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  1. Metabolic perturbations of postnatal growth restriction and hyperoxia-induced pulmonary hypertension in a bronchopulmonary dysplasia model

    USDA-ARS?s Scientific Manuscript database

    Introduction: Neonatal pulmonary hypertension (PH) is a common manifestation of bronchopulmonary dysplasia (BPD) and contributes to increased morbidity and mortality of preterm birth. Postnatal growth restriction and hyperoxia are independent contributors to PH development, as indicated by our previ...

  2. 7A.03: TRANSGENERATIONAL INHERITANCE OF GENOME-WIDE DNA METHYLATION PROFILES IN PULMONARY VASCULAR ENDOTHELIAL DYSFUNCTION FOLLOWING EXTRAUTERINE GROWTH RESTRICTION.

    PubMed

    Zhang, L; Du, L; Tang, L; Lao, L; Hu, Q

    2015-06-01

    Early postnatal life is considered as a critical time window for determination of long-term metabolic states and organ functions. Extrauterine growth restriction (EUGR) causes the development of adult onset chronic diseases, including pulmonary hypertension (PH). However, the mechanisms involved and the possibilities of transgenerational transmission on pulmonary vascular consequences in later life are still unclear. Epigenetic information can be inherited and represents a plausible transgenerational carrier of environmental information. Our study was designed to test whether epigenetics dysregulation mediates the cellular memory of this early postnatal event.(Figure is included in full-text article.) : To test this hypothesis, the EUGR pups were established by undernutritional until weaning. We isolated pulmonary vascular endothelial cells (PVEC) by magnetic-activated cell sorting (MACS) from EUGR and control rats. MeDIP-chip (Methyl-DNA immune precipitation chip), genome-scale mapping studies to search for differentially methylated loci. A postnatal insult, nutritional restriction-induced EUGR caused development of an increased PH at 9-week of age in male rats (First-generation of EUGR, F1-EUGR male). We intercrossed female adult control and F1-EUGR-male rats to obtain the second-generation (F2) offspring in two groups: C male-C female, EUGR-male -C-female. We found that significantly decreased pulmonary artery pressure in F2 female offspring in EUGR-male-C-female group (F2-EUGR-female), compared with controls to some degrees. we carried out genome-wide DNA methylation profiles screen for genes in rats between F1-EUGR-male and F2-EUGR-female. The EUGR and control group comparisons revealed consistently and distinctively methylated loci, with 74.8% F1-EUGR-male group and 84.5% F2-EUGR-female group changes in hyper-methylation loci enriched for highly significant group differences. Gene ontology (GO) analysis on no consistent differentially methylated genes

  3. Intrauterine Growth Restriction (IUGR)

    MedlinePlus

    ... Watching growth is done in several ways. A measurement called the uterine fundal height helps estimate a baby's size by measuring a mother's belly from the top of the pubic bone to the top of the uterus. Another way ...

  4. Stillbirth and fetal growth restriction.

    PubMed

    Bukowski, Radek

    2010-09-01

    The association between stillbirth and fetal growth restriction is strong and supported by a large body of evidence and clinically employed for the stillbirth prediction. However, although assessment of fetal growth is a basis of clinical practice, it is not trivial. Essentially, fetal growth is a result of the genetic growth potential of the fetus and placental function. The growth potential is the driving force of fetal growth, whereas the placenta as the sole source of nutrients and oxygen might become the rate limiting element of fetal growth if its function is impaired. Thus, placental dysfunction may prevent the fetus from reaching its full genetically determined growth potential. In this sense fetal growth and its aberration provides an insight into placental function. Fetal growth is a proxy for the test of the effectiveness of placenta, whose function is otherwise obscured during pregnancy.

  5. Fetal growth restriction: current knowledge.

    PubMed

    Nardozza, Luciano Marcondes Machado; Caetano, Ana Carolina Rabachini; Zamarian, Ana Cristina Perez; Mazzola, Jaqueline Brandão; Silva, Carolina Pacheco; Marçal, Vivian Macedo Gomes; Lobo, Thalita Frutuoso; Peixoto, Alberto Borges; Araujo Júnior, Edward

    2017-05-01

    Fetal growth restriction (FGR) is a condition that affects 5-10% of pregnancies and is the second most common cause of perinatal mortality. This review presents the most recent knowledge on FGR and focuses on the etiology, classification, prediction, diagnosis, and management of the condition, as well as on its neurological complications. The Pubmed, SCOPUS, and Embase databases were searched using the term "fetal growth restriction". Fetal growth restriction (FGR) may be classified as early or late depending on the time of diagnosis. Early FGR (<32 weeks) is associated with substantial alterations in placental implantation with elevated hypoxia, which requires cardiovascular adaptation. Perinatal morbidity and mortality rates are high. Late FGR (≥32 weeks) presents with slight deficiencies in placentation, which leads to mild hypoxia and requires little cardiovascular adaptation. Perinatal morbidity and mortality rates are lower. The diagnosis of FGR may be clinical; however, an arterial and venous Doppler ultrasound examination is essential for diagnosis and follow-up. There are currently no treatments to control FGR; the time at which pregnancy is interrupted is of vital importance for protecting both the mother and fetus. Early diagnosis of FGR is very important, because it enables the identification of the etiology of the condition and adequate monitoring of the fetal status, thereby minimizing risks of premature birth and intrauterine hypoxia.

  6. 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

  7. 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

  8. Neurodevelopment after fetal growth restriction.

    PubMed

    Baschat, Ahmet A

    2014-01-01

    Fetal growth restriction (FGR) can emerge as a complication of placental dysfunction and increases the risk for neurodevelopmental delay. Marked elevations of umbilical artery (UA) Doppler resistance that set the stage for cardiovascular and biophysical deterioration with subsequent preterm birth characterize early-onset FGR. Minimal, or absent UA Doppler abnormalities and isolated cerebral Doppler changes with subtle deterioration and a high risk for unanticipated term stillbirth are characteristic for late-onset FGR. Nutritional deficiency manifested in lagging head growth is the most powerful predictor of developmental delay in all forms of FGR. Extremes of blood flow resistance and cardiovascular deterioration, prematurity and intracranial hemorrhage increase the risks for psychomotor delay and cerebral palsy. In late-onset FGR, regional cerebral vascular redistribution correlates with abnormal behavioral domains. Irrespective of the phenotype of FGR, prenatal tests that provide precise and independent stratification of risks for adverse neurodevelopment have yet to be determined.

  9. 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

  10. Ruminant models of prenatal growth restriction.

    PubMed

    Anthony, R V; Scheaffer, A N; Wright, C D; Regnault, T R H

    2003-01-01

    Intrauterine growth restriction (IUGR) is a significant health issue that not only affects infant mortality and morbidity, but may also predispose individuals to coronary heart disease, diabetes, hypertension and stroke as adults. The majority of IUGR pregnancies in humans are characterized by asymmetric fetal growth, resulting from inadequate nutrient transfer to the fetus. Furthermore, most of these pregnancies involve functional placental insufficiency, and may also show altered umbilical velocimetry. As the severity of IUGR increases, the fetus becomes increasingly hypoxic, hypoglycaemic and acidotic. In addition, placental transfer or utilization of some amino acids is known to be altered in IUGR pregnancies. Although a great deal has been learned from clinical studies of human IUGR, appropriate animal models are required to define completely the mechanisms involved in the development of IUGR. The pregnant sheep is a long-standing model for placental-fetal interactions, and fetal growth restriction can be induced in pregnant sheep by maternal nutrient restriction, maternal nutrient excess, administration of glucocorticoid, utero-placental embolization, carunclectomy and maternal hyperthermia. Although all of these sheep models are capable of inducing fetal growth restriction, the degree of restriction is variable. This review compares these sheep models of IUGR with the characteristics of human IUGR.

  11. Dietary restriction, polyamines and monocrotaline-induced pulmonary hypertension.

    PubMed

    Hacker, A D

    1993-06-22

    Dietary restriction (DR), i.e. reduction of total caloric intake, has been shown to result in protection against monocrotaline (MCT)-induced pulmonary hypertension (PH). Restriction of the diet to 8 g/rat/day instead of the usual intake (18 g/rat/day), inhibits the progression of cardiopulmonary changes and prolongs survival after a single dose of MCT. We have shown previously that the development of MCT-induced pulmonary hypertension is associated with inhibition of polyamine biosynthesis in the lungs of MCT-treated rats. In the present study, we tested the hypothesis that DR provides protection against the development of chronic PH in the rat by limiting increases in polyamine and DNA synthesis. We randomly divided animals into four groups each (MCT, MCT + DR, control, and control + DR). We injected rats with a single dose of MCT (60 mg/kg, s.c.) and a corresponding number of control rats with vehicle. Animals in all groups were given free access to food and water prior to administration of MCT. Immediately following injection of MCT both the MCT and control groups were given free access to food and water, while the other groups (MCT + DR and control + DR) we given the restricted diet (8 g/rat/day). Daily measurements were made of body weight and of water and food intake. Animals were killed in each group at 1, 4, 7, 14, and 21 days post MCT to determine right ventricular hypertrophy (RVH), lung wet weight, ornithine decarboxylase (ODC) activity, and polyamine and DNA contents. We measured DNA synthesis 7 days after MCT by determining [3H]thymidine incorporation into the whole lung DNA. We found that 7 days after MCT treatment DNA synthesis increased compared to control. However, DR (MCT + DR) treatmen prevented the increase in DNA synthesis following MCT. Right ventricular hypertrophy, lung wet weight, ODC activity and lung polyamine levels were increased following MCT. Treatment with DR (MCT + DR) prevented increases in RVH, lung wet weight, ODC activity and

  12. Influence of bidirectional superior cavopulmonary anastomosis on pulmonary arterial growth.

    PubMed

    Slavik, Z; Webber, S A; Lamb, R K; Horvath, P; LeBlanc, J G; Keeton, B R; Monro, J L; Tax, P; Tuma, S; Reich, O

    1995-11-15

    Right-sided BSCA provides for satisfactory pulmonary arterial growth in infants and children with complex congenital heart defects, and it could enhance the growth of a small right pulmonary artery. The growth of the left pulmonary artery, particularly in younger patients, needs close attention to confirm the safe role of BSCA in long-term palliation.

  13. 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

  14. Intrauterine Growth Restriction: Hungry for an Answer

    PubMed Central

    Chu, Alison

    2016-01-01

    Intrauterine growth restriction (IUGR) has been defined in several ways, but in general describes a condition in which the fetus exhibits poor growth in utero. This complication of pregnancy poses a significant public health burden as well as increased morbidity and mortality for the offspring. In human IUGR, alteration in fetal glucose and insulin homeostasis occurs in an effort to conserve energy and survive at the expense of fetal growth in an environment of inadequate nutrient provision. Several animal models of IUGR have been utilized to study the effects of IUGR on fetal glucose handling, as well as the postnatal reprogramming of energy metabolite handling, which may be unmasked in adulthood as a maladaptive propensity for cardiometabolic disease. This developmental programming may be mediated in part by epigenetic modification of essential regulators of glucose homeostasis. Several pharmacological therapies and nonpharmacological lifestyle modifications have shown early promise in mitigating the risk for or severity of adult metabolic phenotypes but still require further study of unanticipated and/or untoward side effects. PMID:26889018

  15. Diagnosis and Management of Fetal Growth Restriction

    PubMed Central

    Bamfo, Jacqueline E. A. K.; Odibo, Anthony O.

    2011-01-01

    Fetal growth restriction (FGR) remains a leading contributor to perinatal mortality and morbidity and metabolic syndrome in later life. Recent advances in ultrasound and Doppler have elucidated several mechanisms in the evolution of the disease. However, consistent classification and characterization regarding the severity of FGR is lacking. There is no cure, and management is reliant on a structured antenatal surveillance program with timely intervention. Hitherto, the time to deliver is an enigma. In this paper, the challenges in the diagnosis and management of FGR are discussed. The biophysical profile, Doppler, biochemical and molecular technologies that may refine management are reviewed. Finally, a model pathway for the clinical management of pregnancies complicated by FGR is presented. PMID:21547092

  16. Childhood cognitive development after fetal growth restriction.

    PubMed

    Llurba, E; Baschat, A A; Turan, O M; Harding, J; McCowan, L M

    2013-04-01

    To examine the relationship between prenatal umbilical artery (UA) and internal carotid artery (ICA) Doppler findings and cognitive development at 3 and 6 years in low-birth-weight children. This was a study of 209 low-birth-weight (< 10(th) centile) children born after 28 gestational weeks with UA resistance index (RI) measured within 2 weeks before delivery. Children with normal UA- and ICA-RI were defined as small-for-gestational age (SGA) and those with abnormal UA or ICA Doppler findings as having fetal growth restriction (FGR). Cognitive ability at 3 and 6 years' corrected age was assessed using the fourth edition of the Stanford-Binet Intelligence Scale (SBIS) and compared between SGA and FGR groups. An SBIS score < 85 was considered to indicate delayed development. The median gestational age at diagnosis of abnormal fetal growth was 36.6 (range, 28-41) weeks. There were 87 (41.6%) children classified as having FGR and 122 (58.4%) as SGA. The mean global SBIS score at 3 years was 109.4 (SD, 22.8) and at 6 years it was 110.5 (SD, 13.9). Overall, 22 (10.5%) children had delayed development at 3 years. Total SBIS scores and individual domain scores did not differ between FGR and SGA groups at 3 or 6 years and similar proportions in each group had delayed development. Abnormal prenatal UA and ICA Doppler findings are not associated with lower developmental scores in low-birth-weight children delivered in the third trimester of pregnancy. Copyright © 2013 ISUOG. Published by John Wiley & Sons, Ltd.

  17. 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.

  18. Noninvasive and invasive pulmonary function in mouse models of obstructive and restrictive respiratory diseases.

    PubMed

    Vanoirbeek, Jeroen A J; Rinaldi, Manuela; De Vooght, Vanessa; Haenen, Steven; Bobic, Sonja; Gayan-Ramirez, Ghislaine; Hoet, Peter H M; Verbeken, Erik; Decramer, Marc; Nemery, Benoit; Janssens, Wim

    2010-01-01

    Pulmonary function analysis is an important tool in the evaluation of mouse respiratory disease models, but much controversy still exists on the validity of some tests. Most commonly used pulmonary function variables of humans are not routinely applied in mice, and the question of which pulmonary function is optimal for the monitoring of a particular disease model remains largely unanswered. Our study aimed to delineate the potential and restrictions of existing pulmonary function techniques in different respiratory disease models, and to determine some common variables between humans and mice. A noninvasive (unrestrained plethysmography) and two invasive pulmonary function devices (forced maneuvers system from Buxco Research Systems [Wilmington, NC] and forced oscillation technique from SCIREQ [Montreal, PQ, Canada]) were evaluated in well-established models of asthma (protein and chemical induced): a model of elastase-induced pulmonary emphysema, and a model of bleomycin-induced pulmonary fibrosis. In contrast to noninvasive tests, both invasive techniques were efficacious for the quantification of parenchymal disease via changes in functional residual capacity, total lung capacity, vital capacity, and compliance of the respiratory system. Airflow obstruction and airflow limitation at baseline were only present in emphysema, but could be significantly induced after methacholine challenge in mice with asthma, which correlated best with an increase of respiratory resistance. Invasive pulmonary functions allow distinction between respiratory diseases in mice by clinically relevant variables, and should become standard in the functional evaluation of pathological disease models.

  19. Intrauterine growth restriction: screening, diagnosis, and management.

    PubMed

    Lausman, Andrea; Kingdom, John; Gagnon, Robert; Basso, Melanie; Bos, Hayley; Crane, Joan; Davies, Gregory; Delisle, Marie-France; Hudon, Lynda; Menticoglou, Savas; Mundle, William; Ouellet, Annie; Pressey, Tracy; Pylypjuk, Christy; Roggensack, Anne; Sanderson, Frank

    2013-08-01

    Contexte : Le retard de croissance intra-utérin (RCIU) est une complication obstétricale qui, par définition, serait constatée par dépistage chez 10 % des fœtus au sein de la population générale. Le défi consiste à identifier le sous-ensemble des grossesses qui sont affectées par un retard de croissance pathologique, de façon à permettre la mise en œuvre d’une intervention qui atténuerait les taux de morbidité et de mortalité. Objectif : La présente directive clinique a pour objectif de fournir des déclarations sommaires et des recommandations, ainsi que d’établir un cadre pour le dépistage, le diagnostic et la prise en charge des grossesses affectées par un RCIU. Méthodes : Des grossesses affectées sont comparées à des grossesses dans le cadre desquelles le fœtus présente un poids convenant à son âge gestationnel. Les antécédents, l’examen physique et les analyses de laboratoire (y compris les marqueurs biochimiques et les caractéristiques échographiques du RCIU) sont analysées, et une stratégie de prise en charge est suggérée. Résultats : La littérature publiée en anglais a été récupérée par l’intermédiaire de recherches menées dans PubMed ou MEDLINE, CINAHL et The Cochrane Library en janvier 2013, au moyen d’un vocabulaire contrôlé faisant appel à des termes MeSH (« fetal growth restriction » et « small for gestational age ») et à des mots clés (« fetal growth », « restriction », « growth retardation », « IUGR », « low birth weight », « small for gestational age ») appropriés. Les résultats ont été restreints aux analyses systématiques, aux essais comparatifs randomisés / essais cliniques comparatifs et aux études observationnelles. La littérature grise (non publiée) a été identifiée par l’intermédiaire de recherches menées dans les sites Web d’organismes s’intéressant à l’évaluation des technologies dans le domaine de la santé et d

  20. The prevention and treatment of intrauterine growth restriction.

    PubMed

    Grivell, Rosalie; Dodd, Jodie; Robinson, Jeffrey

    2009-12-01

    Foetal growth restriction is an important and often under-diagnosed complication of pregnancy with important implications for maternal, infant, child and later health. The key to prevention of foetal growth restriction is the recognition of those women at risk and implementation of effective interventions. Ideally, all women should plan pregnancy, providing an opportunity for lifestyle change, reduction of risk factors and optimisation of medical conditions. Failing adequate preconception care, antenatal care should include an assessment of risk factors in early pregnancy, so appropriate interventions may be instituted. Effective interventions are available for women with HIV and also those living in malaria-endemic areas. Antiplatelet agents reduce the risk of pre-eclampsia and small-for-gestational age (SGA) babies in women at risk. Intrauterine treatments offer limited benefit to the baby with foetal growth restriction. The key to management is likely to be optimising the conditions of delivery and minimising neonatal morbidity as much as possible.

