously been associated with Sotos syndrome. Generalized lymphedema has been associated with mutations in several genes including FLT4. This gene is involved in the regulation of VEGFR3, a key governor of lymphatic-endothelial cell development and function. We report on a 28-year-old Caucasian female with a de novo NSD1 intragenic mutation, c.5841_5848dup: p.Leu1950Serfs*22, who presented with characteristic clinical features of Sotos syndrome. Unusually this case includes atypical features of intrauterine growth retardation and post-pubertal onset of primary lymphedema. To our knowledge, no link between Sotos syndrome and generalized lymphedema has previously been described in the literature. We propose a mechanism by which disruptions in NSD1 gene may lead to generalized lymphedema. Aberrations of the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK)-signaling pathway has been identified in both Sotos syndrome and lymphedema. This finding extends the known phenotype of Sotos syndrome through the inclusion of lymphedema. This case also indicates that presence of low birth weight does not exclude the possibility of Sotos syndrome. © 2016 Wiley Periodicals, Inc. PMID:26738611

  6. Glutamine synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma.

    PubMed

    Tardito, Saverio; Oudin, Anaïs; Ahmed, Shafiq U; Fack, Fred; Keunen, Olivier; Zheng, Liang; Miletic, Hrvoje; Sakariassen, Per Øystein; Weinstock, Adam; Wagner, Allon; Lindsay, Susan L; Hock, Andreas K; Barnett, Susan C; Ruppin, Eytan; Mørkve, Svein Harald; Lund-Johansen, Morten; Chalmers, Anthony J; Bjerkvig, Rolf; Niclou, Simone P; Gottlieb, Eyal

    2015-12-01

    L-Glutamine (Gln) functions physiologically to balance the carbon and nitrogen requirements of tissues. It has been proposed that in cancer cells undergoing aerobic glycolysis, accelerated anabolism is sustained by Gln-derived carbons, which replenish the tricarboxylic acid (TCA) cycle (anaplerosis). However, it is shown here that in glioblastoma (GBM) cells, almost half of the Gln-derived glutamate (Glu) is secreted and does not enter the TCA cycle, and that inhibiting glutaminolysis does not affect cell proliferation. Moreover, Gln-starved cells are not rescued by TCA cycle replenishment. Instead, the conversion of Glu to Gln by glutamine synthetase (GS; cataplerosis) confers Gln prototrophy, and fuels de novo purine biosynthesis. In both orthotopic GBM models and in patients, (13)C-glucose tracing showed that GS produces Gln from TCA-cycle-derived carbons. Finally, the Gln required for the growth of GBM tumours is contributed only marginally by the circulation, and is mainly either autonomously synthesized by GS-positive glioma cells, or supplied by astrocytes. PMID:26595383

  7. Glutamine Synthetase activity fuels nucleotide biosynthesis and supports growth of glutamine-restricted glioblastoma

    PubMed Central

    Tardito, Saverio; Oudin, Anaïs; Ahmed, Shafiq U.; Fack, Fred; Keunen, Olivier; Zheng, Liang; Miletic, Hrvoje; Sakariassen, Per Øystein; Weinstock, Adam; Wagner, Allon; Lindsay, Susan L.; Hock, Andreas K.; Barnett, Susan C.; Ruppin, Eytan; Mørkve, Svein Harald; Lund-Johansen, Morten; Chalmers, Anthony J.; Bjerkvig, Rolf; Niclou, Simone P.; Gottlieb, Eyal

    2015-01-01

    L-Glutamine (Gln) functions physiologically to balance tissue requirements of carbon and nitrogen. It has been proposed that in cancer cells undergoing aerobic glycolysis, accelerated anabolism is sustained by Gln-derived carbons, which replenish the tricarboxylic acid (TCA) cycle (anaplerosis). However, it is shown here that in glioblastoma (GBM) cells, almost half of the Gln-derived glutamate (Glu) is secreted and does not enter the TCA cycle and, that inhibiting glutaminolysis does not affect proliferation. Moreover, Gln-starved cells are not rescued by TCA cycle replenishment. Instead, the conversion of Glu to Gln by Glutamine Synthetase (GS) (cataplerosis) confers Gln prototrophy, and fuels de novo purine biosynthesis. In both orthotopic GBM models and in patients, 13C-glucose tracing showed that GS produces Gln from TCA cycle-derived carbons. Finally, while it is contributed only marginally by the circulation, the Gln required for the growth of GBM tumours is either autonomously synthesized by GS-positive glioma cells, or supplied by astrocytes. PMID:26595383

  8. mir-329 restricts tumor growth by targeting grb2 in pancreatic cancer

    PubMed Central

    Wen, Chenlei; Shi, Minmin; Tang, Xiaomei; Chen, Hao; Peng, Chenghong; Li, Hongwei; Fang, Yuan; Deng, Xiaxing; Shen, Baiyong

    2016-01-01

    Pancreatic cancer is one of the most lethal malignancies worldwide. To illustrate the pathogenic mechanism(s), we looked into the expression and function of miR-329 associated with pancreatic cancer development. It was found that miR-329 expression was downregulated in the pancreatic cancer patients who demonstrated significantly shorter overall survival than the patients having upregulated expression. Also, more advanced pT stage cases were observed in the low miR-329 expression group of patients. Interestingly, our studies uncovered that miR-329 overexpression inhibited proliferation and induced apoptosis of pancreatic cancer cells, in contrast the miR-329 inhibitor reversed this phenomenon dramatically. Additionally, overexpression of miR-329 significantly limited tumor growth in the xenograft model. In the mechanistic study, we identified GRB2 as a direct target of miR-329 in pancreatic cancer cells, and expression of GRB2 was inversely correlated with miR-329 expression in pancreatic cancer patients. Furthermore, GRB2 overexpression in cell line and xenograft model dramatically diminished miR-329 mediated anti-proliferation and apoptosis induction, indicating that GRB2/pERK pathway was mainly downregulated by miR-329 expression. In general, our study has shed light on miR-329 regulated mechanism and, miR-329/GRB2/pERK is potential to be targeted for pancreatic cancer management. PMID:26885689

  9. Maternal Administration of Sildenafil Citrate Alters Fetal and Placental Growth and Fetal-Placental Vascular Resistance in the Growth-Restricted Ovine Fetus.

    PubMed

    Oyston, Charlotte; Stanley, Joanna L; Oliver, Mark H; Bloomfield, Frank H; Baker, Philip N

    2016-09-01

    Intrauterine growth restriction (IUGR) causes short- and long-term morbidity. Reduced placental perfusion is an important pathogenic component of IUGR; substances that enhance vasodilation in the uterine circulation, such as sildenafil citrate (sildenafil), may improve placental blood flow and fetal growth. This study aimed to examine the effects of sildenafil in the growth-restricted ovine fetus. Ewes carrying singleton pregnancies underwent insertion of vascular catheters, and then, they were randomized to receive uterine artery embolization (IUGR) or to a control group. Ewes in the IUGR group received a daily infusion of sildenafil (IUGR+SC; n=10) or vehicle (IUGR+V; n=8) for 21 days. The control group received no treatment (n=9). Umbilical artery blood flow was measured using Doppler ultrasound and the resistive index (RI) calculated. Fetal weight, biometry, and placental weight were obtained at postmortem after treatment completion. Umbilical artery RI in IUGR+V fell less than in controls; the RI of IUGR+SC was intermediate to that of the other 2 groups (mean±SEM for control versus IUGR+V versus IUGR+SC: ∆RI, 0.09±0.03 versus -0.01±0.02 versus 0.03±0.02; F(2, 22)=4.21; P=0.03). Compared with controls, lamb and placental weights were reduced in IUGR+V but not in IUGR+SC (control versus IUGR+V versus IUGR+SC: fetal weight, 4381±247 versus 3447±235 versus 3687±129 g; F(2, 24)=5.49; P=0.01 and placental weight: 559.7±35.0 versus 376.2±32.5 versus 475.2±42.5 g; F(2, 24)=4.64; P=0.01). Sildenafil may be a useful adjunct in the management of IUGR. An increase in placental weight and fall in fetal-placental resistance suggests that changes to growth are at least partly mediated by changes to placental growth rather than alterations in placental efficiency. PMID:27432857

  10. Subfertility and growth restriction in a new galactose-1 phosphate uridylyltransferase (GALT) - deficient mouse model

    PubMed Central

    Tang, Manshu; Siddiqi, Anwer; Witt, Benjamin; Yuzyuk, Tatiana; Johnson, Britt; Fraser, Nisa; Chen, Wyman; Rascon, Rafael; Yin, Xue; Goli, Harish; Bodamer, Olaf A; Lai, Kent

    2014-01-01

    The first GalT gene knockout (KO) mouse model for Classic Galactosemia (OMIM 230400) accumulated some galactose and its metabolites upon galactose challenge, but was seemingly fertile and symptom free. Here we constructed a new GalT gene-trapped mouse model by injecting GalT gene-trapped mouse embryonic stem cells into blastocysts, which were later implanted into pseudo-pregnant females. High percentage GalT gene-trapped chimera obtained were used to generate heterozygous and subsequently, homozygous GalT gene-trapped mice. Biochemical assays confirmed total absence of galactose-1 phosphate uridylyltransferase (GALT) activity in the homozygotes. Although the homozygous GalT gene-trapped females could conceive and give birth when fed with normal chow, they had smaller litter size (P=0.02) and longer time-to-pregnancy (P=0.013) than their wild-type littermates. Follicle-stimulating hormone levels of the mutant female mice were not significantly different from the age-matched, wild-type females, but histological examination of the ovaries revealed fewer follicles in the homozygous mutants (P=0.007). Administration of a high-galactose (40% w/w) diet to lactating homozygous GalT gene-trapped females led to lethality in over 70% of the homozygous GalT gene-trapped pups before weaning. Cerebral edema, abnormal changes in the Purkinje and the outer granular cell layers of the cerebellum, as well as lower blood GSH/GSSG ratio were identified in the galactose-intoxicated pups. Finally, reduced growth was observed in GalT gene-trapped pups fed with normal chow and all pups fed with high-galactose (20% w/w) diet. This new mouse model presents several of the complications of Classic Galactosemia and will be useful to investigate pathogenesis and new therapies. PMID:24549051

  11. Subfertility and growth restriction in a new galactose-1 phosphate uridylyltransferase (GALT) - deficient mouse model.

    PubMed

    Tang, Manshu; Siddiqi, Anwer; Witt, Benjamin; Yuzyuk, Tatiana; Johnson, Britt; Fraser, Nisa; Chen, Wyman; Rascon, Rafael; Yin, Xue; Goli, Harish; Bodamer, Olaf A; Lai, Kent

    2014-10-01

    The first GalT gene knockout (KO) mouse model for Classic Galactosemia (OMIM 230400) accumulated some galactose and its metabolites upon galactose challenge, but was seemingly fertile and symptom free. Here we constructed a new GalT gene-trapped mouse model by injecting GalT gene-trapped mouse embryonic stem cells into blastocysts, which were later implanted into pseudo-pregnant females. High percentage GalT gene-trapped chimera obtained were used to generate heterozygous and subsequently, homozygous GalT gene-trapped mice. Biochemical assays confirmed total absence of galactose-1 phosphate uridylyltransferase (GALT) activity in the homozygotes. Although the homozygous GalT gene-trapped females could conceive and give birth when fed with normal chow, they had smaller litter size (P=0.02) and longer time-to-pregnancy (P=0.013) than their wild-type littermates. Follicle-stimulating hormone levels of the mutant female mice were not significantly different from the age-matched, wild-type females, but histological examination of the ovaries revealed fewer follicles in the homozygous mutants (P=0.007). Administration of a high-galactose (40% w/w) diet to lactating homozygous GalT gene-trapped females led to lethality in over 70% of the homozygous GalT gene-trapped pups before weaning. Cerebral edema, abnormal changes in the Purkinje and the outer granular cell layers of the cerebellum, as well as lower blood GSH/GSSG ratio were identified in the galactose-intoxicated pups. Finally, reduced growth was observed in GalT gene-trapped pups fed with normal chow and all pups fed with high-galactose (20% w/w) diet. This new mouse model presents several of the complications of Classic Galactosemia and will be useful to investigate pathogenesis and new therapies. PMID:24549051

  12. Detection of expressional changes induced by intrauterine growth restriction in the developing rat pancreas.

    PubMed

    Zhang, Lin; Chen, Wei; Dai, Yuee; Zhu, Ziyang; Liu, Qianqi

    2016-07-01

    Intrauterine growth retardation (IUGR) is a disorder that can result in permanent changes in the physiology and metabolism of the newborn, which increased the risk of disease in adulthood. Evidence supports IUGR as a risk factor for the development of diabetes mellitus, which could reflect changes in pancreas developmental pathways. We sought to characterize the IUGR-induced alterations of the complex pathways of pancreas development in a rat model of IUGR. We analyzed the pancreases of Sprague Dawley rats after inducing IUGR by feeding a maternal low calorie diet from gestational day 1 until term. IUGR altered the pancreatic structure, islet areas, and islet quantities and resulted in abnormal morphological changes during pancreatic development, as determined by HE staining and light microscopy. We identified multiple differentially expressed genes in the pancreas by RT-PCR. The genes of the insulin/FoxO1/Pdx1/MafA signaling pathway were first expressed at embryonic day 14 (E14). The expressions of insulin and MafA increased as the fetus grew while the expressions of FoxO1 and Pdx1 decreased. Compared with the control rats, the expressions of FoxO1, Pdx1, and MafA were lower in the IUGR rats, whereas insulin levels showed no change. Microarray profiling, in combination with quantitative real-time PCR, uncovered a subset of microRNAs that changed in their degree of expression throughout pancreatic development. In conclusion, our data support the hypothesis that IUGR influences the development of the rat pancreas. We also identified new pathways that appear to be programmed by IUGR. PMID:27190278

  13. Detection of pulmonary nodule growth with dose reduced chest tomosynthesis: a human observer study using simulated nodules

    NASA Astrophysics Data System (ADS)

    Söderman, Christina; Johnsson, Ã. se; Vikgren, Jenny; Rossi Norrlund, Rauni; Molnar, David; Mirzai, Maral; Svalkvist, Angelica; Mânsson, Lars Gunnar; Bâth, Magnus

    2016-03-01

    Chest tomosynthesis may be a suitable alternative to computed tomography for the clinical task of follow up of pulmonary nodules. The aim of the present study was to investigate the detection of pulmonary nodule growth suggestive of malignancy using chest tomosynthesis. Previous studies have indicated remained levels of detection of pulmonary nodules at dose levels corresponding to that of a conventional lateral radiograph, approximately 0.04 mSv, which motivated to perform the present study this dose level. Pairs of chest tomosynthesis image sets, where the image sets in each pair were acquired of the same patient at two separate occasions, were included in the study. Simulated nodules with original diameters of approximately 8 mm were inserted in the pairs of image sets, simulating situations where the nodule had remained stable in size or increased isotropically in size between the two different imaging occasions. Four different categories of nodule growth were included, corresponding to a volume increase of approximately 21 %, 68 %, 108 % and 250 %. All nodules were centered in the depth direction in the tomosynthesis images. All images were subjected to a simulated dose reduction, resulting in images corresponding to an effective dose of 0.04 mSv. Four observers were given the task of rating their confidence that the nodule was stable in size or not on a five-level rating scale. This was done both before any size measurements were made of the nodule as well as after measurements were performed. Using Receiver operating characteristic analysis, the rating data for the nodules that were stable in size was compared to the rating data for the nodules simulated to have increased in size. Statistically significant differences between the rating distributions for the stable nodules and all of the four nodule growth categories were found. For the three largest nodule growths, nearly perfect detection of nodule growth was seen. In conclusion, the present study

  14. Role of platelet-derived growth factor/platelet-derived growth factor receptor axis in the trafficking of circulating fibrocytes in pulmonary fibrosis.

    PubMed

    Aono, Yoshinori; Kishi, Masami; Yokota, Yuki; Azuma, Momoyo; Kinoshita, Katsuhiro; Takezaki, Akio; Sato, Seidai; Kawano, Hiroshi; Kishi, Jun; Goto, Hisatsugu; Uehara, Hisanori; Izumi, Keisuke; Nishioka, Yasuhiko

    2014-12-01

    Circulating fibrocytes have been reported to migrate into the injured lungs, and contribute to fibrogenesis via CXCL12-CXCR4 axis. In contrast, we report that imatinib mesylate prevented bleomycin (BLM)-induced pulmonary fibrosis in mice by inhibiting platelet-derived growth factor receptor (PDGFR), even when it was administered only in the early phase. The goal of this study was to test the hypothesis that platelet-derived growth factor (PDGF) might directly contribute to the migration of fibrocytes to the injured lungs. PDGFR expression in fibrocytes was examined by flow cytometry and RT-PCR. The migration of fibrocytes was evaluated by using a chemotaxis assay for human fibrocytes isolated from peripheral blood. The numbers of fibrocytes triple-stained for CD45, collagen-1, and CXCR4 were also examined in lung digests of BLM-treated mice. PDGFR mRNA levels in fibrocytes isolated from patients with idiopathic pulmonary fibrosis were investigated by real-time PCR. Fibrocytes expressed both PDGFR-α and -β, and migrated in response to PDGFs. PDGFR inhibitors (imatinib, PDGFR-blocking antibodies) suppressed fibrocyte migration in vitro, and reduced the number of fibrocytes in the lungs of BLM-treated mice. PDGF-BB was a stronger chemoattractant than the other PDGFs in vitro, and anti-PDGFR-β-blocking antibody decreased the numbers of fibrocytes in the lungs compared with anti-PDGFR-α antibody in vivo. Marked expression of PDGFR-β was observed in fibrocytes from patients with idiopathic pulmonary fibrosis compared with healthy subjects. These results suggest that PDGF directly functions as a strong chemoattractant for fibrocytes. In particular, the PDGF-BB-PDGFR-β biological axis might play a critical role in fibrocyte migration into the fibrotic lungs. PMID:24885373

  15. The Nexus of Prematurity, Birth Defects, and Intrauterine Growth Restriction: A Role for Plac1-Regulated Pathways

    PubMed Central

    Fant, Michael E.; Fuentes, Juan; Kong, Xiaoyuan; Jackman, Suzanne

    2013-01-01

    Epidemiological studies have demonstrated an increased prevalence of birth defects and intrauterine growth restriction (IUGR) among infants born prematurely suggesting they share common biological determinants. The identification of key regulatory pathways contributing to this nexus is essential to ongoing efforts to develop effective intervention strategies. Plac1 is a paternally imprinted and X-linked gene that conforms to this paradigm. Examination of a mutant mouse model has confirmed that Plac1 is essential for normal placental development and function. Moreover, it is expressed throughout the developing embryo indicating that it also has broad relevance to embryogenesis. Most notably, its absence in the developing embryo is associated with abnormal brain development and an increased risk of lethal, postnatal hydrocephalus identifying it as a novel, X-linked determinant of brain development. The essential and non-redundant roles of Plac1 in placental and neurological development represent a novel regulatory paradigm for embryonic growth and pregnancy maintenance. Regulatory pathways influenced, in part, by Plac1 are likely to contribute to the observed nexus of IUGR, prematurity, and birth defects. PMID:24600606