  1. Extrauterine growth restriction in very-low-birthweight infants.

    PubMed

    De Curtis, M; Rigo, J

    2004-12-01

    Postnatal growth failure of very-low-birthweight (VLBW) infants may result from a complex interaction of genetic and environmental factors, including inadequate nutrition, morbidities affecting nutrient requirements, endocrine abnormalities and treatments. Among VLBW infants, those small for gestational age (SGA) at birth and those with postnatal growth restriction at the time of discharge are at higher risk of later growth failure and long-term consequences. Nutritional intervention with an "aggressive nutrition" during the first weeks of life may be able to minimize the interruption of nutrients that occurs at birth, and reduce as much as possible the incidence of growth restriction at the time of discharge and later. Even though aggressive parenteral and enteral nutrition appear to be effective and safe in VLBW infants, further evaluations of their long-term effect on growth and health consequences are needed. Several studies evaluating the effect of enriched nutrient formulas after hospital discharge on growth and neurodevelopment have produced conflicting results, whereas the potential deleterious long-term effects of prolonged use of high protein and/or of later catch-up growth have been questioned. In contrast, recent data seem to indicate that the use of human milk after hospital discharge could be the most beneficial diet for subsequent health and development. VLBW infants SGA at birth and those with early postnatal growth restriction are at high risk of later growth failure and long-term consequences. Therefore, the first objective of early nutrition should be to reduce the incidence of growth restriction at the time of discharge. Further studies on VLBW infants to evaluate the safety and beneficial effects of prolonged dietary manipulation during the first year of life are needed.

  2. Segmental Maternal UPD6 with Prenatal Growth Restriction.

    PubMed

    Poke, G; Doody, M; Prado, J; Gattas, M

    2013-01-01

    We report a child with segmental maternal uniparental isodisomy of chromosome 6, involving most of the long arm distal to 6q16, detected by SNP microarray. Clinical features include prenatal growth restriction, global developmental delay, and severe gastro-esophageal reflux disease. Maternal uniparental disomy (UPD) of chromosome 6 has previously been reported to cause intrauterine growth restriction. Paternal UPD of this chromosome is well known to cause transient neonatal diabetes mellitus. We discuss reported cases of maternal UPD of chromosome 6 and consider whether our patient's features may be due to disordered imprinting or unmasking of an autosomal recessive condition.

  3. Segmental Maternal UPD6 with Prenatal Growth Restriction

    PubMed Central

    Poke, G.; Doody, M.; Prado, J.; Gattas, M.

    2013-01-01

    We report a child with segmental maternal uniparental isodisomy of chromosome 6, involving most of the long arm distal to 6q16, detected by SNP microarray. Clinical features include prenatal growth restriction, global developmental delay, and severe gastro-esophageal reflux disease. Maternal uniparental disomy (UPD) of chromosome 6 has previously been reported to cause intrauterine growth restriction. Paternal UPD of this chromosome is well known to cause transient neonatal diabetes mellitus. We discuss reported cases of maternal UPD of chromosome 6 and consider whether our patient's features may be due to disordered imprinting or unmasking of an autosomal recessive condition. PMID:23599697

  4. Novel role of NPY in neuroimmune interaction and lung growth after intrauterine growth restriction.

    PubMed

    Thangaratnarajah, Chansutha; Dinger, Katharina; Vohlen, Christina; Klaudt, Christian; Nawabi, Jawed; Lopez Garcia, Eva; Kwapiszewska, Grazyna; Dobner, Julia; Nüsken, Kai D; van Koningsbruggen-Rietschel, Silke; von Hörsten, Stephan; Dötsch, Jörg; Alejandre Alcázar, Miguel A

    2017-09-01

    Individuals with intrauterine growth restriction (IUGR) are at risk for chronic lung disease. Using a rat model, we showed in our previous studies that altered lung structure is related to IL-6/STAT3 signaling. As neuropeptide Y (NPY), a coneurotransmitter of the sympathetic nervous system, regulates proliferation and immune response, we hypothesized that dysregulated NPY after IUGR is linked to IL-6, impaired myofibroblast function, and alveolar growth. IUGR was induced in rats by isocaloric low-protein diet; lungs were analyzed on embryonic day (E) 21, postnatal day (P) 3, P12, and P23. Finally, primary neonatal lung myofibroblasts (pnF) and murine embryonic fibroblasts (MEF) were used to assess proliferation, apoptosis, migration, and IL-6 expression. At E21, NPY and IL-6 expression was decreased, and AKT/PKC and STAT3/AMPKα signaling was reduced. Early reduction of NPY/IL-6 was associated with increased chord length in lungs after IUGR at P3, indicating reduced alveolar formation. At P23, however, IUGR rats exhibited a catch-up of body weight and alveolar growth coupled with more proliferating myofibroblasts. These structural findings after IUGR were linked to activated NPY/PKC, IL-6/AMPKα signaling. Complementary, IUGR-pnF showed increased survival, impaired migration, and reduced IL-6 compared with control-pnF (Co-pnF). In contrast, NPY induced proliferation, migration, and increased IL-6 synthesis in fibroblasts. Additionally, NPY(-/-) mice showed reduced IL-6 signaling and less proliferation of lung fibroblasts. Our study presents a novel role of NPY during alveolarization: NPY regulates 1) IL-6 and lung STAT3/AMPKα signaling, and 2) proliferation and migration of myofibroblasts. These new insights in pulmonary neuroimmune interaction offer potential strategies to enable lung growth. Copyright © 2017 the American Physiological Society.

  5. Early postnatal caloric restriction protects adult male intrauterine growth-restricted offspring from obesity.

    PubMed

    Garg, Meena; Thamotharan, Manikkavasagar; Dai, Yun; Thamotharan, Shanthie; Shin, Bo-Chul; Stout, David; Devaskar, Sherin U

    2012-06-01

    Postnatal ad libitum caloric intake superimposed on intrauterine growth restriction (IUGR) is associated with adult-onset obesity, insulin resistance, and type 2 diabetes mellitus (T2DM). We hypothesized that this paradigm of prenatal nutrient deprivation-induced programming can be reversed with the introduction of early postnatal calorie restriction. Ten-month-old male rats exposed to either prenatal nutrient restriction with ad libitum postnatal intake (IUGR), pre- and postnatal nutrient restriction (IPGR), or postnatal nutrient restriction limited to the suckling phase (50% from postnatal [PN]1 to PN21) (PNGR) were compared with age-matched controls (CON). Visceral adiposity, metabolic profile, and insulin sensitivity by hyperinsulinemic-euglycemic clamps were examined. The 10-month-old male IUGR group had a 1.5- to 2.0-fold increase in subcutaneous and visceral fat (P < 0.0002) while remaining euglycemic, insulin sensitive, inactive, and exhibiting metabolic inflexibility (Vo(2)) versus CON. The IPGR group remained lean, euglycemic, insulin sensitive, and active while maintaining metabolic flexibility. The PNGR group was insulin sensitive, similar to IPGR, but less active while maintaining metabolic flexibility. We conclude that IUGR resulted in obesity without insulin resistance and energy metabolic perturbations prior to development of glucose intolerance and T2DM. Postnatal nutrient restriction superimposed on IUGR was protective, restoring metabolic normalcy to a lean and active phenotype.

  6. Placental weight and birth weight to placental weight ratio in monochorionic and dichorionic growth-restricted and non-growth-restricted twins

    PubMed Central

    Souza, Mariângela Alves; de Lourdes Brizot, Maria; Biancolin, Sckarlet Ernandes; Schultz, Regina; de Carvalho, Mário Henrique Burlacchini; Francisco, Rossana Pulcineli Vieira; Zugaib, Marcelo

    2017-01-01

    OBJECTIVE: The aim of the present study was to compare the placental weight and birth weight/placental weight ratio for intrauterine growth-restricted and non-intrauterine growth-restricted monochorionic and dichorionic twins. METHODS: This was a retrospective analysis of placentas from twin pregnancies. Placental weight and the birth weight/placental weight ratio were compared in intrauterine growth-restricted and non-intrauterine growth-restricted monochorionic and dichorionic twins. The association between cord insertion type and placental lesions in intrauterine growth-restricted and non-intrauterine growth-restricted monochorionic and dichorionic twins was also investigated. RESULTS: A total of 105 monochorionic (intrauterine growth restriction=40; non-intrauterine growth restriction=65) and 219 dichorionic (intrauterine growth restriction=57; non-intrauterine growth restriction=162) placentas were analyzed. A significantly lower placental weight was observed in intrauterine growth-restricted monochorionic (p=0.022) and dichorionic (p<0.001) twins compared to non-intrauterine growth-restricted twins. There was no difference in the birth weight/placental weight ratio between the intrauterine growth restriction and non-intrauterine growth restriction groups for either monochorionic (p=0.36) or dichorionic (p=0.68) twins. Placental weight and the birth weight/placental weight ratio were not associated with cord insertion type or with placental lesions. CONCLUSION: Low placental weight, and consequently reduced functional mass, appears to be involved in fetal growth restriction in monochorionic and dichorionic twins. The mechanism by which low placental weight influences the birth weight/placental weight ratio in intrauterine growth-restricted monochorionic and dichorionic twins needs to be determined in larger prospective studies. PMID:28591337

  7. Maternal Nutrient Restriction in Guinea Pigs as an Animal Model for Inducing Fetal Growth Restriction.

    PubMed

    Elias, Alexander A; Ghaly, Andrew; Matushewski, Brad; Regnault, Timothy R H; Richardson, Bryan S

    2016-02-01

    We determined the impact of moderate maternal nutrient restriction (MNR) in guinea pigs on pregnancy outcomes, maternal/fetal growth parameters, and blood analytes to further characterize the utility of this model for inducing fetal growth restriction (FGR). Thirty guinea pig sows were fed ad libitum (Control) or 70% of the control diet prepregnant switching to 90% at midpregnancy (MNR). Animals were necropsied near term with weights obtained on all sows, fetuses, and placenta. Fetal blood sampling and organ dissection were undertaken in appropriate for gestational age (AGA) fetuses from Control litters and FGR fetuses from MNR litters using > or < 80 g which approximated the 10th percentile for the population weight distribution of the Control fetuses. MNR fetal demise rates (1/43) were extremely low in contrast to that seen with uterine artery ligation/ablation models, albeit with increased preterm delivery in MNR sows (3 of 15). We confirm that MNR fetuses are smaller and have increased placental/fetal weight ratios as often seen in human FGR infants. We provide justification for using a fetal weight threshold for categorizing AGA Control and FGR-MNR cohorts reducing population variance, and show that FGR-MNR fetuses have asymmetrical organ growth, and are polycythemic and hypoglycemic which are also well associated with moderate FGR in humans. These findings further support the utility of moderate MNR in guinea pigs for inducing FGR with many similarities to that in humans with moderate growth restriction whether resulting from maternal undernourishment or placental insufficiency.

  8. Maternal smoking, intrauterine growth restriction, and placental apoptosis.

    PubMed

    Vogt Isaksen, Christina

    2004-01-01

    Pregnant women who smoke are at greater risk of delivering a growth-restricted infant than nonsmoking mothers. We wanted to see if apoptosis could be involved in the mechanisms behind smoke-induced growth restriction, and our aim was to compare apoptosis in the placenta of smoking mothers giving birth to growth-restricted infants and nonsmoking mothers with infants of appropriate weight. The project was conducted at the Magee--Womens Hospital and Magee--Womens Research Institute, University of Pittsburgh, PA. Histological sections from 20 placentas were selected from smoking mothers who had given birth to small-for-gestational-age infants (birth weight < or = 2 SD). The controls were gestational-age matched nonsmoking mothers with infants having appropriate-for-gestational-age weight. The TUNEL method was used to demonstrate DNA fragmentation in nuclei, and a monoclonal antibody M30, specific for a neo-epitope on cytokeratin 18, was used to identify apoptotic epithelial cells. The positive nuclei (TUNEL) and positive cells (M30-positive cytoplasm) were counted blindly both in villous tissue and in decidual/basal plate tissue. M30-positive cells in villous tissues were significantly increased in placentas from smoking mothers compared to nonsmoking mothers. When evaluated by the TUNEL method, the difference between the two groups of women was not significant. Our study shows that apoptosis was increased in the placentas of smoking mothers with growth-restricted infants. The difference between the two groups was mainly in the syncytiotrophoblast layer and in connection with perivillous fibrin deposition. Cigarette smoke with reduction in blood flow has previously been shown to increase apoptosis, and it is possible that this could be one of the mechanisms playing a role in the growth restriction.

  9. Placental Amino Acids Transport in Intrauterine Growth Restriction

    PubMed Central

    Avagliano, Laura; Garò, Chiara; Marconi, Anna Maria

    2012-01-01

    The placenta represents a key organ for fetal growth as it acts as an interface between mother and fetus, regulating the fetal-maternal exchange of nutrients, gases, and waste products. During pregnancy, amino acids represent one of the major nutrients for fetal life, and both maternal and fetal concentrations are significantly different in pregnancies with intrauterine growth restriction when compared to uncomplicated pregnancies. The transport of amino acids across the placenta is a complex process that includes the influx of neutral, anionic, and cationic amino acids across the microvilluos plasma membrane of the syncytiotrophoblast, the passage through the cytoplasm of the trophoblasts, and the transfer outside the trophoblasts across the basal membrane into the fetal circulation. In this paper, we review the transport mechanisms of amino acids across the placenta in normal pregnancies and in pregnancies complicated by intrauterine growth restriction. PMID:22997583

  10. 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. PMID:27417785

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

    PubMed

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

    2015-07-28

    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. Consecutive patients seen in the PH Clinic at Mayo Clinic in Florida from June to November 2013. 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. 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.

  12. Third trimester growth restriction patterns: individualized assessment using a fetal growth pathology score.

    PubMed

    Deter, Russell L; Lee, Wesley; Sangi-Haghpeykar, Haleh; Kingdom, John; Romero, Roberto

    2017-07-06

    To qualitatively and quantitatively characterize third trimester growth patterns in fetuses/neonates with growth restriction using Individualized Growth Assessment. Serial fetal size measurements from 73 fetuses with proven growth restriction were evaluated using a novel composite parameter, the Fetal Growth Pathology Score (FGPS1). Third trimester FGPS1 measurements plotted against fetal age were examined for patterns. Identified patterns were characterized using the four components of the FGP1 [head circumference (HC), abdominal circumference (AC), femur diaphysis length (FDL), estimated weight (EWT)]. A secondary characterization using age of onset, duration and magnitude of the growth abnormality process was also performed. Frequencies and magnitudes of abnormal values in different FGPS1 patterns were compared. Five growth restriction patterns were found in 70/73 (95.9%) of the cases, with progressive worsening [Pattern 1 (37.0%)] and abnormal growth identified only at last scan [Pattern 2 (27.4%)] being the most common. These two patterns were usually statistically different from each other and the other three with respect to size parameter abnormalities and abnormal growth process characteristics (MANOVA). Growth abnormalities in all parameters of the FGPS1 contributed to the five abnormality patterns although AC and EWT were most important. The age of onset, duration and magnitude were similar between patterns except for Pattern 2, which had a late onset and a short duration (GLM + contrasts). Our study represents the first detailed evaluation of third trimester growth restriction using methods that consider the growth potential of each fetus. Five distinctive and repetitive patterns were found, suggesting that fetal growth restriction evolves in different ways. Further research is needed to determine the relationships of these patterns to physiological/biochemical changes and adverse outcomes associated with growth restriction.

  13. Differential methylation of imprinted genes in growth-restricted placentas.

    PubMed

    Lambertini, Luca; Lee, Tin-Lap; Chan, Wai-Yee; Lee, Men-Jean; Diplas, Andreas; Wetmur, James; Chen, Jia

    2011-11-01

    A complex network of epigenetic factors participates in regulating the monoallelic expression of a small subset of genes (~1%) in the human genome. This phenomenon goes under the definition of genomic imprinting, a parent-of-origin effect that, when altered during early embryogenesis, may influence fetal development into adulthood. Pertubations in genomic imprinting have been associated with placental and fetal growth restrictions. We analyzed the differential DNA methylation of all known imprinted genes on 10 appropriate-for-gestational-age, clinically normal, placentas and 7 severe intrauterine growth-restricted placentas. Samples were pooled according to the diagnosis and analyzed by methylated DNA immunoprecipitation (MeDIP) on a tiling microarray platform. The distribution of the differentially methylated regions (DMRs) identified in growth-restricted placentas showed a slight tendency toward hypermethylation. Imprinted genes not expressed in placenta showed a unique DMR profile with the fewest hyper- and hypomethylated DMRs. Promoter and CpG island DMRs were sporadic and randomly distributed. The vast majority of DMR identified (~99%) were mapped in introns, showing no common sequence features. Also, by using the more advanced array data mining softwares, no significant patterns emerged. In contrast, differential methylation showed a highly significant correlation with gene length. Overall these data suggest that differential methylation changes in growth-restricted placentas occur throughout the genomic regions, encompassing genes actively expressed in the placenta. These findings warrant caution in interpreting the significance of genes carrying clustered DMRs because the distribution of DMRs in a gene may be attributed as a function of its length rather than as a specific biological role.

  14. 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.

  15. 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

  16. Modeling of the metabolic energy dissipation for restricted tumor growth.

    PubMed

    Pajic-Lijakovic, Ivana; Milivojevic, Milan

    2017-08-29

    Energy dissipation mostly represents unwanted outcome but in the biochemical processes it may alter the biochemical pathways. However, it is rarely considered in the literature although energy dissipation and its alteration due to the changes in cell microenvironment may improve methods for guiding chemical and biochemical processes in the desired directions. Deeper insight into the changes of metabolic activity of tumor cells exposed to osmotic stress or irradiation may offer the possibility of tumor growth reduction. In this work effects of the osmotic stress and irradiation on the thermodynamical affinity of tumor cells and their damping effects on metabolic energy dissipation were investigated and modeled. Although many various models were applied to consider the tumor restrictive growth they have not considered the metabolic energy dissipation. In this work a pseudo rheological model in the form of "the metabolic spring-pot element" is formulated to describe theoretically the metabolic susceptibility of tumor spheroid. This analog model relates the thermodynamical affinity of cell growth with the volume expansion of tumor spheroid under isotropic loading conditions. Spheroid relaxation induces anomalous nature of the metabolic energy dissipation which causes the damping effects on cell growth. The proposed model can be used for determining the metabolic energy "structure" in the context of restrictive cell growth as well as for predicting optimal doses for cancer curing in order to tailor the clinical treatment for each person and each type of cancer.

  17. 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

  18. Offspring metabolomic response to maternal protein restriction in a rat model of intrauterine growth restriction (IUGR).

    PubMed

    Alexandre-Gouabau, Marie-Cécile; Courant, Frédérique; Le Gall, Gwénaëlle; Moyon, Thomas; Darmaun, Dominique; Parnet, Patricia; Coupé, Bérengère; Antignac, Jean-Philippe

    2011-07-01

    Intrauterine growth restriction (IUGR), along with postnatal growth trajectory, is closely linked with metabolic diseases and obesity at adulthood. The present study reports the time-dependent metabolomic response of male offspring of rat dams exposed to maternal adequate protein diet during pregnancy and lactation (CC) or protein deprivation during pregnancy only (IUGR with rapid catch-up growth, RC) or through pregnancy and lactation (IUGR with slow postnatal growth, RR). Plasma LC-HRMS metabolomic fingerprints for 8 male rats per group, combined with multivariate statistical analysis (PLS-DA and HCA), were used to study the impact of IUGR and postnatal growth velocity on the offspring metabolism in early life (until weaning) and once they reached adulthood (8 months). Compared with CC rats, RR pups had clear-cut alterations in plasma metabolome during suckling, but none at adulthood; in contrast, in RC pups, alterations in metabolome were minimal in early life but more pronounced in the long run. In particular, our results pinpoint transient alterations in proline, arginine, and histidine in RR rats, compared to CC rats, and persistent differences in tyrosine and carnitine, compared to RC rats at adulthood. These findings suggest that the long-term deregulation in feeding behavior and fatty acid metabolism in IUGR rats depends on postnatal growth velocity.

  19. Cytosine Methylation Dysregulation in Neonates Following Intrauterine Growth Restriction

    PubMed Central

    Bhagat, Tushar D.; Fazzari, Melissa J.; Verma, Amit; Barzilai, Nir; Greally, John M.

    2010-01-01

    Background Perturbations of the intrauterine environment can affect fetal development during critical periods of plasticity, and can increase susceptibility to a number of age-related diseases (e.g., type 2 diabetes mellitus; T2DM), manifesting as late as decades later. We hypothesized that this biological memory is mediated by permanent alterations of the epigenome in stem cell populations, and focused our studies specifically on DNA methylation in CD34+ hematopoietic stem and progenitor cells from cord blood from neonates with intrauterine growth restriction (IUGR) and control subjects. Methods and Findings Our epigenomic assays utilized a two-stage design involving genome-wide discovery followed by quantitative, single-locus validation. We found that changes in cytosine methylation occur in response to IUGR of moderate degree and involving a restricted number of loci. We also identify specific loci that are targeted for dysregulation of DNA methylation, in particular the hepatocyte nuclear factor 4α (HNF4A) gene, a well-known diabetes candidate gene not previously associated with growth restriction in utero, and other loci encoding HNF4A-interacting proteins. Conclusions Our results give insights into the potential contribution of epigenomic dysregulation in mediating the long-term consequences of IUGR, and demonstrate the value of this approach to studies of the fetal origin of adult disease. PMID:20126273

  20. Amphetamine treatment during early postnatal development transiently restricts somatic growth

    PubMed Central

    Smith, Andrew M.; Chen, Wei-Jung A.

    2010-01-01

    Aims Restricted somatic growth during fetal or early postnatal periods has been suggested to serve as a predictive indicator for neuroanatomical changes and behavioral impairments during adulthood. Here, the effects of d-amphetamine sulphate (AMPH) exposure during the brain growth spurt period on this potential indicator were evaluated. Main Methods Rats received 0, 5, 15 or 25 mg/kg/day of AMPH via two daily intragastric intubations from PD4-9. Body weight data were collected every other day from PD1 to 21, and then weekly until PD59. On PD9, a subset of animals was terminated 90 min after the last amphetamine treatment and the weights of the cortex, cerebellum, and brainstem were collected. Weights of these brain regions from young adult rats were also assessed on PD68. Key Findings AMPH exposure during early postnatal development limited somatic growth in a dose-related manner, with significantly lower body weights in animals assigned to the AMPH 25 and AMPH 15 groups. However, this was transient in nature, with no significant difference in weight observed after pups were weaned on PD21. Further, no differences in brain weight were observed at either age as a result of AMPH exposure. Significance These findings support the idea that developmental AMPH exposure transiently restricts somatic growth. Moreover, the lack of effect on brain weight shows that AMPH differentially affects somatic and brain growth. The current findings suggest that in addition to the immediate effects on body weight, amphetamine may alter the rate of growth, and increase the risk for weight-related adult diseases. PMID:20153755

  1. Therapeutic potential of growth factors in pulmonary emphysematous condition.

    PubMed

    Muyal, Jai Prakash; Muyal, Vandana; Kotnala, Sudhir; Kumar, Dhananjay; Bhardwaj, Harsh

    2013-04-01

    Pulmonary emphysema is a major manifestation of chronic obstructive pulmonary disease (COPD), which is characterized by progressive destruction of alveolar parenchyma with persistent inflammation of the small airways. Such destruction in the distal respiratory tract is irreversible and irreparable. All-trans-retinoic acid was suggested as a novel therapy for regeneration of lost alveoli in emphysema. However, profound discrepancies were evident between studies. At present, no effective therapeutic options are available that allow for the regeneration of lost alveoli in emphysematous human lungs. Recently, some reports on rodent's models have suggested the beneficial effects of various growth factors toward alveolar maintenance and repair processes.

  2. Surface growth on diluted lattices using a restricted curvature model

    NASA Astrophysics Data System (ADS)

    Lee, Sang Bub

    2016-11-01

    Surface growth using the equilibrium restricted curvature model was studied on diluted lattices, i.e. on percolation networks, embedded in a square lattice. The growth exponent β and the roughness exponent α were measured on infinite networks for the percolation probability {{p}c}≤slant p≤slant 1 and backbone networks at p c , where p c is the percolation threshold. For p  =  p c , both the infinite network and backbone network are known to be fractals with fractal dimensions different from each other, whereas for p  >  p c they are Euclidean. Therefore, our work for p  =  p c is regarded as the surface growth on random fractal substrates. The results were compared to the predicted results using power counting for the fractional Herring-Mullins equation with a noise restriction modified for the fractal substrates. For p  >  p c , the exponents appeared to be similar to those for the regular lattice, whereas for p  =  p c they were consistent with the predictions for both an infinite network and a backbone network. The scaling relation 2α +{{d}\\text{f}}=z was satisfied for both cases, where d f is the fractal dimension of the substrate and z is the dynamic exponent given as z=α /β .

  3. Region-specific growth restriction of brain following preterm birth

    PubMed Central

    Iwata, Sachiko; Katayama, Reiji; Kinoshita, Masahiro; Saikusa, Mamoru; Araki, Yuko; Takashima, Sachio; Abe, Toshi; Iwata, Osuke

    2016-01-01

    Regional brain sizes of very-preterm infants at term-equivalent age differ from those of term-born peers, which have been linked with later cognitive impairments. However, dependence of regional brain volume loss on gestational age has not been studied in detail. To investigate the spatial pattern of brain growth in neonates without destructive brain lesions, head MRI of 189 neonates with a wide range of gestational age (24–42 weeks gestation) was assessed using simple metrics measurements. Dependence of MRI findings on gestational age at birth (Agebirth) and the corrected age at MRI scan (AgeMRI) were assessed. The head circumference was positively correlated with AgeMRI, but not Agebirth. The bi-parietal width, deep grey matter area and the trans-cerebellar diameter were positively correlated with both Agebirth and AgeMRI. The callosal thickness (positive), atrial width of lateral ventricle (negative) and the inter-hemispheric distance (negative) were exclusively correlated with Agebirth. The callosal thickness and cerebral/cerebellar transverse diameters showed predominant dependence on Agebirth over AgeMRI, suggesting that brain growth after preterm-birth was considerably restricted or even became negligible compared with that in utero. Such growth restriction after preterm birth may extensively affect relatively more matured infants, considering the linear relationships observed between brain sizes and Agebirth. PMID:27658730

  4. Early childhood neurodevelopment after intrauterine growth restriction: a systematic review.

    PubMed

    Levine, Terri A; Grunau, Ruth E; McAuliffe, Fionnuala M; Pinnamaneni, RagaMallika; Foran, Adrienne; Alderdice, Fiona A

    2015-01-01

    Children who experienced intrauterine growth restriction (IUGR) may be at increased risk for adverse developmental outcomes in early childhood. The objective of this study was to carry out a systematic review of neurodevelopmental outcomes from 6 months to 3 years after IUGR. PubMed, Embase, PsycINFO, Maternity and Infant Care, and CINAHL databases were searched by using the search terms intrauterine, fetal, growth restriction, child development, neurodevelopment, early childhood, cognitive, motor, speech, language. Studies were eligible for inclusion if participants met specified criteria for growth restriction, follow-up was conducted within 6 months to 3 years, methods were adequately described, non-IUGR comparison groups were included, and full English text of the article was available. A specifically designed data extraction form was used. The methodological quality of included studies was assessed using well-documented quality-appraisal guidelines. Of 731 studies reviewed, 16 were included. Poorer neurodevelopmental outcomes after IUGR were described in 11. Ten found motor, 8 cognitive, and 7 language delays. Other delays included social development, attention, and adaptive behavior. Only 8 included abnormal Doppler parameters in their definitions of IUGR. Evidence suggests that children are at risk for poorer neurodevelopmental outcomes following IUGR from 6 months to 3 years of age. The heterogeneity of primary outcomes, assessment measures, adjustment for confounding variables, and definitions of IUGR limits synthesis and interpretation. Sample sizes in most studies were small, and some examined preterm IUGR children without including term IUGR or AGA comparison groups, limiting the value of extant studies. Copyright © 2015 by the American Academy of Pediatrics.

  5. [Impairments of placental amino acid metabolism in fetal growth restriction].

    PubMed

    Pogorelova, T N; Gunko, V O; Avrutskaya, V V; Kaushanskaya, L V; Durnitsyna, O A

    2017-05-01

    The content of the amino acids in the placenta during physiological pregnancy and fetal growth restriction (FGR) has been investigated my means of the method of ion-exchange chromatography. It has been found that in FGR the placental amino acid pool is characterized by a decreased content of arginine, proline, alanine, serine, cysteine, methionine, tryptophan, leucine, threonine, tyrosine, phenylalanine, glutamine and an increased content of dicarboxylic amino acids, lysine, histidine and glycine. These changes are accompanied by altered activity of some enzymes of amino acid metabolism, and the degree of these changes correlates with the level of corresponding amino acids.

  6. [Maternal cannabis use and intra-uterine growth restriction].

    PubMed

    Davitian, C; Uzan, M; Tigaizin, A; Ducarme, G; Dauphin, H; Poncelet, C

    2006-01-01

    Marijuana is the most commonly used illegal drug, especially among young women in Western societies. The effects of cannabis use during pregnancy have been studied for many years. The vast majority of studies have shown a link between maternal consumption of cannabis and foetal development. Foetal growth restriction seems to be the major complication of cannabis exposure. Nevertheless, all these studies have suffered from several methodological biases. The maternal marijuana use should be first and foremost detected in pregnant women for a specific addiction management and pregnancy follow-up.

  7. Prenatal Programming of Insulin Secretion in Intrauterine Growth Restriction

    PubMed Central

    Gatford, Kathryn L.; Simmons, Rebecca A.

    2014-01-01

    Intrauterine growth restriction (IUGR) impairs insulin secretion in humans and in animal models of IUGR. Several underlying mechanisms have been implicated, including decreased expression of molecular regulators of β-cell mass and function, in some cases shown to be due to epigenetic changes initiated by an adverse fetal environment. Alterations in cell cycle progression contribute to loss of β-cell mass, whereas decreased islet vascularity and mitochondrial dysfunction impair β-cell function in IUGR rodents. Animal models of IUGR sharing similar insulin secretion outcomes as the IUGR human are allowing underlying mechanisms to be identified. This review will focus on models of uteroplacental in sufficiency. PMID:23820120

  8. Prenatal programming of insulin secretion in intrauterine growth restriction.

    PubMed

    Gatford, Kathryn L; Simmons, Rebecca A

    2013-09-01

    Intrauterine growth restriction (IUGR) impairs insulin secretion in humans and in animal models of IUGR. Several underlying mechanisms have been implicated, including decreased expression of molecular regulators of β-cell mass and function, in some cases shown to be due to epigenetic changes initiated by an adverse fetal environment. Alterations in cell cycle progression contribute to loss of β-cell mass, whereas decreased islet vascularity and mitochondrial dysfunction impair β-cell function in IUGR rodents. Animal models of IUGR sharing similar insulin secretion outcomes as the IUGR human are allowing underlying mechanisms to be identified. This review will focus on models of uteroplacental insufficiency.

  9. 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

  10. 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.

  11. Growth, nitrogen uptake and flow in maize plants affected by root growth restriction.

    PubMed

    Xu, Liangzheng; Niu, Junfang; Li, Chunjian; Zhang, Fusuo

    2009-07-01

    The objective of the present study was to investigate the influence of a reduced maize root-system size on root growth and nitrogen (N) uptake and flow within plants. Restriction of shoot-borne root growth caused a strong decrease in the absorption of root: shoot dry weight ratio and a reduction in shoot growth. On the other hand, compensatory growth and an increased N uptake rate in the remaining roots were observed. Despite the limited long-distance transport pathway in the mesocotyl with restriction of shoot-borne root growth, N cycling within these plants was higher than those in control plants, implying that xylem and phloem flow velocities via the mesocotyl were considerably higher than in plants with an intact root system. The removal of the seminal roots in addition to restricting shoot-borne root development did not affect whole plant growth and N uptake, except for the stronger compensatory growth of the primary roots. Our results suggest that an adequate N supply to maize plant is maintained by compensatory growth of the remaining roots, increased N uptake rate and flow velocities within the xylem and phloem via the mesocotyl, and reduction in the shoot growth rate.

  12. Fetal growth restriction and 18-year growth and nutritional status: Aboriginal birth cohort 1987-2007.

    PubMed

    Sayers, Susan; Mott, Susan; Singh, Gurmeet

    2011-01-01

    The main objective of the work is to compare the growth and nutritional status of Australian Aboriginal term infants born with (n = 81) and without fetal growth restriction (n = 260). A prospective birth cohort study of 341 Aboriginal babies from the Top End of the Northern Territory of Australia was recruited at birth (1987-1990) and re-examined at a mean age of 18.3 years (2006-2008) for outcome measures of growth and nutrition status. Those with growth restriction at birth were 3 cm shorter (P = 0.0026) and 9 kg lighter (P = 0.0001) with head circumferences 0.95 cm smaller (P = 0.0008) than those without growth restriction. The proportions of growth restricted participants with body mass index <18.5 kg/m(2) were significantly greater (P = 0.028), and those with BMI > 25 kg/m(2) and with fat percentage >85th percentile were significantly smaller (P = 0.012 and 0.004, respectively). In this cohort, those Aboriginal babies born smaller and lighter have remained smaller and lighter at 18 years of age. However, the highest risk of later chronic noncommunicable disease has been reported in subjects who were born small and become relatively larger in later life. The continued study of this Aboriginal birth cohort will give us an opportunity to determine if and when in later life the effects of birth weight are modified by environmental nutritional factors.

  13. 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.

  14. Prognostic Value of Fetal Thymus Size in Intrauterine Growth Restriction.

    PubMed

    Ekin, Atalay; Gezer, Cenk; Taner, Cuneyt Eftal; Solmaz, Ulas; Gezer, Naciye Sinem; Ozeren, Mehmet

    2016-03-01

    Our aim was to evaluate the size of the fetal thymus by sonography in pregnancies with intrauterine growth restriction (IUGR) and to search for a possible relationship between a small fetal thymus and adverse perinatal outcomes. The transverse diameter of the fetal thymus was prospectively measured in 150 healthy and 143 IUGR fetuses between 24 and 40 weeks' gestation. The fetuses with IUGR were further divided according to normal or abnormal Doppler assessment of the umbilical and middle cerebral arteries and ductus venosus. Measurements were compared with reference ranges from controls. To determine which perinatal outcomes were independently associated with a small fetal thymus, a multivariate logistic regression analysis was performed. Thymus size was significantly lower in IUGR fetuses compared to controls (P < .05). Among IUGR fetuses, thymus size was significantly smaller in IUGR fetuses with abnormal Doppler flow compared to normal flow (P < .05). A small thymus in IUGR fetuses was independently associated with early delivery (odds ratio [OR], 1.24; 95% confidence interval [CI], 1.05-1.49; P= .023), respiratory distress syndrome (OR, 1.36; 95% CI, 1.09-1.78; P= .005), early neonatal sepsis (OR, 1.65; 95% CI, 1.11-2.42; P= .001), and a longer stay in the neonatal intensive care unit (OR, 1.33; 95% CI, 1.08-1.71; P = .017). Intrauterine growth restriction is associated with fetal thymic involution, and a small fetal thymus is an early indicator of adverse perinatal outcomes in pregnancies complicated by IUGR. © 2016 by the American Institute of Ultrasound in Medicine.

  15. Chronic Embolic Pulmonary Hypertension Caused by Pulmonary Embolism and Vascular Endothelial Growth Factor Inhibition.

    PubMed

    Neto-Neves, Evandro M; Brown, Mary B; Zaretskaia, Maria V; Rezania, Samin; Goodwill, Adam G; McCarthy, Brian P; Persohn, Scott A; Territo, Paul R; Kline, Jeffrey A

    2017-04-01

    Our understanding of the pathophysiological basis of chronic thromboembolic pulmonary hypertension (CTEPH) will be accelerated by an animal model that replicates the phenotype of human CTEPH. Sprague-Dawley rats were administered a combination of a single dose each of plastic microspheres and vascular endothelial growth factor receptor antagonist in polystyrene microspheres (PE) + tyrosine kinase inhibitor SU5416 (SU) group. Shams received volume-matched saline; PE and SU groups received only microspheres or SU5416, respectively. PE + SU rats exhibited sustained pulmonary hypertension (62 ± 13 and 53 ± 14 mmHg at 3 and 6 weeks, respectively) with reduction of the ventriculoarterial coupling in vivo coincident with a large decrement in peak rate of oxygen consumption during aerobic exercise, respectively. PE + SU produced right ventricular hypokinesis, dilation, and hypertrophy observed on echocardiography, and 40% reduction in right ventricular contractile function in isolated perfused hearts. High-resolution computed tomographic pulmonary angiography and Ki-67 immunohistochemistry revealed abundant lung neovascularization and cellular proliferation in PE that was distinctly absent in the PE + SU group. We present a novel rodent model to reproduce much of the known phenotype of CTEPH, including the pivotal pathophysiological role of impaired vascular endothelial growth factor-dependent vascular remodeling. This model may reveal a better pathophysiological understanding of how PE transitions to CTEPH in human treatments.

  16. Serum cholesterol acceptor capacity in intrauterine growth restricted fetuses.

    PubMed

    Pecks, Ulrich; Rath, Werner; Bauerschlag, Dirk O; Maass, Nicolai; Orlikowsky, Thorsten; Mohaupt, Markus G; Escher, Geneviève

    2017-02-14

    Intrauterine growth restriction (IUGR) is an independent risk factor for the development of cardiovascular diseases later in life. The mechanisms whereby slowed intrauterine growth confers vascular risk are not clearly established. In general, a disturbed cholesterol efflux has been linked to atherosclerosis. The capacity of serum to accept cholesterol has been repeatedly evaluated in clinical studies by the use of macrophage-based cholesterol efflux assays and, if disturbed, precedes atherosclerotic diseases years before the clinical diagnosis. We now hypothesized that circulating cholesterol acceptors in IUGR sera specifically interfere with cholesterol transport mechanisms leading to diminished cholesterol efflux. RAW264.7 cells were used to determine efflux of [3H]-cholesterol in response to [umbilical cord serum (IUGR), n=20; controls (CTRL), n=20]. Cholesterol efflux was lower in IUGR as compared to controls [controls: mean 7.7% fractional [3H]-cholesterol efflux, standard deviation (SD)=0.98; IUGR: mean 6.3%, SD=0.79; P<0.0001]. Values strongly correlated to HDL (ρ=0.655, P<0.0001) and apoE (ρ=0.510, P=0.0008), and mildly to apoA1 (ρ=0.3926, P=0.0122) concentrations. Reduced cholesterol efflux in IUGR could account for the enhanced risk of developing cardiovascular diseases later in life.