  16. Subtle increases in heart size persist into adulthood in growth restricted babies: the Cardiovascular Risk in Young Finns Study

    PubMed Central

    Arnott, Clare; Skilton, Michael R; Ruohonen, Saku; Juonala, Markus; Viikari, Jorma S A; Kähönen, Mika; Lehtimäki, Terho; Laitinen, Tomi; Celermajer, David S; Raitakari, Olli T

    2015-01-01

    Background and objectives Impaired fetal growth is associated with increased cardiovascular morbidity and mortality in adulthood. We sought to determine whether adults born with intrauterine growth restriction have primary maladaptive changes in cardiac structure. Methods Study participants were adults (34–49 years) who attended the 31-year follow-up of the Cardiovascular Risk in Young Finns Study (longitudinal cohort). Transthoracic echocardiograms and demographic and cardiovascular risk surveys were completed for 157 adults born small for gestational age (SGA, birth weight <10th population centile) and 627 born average for gestational age (average for gestational age (AGA), birth weight 50th–90th population centile). Results Those born growth restricted had subtly enlarged hearts with indexed left ventricular (LV) end-systolic and end-diastolic diameters slightly greater in the SGA individuals than the AGA group (LVESD 18.7 mm/m2 SGA vs 18.1 mm/m2 AGA, p<0.01; LVEDD 27.5 mm/m2 SGA vs 26.6 mm/m2 AGA, p<0.01); LV base-to-apex length (47.4 mm/m2 SGA vs 46.0 mm/m2 AGA, p<0.01); LV basal diameter (26.4 mm/m2 SGA vs 25.7 mm/m2 AGA, p<0.01); and right ventricular base-to-apex length (40.1 mm/m2 SGA vs 39.2 mm/m2 AGA, p=0.02). LV stroke volume was greater in those born AGA (74.5 mL SGA vs 78.8 mL AGA, p<0.01), with no significant difference in cardiac output (5 L/min SGA vs 5.2 L/min AGA, p=0.06), heart rate, diastolic indices or sphericity index. Conclusions Adults born SGA have some statistically significant but subtle changes in cardiac structure and function, which are less marked than have been described in childhood, and are unlikely to play a pathogenic role in their elevated cardiovascular risk. PMID:26339495

  17. Effect of feeding restriction on growth and dressing percentages in Mexican hairless pig.

    PubMed

    Rodríguez-González, L A; Trejo-Lizama, W; Santos-Ricalde, R H

    2016-08-01

    Twenty-four male Mexican hairless pigs, weighing 16 ± 1.12 kg, were used to evaluate growth performance and carcass yield in pigs fed 2 (L), 3 (M) and 4 (H) times the Metabolizable Energy (ME) required for maintenance. The pigs were assigned randomly to two experimental rearing systems (indoors and outdoors). They were fed daily according to their respective feeding regimen (FR). The indoor pigs were fed ad libitum with chopped star grass forage (Cynodon nlemfuensis). The outdoor pigs had access during 16 h to a paddock of star grass. The pigs were slaughtered when they achieve 70 kg of live weight. No significant differences between indoors and outdoors were observed in any of the variables evaluated (P > 0.05). A significant reduction of daily live weight gain (P < 0.05) was observed conforming to FR reductions (0.501, 0.438 and 0.300 kg/day for H, M and L, respectively). Days to achieve 70 kg of live weight increase (P < 0.05) as FR reduces (110, 124 and 180 days for H, M and L, respectively) were recorded. Forage consumption in pigs reared indoors reduces (P < 0.05) conforming to FR increases (0.092, 0.121 and 0.307 kg DM/day for H, M and L respectively). Fat carcass yield reduces significantly (P < 0.05) according FR reductions (24.5, 22.8 y 18.9 kg, for H, M and L respectively). Also, carcass meat yield was higher (P < 0.05) in pigs from L regimen (25.0 kg) than in pigs from M and H regimen (22.0 and 22.8 kg, respectively). Results obtained indicate a reduction in daily live weight gain conforming to daily feed intake reductions; however, improvement in carcass meat yield, accompanied with a reduction in carcass fat yield, was observed. PMID:27154215

  18. Effects of restricted nursing on milk production and collection, kid growth and plasma prolactin and growth hormone concentrations in dairy goats.

    PubMed

    Hernández, H; Delgadillo, J A; Flores, J A; Rodríguez, A D; Serafín, N; Kann, G; Marnet, P G; Poindron, P

    2007-03-01

    The milk production of dairy goats under various regimes of mother-young contact from day 4 post partum were studied during the first 2 months of lactation, together with the prolactin (PRL) and growth hormone (GH) responses to udder stimulation. In the control group, 13 goats and their kids were left in permanent contact and did not undergo milking. In two additional groups, goats were machine milked once a day in the morning (at 0800 h) and kids were allowed 10 hours (from 1000 to 2000 h; 10H group, n = 11) or 5 h (from 1000 to 2000 h; 5H group, n = 11) of mother-young interaction per day. In the last group (MO, n = 10), mothers were permanently separated from their kids on day 4 post partum and milked once a day. Milk production during a 24-h period at 37 days post partum performed by controlled nursing and weighing of the kids (groups with kids) or by two machine milking 12 h apart (milking only group) revealed a higher production in the three groups with some mother-young contact than in the MO group. Total milk collected by milking over the 2 months of the study did not differ between the three groups that underwent milking. Kid weights at 2 months were 3.4 to 4.8 kg. lighter in the groups that underwent milking than in the control group. Hormonal profiles were significantly affected by restricted mother-young contact, with highest pre-stimulation concentrations of PRL and GH in the 5H group. Restricting mother-young contact from the first week postpartum can permit an early collection of milk without major effects on kid growth, when compared with one daily milking in goats totally separated from their young. PMID:22444289

  19. A network model of correlated growth of tissue stiffening in pulmonary fibrosis

    NASA Astrophysics Data System (ADS)

    Oliveira, Cláudio L. N.; Bates, Jason H. T.; Suki, Béla

    2014-06-01

    During the progression of pulmonary fibrosis, initially isolated regions of high stiffness form and grow in the lung tissue due to collagen deposition by fibroblast cells. We have previously shown that ongoing collagen deposition may not lead to significant increases in the bulk modulus of the lung until these local remodeled regions have become sufficiently numerous and extensive to percolate in a continuous path across the entire tissue (Bates et al 2007 Am. J. Respir. Crit. Care Med. 176 617). This model, however, did not include the possibility of spatially correlated deposition of collagen. In the present study, we investigate whether spatial correlations influence the bulk modulus in a two-dimensional elastic network model of lung tissue. Random collagen deposition at a single site is modeled by increasing the elastic constant of the spring at that site by a factor of 100. By contrast, correlated collagen deposition is represented by stiffening the springs encountered along a random walk starting from some initial spring, the rationale being that excess collagen deposition is more likely in the vicinity of an already stiff region. A combination of random and correlated deposition is modeled by performing random walks of length N from randomly selected initial sites, the balance between the two processes being determined by N. We found that the dependence of bulk modulus, B(N,c), on both N and the fraction of stiff springs, c, can be described by a strikingly simple set of empirical equations. For c<0.3, B(N,c) exhibits exponential growth from its initial value according to B(N,c)\\approx {{B}_{0}}exp (2c)\\left[ 1+{{c}^{\\beta }}ln \\left( {{N}^{{{a}_{I}}}} \\right) \\right], where \\beta =0.994+/- 0.024 and {{a}_{I}}=0.54+/- 0.026. For intermediate concentrations of stiffening, 0.3\\leqslant c\\leqslant 0.8, another exponential rule describes the bulk modulus as B(N,c)=4{{B}_{0}}exp \\left[ {{a}_{II}}\\left( c-{{c}_{c}} \\right) \\right], where {{a

  20. First trimester fetal growth restriction and cardiovascular risk factors in school age children: population based cohort study

    PubMed Central

    de Jonge, Layla L; Hofman, Albert; Franco, Oscar H; Steegers, Eric A P; Gaillard, Romy

    2014-01-01

    Objective To examine whether first trimester fetal growth restriction correlates with cardiovascular outcomes in childhood. Design Population based prospective cohort study. Setting City of Rotterdam, the Netherlands. Participants 1184 children with first trimester fetal crown to rump length measurements, whose mothers had a reliable first day of their last menstrual period and a regular menstrual cycle. Main outcomes measures Body mass index, total and abdominal fat distribution, blood pressure, and blood concentrations of cholesterol, triglycerides, insulin, and C peptide at the median age of 6.0 (90% range 5.7-6.8) years. Clustering of cardiovascular risk factors was defined as having three or more of: high android fat mass; high systolic or diastolic blood pressure; low high density lipoprotein cholesterol or high triglycerides concentrations; and high insulin concentrations. Results One standard deviation score greater first trimester fetal crown to rump length was associated with a lower total fat mass (−0.30%, 95% confidence interval −0.57% to −0.03%), android fat mass (−0.07%, −0.12% to −0.02%), android/gynoid fat mass ratio (−0.53, −0.89 to −0.17), diastolic blood pressure (−0.43, −0.84 to −0.01, mm Hg), total cholesterol (−0.05, −0.10 to 0, mmol/L), low density lipoprotein cholesterol (−0.04, −0.09 to 0, mmol/L), and risk of clustering of cardiovascular risk factors (relative risk 0.81, 0.66 to 1.00) in childhood. Additional adjustment for gestational age and weight at birth changed these effect estimates only slightly. Childhood body mass index fully explained the associations of first trimester fetal crown to rump length with childhood total fat mass. First trimester fetal growth was not associated with other cardiovascular outcomes. Longitudinal growth analyses showed that compared with school age children without clustering of cardiovascular risk factors, those with clustering had a smaller first trimester fetal crown

  1. Pulmonary embolism

    SciTech Connect

    Dunnick, N.R.; Newman, G.E.; Perlmutt, L.M.; Braun, S.D.