  17. Effect of placenta previa on fetal growth restriction and stillbirth.

    PubMed

    Yeniel, A Ozgur; Ergenoglu, A Mete; Itil, Ismail Mete; Askar, Niyazi; Meseri, Reci

    2012-08-01

    To examine the association between placenta previa and adverse perinatal outcomes such as low birth weight, preterm delivery, stillbirth and fetal growth restriction (FGR). This retrospective cohort study includes 12,034 delivered pregnant women who were recruited for the study between 2004 and 2010 in Ege University Hospital. Data were collected by browsing the clinic's archives. The association between placenta previa and adverse perinatal outcomes was determined via Chi-square tests and Student's t test. Logistic regression analysis was used to adjust for confounding factors in evaluating the association between placenta previa and the adverse perinatal outcomes. There was no significant relationship between placenta previa and FGR or stillbirth. Low birth weight and preterm delivery were significantly higher in the placenta previa group. According to logistic regression analysis, low birth weight was associated with an OR of 3.01 (95 % CI 2.05-4.52) and preterm delivery was associated with an OR of 8.14 (95 % CI 5.60-11.83); while, placenta previa did not affect FGR and stillbirth significantly. Although there is no consensus on the association between placenta previa and FGR in previous studies, we suggest that placenta previa is not a reason for placental insufficiency. Management of placenta previa especially depends on maternal hemodynamic parameters such as heavy hemorrhage and hypotensive shock rather than fetal well-being protocols based on serial growth ultrasound and fetal Doppler investigation.

  18. [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. Copyright © 2016 Sociedad Chilena de Pediatría. Publicado por Elsevier España, S.L.U. All rights reserved.

  19. Consensus definition of fetal growth restriction: a Delphi procedure.

    PubMed

    Gordijn, S J; Beune, I M; Thilaganathan, B; Papageorghiou, A; Baschat, A A; Baker, P N; Silver, R M; Wynia, K; Ganzevoort, W

    2016-09-01

    To determine, by expert consensus, a definition for early and late fetal growth restriction (FGR) through a Delphi procedure. A Delphi survey was conducted among an international panel of experts on FGR. Panel members were provided with 18 literature-based parameters for defining FGR and were asked to rate the importance of these parameters for the diagnosis of both early and late FGR on a 5-point Likert scale. Parameters were described as solitary parameters (parameters that are sufficient to diagnose FGR, even if all other parameters are normal) and contributory parameters (parameters that require other abnormal parameter(s) to be present for the diagnosis of FGR). Consensus was sought to determine the cut-off values for accepted parameters. A total of 106 experts were approached, of whom 56 agreed to participate and entered the first round, and 45 (80%) completed all four rounds. For early FGR (< 32 weeks), three solitary parameters (abdominal circumference (AC) < 3(rd) centile, estimated fetal weight (EFW) < 3(rd) centile and absent end-diastolic flow in the umbilical artery (UA)) and four contributory parameters (AC or EFW < 10(th) centile combined with a pulsatility index (PI) > 95(th) centile in either the UA or uterine artery) were agreed upon. For late FGR (≥ 32 weeks), two solitary parameters (AC or EFW < 3(rd) centile) and four contributory parameters (EFW or AC < 10(th) centile, AC or EFW crossing centiles by > two quartiles on growth charts and cerebroplacental ratio < 5(th) centile or UA-PI > 95(th) centile) were defined. Consensus-based definitions for early and late FGR, as well as cut-off values for parameters involved, were agreed upon by a panel of experts. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

  20. 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.

  1. Intrauterine growth restriction: effects of physiological fetal growth determinants on diagnosis.

    PubMed

    Haram, Kjell; Søfteland, Eirik; Bukowski, Radek

    2013-01-01

    The growth of the fetus, which is strongly associated with the outcome of pregnancy, reflects interplay of several physiological and pathological factors. The assessment of fetal growth is based on comparison of birthweight (BW) or estimated fetal weight (EFW) to standards which define reference ranges at a spectrum of gestational ages. Most birthweight standards do not take into account effects of physiological determinants of fetal growth. Additionally, gestational age in many standards is based on the menstrual history and is often inaccurate. Fetal growth norms should be based on an early ultrasound estimate of gestational age. Customized standards, which have included only ultrasound-dated pregnancies, seem to be superior to population-based birthweight norms in predicting perinatal mortality and morbidity. Adjustment for individual variation in customized growth curves reduces false-positive diagnosis of IUGR and may lead to a very significant reduction in intervention for suspected IUGR. Customized growth potential identifies better the risk for adverse outcome than the currently used national standards, but customized charts may fail in detecting growth-restricted stillbirth. An individual's birthweight is the sum of physiological and pathological influences operating during pregnancy. Growth potential norms are a better discriminator of aberrations of fetal growth than population, ultrasound, and customized norms.

  2. Intrauterine Growth Restriction: Effects of Physiological Fetal Growth Determinants on Diagnosis

    PubMed Central

    Haram, Kjell

    2013-01-01

    The growth of the fetus, which is strongly associated with the outcome of pregnancy, reflects interplay of several physiological and pathological factors. The assessment of fetal growth is based on comparison of birthweight (BW) or estimated fetal weight (EFW) to standards which define reference ranges at a spectrum of gestational ages. Most birthweight standards do not take into account effects of physiological determinants of fetal growth. Additionally, gestational age in many standards is based on the menstrual history and is often inaccurate. Fetal growth norms should be based on an early ultrasound estimate of gestational age. Customized standards, which have included only ultrasound-dated pregnancies, seem to be superior to population-based birthweight norms in predicting perinatal mortality and morbidity. Adjustment for individual variation in customized growth curves reduces false-positive diagnosis of IUGR and may lead to a very significant reduction in intervention for suspected IUGR. Customized growth potential identifies better the risk for adverse outcome than the currently used national standards, but customized charts may fail in detecting growth-restricted stillbirth. An individual's birthweight is the sum of physiological and pathological influences operating during pregnancy. Growth potential norms are a better discriminator of aberrations of fetal growth than population, ultrasound, and customized norms. PMID:23864862

  3. [Factors associated with false diagnosis of fetal growth restriction].

    PubMed

    Mendes, Renata Franco Pimentel; Martinelli, Silvio; Bittar, Roberto Eduardo; Francisco, Rossana Pulcineli Vieira; Zugaib, Marcelo

    2014-06-01

    The aim of this study was to analize and describe some characteristics related to a false diagnosis of intrauterine growth restriction (IUGR). We retrospectively included 48 pregnant women referred to our service with a suspected diagnosis of IUGR that was not confirmed after birth and we compared them to another group with confirmed IUGR. We then analyzed the characteristics of the false-positive results. The results of the study were divided into continuous and categorical variables for analysis. The χ2test or Fisher exact test was applied to compare proportions. The level of significance was set at p<0.05 for all tests. In our sample, pregnant women with a false diagnosis of IUGR had the following characteristics: they were referred earlier (mean gestational age of 32.8 weeks); were submitted to 2 to 6 ultrasound examinations before been registered in our service; in 25% of cases ultrasound examination was performed before 12 weeks; in 66.7% of cases the symphysis-fundal height measurement was normal; in 52.1% of cases they had at least 1 sonographic exam above the 10th percentile; on average, the last ultrasound examination (performed on average at 36 weeks) was above the 18th percentile; the women were submitted to a mean number of 5 ultrasound examinations and to a mean number of 4.6 vitality exams. The false diagnosis of IUGR involves high hospital costs and higher demand for specialists. The symphysis-fundal height measurement must be valued, and the diagnosis of IUGR must be confirmed with ultrasonography in the last weeks of pregnancy before any obstetric management is taken.

  4. Pulmonary hypertension impairs alveolarization and reduces lung growth in the ovine fetus.

    PubMed

    Grover, Theresa R; Parker, Thomas A; Balasubramaniam, Vivek; Markham, Neil E; Abman, Steven H

    2005-04-01

    Persistent pulmonary hypertension of the newborn (PPHN) is a clinical disorder characterized by abnormal vascular structure, growth, and reactivity. Disruption of vascular growth during early postnatal lung development impairs alveolarization, and newborns with lung hypoplasia often have severe pulmonary hypertension. To determine whether pulmonary hypertension can directly impair vascular growth and alveolarization in the fetus, we studied the effects of chronic intrauterine pulmonary hypertension on lung growth in fetal lambs. We performed surgery, which included partial constriction of the ductus arteriosus (DA) to induce pulmonary hypertension (PH, n = 14) or sham surgery (controls, n = 13) in fetal lambs at 112-125 days (term = 147 days). Tissues were harvested near term for measurement of right ventricular hypertrophy (RVH), radial alveolar counts (RAC), mean linear intercepts (MLI), wall thickness, and vessel density of small pulmonary arteries. Chronic DA constriction caused RVH (P < 0.0001), increased wall thickness of small pulmonary arteries (P < 0.002), and reduced small pulmonary artery density (P < 0.005). PH also reduced alveolarization, causing a 27% reduction in RAC and 20% increase in MLI. Furthermore, prolonged DA constriction (21 days) not only decreased RAC and increased MLI by 30% but also caused a 25% reduction of lung-body weight ratio. We conclude that chronic PH reduces pulmonary arterial growth, decreases alveolar complexity, and impairs lung growth. We speculate that chronic hypertension impairs vascular growth, which disrupts critical signaling pathways regulating lung vascular and alveolar development, thereby interfering with alveolarization and ultimately resulting in lung hypoplasia.

  5. Communication Profile of Primary School-Aged Children with Foetal Growth Restriction

    ERIC Educational Resources Information Center

    Partanen, Lea Aulikki; Olsén, Päivi; Mäkikallio, Kaarin; Korkalainen, Noora; Heikkinen, Hanna; Heikkinen, Minna; Yliherva, Anneli

    2017-01-01

    Foetal growth restriction is associated with problems in neurocognitive development. In the present study, prospectively collected cohorts of foetal growth restricted (FGR) and appropriate for gestational age grown (AGA) children were examined at early school-age by using the Children's Communication Checklist-2 (CCC-2) to test the hypothesis that…

  6. Communication Profile of Primary School-Aged Children with Foetal Growth Restriction

    ERIC Educational Resources Information Center

    Partanen, Lea Aulikki; Olsén, Päivi; Mäkikallio, Kaarin; Korkalainen, Noora; Heikkinen, Hanna; Heikkinen, Minna; Yliherva, Anneli

    2017-01-01

    Foetal growth restriction is associated with problems in neurocognitive development. In the present study, prospectively collected cohorts of foetal growth restricted (FGR) and appropriate for gestational age grown (AGA) children were examined at early school-age by using the Children's Communication Checklist-2 (CCC-2) to test the hypothesis that…

  7. 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.

  8. 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.

  9. 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

  10. 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

  11. Perinatal growth restriction decreases diuretic action of furosemide in adult rats

    PubMed Central

    DuBois, Barent N.; Pearson, Jacob; Mahmood, Tahir; Nguyen, Duc; Thornburg, Kent; Cherala, Ganesh

    2014-01-01

    Perinatal growth restriction programs higher risk for chronic disease during adulthood via morphological and physiological changes in organ systems. Perinatal growth restriction is highly correlated with a decreased nephron number, altered renal function and subsequent hypertension. We hypothesize that such renal maladaptations result in altered pharmacologic patterns for life. Maternal protein restriction during gestation and lactation was used to induce perinatal growth restriction in the current study. The diuretic response of furosemide (2mg/kg single i.p dose) in perinatally growth restricted rats during adulthood was investigated. Diuresis, natriuresis and renal excretion of furosemide were significantly reduced relative to controls, indicative of decreased efficacy. While a modest 12% decrease in diuresis was observed in males, females experienced 26% reduction. It is important to note that the baseline urine output and natriuresis was similar between treatment groups. The in vitro renal and hepatic metabolism of furosemide, the in vivo urinary excretion of the metabolite, and the expression of renal drug transporters was unaltered. Creatinine clearance was significantly reduced by 15% and 19% in perinatally growth restricted male and female rats, respectively. Further evidence of renal insufficiency was suggested by decreased uric acid clearance. Renal protein expression of sodium-potassium-chloride cotransporter, a pharmacodynamic target, was unaltered. In summary, perinatal growth restriction could permanently imprint pharmacokinetic processes affecting drug response. PMID:24508521

  12. Influence of gestational salt restriction in fetal growth and in development of diseases in adulthood.

    PubMed

    Sakuyama, Hiroe; Katoh, Minami; Wakabayashi, Honoka; Zulli, Anthony; Kruzliak, Peter; Uehara, Yoshio

    2016-01-20

    Recent studies reported the critical role of the intrauterine environment of a fetus in growth or the development of disease in adulthood. In this article we discussed the implications of salt restriction in growth of a fetus and the development of growth-related disease in adulthood. Salt restriction causes retardation of fatal growth or intrauterine death thereby leading to low birth weight or decreased birth rate. Such retardation of growth along with the upregulation of the renin angiotensin system due to salt restriction results in the underdevelopment of cardiovascular organs or decreases the number of the nephron in the kidney and is responsible for onset of hypertension in adulthood. In addition, gestational salt restriction is associated with salt craving after weaning. Moreover, salt restriction is associated with a decrease in insulin sensitivity. A series of alterations in metabolism due to salt restriction are probably mediated by the upregulation of the renin angiotensin system and an epigenetic mechanism including proinflammatory substances or histone methylation. Part of the metabolic disease in adulthood may be programmed through such epigenetic changes. The modification of gene in a fetus may be switched on through environment factors or life style after birth. The benefits of salt restriction have been assumed thus far; however, more precise investigation is required of its influence on the health of fetuses and the onset of various diseases in adulthood.

  13. Developmental Programming of Cardiovascular Disease Following Intrauterine Growth Restriction: Findings Utilising A Rat Model of Maternal Protein Restriction

    PubMed Central

    Zohdi, Vladislava; Lim, Kyungjoon; Pearson, James T.; Black, M. Jane

    2014-01-01

    Over recent years, studies have demonstrated links between risk of cardiovascular disease in adulthood and adverse events that occurred very early in life during fetal development. The concept that there are embryonic and fetal adaptive responses to a sub-optimal intrauterine environment often brought about by poor maternal diet that result in permanent adverse consequences to life-long health is consistent with the definition of “programming”. The purpose of this review is to provide an overview of the current knowledge of the effects of intrauterine growth restriction (IUGR) on long-term cardiac structure and function, with particular emphasis on the effects of maternal protein restriction. Much of our recent knowledge has been derived from animal models. We review the current literature of one of the most commonly used models of IUGR (maternal protein restriction in rats), in relation to birth weight and postnatal growth, blood pressure and cardiac structure and function. In doing so, we highlight the complexity of developmental programming, with regards to timing, degree of severity of the insult, genotype and the subsequent postnatal phenotype. PMID:25551250

  14. Developmental programming of cardiovascular disease following intrauterine growth restriction: findings utilising a rat model of maternal protein restriction.

    PubMed

    Zohdi, Vladislava; Lim, Kyungjoon; Pearson, James T; Black, M Jane

    2014-12-29

    Over recent years, studies have demonstrated links between risk of cardiovascular disease in adulthood and adverse events that occurred very early in life during fetal development. The concept that there are embryonic and fetal adaptive responses to a sub-optimal intrauterine environment often brought about by poor maternal diet that result in permanent adverse consequences to life-long health is consistent with the definition of "programming". The purpose of this review is to provide an overview of the current knowledge of the effects of intrauterine growth restriction (IUGR) on long-term cardiac structure and function, with particular emphasis on the effects of maternal protein restriction. Much of our recent knowledge has been derived from animal models. We review the current literature of one of the most commonly used models of IUGR (maternal protein restriction in rats), in relation to birth weight and postnatal growth, blood pressure and cardiac structure and function. In doing so, we highlight the complexity of developmental programming, with regards to timing, degree of severity of the insult, genotype and the subsequent postnatal phenotype.

  15. Comparative efficiency of measures of early fetal growth restriction for predicting adverse perinatal outcomes.

    PubMed

    Tuuli, Methodius G; Cahill, Alison; Stamilio, David; Macones, George; Odibo, Anthony O

    2011-06-01

    To estimate the comparative efficiency of first-trimester fetal growth restriction, second-trimester fetal growth restriction, and first-to-second-trimester growth lag for predicting adverse perinatal outcomes. This is a retrospective cohort study of pregnancies with reliable dating based on last menstrual periods and first-trimester ultrasound examinations. Pregnancies with multiple fetuses, aneuploidy, and major structural anomalies were excluded. Fetal crown-rump lengths at 10-14 weeks, estimated fetal weights based on fetal biometry at 18-22 weeks, and interval growth were measured and converted to gestational age-adjusted Z-scores. The primary outcome was small for gestational age (SGA) at delivery. Secondary outcomes were low birth weight, preterm delivery, stillbirth, and preeclampsia. Receiver-operating characteristics curves were used to identify the optimal definitions of early fetal growth restriction associated with SGA and to compare screening efficiencies. Multivariable logistic regression was used to adjust for confounders. Among 8,978 pregnancies meeting inclusion criteria, 551 (6.5%) neonates were SGA. Crown-rump length Z-score less than -1.0, estimated fetal weights Z-score less than -1.0, and growth Z-score less than -1.0 were identified as the optimal definitions of early fetal growth restriction associated with SGA (adjusted odds ratio 1.41 [95% confidence interval (CI) 1.13-1.74], 3.44 [95% CI 2.85-4.15] and 2.61 [95% CI 2.09-3.25], respectively). The sensitivity and specificity of first- and second-trimester fetal growth restriction for predicting SGA were 21.4% and 83.4%, and 37.2% and 85.5%, respectively. The area under the receiver-operating characteristics curve for second-trimester fetal growth restriction was greater than that for first-trimester fetal growth restriction and first-to-second-trimester growth lag (0.70 compared with 0.59 and 0.66, P<.001). Second-trimester fetal growth restriction is superior to first-trimester fetal

  16. Gold-functionalized magnetic nanoparticles restrict growth of Pseudomonas aeruginosa

    PubMed Central

    Niemirowicz, Katarzyna; Swiecicka, Izabela; Wilczewska, Agnieszka Z; Misztalewska, Iwona; Kalska-Szostko, Beata; Bienias, Kamil; Bucki, Robert; Car, Halina

    2014-01-01

    Superparamagnetic iron oxide nanoparticles (SPIONs) and their derivatives (aminosilane and gold-coated) have been widely investigated in numerous medical applications, including their potential to act as antibacterial drug carriers that may penetrate into bacteria cells and biofilm mass. Pseudomonas aeruginosa is a frequent cause of infection in hospitalized patients, and significant numbers of currently isolated clinical strains are resistant to standard antibiotic therapy. Here we describe the impact of three types of SPIONs on the growth of P. aeruginosa during long-term bacterial culture. Their size, structure, and physicochemical properties were determined using transmission electron microscopy, X-ray diffraction analysis, and Fourier transform infrared spectroscopy. We observed significant inhibition of P. aeruginosa growth in bacterial cultures continued over 96 hours in the presence of gold-functionalized nanoparticles (Fe3O4@Au). At the 48-hour time point, growth of P. aeruginosa, as assessed by the number of colonies grown from treated samples, showed the highest inhibition (decreased by 40%). These data provide strong evidence that Fe3O4@Au can dramatically reduce growth of P. aeruginosa and provide a platform for further study of the antibacterial activity of this nanomaterial. PMID:24855358

  17. Gold-functionalized magnetic nanoparticles restrict growth of Pseudomonas aeruginosa.

    PubMed

    Niemirowicz, Katarzyna; Swiecicka, Izabela; Wilczewska, Agnieszka Z; Misztalewska, Iwona; Kalska-Szostko, Beata; Bienias, Kamil; Bucki, Robert; Car, Halina

    2014-01-01

    Superparamagnetic iron oxide nanoparticles (SPIONs) and their derivatives (aminosilane and gold-coated) have been widely investigated in numerous medical applications, including their potential to act as antibacterial drug carriers that may penetrate into bacteria cells and biofilm mass. Pseudomonas aeruginosa is a frequent cause of infection in hospitalized patients, and significant numbers of currently isolated clinical strains are resistant to standard antibiotic therapy. Here we describe the impact of three types of SPIONs on the growth of P. aeruginosa during long-term bacterial culture. Their size, structure, and physicochemical properties were determined using transmission electron microscopy, X-ray diffraction analysis, and Fourier transform infrared spectroscopy. We observed significant inhibition of P. aeruginosa growth in bacterial cultures continued over 96 hours in the presence of gold-functionalized nanoparticles (Fe₃O₄@Au). At the 48-hour time point, growth of P. aeruginosa, as assessed by the number of colonies grown from treated samples, showed the highest inhibition (decreased by 40%). These data provide strong evidence that Fe₃O₄@Au can dramatically reduce growth of P. aeruginosa and provide a platform for further study of the antibacterial activity of this nanomaterial.