    1988-11-01

    Pulmonary embolism is a common medical problem whose incidence is likely to increase in our aging population. Although it is life-threatening, effective therapy exists. The treatment is not, however, without significant complications. Thus, accurate diagnosis is important. Unfortunately, the clinical manifestations of pulmonary embolism are nonspecific. Furthermore, in many patients the symptoms of an acute embolism are superimposed on underlying chronic heart or lung disease. Thus, a high index of suspicion is needed to identify pulmonary emboli. Laboratory parameters, including arterial oxygen tensions and electrocardiography, are as nonspecific as the clinical signs. They may be more useful in excluding another process than in diagnosing pulmonary embolism. The first radiologic examination is the chest radiograph, but the clinical symptoms are frequently out of proportion to the findings on the chest films. Classic manifestations of pulmonary embolism on the chest radiograph include a wedge-shaped peripheral opacity and a segmental or lobar diminution in vascularity with prominent central arteries. However, these findings are not commonly seen and, even when present, are not specific. Even less specific findings include cardiomegaly, pulmonary infiltrate, elevation of a hemidiaphragm, and pleural effusion. Many patients with pulmonary embolism may have a normal chest radiograph. The chest radiograph is essential, however, for two purposes. First, it may identify another cause of the patient's symptoms, such as a rib fracture, dissecting aortic aneurysm, or pneumothorax. Second, a chest radiograph is essential to interpretation of the radionuclide V/Q scan. The perfusion scan accurately reflects the perfusion of the lung. However, a perfusion defect may result from a variety of etiologies. Any process such as vascular stenosis or compression by tumor may restrict blood flow. 84 references.

  2. Effect of placental restriction and neonatal exendin-4 treatment on postnatal growth, adult body composition, and in vivo glucose metabolism in the sheep.

    PubMed

    Liu, Hong; Schultz, Christopher G; De Blasio, Miles J; Peura, Anita M; Heinemann, Gary K; Harryanto, Himawan; Hunter, Damien S; Wooldridge, Amy L; Kind, Karen L; Giles, Lynne C; Simmons, Rebecca A; Owens, Julie A; Gatford, Kathryn L

    2015-09-15

    Intrauterine growth restriction (IUGR) increases the risk of adult type 2 diabetes (T2D) and obesity. Neonatal exendin-4 treatment can prevent diabetes in the IUGR rat, but whether this will be effective in a species where the pancreas is more mature at birth is unknown. Therefore, we evaluated the effects of neonatal exendin-4 administration after experimental restriction of placental and fetal growth on growth and adult metabolic outcomes in sheep. Body composition, glucose tolerance, and insulin secretion and sensitivity were assessed in singleton-born adult sheep from control (CON; n = 6 females and 4 males) and placentally restricted pregnancies (PR; n = 13 females and 7 males) and in sheep from PR pregnancies that were treated with exendin-4 as neonates (daily sc injections of 1 nmol/kg exendin-4; PR + exendin-4; n = 11 females and 7 males). Placental restriction reduced birth weight (by 29%) and impaired glucose tolerance in the adult but did not affect adult adiposity, insulin secretion, or insulin sensitivity. Neonatal exendin-4 suppressed growth during treatment, followed by delayed catchup growth and unchanged adult adiposity. Neonatal exendin-4 partially restored glucose tolerance in PR progeny but did not affect insulin secretion or sensitivity. Although the effects on glucose tolerance are promising, the lack of effects on adult body composition, insulin secretion, and insulin sensitivity suggest that the neonatal period may be too late to fully reprogram the metabolic consequences of IUGR in species that are more mature at birth than rodents. PMID:26219868

  3. Hypothesis: Neuroendocrine Mechanisms (Hypothalamus–Growth Hormone–STAT5 Axis) Contribute to Sex Bias in Pulmonary Hypertension

    PubMed Central

    Sehgal, Pravin B; Yang, Yang-Ming; Miller, Edmund J

    2015-01-01

    Pulmonary hypertension (PH) is a disease with high morbidity and mortality. The prevalence of idiopathic pulmonary arterial hypertension (IPAH) and hereditary pulmonary arterial hypertension (HPAH) is approximately two- to four-fold higher in women than in men. Paradoxically, there is an opposite male bias in typical rodent models of PH (chronic hypoxia or monocrotaline); in these models, administration of estrogenic compounds (for example, estradiol-17β [E2]) is protective. Further complexities are observed in humans ingesting anorexigens (female bias) and in rodent models, such as after hypoxia plus SU5416/Sugen (little sex bias) or involving serotonin transporter overexpression or dexfenfluramine administration (female bias). These complexities in sex bias in PH remain incompletely understood. We recently discovered that conditional deletion of signal transducer and activator of transcription 5a/b (STAT5a/b) in vascular smooth muscle cells abrogated the male bias in PH in hypoxic mice and that late-stage obliterative lesions in patients of both sexes with IPAH and HPAH showed reduced STAT5a/b, reduced Tyr-P-STAT5 and reduced B-cell lymphoma 6 protein (BCL6). In trying to understand the significance of these observations, we realized that there existed a well-characterized E2-sensitive central neuroendocrine mechanism of sex bias, studied over the last 40 years, that, at its peripheral end, culminated in species-specific male (“pulsatile”) versus female (“more continuous”) temporal patterns of circulating growth hormone (GH) levels leading to male versus female patterned activation of STAT5a/b in peripheral tissues and thus sex-biased expression of hundreds of genes. In this report, we consider the contribution of this neuroendocrine mechanism (hypothalamus-GH-STAT5) in the generation of sex bias in different PH situations. PMID:26252185

  4. Validating growth and development of a seabird as an indicator of food availability: captive-reared Caspian Tern chicks fed ad libitum and restricted diets

    USGS Publications Warehouse

    Lyons, Donald E.; Roby, Daniel D.

    2011-01-01

    For seabirds raising young under conditions of limited food availability, reducing chick provisioning and chick growth rates are the primary means available to avoid abandonment of a breeding effort. For most seabirds, however, baseline data characterizing chick growth and development under known feeding conditions are unavailable, so it is difficult to evaluate chick nutritional status as it relates to foraging conditions near breeding colonies. To address this need, we examined the growth and development of young Caspian Terns (Hydroprogne caspia), a cosmopolitan, generalist piscivore, reared in captivity and fed ad libitum and restricted (ca. one-third lower caloric intake) diets. Ad libitum-fed chicks grew at similar rates and achieved a similar size at fledging as previously documented for chicks in the wild and had energetic demands that closely matched allometric predictions. We identified three general characteristics of food-restricted Caspian Tern chicks compared to ad libitum chicks: (1) lower age-specific body mass, (2) lower age-specific skeletal and feather size, such as wing chord length, and (3) heightened levels of corticosterone in blood, both for baseline levels and in response to acute stress. Effects of diet restriction on feather growth (10-11% slower growth in diet-restricted chicks) were less pronounced than effects on structural growth (37-52% slower growth) and body mass (24% lower at fledging age), apparently due to preferential allocation of food resources to maintain plumage growth. Our results suggest that measurements of chick body mass and feather development (e.g., wing chord or primary length) or measurement of corticosterone levels in the blood would allow useful evaluation of the nutritional status of chicks reared in the wild and of food availability in the foraging range of adults. Such evaluations could also inform demography studies (e.g., predict future recruitment) and assist in evaluating designated piscivorous waterbird

  5. Ovine Surgical Model of Uterine Space Restriction: Interactive Effects of Uterine Anomalies and Multifetal Gestations on Fetal and Placental Growth1

    PubMed Central

    Meyer, Katie M.; Koch, Jill M.; Ramadoss, Jayanth; Kling, Pamela J.; Magness, Ronald R.

    2010-01-01

    Intrauterine growth restriction (IUGR) is observed in conditions with limitations in uterine space (e.g., uterine anomalies and multifetal gestations). IUGR is associated with reduced fetal weight, organ growth, and a spectrum of adult-onset diseases. To examine the interaction of uterine anomalies and multifetal gestations, we developed a surgical uterine space restriction model with a unilateral uterine horn ligation before breeding (unilateral surgery). Placentas and fetuses were studied on Gestational Day (GD) 120 and GD 130 (term = 147 days). Unilateral surgery decreased placentome numbers in singleton and twin pregnancies (25% and 50%, respectively) but not unilateral triplets. Unilateral surgery decreased total placentome weight in twin pregnancies (decreased 24%). Fetuses categorized as uterine space restricted (unilateral twin and both groups of triplets) had 51% fewer placentomes per fetus and a 31% reduction in placentomal weight per fetus compared to the nonrestricted group (control singleton, unilateral singleton, and control twin). By GD 130, uterine space-restricted fetuses exhibited decreased weight, smaller crown-rump, abdominal girth, and thoracic girth as well as decreased fetal heart, kidney, liver, spleen, and thymus weights. Lung and brain weights were unaffected, demonstrating asymmetric IUGR. At GD 130, placental efficiency (fetal weight per total placentomal weight) was elevated in uterine space-restricted fetuses. However, fetal arterial creatinine, blood urea nitrogen, and cholesterol were elevated, suggesting insufficient placental clearance. Maternal-to-fetal glucose and triglycerides ratios were elevated in the uterine space-restricted pregnancies, suggesting placental nutrient transport insufficiency. This model allows for examination of interactive effects of uterine space restriction-induced IUGR on placental adaptation and fetal organ growth. PMID:20574052

  6. Antisense Suppression of the Small Chloroplast Protein CP12 in Tobacco Alters Carbon Partitioning and Severely Restricts Growth1[W

    PubMed Central

    Howard, Thomas P.; Fryer, Michael J.; Singh, Prashant; Metodiev, Metodi; Lytovchenko, Anna; Obata, Toshihiro; Fernie, Alisdair R.; Kruger, Nicholas J.; Quick, W. Paul; Lloyd, Julie C.; Raines, Christine A.