  18. Elastic force restricts growth of the murine utricle

    PubMed Central

    Gnedeva, Ksenia; Jacobo, Adrian; Salvi, Joshua D; Petelski, Aleksandra A; Hudspeth, A J

    2017-01-01

    Dysfunctions of hearing and balance are often irreversible in mammals owing to the inability of cells in the inner ear to proliferate and replace lost sensory receptors. To determine the molecular basis of this deficiency we have investigated the dynamics of growth and cellular proliferation in a murine vestibular organ, the utricle. Based on this analysis, we have created a theoretical model that captures the key features of the organ’s morphogenesis. Our experimental data and model demonstrate that an elastic force opposes growth of the utricular sensory epithelium during development, confines cellular proliferation to the organ’s periphery, and eventually arrests its growth. We find that an increase in cellular density and the subsequent degradation of the transcriptional cofactor Yap underlie this process. A reduction in mechanical constraints results in accumulation and nuclear translocation of Yap, which triggers proliferation and restores the utricle’s growth; interfering with Yap’s activity reverses this effect. DOI: http://dx.doi.org/10.7554/eLife.25681.001 PMID:28742024

  19. Synaptic development and neuronal myelination are altered with growth restriction in fetal guinea pigs.

    PubMed

    Piorkowska, Karolina; Thompson, Jennifer; Nygard, Karen; Matushewski, Brad; Hammond, Robert; Richardson, Bryan

    2014-01-01

    This study examines aberrant synaptogenesis and myelination of neuronal connections as possible links to neurological sequelae in growth-restricted fetuses. Pregnant guinea pig sows were subjected to uterine blood flow restriction or sham surgeries at midgestation. The animals underwent necropsy at term with fetuses grouped according to body weight and brain-to-liver weight ratios as follows: appropriate for gestational age (n = 12); asymmetrically fetal growth restricted (aFGR; n = 8); symmetrically fetal growth restricted (sFGR; n = 8), and large for gestational age (n = 8). Fetal brains were perfusion fixed and paraffin embedded to determine immunoreactivity for synaptophysin and synaptopodin as markers of synaptic development and maturation, respectively, and for myelin basic protein as a marker for myelination, which was further assessed using Luxol fast blue staining. The most pertinent findings were that growth-restricted guinea pig fetuses exhibited reduced synaptogenesis and synaptic maturation as well as reduced myelination, which were primarily seen in subareas of the hippocampus and associated efferent tracts. These neurodevelopmental changes were more pronounced in the sFGR compared to the aFGR animals. Accordingly, altered hippocampal development involving synaptogenesis and myelination may represent a mechanism by which cognitive deficits manifest in human growth-restricted offspring in later life. © 2014 S. Karger AG, Basel.

  20. Graphene Oxide Restricts Growth and Recrystallization of Ice Crystals.

    PubMed

    Geng, Hongya; Liu, Xing; Shi, Guosheng; Bai, Guoying; Ma, Ji; Chen, Jingbo; Wu, Zhuangyuan; Song, Yanlin; Fang, Haiping; Wang, Jianjun

    2017-01-19

    We show graphene oxide (GO) greatly suppresses the growth and recrystallization of ice crystals, and ice crystals display a hexagonal shape in the GO dispersion. Preferred adsorption of GO on the ice crystal surface in liquid water leads to curved ice crystal surface. Therefore, the growth of ice crystal is suppressed owing to the Gibbs-Thompson effect, that is, the curved surface lowers the freezing temperature. Molecular dynamics simulation analysis reveals that oxidized groups on the basal plane of GO form more hydrogen bonds with ice in comparison with liquid water because of the honeycomb hexagonal scaffold of graphene, giving a molecular-level mechanism for controlling ice formation. Application of GO for cryopreservation shows that addition of only 0.01 wt % of GO to a culture medium greatly increases the motility (from 24.3 % to 71.3 %) of horse sperms. This work reports the control of growth of ice with GO, and opens a new avenue for the application of 2D materials.

  1. Dilated cerebral venous system observed in growth restricted fetuses.

    PubMed

    Baron, Joel; Mastrolia, Salvatore Andrea; Shelef, Ilan; Tirosh, Dan; Daniel-Spiegel, Etty; Hershkovitz, Reli

    2017-04-03

    The dilation of the fetal cerebral veins is a rare phenomena that may be associated to a bad obstetric outcome, and is usually connected to antenatal thrombosis of the posterior dural venous sinuses. There are several descriptions of cerebral vein distension on magnetic resonance imaging (MRI), but all of them are detected postnatally. We present herein two cases of fetal antenatal cerebral dilation of the venous system, without any association to any sign of vein thrombosis, and a systematic review of literature regarding pathogenesis, diagnosis and outcomes associated to the antenatal detection of this condition with the use of MRI. To identify potentially eligible studies, we searched PubMed, Scopus, Cochrane Library (all from inception to October 20(th), 2016) and applied no language restrictions. The electronic database search provided a total of 22843 results. After the exclusion of duplicates, manuscripts that resulted not relevant to the review based on title and abstract screening, and analysis of manuscripts eligible for full-text assessment, no papers were found related to the subject reported in the present manuscript.

  2. Comparison of Fetal and Neonatal Growth Curves in Detecting Growth Restriction

    PubMed Central

    Marconi, Anna Maria; Ronzoni, Stefania; Bozzetti, Patrizia; Vailati, Simona; Morabito, Alberto; Battaglia, Frederick C

    2009-01-01

    Objective To evaluate the outcome of intrauterine growth restriction (IUGR) infants with abnormal pulsatility index of the umbilical artery according to the neonatal birth weight/gestational age standards and the intrauterine growth charts. Methods We analyzed 53 pregnancies with severe IUGR classified as Group 2 (22 IUGR: abnormal pulsatility index and normal fetal heart rate) and Group 3 (31 IUGR: abnormal pulsatility index and fetal heart rate). Neonatal birth weight/gestational age distribution, body size measurements, maternal characteristics and obstetric outcome, and neonatal major and minor morbidity and mortality were compared with those obtained in 79 singleton pregnancies with normal fetal growth and pulsatility index, matched for gestational age [appropriate for gestational age (AGA) group]. Differences were analyzed with the χ2 test and the Student’s t test. Differences between means corrected for gestational age in the different groups were assessed by analysis of covariance test. A P value <0.05 was considered significant. Results At delivery, utilizing the neonatal standards, 25/53 (47%) IUGR showed a birthweight above the 10th percentile (IUGRAGA) whereas in 28, birthweight was below the 10th percentile (IUGRSGA). All body size measurements were significantly higher in AGA than in IUGRAGA and IUGRSGA. Forty-nine out of 79 (62%) AGA and 49/53 (92%) IUGR were admitted in the neonatal intensive care unit (p<0.001). One out of 79 (1%) AGA and 6/53 (11%) IUGR newborns died within 28 days (p<0.02). Major and minor morbidity was not different. Conclusion This study shows that neonatal outcome is similar in IUGR of the same clinical severity, whether or not they could be defined AGA or SGA according to the neonatal standards. Neonatal curves are misleading in detecting low birthweight infants and should be utilized only when obstetrical data are unavailable. PMID:19037030

  3. Sex Differences in Placental Mitochondrial Function Associated with Ozone-Induced Fetal Growth Restriction.

    EPA Science Inventory

    Fetal growth restriction is a major underlying cause of infant mortality worldwide. Unfortunately little is known about the mechanisms that drive compromised growth and the role of placental maladaptation on fetal development. In the current study placentas from male and female r...

  4. Early retinal blood vessel growth in normal and growth restricted rat pups raised in oxygen and room air.

    PubMed

    Dhaliwal, C A; Wade, J; Gillespie, T; Aspinall, P; McIntosh, N; Fleck, B W

    2011-11-01

    Premature infants are born with incompletely vascularised retinas and are at a risk of developing retinopathy of prematurity (ROP). Rate of prenatal and postnatal body growth is important in the pathogenesis of ROP. The aim of this study was to develop a physiology-based rat model in order to study the effect of growth restriction and oxygen on early retinal vascular development. Rat mothers were fed either a normal (18% casein) or low (9% casein) protein diet (to cause pup growth restriction) from the last week of gestation. After birth, mother and pups were placed in either room air or a specialised oxygen chamber that delivered a rapidly fluctuating hyperoxic oxygen profile. The oxygen profile was based on that from a premature infant who developed severe ROP. On day 14, retinas were dissected, flat-mounted and stained using biotinylated lectin. Images were captured by confocal microscopy. The avascular areas of the retinas were measured and compared. Growth restricted rat pups had significantly larger retinal avascular areas than 'normally grown' rat pups (Mann-Whitney U test, p<0.001). Growth restricted rat pups raised in fluctuating oxygen had significantly larger retinal avascular areas than growth restricted rat pups raised in room air (Mann-Whitney U test, p=0.001). The authors have developed a novel model for ROP that involves inducing both intrauterine and postnatal growth restriction and also exposes neonatal rat pups to fluctuating oxygen. This physiology-based model can be used to study the effects of growth, nutrition and oxygen on early retinal vascular development.

  5. Rapamycin Prevents Transforming Growth Factor-α–Induced Pulmonary Fibrosis

    PubMed Central

    Korfhagen, Thomas R.; Le Cras, Timothy D.; Davidson, Cynthia R.; Schmidt, Stephanie M.; Ikegami, Machiko; Whitsett, Jeffrey A.; Hardie, William D.

    2009-01-01

    Transforming growth factor (TGF)-α is a ligand for the epidermal growth factor receptor (EGFR). EGFR activation is associated with fibroproliferative processes in human lung disease and animal models of pulmonary fibrosis. Overexpression of TGF-α in transgenic mice causes progressive and severe pulmonary fibrosis; however, the intracellular signaling pathways downstream of EGFR mediating this response are unknown. Using a doxycycline-regulatable transgenic mouse model of lung-specific TGF-α expression, we observed increased PCNA protein and phosphorylation of Akt and p70S6K in whole lung homogenates in association with induction of TGF-α. Induction in the lung of TGF-α caused progressive pulmonary fibrosis over a 7-week period. Daily administration of rapamycin prevented accumulation of total lung collagen, weight loss, and changes in pulmonary mechanics. Treatment of mice with rapamycin 4 weeks after the induction of TGF-α prevented additional weight loss, increases in total collagen, and changes in pulmonary mechanics. Rapamycin prevented further increases in established pulmonary fibrosis induced by EGFR activation. This study demonstrates that mammalian target of rapamycin (mTOR) is a major effector of EGFR-induced pulmonary fibrosis, providing support for further studies to determine the role of mTOR in the pathogenesis and treatment of pulmonary fibrosis. PMID:19244201

  6. Antenatal glucocorticoid treatment of the growth-restricted fetus: benefit or cost?

    PubMed

    Morrison, Janna L; Orgeig, Sandra

    2009-06-01

    Women at risk of preterm labor are commonly treated with antenatal glucocorticoids to reduce neonatal complications, including respiratory distress syndrome. Despite the benefits of antenatal glucocorticoid for neonatal lung function, they are associated with negative cardiovascular outcomes. Among this population, there is a group of intrauterine growth-restricted fetuses in which substrate supply is reduced and these fetuses must undergo a range of cardiovascular adaptations to survive. Interestingly, the cardiovascular changes caused by antenatal glucocorticoid in normally grown fetuses are contrary to the cardiovascular adaptations that the intrauterine growth-restricted fetus must make to survive. Hence, the possibility exists that antenatal glucocorticoid in intrauterine growth-restricted infants may compromise cardiovascular development. This review first provides an overview of general antenatal glucocorticoid effects, before outlining the effects on cardiorespiratory development in normally grown fetuses, the cardiovascular adaptations that occur in the intrauterine growth-restricted fetus and finally integrating this with the very limited evidence for the effect of antenatal glucocorticoid in intrauterine growth-restricted infants.

  7. The effect of quantitative feed restriction on allometric growth in broilers.

    PubMed

    van der Klein, S A S; Silva, F A; Kwakkel, R P; Zuidhof, M J

    2017-01-01

    Feed restriction in broilers is aimed at preventing metabolic disorders, increasing feed efficiency, or manipulating carcass conformation. The purpose of the current study was to investigate the effects of modest graded levels feed restriction during the second and third wk of life. Mixed-sex chickens were raised in pens with 4 replications per treatment to 35 d of age. Chickens were fed ad libitum throughout the trial, or 90, 80, or 70% of expected ad libitum feed intake during the second wk of life, or 95, 90, 85, or 80% of expected ad libitum feed intake during the third wk of life. Feed intake, BW, ADG, and feed conversion ratio (FCR) were measured and weekly dissections were conducted to characterize allometric growth of the breast muscle, legs, abdominal fat pad, liver, gastro-intestinal tract (GIT), and heart. Feeding 70% of ad libitum during wk 2 and 80% during wk 3 reduced ADG during the restriction period and reduced BW at the end of the restriction period, but chickens exhibited complete compensatory growth within one wk after the restriction period. No significant effects of restriction treatment were found on BW, FCR, fat pad, empty GIT, breast muscle, heart, legs, and liver weight at d 35, but allometric growth curve for breast muscle was lower in birds fed 80 and 85% of ad libitum during wk 3, and for birds fed 70% of ad libitum in wk 2. Allometric growth curves for all body parts were different between males and females, except for the liver. Females had higher relative fat pad, breast muscle, and liver weight and a lower GIT and heart and leg weight compared with males at d 35. Feed restriction could differentially affect males and females. This study showed that feeding 70% of ad libitum in wk 2 might be beneficial to reduce fat pad, but later feed restriction in wk 3 may reduce breast muscle weight at broiler processing age.

  8. Effect of postnatal nutrition restriction on the oxidative status of neonates with intrauterine growth restriction in a pig model.

    PubMed

    Che, Lianqiang; Xuan, Yue; Hu, Liang; Liu, Yan; Xu, Qin; Fang, Zhengfeng; Lin, Yan; Xu, Shengyu; Wu, De; Zhang, Keying; Chen, Daiwen

    2015-01-01

    In offspring with intrauterine growth restriction (IUGR), where oxidative stress may play an important role in inducing metabolic syndrome, nutrition restriction has been shown to improve oxidative status. In this study, we aimed to investigate the effect of postnatal nutrition restriction on the oxidative status of IUGR neonates. A total of twelve pairs of piglets, of normal birth-weight (NBW) and with IUGR (7 days old), respectively, were randomly allocated to have adequate nutritional intake (ANI) and restricted nutritional intake (RNI) for a period of 21 days, respectively. This design produced 4 experimental groups: NBW-ANI, IUGR-ANI, NBW-RNI and IUGR-RNI (n = 6 per group). Serum, ileum and liver samples were analyzed for antioxidant parameters and the mRNA expression of genes with regard to oxidative status. The data were subjected to general linear model analysis and Duncan's test with a 5% significance level. Irrespective of nutritional intake, the IUGR pigs had markedly lower activity of glutathione peroxidase (GPX), gene expressions of liver mitochondrial manganese superoxide dismutase (Mn-SOD) and ileum cytoplasmic copper/zinc (CuZn)-SOD and, accordingly, there was a markedly higher malondialdehyde concentration in the liver of these pigs compared to in the NBW pigs. Irrespective of body weight, pigs receiving ANI treatment had significantly lower activities of antioxidant enzymes in the serum (total antioxidative capability, CuZn-SOD and GPX) and liver (total SOD and glutathione reductase) and decreased gene expression of liver CuZn-SOD and Mn-SOD compared to the pigs receiving RNI. In addition, the IUGR pigs had a markedly lower concentration of liver reduced glutathione (GSH), ratio of GSH to oxidized glutathione, gene expression of ileum CuZn-SOD and extracellular SOD than the NBW pigs when receiving ANI, but not all of these differences were observed in those receiving RNI. IUGR neonates may have poor antioxidant defense systems, and postnatal

  9. The use of ultrasound to assess fetal growth in a guinea pig model of fetal growth restriction.

    PubMed

    Swanson, A M; Mehta, V; Ofir, K; Rowe, M; Rossi, C; Ginsberg, Y; Griffin, H; Barker, H; White, T; Boyd, M; David, A L

    2017-04-01

    Fetal growth restriction (FGR) is a common and potentially severe pregnancy complication. Currently there is no treatment available. The guinea pig is an attractive model of human pregnancy as placentation is morphologically very similar between the species. Nutrient restriction of the dam creates growth-restricted fetuses while leaving an intact uteroplacental circulation, vital for evaluating novel therapies for FGR. Growth-restricted fetuses were generated by feeding Dunkin Hartley guinea pig dams 70% of ad libitum intake from four weeks before and throughout pregnancy. The effect of maternal nutrient restriction (MNR) on dams and fetuses was carefully monitored, and ultrasound measurements of pups collected. There was no difference in maternal weight at conception, however by five weeks post conception MNR dams were significantly lighter ( P < 0.05). MNR resulted in significantly smaller pup size from 0.6-0.66 gestation. Ultrasound is a powerful non-invasive tool for assessing the effect of therapeutic interventions on fetal growth, allowing longitudinal measurement of fetuses. This model and method yield data applicable to the human condition without the need for animal sacrifice and will be useful in the translation of therapies for FGR into the clinic.