    2011-01-01

    The thioredoxin-regulated chloroplast protein CP12 forms a multienzyme complex with the Calvin-Benson cycle enzymes phosphoribulokinase (PRK) and glyceraldehyde-3-phosphate dehydrogenase (GAPDH). PRK and GAPDH are inactivated when present in this complex, a process shown in vitro to be dependent upon oxidized CP12. The importance of CP12 in vivo in higher plants, however, has not been investigated. Here, antisense suppression of CP12 in tobacco (Nicotiana tabacum) was observed to impact on NAD-induced PRK and GAPDH complex formation but had little effect on enzyme activity. Additionally, only minor changes in photosynthetic carbon fixation were observed. Despite this, antisense plants displayed changes in growth rates and morphology, including dwarfism and reduced apical dominance. The hypothesis that CP12 is essential to separate oxidative pentose phosphate pathway activity from Calvin-Benson cycle activity, as proposed in cyanobacteria, was tested. No evidence was found to support this role in tobacco. Evidence was seen, however, for a restriction to malate valve capacity, with decreases in NADP-malate dehydrogenase activity (but not protein levels) and pyridine nucleotide content. Antisense repression of CP12 also led to significant changes in carbon partitioning, with increased carbon allocation to the cell wall and the organic acids malate and fumarate and decreased allocation to starch and soluble carbohydrates. Severe decreases were also seen in 2-oxoglutarate content, a key indicator of cellular carbon sufficiency. The data presented here indicate that in tobacco, CP12 has a role in redox-mediated regulation of carbon partitioning from the chloroplast and provides strong in vivo evidence that CP12 is required for normal growth and development in plants. PMID:21865489

  7. Sildenafil Therapy Normalizes the Aberrant Metabolomic Profile in the Comt−/− Mouse Model of Preeclampsia/Fetal Growth Restriction

    PubMed Central

    Stanley, Joanna L.; Sulek, Karolina; Andersson, Irene J.; Davidge, Sandra T.; Kenny, Louise C.; Sibley, Colin P.; Mandal, Rupasri; Wishart, David S.; Broadhurst, David I.; Baker, Philip N.

    2015-01-01

    Preeclampsia (PE) and fetal growth restriction (FGR) are serious complications of pregnancy, associated with greatly increased risk of maternal and perinatal morbidity and mortality. These complications are difficult to diagnose and no curative treatments are available. We hypothesized that the metabolomic signature of two models of disease, catechol-O-methyl transferase (COMT−/−) and endothelial nitric oxide synthase (Nos3−/−) knockout mice, would be significantly different from control C57BL/6J mice. Further, we hypothesised that any differences in COMT−/− mice would be resolved following treatment with Sildenafil, a treatment which rescues fetal growth. Targeted, quantitative comparisons of serum metabolic profiles of pregnant Nos3−/−, COMT−/− and C57BL/6J mice were made using a kit from BIOCRATES. Significant differences in 4 metabolites were observed between Nos3−/− and C57BL/6J mice (p < 0.05) and in 18 metabolites between C57BL/6J and COMT−/− mice (p < 0.05). Following treatment with Sildenafil, only 5 of the 18 previously identified differences in metabolites (p < 0.05) remained in COMT−/− mice. Metabolomic profiling of mouse models is possible, producing signatures that are clearly different from control animals. A potential new treatment, Sildenafil, is able to normalize the aberrant metabolomic profile in COMT−/− mice; as this treatment moves into clinical trials, this information may assist in assessing possible mechanisms of action. PMID:26667607

  8. Detection of Expressional Changes Induced by Intrauterine Growth Restriction in the Developing Rat Mammary Gland via Exploratory Pathways Analysis

    PubMed Central

    Beinder, Lea; Faehrmann, Nina; Wachtveitl, Rainer; Winterfeld, Ilona; Hartner, Andrea; Menendez-Castro, Carlos; Rauh, Manfred; Ruebner, Matthias; Huebner, Hanna; Noegel, Stephanie C.; Doerr, Helmuth G.; Rascher, Wolfgang; Fahlbusch, Fabian B.

    2014-01-01

    Background Intrauterine growth restriction (IUGR) is thought to lead to fetal programming that in turn contributes to developmental changes of many organs postnatally. There is evidence that IUGR is a risk factor for the development of metabolic and cardiovascular disease later in life. A higher incidence of breast cancer was also observed after IUGR. This could be due to changes in mammary gland developmental pathways. We sought to characterise IUGR-induced alterations of the complex pathways of mammary development at the level of the transcriptome in a rat model of IUGR, using pathways analysis bioinformatics. Methodology/Principal Findings We analysed the mammary glands of Wistar rats with IUGR induced by maternal low protein (LP) diet at the beginning (d21) and the end (d28) of pubertal ductal morphogenesis. Mammary glands of the LP group were smaller in size at d28, however did not show morphologic changes. We identified multiple differentially expressed genes in the mammary gland using Agilent SurePrint arrays at d21 and d28. In silico analysis was carried out using Ingenuity Pathways Analysis. In mammary gland tissue of LP rats at d21 of life a prominent upregulation of WT1 and CDKN1A (p21) expression was observed. Differentially regulated genes were associated with the extracellular regulated kinase (ERK)-1/-2 pathway. Western Blot analysis showed reduced levels of phosphorylated ERK-1/-2 in the mammary glands of the LP group at d21. To identify possible changes in circulating steroid levels, serum LC-Tandem mass-spectrometry was performed. LP rats showed higher serum progesterone levels and an increased corticosterone/dehydrocorticosterone-ratio at d28. Conclusions/Significance Our data obtained from gene array analysis support the hypothesis that IUGR influences pubertal development of the rat mammary gland. We identified prominent differential regulation of genes and pathways for factors regulating cell cycle and growth. Moreover, we detected new

  9. Intrauterine growth restriction leads to changes in sulfur amino acid metabolism, but not global DNA methylation, in Yucatan miniature piglets.

    PubMed

    MacKay, Dylan S; Brophy, Julie D; McBreairty, Laura E; McGowan, Ross A; Bertolo, Robert F

    2012-09-01

    Intrauterine growth restriction (IUGR), in both animals and humans, has been linked to metabolic syndrome later in life. There has been recent evidence that perturbations in sulfur amino acid metabolism may be involved in this early programming phenomenon. Methionine is the precursor for cellular methylation reactions and for the synthesis of cysteine. It has been suggested that the mechanism behind the "fetal origins" of adult diseases may be epigenetic, involving DNA methylation. Because we have recently demonstrated the fetal origins phenomenon in Yucatan miniature swine, we hypothesized that sulfur amino acid metabolism is altered in IUGR piglets. In this study, metabolites and the activities of sulfur amino acid cycle enzymes were analyzed in liver samples of 3- to 5-day-old runt (IUGR: 0.85±0.13 kg) and large (1.36±0.21 kg) Yucatan miniature pig littermates (n=6 pairs). The IUGR piglets had significantly lower specific and total activities of betaine-homocysteine methyltransferase (BHMT) and cystathionine γ-lyase (CGL) than larger littermates (P<.05). Expression of CGL (but not BHMT) mRNA was also lower in IUGR piglets (P<.05). This low CGL reduced cysteine and taurine concentrations in IUGR pigs and led to an accumulation of hepatic cystathionine, with lower homocysteine concentrations. Methylation index and liver global DNA methylation were unaltered. Reduced prenatal growth in Yucatan miniature piglets impairs their remethylation capacity as well as their ability to remove cystathionine and synthesize cysteine and taurine, which could have important implications on long-term health outcomes of IUGR neonates. PMID:22137257

  10. Placental Underperfusion in a Rat Model of Intrauterine Growth Restriction Induced by a Reduced Plasma Volume Expansion

    PubMed Central

    Bibeau, Karine; Sicotte, Benoit; Béland, Mélanie; Bhat, Menakshi; Gaboury, Louis; Couture, Réjean; St-Louis, Jean; Brochu, Michèle

    2016-01-01

    Lower maternal plasma volume expansion was found in idiopathic intrauterine growth restriction (IUGR) but the link remains to be elucidated. An animal model of IUGR was developed by giving a low-sodium diet to rats over the last week of gestation. This treatment prevents full expansion of maternal circulating volume and the increase in uterine artery diameter, leading to reduced placental weight compared to normal gestation. We aimed to verify whether this is associated with reduced remodeling of uteroplacental circulation and placental hypoxia. Dams were divided into two groups: IUGR group and normal-fed controls. Blood velocity waveforms in the main uterine artery were obtained by Doppler sonography on days 14, 18 and 21 of pregnancy. On day 22 (term = 23 days), rats were sacrificed and placentas and uterine radial arteries were collected. Diameter and myogenic response of uterine arteries supplying placentas were determined while expression of hypoxia-modulated genes (HIF-1α, VEGFA and VEGFR2), apoptotic enzyme (Caspase -3 and -9) and glycogen cells clusters were measured in control and IUGR term-placentas. In the IUGR group, impaired blood velocity in the main uterine artery along with increased resistance index was observed without alteration in umbilical artery blood velocity. Radial uterine artery diameter was reduced while myogenic response was increased. IUGR placentas displayed increased expression of hypoxia markers without change in the caspases and increased glycogen cells in the junctional zone. The present data suggest that reduced placental and fetal growth in our IUGR model may be mediated, in part, through reduced maternal uteroplacental blood flow and increased placental hypoxia. PMID:26727492

  11. Intrauterine growth restriction

    MedlinePlus

    ... the developing baby. These include: Cytomegalovirus Rubella Syphilis Toxoplasmosis Risk factors in the mother that may contribute ... safe drinking Eclampsia Preeclampsia Rubella Substance use disorder Toxoplasmosis Ultrasound Update Date 11/16/2014 Updated by: ...

  12. Intrauterine growth restriction

    MedlinePlus

    ... may contribute to IUGR include: Alcohol abuse Smoking Drug addiction Clotting disorders High blood pressure or heart disease Kidney disease Poor nutrition If the mother is small, it may be ... head may be normal size while the rest of the body is small.

  13. Intrauterine Growth Restriction

    MedlinePlus

    ... height? Your baby will probably catch up in size and have a normal height by about 2 years of age. ... If the mother has an infection, high blood pressure, kidney disease, heart disease or sickle cell anemia, or ...

  14. Intrauterine Growth Restriction (IUGR)

    MedlinePlus

    ... the baby's gestational age by accurately dating the pregnancy. At first, gestational age is estimated using the first day of a woman's last menstrual period. Later in the pregnancy (usually between weeks 8 ... Once a baby's gestational age is known, doctors use it to watch the ...

  15. Heart morphology differences induced by intrauterine growth restriction and preterm birth measured on the ECG at preadolescent age.

    PubMed

    Ortigosa, Nuria; Rodriguez-Lopez, Merida; Bailón, Raquel; Sarvari, Sebastian Imre; Sitges, Marta; Gratacos, Eduard; Bijnens, Bart; Crispi, Fatima; Laguna, Pablo

    2016-01-01

    Intrauterine Growth Restriction (IUGR) and premature birth are associated with higher risk of cardiovascular diseases throughout adulthood. The aim of this study was to evaluate the influence of these factors in ventricular electrical remodeling in preadolescents. Electrocardiography was performed in a cohort of 33-IUGR, 32-preterm with appropriate weight and 60 controls. Depolarization and repolarization processes were studied by means of the surface ECG, including loops and angles corresponding to QRS and T-waves. The angles between the dominant vector of QRS and the frontal plane XY were different among the study groups: controls [20.03°(10.11°-28.64°)], preterm [25.48°(19.79°-33.56°)], and IUGR [27.77°(16.59°-33.23°)]. When compared to controls, IUGR subjects also presented wider angles between the difference of QRS and T-wave dominant vectors and the XY-plane [5.28°±12.15° vs 0.49°±14.15°, p<0.05] while preterm ones showed smaller frontal QRS-T angle [4.68°(2.20°-12.89°) vs 6.57°(2.72°-11.31°), p<0.05]. Thus, electrical remodeling is present in IUGR and preterm preadolescents, and might predispose them to cardiovascular diseases in adulthood. Follow-up studies are warranted. PMID:27036371

  16. Inflammation in rat pregnancy inhibits spiral artery remodeling leading to fetal growth restriction and features of preeclampsia

    PubMed Central

    Cotechini, Tiziana; Komisarenko, Maria; Sperou, Arissa; Macdonald-Goodfellow, Shannyn; Adams, Michael A.

    2014-01-01

    Fetal growth restriction (FGR) and preeclampsia (PE) are often associated with abnormal maternal inflammation, deficient spiral artery (SA) remodeling, and altered uteroplacental perfusion. Here, we provide evidence of a novel mechanistic link between abnormal maternal inflammation and the development of FGR with features of PE. Using a model in which pregnant rats are administered low-dose lipopolysaccharide (LPS) on gestational days 13.5–16.5, we show that abnormal inflammation resulted in FGR mediated by tumor necrosis factor-α (TNF). Inflammation was also associated with deficient trophoblast invasion and SA remodeling, as well as with altered uteroplacental hemodynamics and placental nitrosative stress. Moreover, inflammation increased maternal mean arterial pressure (MAP) and was associated with renal structural alterations and proteinuria characteristic of PE. Finally, transdermal administration of the nitric oxide (NO) mimetic glyceryl trinitrate prevented altered uteroplacental perfusion, LPS-induced inflammation, placental nitrosative stress, renal structural and functional alterations, increase in MAP, and FGR. These findings demonstrate that maternal inflammation can lead to severe pregnancy complications via a mechanism that involves increased maternal levels of TNF. Our study provides a rationale for the use of antiinflammatory agents or NO-mimetics in the treatment and/or prevention of inflammation-associated pregnancy complications. PMID:24395887

  17. Guidance Molecule SEMA3A Restricts Tumor Growth by Differentially Regulating the Proliferation of Tumor-Associated Macrophages.

    PubMed

    Wallerius, Majken; Wallmann, Tatjana; Bartish, Margarita; Östling, Jeanette; Mezheyeuski, Artur; Tobin, Nicholas P; Nygren, Emma; Pangigadde, Pradeepa; Pellegrini, Paola; Squadrito, Mario Leonardo; Pontén, Fredrik; Hartman, Johan; Bergh, Jonas; De Milito, Angelo; De Palma, Michele; Östman, Arne; Andersson, John; Rolny, Charlotte

    2016-06-01

    Accumulation of tumor-associated macrophages (TAM) correlates with malignant progression, immune suppression, and poor prognosis. In this study, we defined a critical role for the cell-surface guidance molecule SEMA3A in differential proliferative control of TAMs. Tumor cell-derived SEMA3A restricted the proliferation of protumoral M2 macrophages but increased the proliferation of antitumoral M1, acting through the SEMA3A receptor neuropilin 1. Expansion of M1 macrophages in vivo enhanced the recruitment and activation of natural killer (NK) cells and cytotoxic CD8(+) T cells to tumors, inhibiting their growth. In human breast cancer specimens, we found that immunohistochemical levels of SEMA3A correlated with the expression of genes characteristic of M1 macrophages, CD8(+) T cells, and NK cells, while inversely correlating with established characters of malignancy. In summary, our results illuminate a mechanism whereby the TAM phenotype is controlled and identify the cell-surface molecule SEMA3A as a candidate for therapeutic targeting. Cancer Res; 76(11); 3166-78. ©2016 AACR. PMID:27197153

  18. Increased Fetal Plasma Erythropoietin in Monochorionic Twin Pregnancies With Selective Intrauterine Growth Restriction and Abnormal Umbilical Artery Doppler.

    PubMed

    Chang, Yao-Lung; Chao, An-Shine; Peng, Hsiu-Huei; Chang, Shuenn-Dyh; Su, Sheng-Yuan; Chen, Kuan-Ju; Cheng, Po-Jen; Wang, Tzu-Hao

    2016-08-01

    Hypoxia is the primary stimulus for the production of erythropoietin (EPO) in both fetal and adult life. Here, we investigated fetal plasma EPO concentrations in monochorionic (MC) twin pregnancies with selective intrauterine growth restriction (sIUGR) and abnormal umbilical artery (UA) Doppler. We diagnosed sIUGR in presence of (1) birth-weight discordance >20% and (2) either twin with a birth weight <10th percentile. An abnormal UA Doppler was defined as a persistent absent-reverse end diastolic flow (AREDF). The intertwin EPO ratio was calculated as the plasma EPO level of the smaller (or small-for-gestational-age) twin divided by the EPO concentration of the larger (or appropriate-for-gestational-age (AGA)) twin. Thirty-two MC twin pairs were included. Of these, 17 pairs were normal twins (Group 1), seven pairs were twins with sIUGR without UA Doppler abnormalities (Group 2), and eight pairs were twins with sIUGR and UA Doppler abnormalities (Group 3). The highest EPO ratio was identified in Group 3 (p < .001) but no significant differences were observed between Groups 1 and 2. Fetal hemoglobin levels did not differ significantly in the three groups, and fetal EPO concentration did not correlate with gestational age at birth. We conclude that fetal plasma EPO concentrations are selectively increased in MC twin pregnancies with sIUGR and abnormal UA Doppler, possibly as a result of uncompensated hypoxia. PMID:27161360

  19. Cadmium-induced neural tube defects and fetal growth restriction: Association with disturbance of placental folate transport.

    PubMed

    Zhang, Gui-Bin; Wang, Hua; Hu, Jun; Guo, Min-Yin; Wang, Ying; Zhou, Yan; Yu, Zhen; Fu, Lin; Chen, Yuan-Hua; Xu, De-Xiang

    2016-09-01

    Previous studies found that maternal Cd exposure on gestational day (GD)9 caused forelimb ectrodactyly and tail deformity, the characteristic malformations. The aim of the present study was to investigate whether maternal Cd exposure on GD8 induces fetal neural tube defects (NTDs). Pregnant mice were intraperitoneally injected with CdCl2 (2.5 or 5.0mg/kg) on GD8. Neither forelimb ectrodactyly nor tail deformity was observed in mice injected with CdCl2 on GD8. Instead, maternal Cd exposure on GD8 resulted in the incidence of NTDs. Moreover, maternal Cd exposure on GD8 resulted in fetal growth restriction. In addition, maternal Cd exposure on GD8 reduced placental weight and diameter. The internal space of maternal and fetal blood vessels in the labyrinth layer was decreased in the placentas of mice treated with CdCl2. Additional experiment showed that placental PCFT protein and mRNA, a critical folate transporter, was persistently decreased when dams were injected with CdCl2 on GD8. Correspondingly, embryonic folate content was markedly decreased in mice injected with CdCl2 on GD8, whereas Cd had little effect on folate content in maternal serum. Taken together, these results suggest that maternal Cd exposure during organogenesis disturbs transport of folate from maternal circulation to the fetuses through down-regulating placental folate transporters. PMID:27417525

  20. Prenatal growth restriction, retinal dystrophy, diabetes insipidus and white matter disease: expanding the spectrum of PRPS1-related disorders.