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

    PubMed Central

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

    2015-01-01

    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

  11. Postnatal growth restriction and gene expression changes in a mouse model of fetal alcohol syndrome.

    PubMed

    Kaminen-Ahola, Nina; Ahola, Arttu; Flatscher-Bader, Traute; Wilkins, Sarah J; Anderson, Greg J; Whitelaw, Emma; Chong, Suyinn

    2010-10-01

    Growth restriction, craniofacial dysmorphology, and central nervous system defects are the main diagnostic features of fetal alcohol syndrome. Studies in humans and mice have reported that the growth restriction can be prenatal or postnatal, but the underlying mechanisms remain unknown.We recently described a mouse model of moderate gestational ethanol exposure that produces measurable phenotypes in line with fetal alcohol syndrome (e.g., craniofacial changes and growth restriction in adolescent mice). In this study, we characterize in detail the growth restriction phenotype by measuring body weight at gestational day 16.5, cross-fostering from birth to weaning, and by extending our observations into adulthood. Furthermore, in an attempt to unravel the molecular events contributing to the growth phenotype, we have compared gene expression patterns in the liver and kidney of nonfostered, ethanol-exposed and control mice at postnatal day 28.We find that the ethanol-induced growth phenotype is not detectable prior to birth, but is present at weaning, even in mice that have been cross-fostered to unexposed dams. This finding suggests a postnatal growth restriction phenotype that is not due to deficient postpartum care by dams that drank ethanol, but rather a physiologic result of ethanol exposure in utero. We also find that, despite some catch-up growth after 5 weeks of age, the effect extends into adulthood, which is consistent with longitudinal studies in humans.Genome-wide gene expression analysis revealed interesting ethanol-induced changes in the liver, including genes involved in the metabolism of exogenous and endogenous compounds, iron homeostasis, and lipid metabolism.

  12. 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.

  13. 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.

  14. Expectant management of severe preterm preeclampsia: is intrauterine growth restriction an indication for immediate delivery?

    PubMed

    Chammas, M F; Nguyen, T M; Li, M A; Nuwayhid, B S; Castro, L C

    2000-10-01

    Expectant management of severe preterm preeclampsia is gaining widespread acceptance in clinical practice. The objective of our study was 2-fold-to determine the frequency of fetal deterioration with expectant management of severe preterm preeclampsia and to evaluate whether the presence of intrauterine growth restriction on admission is associated with a shorter admission-to-delivery interval or more deliveries resulting from nonreassuring fetal status in comparison with pregnancies with preeclampsia but without intrauterine growth restriction. This was an observational study of women with singleton pregnancies at <34 completed weeks' gestation who were admitted to the hospital with the diagnosis of severe preeclampsia and managed expectantly. Fetal status on admission, admission-to-delivery interval, indication for delivery, and neonatal outcome were examined. Forty-seven women were studied during a 3-year period (1996-1999). Gestational age at admission was 29.8 +/- 2.6 weeks. The mean admission-to-delivery interval for the entire group was 6.0 +/- 5.1 days; in 42.5% delivery was for fetal indications. In comparison with the absence of intrauterine growth restriction, the presence of intrauterine growth restriction at admission resulted in a significantly shorter admission-to-delivery interval (3.1 +/- 2.1 vs 6.6 +/- 6.1 days; P <.05). Most fetuses with intrauterine growth restriction (85.7%) were delivered before 1 week. Although 57% of fetuses with intrauterine growth restriction were delivered for fetal indications, versus 39% of fetuses without intrauterine growth restriction, these rates were not found to be significantly different. Neonatal outcomes, as reflected by Apgar scores, number of admissions to and duration of stay in the neonatal intensive care unit, and neonatal mortality rates, were similar. Pregnancies complicated by severe preterm preeclampsia and the presence of intrauterine growth restriction at admission may not benefit from expectant

  15. Early and Late Postnatal Myocardial and Vascular Changes in a Protein Restriction Rat Model of Intrauterine Growth Restriction

    PubMed Central

    Menendez-Castro, Carlos; Fahlbusch, Fabian; Cordasic, Nada; Amann, Kerstin; Münzel, Kathrin; Plank, Christian; Wachtveitl, Rainer; Rascher, Wolfgang; Hilgers, Karl F.; Hartner, Andrea

    2011-01-01

    Intrauterine growth restriction (IUGR) is a risk factor for cardiovascular disease in later life. Early structural and functional changes in the cardiovascular system after IUGR may contribute to its pathogenesis. We tested the hypothesis that IUGR leads to primary myocardial and vascular alterations before the onset of hypertension. A rat IUGR model of maternal protein restriction during gestation was used. Dams were fed low protein (LP; casein 8.4%) or isocaloric normal protein diet (NP; casein 17.2%). The offspring was reduced to six males per litter. Immunohistochemical and real-time PCR analyses were performed in myocardial and vascular tissue of neonates and animals at day 70 of life. In the aortas of newborn IUGR rats expression of connective tissue growth factor (CTGF) was induced 3.2-fold. At day 70 of life, the expression of collagen I was increased 5.6-fold in aortas of IUGR rats. In the hearts of neonate IUGR rats, cell proliferation was more prominent compared to controls. At day 70 the expression of osteopontin was induced 7.2-fold. A 3- to 7-fold increase in the expression of the profibrotic cytokines TGF-β and CTGF as well as of microfibrillar matrix molecules was observed. The myocardial expression and deposition of collagens was more prominent in IUGR animals compared to controls at day 70. In the low-protein diet model, IUGR leads to changes in the expression patterns of profibrotic genes and discrete structural abnormalities of vessels and hearts in adolescence, but, with the exception of CTGF, not as early as at the time of birth. Invasive and non-invasive blood pressure measurements confirmed that IUGR rats were normotensive at the time point investigated and that the changes observed occurred independently of an increased blood pressure. Hence, altered matrix composition of the vascular wall and the myocardium may predispose IUGR animals to cardiovascular disease later in life. PMID:21655297

  16. The growth-restricted fetus: risk of mortality by each additional week of expectant management.

    PubMed

    Pilliod, Rachel A; Page, Jessica M; Sparks, Teresa N; Caughey, Aaron B

    2017-10-03

    To compare fetal/infant mortality risk associated with each additional week of expectant management with the infant mortality risk of immediate delivery in growth-restricted pregnancies. A retrospective cohort study was conducted of singleton, nonanomalous pregnancies from the 2005-2008 California Birth Registry comparing pregnancies affected and unaffected by growth restriction, defined using birth weights as a proxy for fetal growth restriction (FGR). Birth weights were subdivided as greater than the 90th percentile, between the 10th percentile and 90th percentile, and less than the 10th percentile. Cases greater than the 90th percentile were excluded from analysis. Cases less than the 10th percentile were considered to have FGR and were further subcategorized into <10th percentile, <5th percentile, and <3rd percentile. We compared the risk of infant death at each gestational age week against a composite risk representing the mortality risk of one additional week of expectant management. We identified 1,641,000 births, of which 110,748 (6.7%) were less than 10th percentile. The risk of stillbirth increased with gestational age with the risk of stillbirth at each week of gestation inversely proportional to growth percentile. The risks of fetal and infant mortality with expectant management outweighed the risk of infant death for all FGR categories analyzed beginning at 38 weeks. However, the absolute risks differed by growth percentiles, with the highest risks of infant death and stillbirth in the <3rd percentile cohort. At 39 weeks, absolute risks were low, although the number needed to deliver to prevent 1 death ranged from 413 for <3rd percentile to 2667 in unaffected pregnancies. At 38 weeks, the mortality risk of expectant management for one additional week exceeds the risk of delivery across all growth-restricted cohorts, despite variation in absolute risk by degree of growth restriction.

  17. Developmental indices of nutritionally induced placental growth restriction in the adolescent sheep.

    PubMed

    Lea, Richard G; Hannah, Lisa T; Redmer, Dale A; Aitken, Raymond P; Milne, John S; Fowler, Paul A; Murray, Joanne F; Wallace, Jacqueline M

    2005-04-01

    Most intrauterine growth restriction cases are associated with reduced placental growth. Overfeeding adolescent ewes undergoing singleton pregnancies restricts placental growth and reduces lamb birth weight. We used this sheep model of adolescent pregnancy to investigate whether placental growth restriction is associated with altered placental cell proliferation and/or apoptosis at d 81 of pregnancy, equivalent to the apex in placental growth. Adolescent ewes with singleton pregnancies were offered a high or moderate level of a complete diet designed to induce restricted or normal placental size at term, respectively. Bromodeoxyuridine (Brd-U) was administered to H and M ewes 1 h before slaughter. Placental tissues were examined for a) Brd-U (immunohistochemistry) and b) apoptosis regulatory genes by in situ hybridization, Northern analyses (bax, mcl-1), immunohistochemistry, and Western analyses (bax). Quantification was carried out by image analysis. Total placentome weights were equivalent between groups. Brd-U predominantly localized to the trophectoderm and was significantly lower in the H group. Bax and mcl-1 mRNA were localized to the maternal-fetal interface. Bax protein was significantly increased in the H group and predominant in the uninuclear fetal trophectoderm. These observations indicate that reduced placental size at term may be due to reduced placental cell proliferation and possibly increased apoptosis occurring much earlier in gestation.

  18. Plasma vascular endothelial growth factor A and placental growth factor: novel biomarkers of pulmonary hypertension in congenital diaphragmatic hernia.

    PubMed

    Patel, Neil; Moenkemeyer, Florian; Germano, Susie; Cheung, Michael M H

    2015-02-15

    Pulmonary hypertension (PH) due to abnormal pulmonary vascular development is an important determinant of illness severity in congenital diaphragmatic hernia (CDH). Vascular endothelial growth factor A (VEGFA) and placental growth factor (PLGF) may be important mediators of pulmonary vascular development in health and disease. This prospective study investigated the relationship between plasma VEGFA and PLGF and measures of pulmonary artery pressure, oxygenation, and cardiac function in CDH. A cohort of 10 infants with CDH consecutively admitted to a surgical neonatal intensive care unit (NICU) was recruited. Eighty serial plasma samples were obtained and analyzed by multiplex immunoassay to quantify VEGFA and PLGF. Concurrent assessment of pulmonary artery pressure (PAP) and cardiac function were made by echocardiography. Plasma VEGFA was higher and PLGF was lower in CDH compared with existing normative data. Combined plasma VEGFA:PLGF ratio correlated positively with measures of PAP, diastolic ventricular dysfunction, and oxygenation index. Nonsurvivors had higher VEGFA:PLGF ratio than survivors at days 3-4 of life and in the second week of life. These findings suggest that increased plasma VEGFA and reduced PLGF correlate with clinical severity of pulmonary vascular disease and may be associated with adverse outcome in CDH. This potential role for combined plasma VEGFA and PLGF in CDH as disease biomarkers, pathogenic mediators, and therapeutic targets merits further investigation.

  19. Neuropsychological development in preschool children born with asymmetrical intrauterine growth restriction and impact of postnatal head growth.

    PubMed

    Klaric, Andrea Simić; Galić, Slavka; Kolundzić, Zdravko; Bosnjak, Vlatka Mejaski

    2013-07-01

    Neuropsychological development and the impact of postnatal head growth were studied in preschool children with asymmetrical intrauterine growth restriction. Examinees born at term with a birth weight below the 10th percentile were matched to the control group according to chronological and gestational age, gender, and maternal education. Fifty children were in each group, with a mean age of 6 years, 4 months. The Touwen neurological examination, the Čuturić developmental test, an imitative hand positions test, and a visual attention test were performed. There were significant differences (P< .03) in motor variables, the developmental quotient, and the imitative hand positions test. Fine motor skills had the most discriminative power. Relative growth of the head in relation to weight gain was positively correlated to neurocognitive outcome. Intrauterine growth-restricted children with a current head circumference ≤10th percentile had poorer outcomes. Conclusively, intrauterine growth restriction has a negative impact on neurocognitive development. Slow postnatal head growth is correlated with a poorer neuropsychological outcome.

  20. Neurobehavioral determinants of nutritional security in fetal growth-restricted individuals.

    PubMed

    Portella, André Krumel; Silveira, Patrícia Pelufo

    2014-12-01

    Fetal growth restriction results from a failure to achieve a higher growth potential and has been associated with many maternal conditions, such as chronic diseases (infections, hypertension, and some cases of diabetes and obesity), exposures (tobacco smoke, drugs), and malnutrition. This early adversity induces a series of adaptive physiological responses aimed at improving survival, but imposing increased risk for developing chronic nontransmittable diseases (obesity, type II diabetes, cardiovascular disease) in the long term. Recently, mounting evidence has shown that fetal growth impairment is related to altered feeding behavior and preferences through the life course. When living in countries undergoing nutritional transition, in which individuals experience the coexistence of underweight and overweight problems (the "double burden of malnutrition"), fetal growth-restricted children can be simultaneously growth restricted and overweight-a double burden of malnutrition at the individual level. Considering food preferences as an important aspect of nutrition security, we will summarize the putative neurobiological mechanisms at the core of the relationship between fetal growth and nutrition security over the life course and the evidence linking early life adversity to later food preferences.

  1. RNA Sequencing Exposes Adaptive and Immune Responses to Intrauterine Growth Restriction in Fetal Sheep Islets.

    PubMed

    Kelly, Amy C; Bidwell, Christopher A; McCarthy, Fiona M; Taska, David J; Anderson, Miranda J; Camacho, Leticia E; Limesand, Sean W

    2017-04-01

    The risk of type 2 diabetes is increased in children and adults who exhibited fetal growth restriction. Placental insufficiency and intrauterine growth restriction (IUGR) are common obstetrical complications associated with fetal hypoglycemia and hypoxia that reduce the β-cell mass and insulin secretion. In the present study, we have defined the underlying mechanisms of reduced growth and proliferation, impaired metabolism, and defective insulin secretion previously established as complications in islets from IUGR fetuses. In an IUGR sheep model that recapitulates human IUGR, high-throughput RNA sequencing showed the transcriptome of islets isolated from IUGR and control sheep fetuses and identified the transcripts that underlie β-cell dysfunction. Functional analysis expanded mechanisms involved in reduced proliferation and dysregulated metabolism that include specific cell cycle regulators and growth factors and mitochondrial, antioxidant, and exocytotic genes. These data also identified immune responses, wnt signaling, adaptive stress responses, and the proteasome as mechanisms of β-cell dysfunction. The reduction of immune-related gene expression did not reflect a change in macrophage density within IUGR islets. The present study reports the islet transcriptome in fetal sheep and established processes that limit insulin secretion and β-cell growth in fetuses with IUGR, which could explain the susceptibility to premature islet failure in adulthood. Islet dysfunction formed by intrauterine growth restriction increases the risk for diabetes. Copyright © 2017 Endocrine Society.

  2. Placental Vitamin D-Binding Protein Expression in Human Idiopathic Fetal Growth Restriction

    PubMed Central

    Wookey, Alice F.; Chollangi, Tejasvy; Yong, Hannah E. J.

    2017-01-01

    Vitamin D-binding protein is a multifunctional serum protein with multiple actions related to normal health. Vitamin D-binding protein transports vitamin D and influences the metabolism of this key hormone but it also has additional immunomodulatory and actin-clearing properties. We investigated whether vitamin D-binding protein expression is altered in fetal growth restriction-associated placental dysfunction. Protein was extracted from 35 placentae derived from 17 healthy control subjects and 18 gestation-matched subjects with fetal growth restriction (FGR). FGR subjects were further subdivided as idiopathic (n = 9) and nonidiopathic (n = 9). Vitamin D-binding protein and 25(OH) vitamin D were measured by ELISA and normalized to protein concentration. The results showed significantly reduced levels of placental vitamin D-binding protein (control versus FGR, p < 0.05, Student's t-test) that were strongly associated with idiopathic fetal growth restriction (p < 0.01, Kruskal-Wallis), whereas levels of vitamin D-binding protein were not associated with placental 25(OH) vitamin D stores (p = 0.295, Pearson's correlation). As such, vitamin D-binding protein may be a factor in unexplained placental dysfunction associated with idiopathic fetal growth restriction and may potentially serve as a biomarker of this disease. PMID:28293436

  3. Doppler-based fetal heart rate analysis markers for the detection of early intrauterine growth restriction.

    PubMed

    Stroux, Lisa; Redman, Christopher W; Georgieva, Antoniya; Payne, Stephen J; Clifford, Gari D

    2017-09-01

    One indicator for fetal risk of mortality is intra-uterine growth restriction (IUGR). Whether markers reflecting the impact of growth restriction on the cardiovascular system, computed from a Doppler-derived heart rate signal, would be suitable in its detection antenatally were studied MATERIAL AND METHODS: We used a cardiotocography archive of 1163 IUGR cases and 1163 healthy controls, matched for gestation and gender. We assessed the discriminative power of short-term variability (STV) and long-term variability (LTV) of the fetal heart rate, computed over episodes of high and low variation aiming to separate growth-restricted fetuses from controls. Metrics characterizing the sleep state distribution within a trace were also considered for inclusion into an IUGR detection model RESULTS: Significant differences in the risk markers comparing growth-restricted with healthy fetuses were found. When used in a logistic regression classifier, their performance for identifying IUGR was considerably superior before 34 weeks gestation. LTV in active sleep was superior to STV (AUROC of 72% compared to 71%). Most predictive was the number of minutes in high variation per hour (AUROC of 75%). A multivariate IUGR prediction model improved the AUROC to 76%. We suggest that heart rate variability markers together with surrogate information on sleep states can contribute to the detection of early-onset IUGR. This article is protected by copyright. All rights reserved. This article is protected by copyright. All rights reserved.

  4. Calcium supplementation does not rescue the programmed adult bone deficits associated with perinatal growth restriction.