    PubMed

    Al-Maawali, Almundher; Dupuis, Lucie; Blaser, Susan; Heon, Elise; Tarnopolsky, Mark; Al-Murshedi, Fathiya; Marshall, Christian R; Paton, Tara; Scherer, Stephen W; Roelofsen, Jeroen; van Kuilenburg, André B P; Mendoza-Londono, Roberto

    2015-03-01

    PRPS1 codes for the enzyme phosphoribosyl pyrophosphate synthetase-1 (PRS-1). The spectrum of PRPS1-related disorders associated with reduced activity includes Arts syndrome, Charcot-Marie-Tooth disease-5 (CMTX5) and X-linked non-syndromic sensorineural deafness (DFN2). We describe a novel phenotype associated with decreased PRS-1 function in two affected male siblings. Using whole exome and Sanger sequencing techniques, we identified a novel missense mutation in PRPS1. The clinical phenotype in our patients is characterized by high prenatal maternal α-fetoprotein, intrauterine growth restriction, dysmorphic facial features, severe intellectual disability and spastic quadraparesis. Additional phenotypic features include macular coloboma-like lesions with retinal dystrophy, severe short stature and diabetes insipidus. Exome sequencing of the two affected male siblings identified a shared putative pathogenic mutation c.586C>T p.(Arg196Trp) in the PRPS1 gene that was maternally inherited. Follow-up testing showed normal levels of hypoxanthine in urine samples and uric acid levels in blood serum. The PRS activity was significantly reduced in erythrocytes of the two patients. Nucleotide analysis in erythrocytes revealed abnormally low guanosine triphosphate and guanosine diphosphate. This presentation is the most severe form of PRPS1-deficiency syndrome described to date and expands the spectrum of PRPS1-related disorders. PMID:24961627

  1. Haploinsufficiency of KDM6A is associated with severe psychomotor retardation, global growth restriction, seizures and cleft palate

    PubMed Central

    Lindgren, Amelia M.; Hoyos, Tatiana; Talkowski, Michael E.; Hanscom, Carrie; Blumenthal, Ian; Chiang, Colby; Ernst, Carl; Pereira, Shahrin; Ordulu, Zehra; Clericuzio, Carol; Drautz, Joanne M.; Rosenfeld, Jill A.; Shaffer, Lisa G.; Velsher, Lea; Pynn, Tania; Vermeesch, Joris; Harris, David J.; Gusella, James F.; Liao, Eric C.

    2013-01-01

    We describe a female subject (DGAP100) with a 46,X,t(X;5)(p11.3;q35.3)inv(5)(q35.3q35.1)dn, severe psychomotor retardation with hypotonia, global postnatal growth restriction, microcephaly, globally reduced cerebral volume, seizures, facial dysmorphia and cleft palate. Fluorescence in situ hybridization and whole-genome sequencing demonstrated that the X chromosome breakpoint disrupts KDM6A in the second intron. No genes were directly disrupted on chromosome 5. KDM6A is a histone 3 lysine 27 demethylase and a histone 3 lysine 4 methyl-transferase. Expression of KDM6A is significantly reduced in DGAP100 lymphoblastoid cells compared to control samples. We identified nine additional cases with neurodevelopmental delay and various other features consistent with the DGAP100 phenotype with copy number variation encompassing KDM6A from microarray databases. We evaluated haploinsufficiency of kdm6a in a zebrafish model. kdm6a is expressed in the pharyngeal arches and ethmoid plate of the developing zebrafish, while a kdm6a morpholino knockdown exhibited craniofacial defects. We conclude KDM6A dosage regulation is associated with severe and diverse structural defects and developmental abnormalities. PMID:23354975

  2. The Long-Term Effects of Prematurity and Intrauterine Growth Restriction on Cardiovascular, Renal, and Metabolic Function

    PubMed Central

    Chan, Patricia Y. L.; Morris, Jonathan M.; Leslie, Garth I.; Kelly, Patrick J.; Gallery, Eileen D. M.

    2010-01-01

    Objective. To determine relative influences of intrauterine growth restriction (IUGR) and preterm birth on risks of cardiovascular, renal, or metabolic dysfunction in adolescent children. Study Design. Retrospective cohort study. 71 periadolescent children were classified into four groups: premature small for gestational age (SGA), premature appropriate for gestational age (AGA), term SGA, and term AGA. Outcome Measures. Systolic blood pressure (SBP), augmentation index (Al), glomerular filtration rate (GFR) following protein load; plasma glucose and serum insulin levels. Results. SGA had higher SBP (average 4.6 mmHg) and lower GFR following protein load (average 28.5 mL/min/1.73 m2) than AGA. There was no effect of prematurity on SBP (P = .4) or GFR (P = .9). Both prematurity and SGA were associated with higher AI (average 9.7%) and higher serum insulin levels 2 hr after glucose load (average 15.5 mIU/L) than all other groups. Conclusion. IUGR is a more significant risk factor than preterm birth for later systolic hypertension and renal dysfunction. Among children born preterm, those who are also SGA are at increased risk of arterial stiffness and metabolic dysfunction. PMID:21197428

  3. RasGRP1 opposes proliferative EGFR–SOS1–Ras signals and restricts intestinal epithelial cell growth

    PubMed Central

    Depeille, Philippe; Henricks, Linda M.; van de Ven, Robert A. H.; Lemmens, Ed; Wang, Chih-Yang; Matli, Mary; Werb, Zena; Haigis, Kevin M.; Donner, David; Warren, Robert; Roose, Jeroen P.

    2015-01-01

    The character of EGFR signals can influence cell fate but mechanistic insights into intestinal EGFR-Ras signalling are limited. Here we show that two distinct Ras nucleotide exchange factors, RasGRP1 and SOS1, lie downstream of EGFR but act in functional opposition. RasGRP1 is expressed in intestinal crypts where it restricts epithelial growth. High RasGRP1 expression in colorectal cancer (CRC) patient samples correlates with a better clinical outcome. Biochemically, we find that RasGRP1 creates a negative feedback loop that limits proliferative EGFR–SOS1–Ras signals in CRC cells. Genetic Rasgrp1 depletion from mice with either an activating mutation in KRas or with aberrant Wnt signalling due to a mutation in Apc resulted in both cases in exacerbated Ras–ERK signalling and cell proliferation. The unexpected opposing cell biological effects of EGFR–RasGRP1 and EGFR–SOS1 signals in the same cell shed light on the intricacy of EGFR-Ras signalling in normal epithelium and carcinoma. PMID:26005835

  4. Placental Expression Patterns of Galectin-1, Galectin-2, Galectin-3 and Galectin-13 in Cases of Intrauterine Growth Restriction (IUGR)

    PubMed Central

    Hutter, Stefan; Knabl, Julia; Andergassen, Ulrich; Hofmann, Simone; Kuhn, Christina; Mahner, Sven; Arck, Petra; Jeschke, Udo

    2016-01-01

    Galectins (gal) are members of the mammalian β-galactoside-binding proteins and recognize Galβ1-4GlcNAc and Galβ1-4GalNac (Thomsen-Friedenreich antigen (TF)) sequences of several cell surface oligosaccharides. In this study, gal-1, -2, -3 and -13 were investigated systematically in the trophoblast and decidua compartment of intrauterine growth restriction (IUGR) placentas and normal third trimester control placentas and stratified by fetal gender and gestational age. Within this study, 29 third trimester placentas after delivery were analyzed. Fetal gender was equally divided within both groups, and immunohistochemical staining was analyzed according to fetal gender and gestational age. Double immune-fluorescence with trophoblast-specific markers was used to identify galectin-expressing cells at the feto-maternal interface in the decidua. Gal-3 was significantly downregulated only in the extravillous trophoblast of IUGR placentas. In contrast, expressions of gal-2 and gal-13 were downregulated in both villous and extravillous trophoblast cells of IUGR placentas. In addition, gal-2 and gal-13 showed a highly correlated expression scheme in the placenta. There are significant gender-specific expression patterns for single prototype galectins with downregulation of gal-2 and gal-13 of male gender placentas in cases of IUGR. Gal-3 as the chimera type galectin shows only little gender-specific differences in expression, which disappear in IUGR cases. PMID:27070577

  5. Placental Expression Patterns of Galectin-1, Galectin-2, Galectin-3 and Galectin-13 in Cases of Intrauterine Growth Restriction (IUGR).

    PubMed

    Hutter, Stefan; Knabl, Julia; Andergassen, Ulrich; Hofmann, Simone; Kuhn, Christina; Mahner, Sven; Arck, Petra; Jeschke, Udo

    2016-01-01

    Galectins (gal) are members of the mammalian β-galactoside-binding proteins and recognize Galβ1-4GlcNAc and Galβ1-4GalNac (Thomsen-Friedenreich antigen (TF)) sequences of several cell surface oligosaccharides. In this study, gal-1, -2, -3 and -13 were investigated systematically in the trophoblast and decidua compartment of intrauterine growth restriction (IUGR) placentas and normal third trimester control placentas and stratified by fetal gender and gestational age. Within this study, 29 third trimester placentas after delivery were analyzed. Fetal gender was equally divided within both groups, and immunohistochemical staining was analyzed according to fetal gender and gestational age. Double immune-fluorescence with trophoblast-specific markers was used to identify galectin-expressing cells at the feto-maternal interface in the decidua. Gal-3 was significantly downregulated only in the extravillous trophoblast of IUGR placentas. In contrast, expressions of gal-2 and gal-13 were downregulated in both villous and extravillous trophoblast cells of IUGR placentas. In addition, gal-2 and gal-13 showed a highly correlated expression scheme in the placenta. There are significant gender-specific expression patterns for single prototype galectins with downregulation of gal-2 and gal-13 of male gender placentas in cases of IUGR. Gal-3 as the chimera type galectin shows only little gender-specific differences in expression, which disappear in IUGR cases. PMID:27070577

  6. Measurement of internal diameter changes and pulse wave velocity in fetal descending aorta using the ultrasonic phased-tracking method in normal and growth-restricted fetuses.