    PubMed

    Romano, Tania; Wark, John D; Wlodek, Mary E

    2010-12-01

    Low birth weight and poor childhood growth program a variety of adult diseases including bone disorders such as osteoporosis. We have previously reported that offspring born small, as a result of uteroplacental insufficiency, have shorter femurs, lower bone mineral content and a bone strength deficit as adults. The aim of this study was to determine the effects of calcium supplementation from adolescence on growth restricted male and female offspring which have a programmed bone deficit. Bilateral uterine vessel ligation (Restricted) or sham surgery (Control) was performed on gestational day 18 in WKY rats to induce uteroplacental insufficiency and growth restriction. At 2 months pups were allocated to one of four diet groups: diet 1-constant normal calcium diet, diet 2-variable normal calcium diet, diet 3-constant high calcium diet, diet 4-variable high calcium diet. Diet groups 1 and 3 were fed their respective diets constantly for the duration of the study. In groups 2 and 4, rats were fed one diet for 5 days, followed by a switch to a low calcium diet for the next 5 days. At 6 months Dual Energy Xray Absorptiometry (DXA) and Peripheral Quantitative Computed Tomography (pQCT) were performed on the right femur. Bone turnover markers were measured at 4 months. Male and female Restricted offspring were born 14% lighter compared to Controls (p<0.05). At 6 months both male and female Restricted offspring remained smaller and had shorter femurs compared to Controls (p<0.05). Restricted males and females had reduced trabecular and cortical content compared to Controls, regardless of diet (p<0.05). Trabecular bone density was lower in Restricted females only (p<0.05). A constant high calcium diet increased cortical BMD in Restricted male and both female groups (p<0.05). Measures of bone geometry indicated that Restricted offspring have narrower bones with preservation of absolute cortical thickness (p<0.05). Importantly, the stress strain index of bone bending strength

  5. Influence of catch up growth on spatial learning and memory in a mouse model of intrauterine growth restriction.

    PubMed

    Duran Fernandez-Feijoo, Cristina; Carrasco Carrasco, Cristina; Villalmazo Francisco, Núria; Cebrià Romero, Judit; Fernández Lorenzo, Jose Ramon; Jiménez-Chillaron, J C; Camprubí Camprubí, Marta

    2017-01-01

    Intrauterine growth restriction (IUGR) and rapid postnatal weight gain or catch up growth (CUG) increase the susceptibility to metabolic syndrome during adult life. Longitudinal studies have also revealed a high incidence of learning difficulties in children with IUGR. The aim of the present study was to investigate the effect of nutrition and CUG on learning memory in an IUGR animal model. We hypothesized that synaptic protein expression and transcription, an essential mechanism for memory consolidation, might be affected by intrauterine undernutrition. IUGR was induced by 50% maternal caloric undernutrition throughout late gestation. During the suckling period, dams were either fed ad libitum or food restricted. The pups were divided into: Normal prenatal diet-Normal postnatal diet (NN), Restricted prenatal diet- Normal postnatal diet + catch up growth (RN+), Normal prenatal diet-Restricted postnatal diet (NR) and Restricted prenatal diet-Restricted postnatal diet (RR). At 4 weeks of age, memory was assessed via a water maze test. To evaluate synaptic function, 2 specific synaptic proteins (postsynaptic density-95 [PSD95], synaptophysin) as well as insulin receptors (IR) were tested by Western Blot and quantitative polymerase chain reaction (qPCR). Brain-derived neurotrophic factor and serum insulin levels were also studied. The RN+ group presented a learning curve similar to the NN animals. The RR animals without CUG showed learning disabilities. PSD95 was lower in the RR group than in the NN and RN+ mice. In contrast, synaptophysin was similar in all groups. IR showed an inverse expression pattern to that of the PSD95. In conclusion, perinatal nutrition plays an important role in learning. CUG after a period of prenatal malnutrition seems to improve learning skills. The functional alterations observed might be related to lower PSD95 activity and a possible dysfunction in the hormone regulation of synaptic plasticity.

  6. Recombinant vascular endothelial growth factor 121 injection for the prevention of fetal growth restriction in a preeclampsia mouse model.

    PubMed

    Sulistyowati, Sri; Bachnas, Muhammad Adrianes; Anggraini, Nuri Dyah; Yuliantara, Eric Edwin; Prabowo, Wisnu; Anggraini, Nutria Widya Purna; Pramono, Mochammad Besari Adi; Adityawarman; Dachlan, Erry Gumilar; Andonotopo, Wiku

    2017-02-01

    To discover the potential role of recombinant VEGF121 (rVEGF121) injection for the prevention of fetal growth restriction in a preeclampsia (PE) mouse model (Mus musculus). This is an experimental study of 30 pregnant mice that were randomly divided into three groups: normal, PE, and PE with rVEGF121 injection. The PE mouse model was created by injecting anti Qa-2 10 ng iv, which is deleterious to Qa-2 expression (homologous to HLA-G), from the first to the fourth day of gestation. PE was validated by measuring serum levels of soluble fms-like tyrosine kinase-1 (sFlt-1) and placental growth factor(PIGF) and also by kidney histopathology. Recombinant VEGF121 was given on the ninth day until the 11th day of pregnancy; mice were terminated on the 16th day. Fetal weights were acquired with a Denver analytical balance. Serum levels of sFlt-1 and PlGF were measured using enzyme-linked immunosorbent assay (ELISA). The data were statistically analyzed via analysis of variance (ANOVA). On average, fetal birth weight was 0.7150 g in the normal group, 0.4936 g in the PE group, and 0.6768 g in the PE with rVEGF121 injection group. ANOVA showed significant growth restriction in the PE group (P=0.006), confirming the use of anti Qa-2 as a suitable PE model. Kidney histopathology results, sFlt-1 levels, and PlGF levels also demonstrated that anti Qa-2 consistently conferred hallmarks of PE in mice. Vascular endothelial growth factor (VEGF) injection prevented fetal growth restriction; comparable fetal weights were observed between the PE model with VEGF treatment and the normal group (P=0.610) but differed from the untreated PE group (P=0.021). Injection of rVEGF121 has the potential to prevent fetal growth restriction in a newly proposed PE mouse model.

  7. Perlecan antagonizes collagen IV and ADAMTS9/GON-1 in restricting the growth of presynaptic boutons.

    PubMed

    Qin, Jianzhen; Liang, Jingjing; Ding, Mei

    2014-07-30

    In the mature nervous system, a significant fraction of synapses are structurally stable over a long time scale. However, the mechanisms that restrict synaptic growth within a confined region are poorly understood. Here, we identified that in the C. elegans neuromuscular junction, collagens Type IV and XVIII, and the secreted metalloprotease ADAMTS/GON-1 are critical for growth restriction of presynaptic boutons. Without these components, ectopic boutons progressively invade into the nonsynaptic region. Perlecan/UNC-52 promotes the growth of ectopic boutons and functions antagonistically to collagen Type IV and GON-1 but not to collagen XVIII. The growth constraint of presynaptic boutons correlates with the integrity of the extracellular matrix basal lamina or basement membrane (BM), which surrounds chemical synapses. Fragmented BM appears in the region where ectopic boutons emerge. Further removal of UNC-52 improves the BM integrity and the tight association between BM and presynaptic boutons. Together, our results unravel the complex role of the BM in restricting the growth of presynaptic boutons and reveal the antagonistic function of perlecan on Type IV collagen and ADAMTS protein.

  8. Root morphological and proteomic responses to growth restriction in maize plants supplied with sufficient N.

    PubMed

    Yan, Huifeng; Li, Ke; Ding, Hong; Liao, Chengsong; Li, Xuexian; Yuan, Lixing; Li, Chunjian

    2011-07-01

    The primary objective of this study was to better understand how root morphological alteration stimulates N uptake in maize plants after root growth restriction, by investigating the changes in length and number of lateral roots, (15)NO(3)(-) influx, the expression level of the low-affinity Nitrate transporter ZmNrt1.1, and proteomic composition of primary roots. Maize seedlings were hydroponically cultured with three different types of root systems: an intact root system, embryonic roots only, or primary roots only. In spite of sufficient N supply, root growth restriction stimulated compensatory growth of remaining roots, as indicated by the increased lateral root number and root density. On the other hand, there was no significant difference in (15)NO(3)(-) influx between control and primary root plants; neither in ZmNrt1.1 expression levels in primary roots of different treatments. Our data suggested that increased N uptake by maize seedlings experiencing root growth restriction is attributed to root morphological adaptation, rather than explained by the variation in N uptake activity. Eight proteins were differentially accumulated in embryonic and primary root plants compared to control plants. These differentially accumulated proteins were closely related to signal transduction and increased root growth.

  9. Transcriptomic regulations in oligodendroglial and microglial cells related to brain damage following fetal growth restriction.

    PubMed

    Rideau Batista Novais, Aline; Pham, Hoa; Van de Looij, Yohan; Bernal, Miguel; Mairesse, Jerome; Zana-Taieb, Elodie; Colella, Marina; Jarreau, Pierre-Henri; Pansiot, Julien; Dumont, Florent; Sizonenko, Stéphane; Gressens, Pierre; Charriaut-Marlangue, Christiane; Tanter, Mickael; Demene, Charlie; Vaiman, Daniel; Baud, Olivier

    2016-12-01

    Fetal growth restriction (FGR) is a major complication of human pregnancy, frequently resulting from placental vascular diseases and prenatal malnutrition, and is associated with adverse neurocognitive outcomes throughout life. However, the mechanisms linking poor fetal growth and neurocognitive impairment are unclear. Here, we aimed to correlate changes in gene expression induced by FGR in rats and abnormal cerebral white matter maturation, brain microstructure, and cortical connectivity in vivo. We investigated a model of FGR induced by low-protein-diet malnutrition between embryonic day 0 and birth using an interdisciplinary approach combining advanced brain imaging, in vivo connectivity, microarray analysis of sorted oligodendroglial and microglial cells and histology. We show that myelination and brain function are both significantly altered in our model of FGR. These alterations, detected first in the white matter on magnetic resonance imaging significantly reduced cortical connectivity as assessed by ultrafast ultrasound imaging. Fetal growth retardation was found associated with white matter dysmaturation as shown by the immunohistochemical profiles and microarrays analyses. Strikingly, transcriptomic and gene network analyses reveal not only a myelination deficit in growth-restricted pups, but also the extensive deregulation of genes controlling neuroinflammation and the cell cycle in both oligodendrocytes and microglia. Our findings shed new light on the cellular and gene regulatory mechanisms mediating brain structural and functional defects in malnutrition-induced FGR, and suggest, for the first time, a neuroinflammatory basis for the poor neurocognitive outcome observed in growth-restricted human infants. GLIA 2016;64:2306-2320.

  10. Sildenafil citrate therapy for severe early-onset intrauterine growth restriction.

    PubMed

    von Dadelszen, P; Dwinnell, S; Magee, L A; Carleton, B C; Gruslin, A; Lee, B; Lim, K I; Liston, R M; Miller, S P; Rurak, D; Sherlock, R L; Skoll, M A; Wareing, M M; Baker, P N

    2011-04-01

    Sildenafil citrate therapy for severe early-onset intrauterine growth restriction. BJOG 2011;118:624-628. Currently, there is no effective therapy for severe early-onset intrauterine growth restriction (IUGR). Sildenafil citrate vasodilates the myometrial arteries isolated from women with IUGR-complicated pregnancies. Women were offered Sildenafil (25 mg three times daily until delivery) if their pregnancy was complicated by early-onset IUGR [abdominal circumference (AC)< 5th percentile] and either the gestational age was <25(+0) weeks or an estimate of the fetal weight was <600 g (excluding known fetal anomaly/syndrome and/or planned termination). Sildenafil treatment was associated with increased fetal AC growth [odds ratio, 12.9; 95% confidence interval (CI), 1.3, 126; compared with institutional Sildenafil-naive early-onset IUGR controls]. Randomised controlled trial data are required to determine whether Sildenafil improves perinatal outcomes for early-onset IUGR-complicated pregnancies.

  11. Impact of bariatric surgery on fetal growth restriction: experience of a perinatal and bariatric surgery center.

    PubMed

    Chevrot, Audrey; Kayem, Gilles; Coupaye, Muriel; Lesage, Ninon; Msika, Simon; Mandelbrot, Laurent

    2016-05-01

    Bariatric surgery is known to improve some pregnancy outcomes, but there is concern that it may increase the risk of small for gestational age. To assess the impact of bariatric surgery on pregnancy outcomes and specifically of the type of bariatric surgery on the risk of fetal growth restriction. A single-center retrospective case-control study. The study group comprised all deliveries in women who had undergone bariatric surgery. To investigate the effects of weight loss on pregnancy outcomes, we compared the study group with a control group matched for presurgery body mass index. Secondly, to assess the specific impact of the type of surgery on the incidence of fetal growth restriction in utero, we distinguished subgroups with restrictive and malabsorptive bariatric surgery, and compared outcomes for each of these subgroups with a second control group, matched for prepregnancy body mass index. Among 139 patients operated, 58 had a malabsorptive procedure (gastric bypass) and 81 a purely restrictive procedure (72 a gastric banding and 9 a sleeve gastrectomy). Compared with controls matched for presurgery body mass index, the study group had a decreased rate of gestational diabetes (12% vs 23%, P = .02) and large for gestational age >90th percentile (11% vs 22%, P = .01) but an increased rate of small for gestational age <10th percentile. The incidence of small for gestational age was higher after gastric bypass (29%) than it was after restrictive surgery (9%) or in controls matched for prepregnancy body mass index (6%) (P < .01 between bypass and controls). In multivariable analysis, after adjustment for other risk factors, gastric bypass remained strongly associated with small for gestational age (adjusted odds ratio, 7.16; 95% confidence interval, 2.74-18.72). Malabsorptive bariatric surgery was associated with an increased risk of fetal growth restriction. Copyright © 2016 Elsevier Inc. All rights reserved.

  12. Moderate maternal food restriction in mice impairs physical growth, behavior, and neurodevelopment of offspring.

    PubMed

    Akitake, Yoshiharu; Katsuragi, Shinji; Hosokawa, Masato; Mishima, Kenichi; Ikeda, Tomoaki; Miyazato, Mikiya; Hosoda, Hiroshi

    2015-01-01

    Intrauterine growth retardation (IUGR) occurs in 3% to 7% of all pregnancies. Recent human studies have indicated that neurodevelopmental disabilities, learning disorders, memory impairment, and mood disturbance are common in IUGR offspring. However, the interactions between IUGR and neurodevelopmental disorders are unclear because of the wide range of causes of IUGR, such as maternal malnutrition, placental insufficiency, pregnancy toxemia, and fetal malformations. Meanwhile, many studies have shown that moderate food restriction enhances spatial learning and improves mood disturbance in adult humans and animals. To date, the effects of maternal moderate food restriction on fetal brain remain largely unknown. In this study, we hypothesized that IUGR would be caused by even moderate food restriction in pregnant females and that the offspring would have neurodevelopmental disabilities. Mid-pregnant mice received moderate food restriction through the early lactation period. The offspring were tested for aspects of physical development, behavior, and neurodevelopment. The results showed that moderate maternal food restriction induced IUGR. Offspring had low birth weight and delayed development of physical and coordinated movement. Moreover, IUGR offspring exhibited mental disabilities such as anxiety and poor cognitive function. In particular, male offspring exhibited significantly impaired cognitive function at 3 weeks of age. These results suggested that a restricted maternal diet could be a risk factor for developmental disability in IUGR offspring and that male offspring might be especially susceptible.

  13. Impaired Angiogenic Potential of Human Placental Mesenchymal Stromal Cells in Intrauterine Growth Restriction

    PubMed Central

    Mandò, Chiara; Razini, Paola; Novielli, Chiara; Anelli, Gaia Maria; Belicchi, Marzia; Erratico, Silvia; Banfi, Stefania; Meregalli, Mirella; Tavelli, Alessandro; Baccarin, Marco; Rolfo, Alessandro; Motta, Silvia

    2016-01-01

    Human placental mesenchymal stromal cells (pMSCs) have never been investigated in intrauterine growth restriction (IUGR). We characterized cells isolated from placental membranes and the basal disc of six IUGR and five physiological placentas. Cell viability and proliferation were assessed every 7 days during a 6-week culture. Expression of hematopoietic, stem, endothelial, and mesenchymal markers was evaluated by flow cytometry. We characterized the multipotency of pMSCs and the expression of genes involved in mitochondrial content and function. Cell viability was high in all samples, and proliferation rate was lower in IUGR compared with control cells. All samples presented a starting heterogeneous population, shifting during culture toward homogeneity for mesenchymal markers and occurring earlier in IUGR than in controls. In vitro multipotency of IUGR-derived pMSCs was restricted because their capacity for adipocyte differentiation was increased, whereas their ability to differentiate toward endothelial cell lineage was decreased. Mitochondrial content and function were higher in IUGR pMSCs than controls, possibly indicating a shift from anaerobic to aerobic metabolism, with the loss of the metabolic characteristics that are typical of undifferentiated multipotent cells. Significance This study demonstrates that the loss of endothelial differentiation potential and the increase of adipogenic ability are likely to play a significant role in the vicious cycle of abnormal placental development in intrauterine growth restriction (IUGR). This is the first observation of a potential role for placental mesenchymal stromal cells in intrauterine growth restriction, thus leading to new perspectives for the treatment of IUGR. PMID:26956210

  14. Inflammasome-Independent NLRP3 Restriction of a Protective Early Neutrophil Response to Pulmonary Tularemia

    PubMed Central

    Periasamy, Sivakumar; Duffy, Ellen B.

    2016-01-01

    Francisella tularensis (Ft) causes a frequently fatal, acute necrotic pneumonia in humans and animals. Following lethal Ft infection in mice, infiltration of the lungs by predominantly immature myeloid cells and subsequent myeloid cell death drive pathogenesis and host mortality. However, following sub-lethal Ft challenge, more mature myeloid cells are elicited and are protective. In addition, inflammasome-dependent IL-1β and IL-18 are important for protection. As Nlrp3 appears dispensable for resistance to infection with Francisella novicida, we considered its role during infection with the virulent Type A strain SchuS4 and the attenuated Type B live vaccine strain LVS. Here we show that both in vitro macrophage and in vivo IL-1β and IL-18 responses to Ft LVS and SchuS4 involve both the Aim2 and Nlrp3 inflammasomes. However, following lethal infection with Francisella, IL-1r-, Caspase-1/11-, Asc- and Aim2-deficient mice exhibited increased susceptibility as expected, while Nlrp3-deficient mice were more resistant. Despite reduced levels of IL-1β and IL-18, in the absence of Nlrp3, Ft infected mice have dramatically reduced lung pathology, diminished recruitment and death of immature myeloid cells, and reduced bacterial burden in comparison to wildtype and inflammasome-deficient mice. Further, increased numbers of mature neutrophil appear in the lung early during lethal Ft infection in Nlrp3-deficient mice. Finally, Ft infection induces myeloid and lung stromal cell death that in part requires Nlrp3, is necrotic/necroptotic in nature, and drives host mortality. Thus, Nlrp3 mediates an inflammasome-independent process that restricts the appearance of protective mature neutrophils and promotes lethal necrotic lung pathology. PMID:27926940

  15. Development of a restricted state space stochastic differential equation model for bacterial growth in rich media.

    PubMed

    Møller, Jan Kloppenborg; Bergmann, Kirsten Riber; Christiansen, Lasse Engbo; Madsen, Henrik

    2012-07-21

    In the present study, bacterial growth in a rich media is analysed in a Stochastic Differential Equation (SDE) framework. It is demonstrated that the SDE formulation and smoothened state estimates provide a systematic framework for data driven model improvements, using random walk hidden states. Bacterial growth is limited by the available substrate and the inclusion of diffusion must obey this natural restriction. By inclusion of a modified logistic diffusion term it is possible to introduce a diffusion term flexible enough to capture both the growth phase and the stationary phase, while concentration is restricted to the natural state space (substrate and bacteria non-negative). The case considered is the growth of Salmonella and Enterococcus in a rich media. It is found that a hidden state is necessary to capture the lag phase of growth, and that a flexible logistic diffusion term is needed to capture the random behaviour of the growth model. Further, it is concluded that the Monod effect is not needed to capture the dynamics of bacterial growth in the data presented. Copyright © 2012 Elsevier Ltd. All rights reserved.

  16. [Comparative study on the effect of restrictive fluid management strategy on the early pulmonary function of patients with severe burn].