    PubMed

    Miyashita, Susumu; Murotsuki, Jun; Muromoto, Jin; Ozawa, Katsusuke; Yaegashi, Nobuo; Hasegawa, Hideyuki; Kanai, Hiroshi

    2015-05-01

    Phased tracking (PT) is an ultrasound-based technique that enables precise measurement of a target velocity. The aims of this study were to use PT to evaluate arterial pulse waveform, pulse wave velocity and fetal pulse pressure in normal and growth-restricted fetuses. One hundred fetuses with normal development and 15 fetuses with growth restriction were analyzed. Ultrasonic raw radiofrequency signals were captured from a direction perpendicular to the vascular axis at the fetal diaphragmatic level for the difference in internal dimensions (DID), or simultaneously from different directions for the pulse wave velocity. Pulsatile movement of the proximal and distal intima of the vessels was analyzed using PT. The fetal DID exhibited no significant changes in growth-restricted fetuses. Pulse wave velocity (3.8 ± 0.32 m/s vs. 2.2 ± 0.069 m/s, p < 0.001) and estimated pulse pressure (6.9 ± 0.90 kPa vs. 2.5 ± 0.18 kPa, p < 0.001) were significantly elevated in growth-restricted fetuses. Assessment of DID and pulse wave velocity of the descending aorta using PT is a feasible, non-invasive approach to evaluation of fetal hemodynamics. PMID:25727918

  7. Glucose restriction can extend normal cell lifespan and impair precancerous cell growth through epigenetic control of hTERT and p16 expression

    PubMed Central

    Li, Yuanyuan; Liu, Liang; Tollefsbol, Trygve O.

    2010-01-01

    Cancer cells metabolize glucose at elevated rates and have a higher sensitivity to glucose reduction. However, the precise molecular mechanisms leading to different responses to glucose restriction between normal and cancer cells are not fully understood. We analyzed normal WI-38 and immortalized WI-38/S fetal lung fibroblasts and found that glucose restriction resulted in growth inhibition and apoptosis in WI-38/S cells, whereas it induced lifespan extension in WI-38 cells. Moreover, in WI-38/S cells glucose restriction decreased expression of hTERT (human telomerase reverse transcriptase) and increased expression of p16INK4a. Opposite effects were found in the gene expression of hTERT and p16 in WI-38 cells in response to glucose restriction. The altered gene expression was partly due to glucose restriction-induced DNA methylation changes and chromatin remodeling of the hTERT and p16 promoters in normal and immortalized WI-38 cells. Furthermore, glucose restriction resulted in altered hTERT and p16 expression in response to epigenetic regulators in WI-38 rather than WI-38/S cells, suggesting that energy stress-induced differential epigenetic regulation may lead to different cellular fates in normal and precancerous cells. Collectively, these results provide new insights into the epigenetic mechanisms of a nutrient control strategy that may contribute to cancer therapy as well as antiaging approaches.—Li, Y., Liu, L., Tollefsbol, T. O. Glucose restriction can extend normal cell lifespan and impair precancerous cell growth through epigenetic control of hTERT and p16 expression. PMID:20019239

  8. In Vivo Detection of Perinatal Brain Metabolite Changes in a Rabbit Model of Intrauterine Growth Restriction (IUGR)

    PubMed Central

    Simões, Rui V.; Muñoz-Moreno, Emma; Carbajo, Rodrigo J.; González-Tendero, Anna; Illa, Miriam; Sanz-Cortés, Magdalena; Pineda-Lucena, Antonio; Gratacós, Eduard

    2015-01-01

    Background Intrauterine growth restriction (IUGR) is a risk factor for abnormal neurodevelopment. We studied a rabbit model of IUGR by magnetic resonance imaging (MRI) and spectroscopy (MRS), to assess in vivo brain structural and metabolic consequences, and identify potential metabolic biomarkers for clinical translation. Methods IUGR was induced in 3 pregnant rabbits at gestational day 25, by 40–50% uteroplacental vessel ligation in one horn; the contralateral horn was used as control. Fetuses were delivered at day 30 and weighted. A total of 6 controls and 5 IUGR pups underwent T2-w MRI and localized proton MRS within the first 8 hours of life, at 7T. Changes in brain tissue volumes and respective contributions to each MRS voxel were estimated by semi-automated registration of MRI images with a digital atlas of the rabbit brain. MRS data were used for: (i) absolute metabolite quantifications, using linear fitting; (ii) local temperature estimations, based on the water chemical shift; and (iii) classification, using spectral pattern analysis. Results Lower birth weight was associated with (i) smaller brain sizes, (ii) slightly lower brain temperatures, and (iii) differential metabolite profile changes in specific regions of the brain parenchyma. Specifically, we found estimated lower levels of aspartate and N-acetylaspartate (NAA) in the cerebral cortex and hippocampus (suggesting neuronal impairment), and higher glycine levels in the striatum (possible marker of brain injury). Our results also suggest that the metabolic changes in cortical regions are more prevalent than those detected in hippocampus and striatum. Conclusions IUGR was associated with brain metabolic changes in vivo, which correlate well with the neurostructural changes and neurodevelopment problems described in IUGR. Metabolic parameters could constitute non invasive biomarkers for the diagnosis and abnormal neurodevelopment of perinatal origin. PMID:26208165

  9. Maternal melatonin administration mitigates coronary stiffness and endothelial dysfunction, and improves heart resilience to insult in growth restricted lambs

    PubMed Central

    Tare, Marianne; Parkington, Helena C; Wallace, Euan M; Sutherland, Amy E; Lim, Rebecca; Yawno, Tamara; Coleman, Harold A; Jenkin, Graham; Miller, Suzanne L

    2014-01-01

    Intrauterine growth restriction (IUGR) is associated with impaired cardiac function in childhood and is linked to short- and long-term morbidities. Placental dysfunction underlies most IUGR, and causes fetal oxidative stress which may impact on cardiac development. Accordingly, we investigated whether antenatal melatonin treatment, which possesses antioxidant properties, may afford cardiovascular protection in these vulnerable fetuses. IUGR was induced in sheep fetuses using single umbilical artery ligation on day 105–110 of pregnancy (term 147). Study 1: melatonin (2 mg h−1) was administered i.v. to ewes on days 5 and 6 after surgery. On day 7 fetal heart function was assessed using a Langendorff apparatus. Study 2: a lower dose of melatonin (0.25 mg h−1) was administered continuously following IUGR induction and the ewes gave birth normally at term. Lambs were killed when 24 h old and coronary vessels studied. Melatonin significantly improved fetal oxygenation in vivo. Contractile function in the right ventricle and coronary flow were enhanced by melatonin. Ischaemia–reperfusion-induced infarct area was 3-fold greater in IUGR hearts than in controls and this increase was prevented by melatonin. In isolated neonatal coronary arteries, endothelium-dependent nitric oxide (NO) bioavailability was reduced in IUGR, and was rescued by modest melatonin treatment. Melatonin exposure also induced the emergence of an indomethacin-sensitive vasodilation. IUGR caused marked stiffening of the coronary artery and this was prevented by melatonin. Maternal melatonin treatment reduces fetal hypoxaemia, improves heart function and coronary blood flow and rescues cardio-coronary deficit induced by IUGR. PMID:24710061

  10. Is the fetoplacental ratio a differential marker of fetal growth restriction in small for gestational age infants?

    PubMed

    Luque-Fernandez, Miguel Angel; Ananth, Cande V; Jaddoe, Vincent W V; Gaillard, Romy; Albert, Paul S; Schomaker, Michael; McElduff, Patrick; Enquobahrie, Daniel A; Gelaye, Bizu; Williams, Michelle A

    2015-04-01

    Higher placental weight relative to birthweight has been described as an adaptive mechanism to fetal hypoxia in small for gestational age (SGA) infants. However, placental weight alone may not be a good marker reflecting intrauterine growth restriction. We hypothesized that fetoplacental ratio (FPR)-the ratio between birthweight and placental weight-may serve as a good marker of SGA after adjustment for surrogates of fetal hypoxemia (maternal iron deficiency anemia, smoking and choriodecidual necrosis). We conducted a within-sibling analysis using data from the US National Collaborative Perinatal Project (1959-1966) of 1,803 women who delivered their first two (or more) consecutive infants at term (n = 3,494). We used variance-component fixed-effect linear regression models to explore the effect of observed time-varying factors on placental weight and conditional logistic regression to estimate the effects of the tertiles of FPRs (1st small, 2nd normal and 3rd large) on the odds of SGA infants. We found placental weights to be 15 g [95 % confidence interval (CI) 8, 23] higher and -7 g (95 % CI -13, -2) lower among women that had anemia and choriodecidual necrosis, respectively. After multivariable adjustment, newborns with a small FPR (1st-tertile ≤7) had twofold higher odds of being SGA (OR 2.0, 95 % CI 1.2, 3.5) than their siblings with a large FPR (3nd-tertile ≥9). A small FPR was associated with higher odds of SGA, suggesting that small FPR may serve as an indicator suggestive of adverse intrauterine environment. This observation may help to distinguish pathological from constitutional SGA. PMID:25630563