    PubMed

    Zhang, Jia-ping; Xiang, Fei; Tong, Da-li; Luo, Qi-zhi; Yuan, Zhi-qiang; Yan, Hong; Li, Xiao-lu; Chen, Jian; Peng, Dai-zhi; Luo, Gao-xing; Peng, Yi-zhi; Huang, Yue-sheng; Wu, Jun

    2012-06-01

    To retrospectively analyze the effect of restrictive fluid management strategy (RFMS) on the early pulmonary function and the prognosis of patients with extremely severe and extensive burn. Thirteen patients with extremely severe burn hospitalized from June 2010 to November 2011, being treated with RFMS in the fluid reabsorption stage, were enrolled as treatment group. Twenty-six patients with extremely severe burn hospitalized from March 2008 to November 2011, being treated with normal fluid therapy in the fluid reabsorption stage, were enrolled as control group. The match proportion between treatment group and control group was 1:2. Fluid intake, fluid output, fluid balance (the difference between fluid intake and output), and plasma albumin level from post burn day (PBD) 3 to 10, pulmonary oxygenation index on PBD 3, 5, 7, 10, and 14, occurrence of lung and blood stream infections from PBD 7 to 14, and occurrence of acute respiratory distress syndrome (ARDS), occurrence of other organ complications, and mortality within 2 weeks post burn (PBW) were recorded and compared. Measurement data were processed with t test and randomized blocks analysis of variance, enumeration data were processed with Fisher's exact test. Daily fluid intake of patients showed a tendency of decrease in both groups from PBD 3 to 10. Except for that of PBD 4, there was no statistically significant difference between two groups in fluid intake (with F values from 0.072 to 1.939, P values all above 0.05). Daily fluid output of patients showed a tendency of increase in both groups from PBD 3 to 10. It peaked on PBD 10 in control group and PBD 6 in treatment group. The mean daily fluid output was higher in treatment group than in control group from PBD 4 to 9, but without statistically significant difference (with F values from 0.001 to 3.026, P values all above 0.05). Fluid balance lowered in both groups, and it was the lowest on PBD 10 in control group and PBD 6 in treatment group. Fluid

  17. Neurodevelopmental Outcomes in Postnatal Growth-Restricted Preterm Infants with Postnatal Head-Sparing

    PubMed Central

    Meyers, Jeffrey M.; Bann, Carla M.; Stoll, Barbara J.; D’Angio, Carl T.; Bell, Edward F.; Duncan, Andrea F.; Guillet, Ronnie

    2016-01-01

    Objective To compare neurodevelopmental outcomes in postnatal growth-restricted infants born < 29 weeks with and without postnatal head-sparing. Study Design We analyzed developmental outcomes at 2 years of age among postnatally growth-restricted infants with and without head-sparing. The primary outcome was Bayley III cognitive composite score; secondary outcomes included Bayley III motor composite score, moderate/severe cerebral palsy, GMFCS level ≥2, and presence or absence of neurodevelopmental impairment (NDI). Results Of 1098 infants evaluated at 18–22 months, 658 were postnatally growth-restricted, of whom 301 had head-sparing. In the multivariate model including independent risk factors for poor growth and poor developmental outcome, infants with head-sparing had higher adjusted motor composite scores (mean difference 4.65, p<0.01), but no differences in other neurodevelopmental outcomes. Conclusion Postnatal head-sparing is associated with improved neurodevelopmental outcome in extremely preterm infants, specifically Bayley III motor scores, but whether beneficial effects of PHS persist later in life is unknown. PMID:27629374

  18. Increased respiratory restriction during phosphate-limited growth in transgenic tobacco cells lacking alternative oxidase.

    PubMed

    Parsons, H L; Yip, J Y; Vanlerberghe, G C

    1999-12-01

    We found that mitochondrial alternative oxidase (AOX) protein and the capacity for CN-resistant respiration are dramatically increased in wild-type tobacco (Nicotiana tabacum) suspension-cultured cells in response to growth under P limitation, and antisense (AS8) tobacco cells unable to induce AOX under these conditions have altered growth and metabolism. Specifically, we found that the respiration of AS8 cells was restricted during P-limited growth, when the potential for severe adenylate control of respiration (at the level of C supply to the mitochondrion and/or at the level of oxidative phosphorylation) is high due to the low cellular levels of ADP and/or inorganic P. As a result of this respiratory restriction, AS8 cells had altered growth, morphology, cellular composition, and patterns of respiratory C flow to amino acid synthesis compared with wild-type cells with abundant AOX protein. Also, AS8 cells under P limitation displayed high in vivo rates of generation of active oxygen species compared with wild-type cells. This difference could be abolished by an uncoupler of mitochondrial oxidative phosphorylation. Our results suggest that induction of non-phosphorylating AOX respiration (like induction of adenylate and inorganic P-independent pathways in glycolysis) is an important plant metabolic adaptation to P limitation. By preventing severe respiratory restriction, AOX acts to prevent both redirections in C metabolism and the excessive generation of harmful active oxygen species in the mitochondrion.

  19. High temperature slows down growth in tobacco hornworms (Manduca sexta larvae) under food restriction.

    PubMed

    Hayes, Matthew B; Jiao, Lihong; Tsao, Tsu-hsuan; King, Ian; Jennings, Michael; Hou, Chen

    2015-03-01

    When fed ad libitum (AL), ectothermic animals usually grow faster and have higher metabolic rate at higher ambient temperature. However, if food supply is limited, there is an energy tradeoff between growth and metabolism. Here we hypothesize that for ectothermic animals under food restriction (FR), high temperature will lead to a high metabolic rate, but growth will slow down to compensate for the high metabolism. We measure the rates of growth and metabolism of 4 cohorts of 5th instar hornworms (Manduca sexta larvae) reared at 2 levels of food supply (AL and FR) and 2 temperatures (20 and 30 °C). Our results show that, compared to the cohorts reared at 20 °C, the ones reared at 30 °C have high metabolic rates under both AL and FR conditions, but a high growth rate under AL and a low growth rate under FR, supporting this hypothesis.

  20. Fetal growth restriction and cardiovascular outcome in early human infancy: a prospective longitudinal study.

    PubMed

    Mäkikallio, Kaarin; Shah, Jyotsna; Slorach, Cameron; Qin, Hong; Kingdom, John; Keating, Sarah; Kelly, Ed; Manlhiot, Cedric; Redington, Andrew; Jaeggi, Edgar

    2016-09-01

    The association between low birth weight and premature cardiovascular disease has led to the "prenatal origin of adult disease-hypothesis". We postulated that fetal growth restriction is associated with cardiovascular changes detectable at birth and in early infancy. Fifty-two appropriately grown fetuses (AGA) and 60 growth-restricted fetuses (FGR) with (n = 20) or without (n = 40) absent or reversed end-diastolic umbilical artery blood flow were prospectively examined by echocardiography before birth, at 1 week and 6 months of life. The impact of growth restriction on postnatal blood pressure, heart rate, cardiovascular dimensions, and function, as well as on vascular morphology of umbilical cord vessels was studied. FGR fetuses displayed significant blood flow redistribution and were delivered earlier with lower birth weights than AGA fetuses. After adjustment for gender, gestational age, and weight at birth, there were no intergroup differences in blood pressure, heart rate, left ventricular morphology, mass, and performance, and in cord vessel morphology. During the first 6 months of life brachioradial pulse wave velocity increased more in FGR fetuses, while other parameters describing vascular stiffness remained comparable between the groups. Fetal growth restriction had no detectable adverse impact on cardiovascular dimensions and function at birth. Cardiovascular findings also remained comparable during the first 6 months of life between the groups except a higher increase in brachioradial pulse wave velocity in the FGR group. Our observations suggest that abnormalities that link reduced intrauterine growth with premature cardiovascular diseases may commence later in childhood, indicating a potential window for screening and prevention.

  1. Association of growth and nutritional parameters with pulmonary function in cystic fibrosis: a literature review

    PubMed Central

    Mauch, Renan Marrichi; Kmit, Arthur Henrique Pezzo; Marson, Fernando Augusto de Lima; Levy, Carlos Emilio; Barros-Filho, Antonio de Azevedo; Ribeiro, José Dirceu

    2016-01-01

    Abstract Objective: To review the literature addressing the relationship of growth and nutritional parameters with pulmonary function in pediatric patients with cystic fibrosis. Data source: A collection of articles published in the last 15 years in English, Portuguese and Spanish was made by research in electronic databases - PubMed, Cochrane, Medline, Lilacs and Scielo - using the keywords cystic fibrosis, growth, nutrition, pulmonary function in varied combinations. Articles that addressed the long term association of growth and nutritional parameters, with an emphasis on growth, with pulmonary disease in cystic fibrosis, were included, and we excluded those that addressing only the relationship between nutritional parameters and cystic fibrosis and those in which the aim was to describe the disease. Data synthesis: Seven studies were included, with a total of 12,455 patients. Six studies reported relationship between growth parameters and lung function, including one study addressing the association of growth parameters, solely, with lung function, and all the seven studies reported relationship between nutritional parameters and lung function. Conclusions: The review suggests that the severity of the lung disease, determined by spirometry, is associated with body growth and nutritional status in cystic fibrosis. Thus, the intervention in these parameters can lead to the better prognosis and life expectancy for cystic fibrosis patients. PMID:27181343

  2. Association of growth and nutritional parameters with pulmonary function in cystic fibrosis: a literature review.

    PubMed

    Mauch, Renan Marrichi; Kmit, Arthur Henrique Pezzo; Marson, Fernando Augusto de Lima; Levy, Carlos Emilio; Barros-Filho, Antonio de Azevedo; Ribeiro, José Dirceu

    2016-12-01

    To review the literature addressing the relationship of growth and nutritional parameters with pulmonary function in pediatric patients with cystic fibrosis. A collection of articles published in the last 15 years in English, Portuguese and Spanish was made by research in electronic databases - PubMed, Cochrane, Medline, Lilacs and Scielo - using the keywords cystic fibrosis, growth, nutrition, pulmonary function in varied combinations. Articles that addressed the long term association of growth and nutritional parameters, with an emphasis on growth, with pulmonary disease in cystic fibrosis, were included, and we excluded those that addressing only the relationship between nutritional parameters and cystic fibrosis and those in which the aim was to describe the disease. Seven studies were included, with a total of 12,455 patients. Six studies reported relationship between growth parameters and lung function, including one study addressing the association of growth parameters, solely, with lung function, and all the seven studies reported relationship between nutritional parameters and lung function. The review suggests that the severity of the lung disease, determined by spirometry, is associated with body growth and nutritional status in cystic fibrosis. Thus, the intervention in these parameters can lead to the better prognosis and life expectancy for cystic fibrosis patients. Copyright © 2016 Sociedade de Pediatria de São Paulo. Publicado por Elsevier Editora Ltda. All rights reserved.

  3. Platelet-derived growth factor receptor-β and epidermal growth factor receptor in pulmonary vasculature of systemic sclerosis-associated pulmonary arterial hypertension versus idiopathic pulmonary arterial hypertension and pulmonary veno-occlusive disease: a case-control study.

    PubMed

    Overbeek, Maria J; Boonstra, Anco; Voskuyl, Alexandre E; Vonk, Madelon C; Vonk-Noordegraaf, Anton; van Berkel, Maria P A; Mooi, Wolter J; Dijkmans, Ben A C; Hondema, Laurens S; Smit, Egbert F; Grünberg, Katrien

    2011-04-14

    Systemic sclerosis (SSc) complicated by pulmonary arterial hypertension (PAH) carries a poor prognosis, despite pulmonary vascular dilating therapy. Platelet-derived growth factor receptor-β (PDGFR-β) and epidermal growth factor receptor (EGFR) are potential therapeutic targets for PAH because of their proliferative effects on vessel remodelling. To explore their role in SScPAH, we compared PDGFR- and EGFR-mmunoreactivity in lung tissue specimens from SScPAH. We compared staining patterns with idiopathic PAH (IPAH) and pulmonary veno-occlusive disease (PVOD), as SScPAH vasculopathy differs from IPAH and sometimes displays features of PVOD. Immunoreactivity patterns of phosphorylated PDGFR-β (pPDGFR-β) and the ligand PDGF-B were evaluated to provide more insight into the patterns of PDGFR-b activation. Lung tissue specimens from five SScPAH, nine IPAH, six PVOD patients and five controls were examined. Immunoreactivity was scored for presence, distribution and intensity. All SScPAH and three of nine IPAH cases (P = 0.03) showed PDGFR-β-immunoreactivity in small vessels (arterioles/venules); of five SScPAH vs. two of nine IPAH cases (P = 0.02) showed venous immunoreactivity. In small vessels, intensity was stronger in SScPAH vs. IPAH. No differences were found between SScPAH and PVOD. One of five normal controls demonstrated focally mild immunoreactivity. There were no differences in PDGF-ligand and pPDGFR-b-immunoreactivity between patient groups; however, pPDGFR-b-immunoreactivity tended to be more prevalent in SScPAH small vasculature compared to IPAH. Vascular EGFR-immunoreactivity was limited to arterial and arteriolar walls, without differences between groups. No immunoreactivity was observed in vasculature of normals. PDGFR-β-immunoreactivity in SScPAH is more common and intense in small- and post-capillary vessels than in IPAH and does not differ from PVOD, fitting in with histomorphological distribution of vasculopathy. PDGFR-β immunoreactivity

  4. Effect of bi-level positive airway pressure (BiPAP) nasal ventilation on the postoperative pulmonary restrictive syndrome in obese patients undergoing gastroplasty.

    PubMed

    Joris, J L; Sottiaux, T M; Chiche, J D; Desaive, C J; Lamy, M L

    1997-03-01

    Upper abdominal surgery results in a postoperative restrictive pulmonary syndrome. Bi-level positive airway pressure (BiPAP System; Respironics Inc; Murrysville, Pa), which combines pressure support ventilation and positive end-expiratory pressure via a nasal mask, could allow alveolar recruitment during inspiration and prevent expiratory alveolar collapse, and therefore limit the postoperative pulmonary restrictive syndrome. This study investigated the effect of BiPAP on postoperative pulmonary function in obese patients after gastroplasty. Prospective controlled randomized study. GI surgical ward in a university hospital. Thirty-three morbidly obese patients scheduled for gastroplasty were studied. The patients were assigned to one of three techniques of ventilatory support during the first 24 h postoperatively: O2 via a face mask, BiPAP System 8/4, with inspiratory and expiratory positive airway pressure set at 8 and 4 cm H2O, respectively, or BiPAP System 12/4 set at 12 and 4 cm H2O. Pulmonary function (FVC, FEV1, and peak expiratory flow rate [PEFR]) were measured the day before surgery, 24 h after surgery, and on days 2 and 3. Oxygen saturation by pulse oximeter (SpO2) was also recorded during room air breathing. Three patients were excluded. After surgery, FVC, FEV1, PEFR, and SpO2 significantly decreased in the three groups. On day 1, FVC and FEV1 were significantly improved in the group BiPAP System 12/4, as compared with no BiPAP; SpO2 was also significantly improved. After removal of BiPAP System 12/4, these benefits were maintained, allowing faster recovery of pulmonary function. No significant effects were observed on PEFR. BiPAP System 8/4 had no significant effect on the postoperative pulmonary restrictive syndrome. Prophylactic use of BiPAP System 12/4 during the first 24 h postoperatively significantly reduces pulmonary dysfunction after gastroplasty in obese patients and accelerates reestablishment of preoperative pulmonary function.

  5. 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

  6. Doppler ultrasonography in obstetrics: from the diagnosis of fetal anemia to the treatment of intrauterine growth-restricted fetuses.

    PubMed

    Mari, Giancarlo

    2009-06-01

    After the adoption of the use of umbilical artery and middle cerebral artery peak systolic velocity in high-risk pregnancies and in pregnancies that are at risk of having an anemic fetus, the main focus of Doppler ultrasonography in obstetrics today is intrauterine growth-restricted fetuses. What is most needed at this time are (1) training of sonographers and sonologists on how to perform a Doppler study, (2) an international classification of intrauterine growth-restricted fetuses, and (3) a study of the natural history of intrauterine growth-restricted fetuses that might contribute to a better understanding of the intrauterine growth-restriction process and to standard treatment of intrauterine growth-restricted fetuses. Future investigations, which would include randomized studies, could be designed from the results of such studies.

  7. Effects of salt restriction on renal growth and glomerular injury in rats with remnant kidneys.

    PubMed

    Lax, D S; Benstein, J A; Tolbert, E; Dworkin, L D

    1992-06-01

    Male Munich-Wistar rats underwent right nephrectomy and infarction of two thirds of the left kidney. Rats were randomly assigned to ingest standard chow (REM) or a moderately salt restricted chow (LS). A third group of rats were fed the low salt diet and were injected with an androgen (LSA). Eight weeks after ablation, glomerular volume and glomerular capillary radius were markedly increased in REM. This increase was prevented by the low salt diet, however, the antihypertrophic effect of the diet was overcome by androgen. Values for glomerular volume and capillary radius were similar in LSA and REM. Morphologic studies revealed that approximately 25% of glomeruli were abnormal in REM. Much less injury was observed in salt restricted rats, however, the protective effect of the low salt diet was significantly abrogated when renal growth was stimulated in salt restricted rats by androgen. Micropuncture studies revealed that glomerular pressure was elevated in all three groups and not affected by diet or androgen. Serum cholesterol was also similar in the three groups. These findings indicate that renal and glomerular hypertrophy are correlated with the development of glomerular injury after reduction in renal mass and suggest that dietary salt restriction lessens renal damage, at least in part, by inhibiting compensatory renal growth.

  8. Transforming growth factor-ß1 genotype and susceptibility to chronic obstructive pulmonary disease

    PubMed Central

    Wu, L; Chau, J; Young, R; Pokorny, V; Mills, G; Hopkins, R; McLean, L; Black, P

    2004-01-01

    Background: Only a few long term smokers develop symptomatic chronic obstructive pulmonary disease (COPD) and this may be due, at least in part, to genetic susceptibility to the disease. Transforming growth factor ß1 (TGF-ß1) has a number of actions that make it a candidate for a role in the pathogenesis of COPD. We have investigated a single nucleotide polymorphism at exon 1 nucleotide position 29 (T→C) of the TGF-ß1 gene that produces a substitution at codon 10 (Leu→Pro). Methods: The frequency of this polymorphism was determined in 165 subjects with COPD, 140 healthy blood donors, and 76 smokers with normal lung function (resistant smokers) using the polymerase chain reaction and restriction enzyme fragment length polymorphism. Results: The distribution of genotypes was Leu-Leu (41.8%), Leu-Pro (50.3%), and Pro-Pro (7.9%) for subjects with COPD, which was significantly different from the control subjects (blood donors: Leu-Leu (29.3%), Leu-Pro (52.1%) and Pro-Pro (18.6%), p = 0.006; resistant smokers: Leu-Leu (28.9%), Leu-Pro (51.3%) and Pro-Pro (19.7%), p = 0.02). The Pro10 allele was less common in subjects with COPD (33%) than in blood donors (45%; OR = 0.62, 95% CI 0.45 to 0.86, p = 0.005) and resistant smokers (45%; OR = 0.59, 95% CI 0.40 to 0.88, p = 0.01). Conclusions: The proline allele at codon 10 of the TGF-ß1 gene occurs more commonly in control subjects than in individuals with COPD. This allele is associated with increased production of TGF-ß1 which raises the possibility that TGF-ß1 has a protective role in COPD. PMID:14760152

  9. Neurodevelopment in children with intrauterine growth restriction: adverse effects and interventions.

    PubMed

    Wang, Yan; Fu, Wei; Liu, Jing

    2016-01-01

    Intrauterine growth restriction (IUGR) is associated with higher rates of fetal, perinatal, and neonatal morbidity and mortality. The consequences of IUGR include short-term metabolic, hematological and thermal disturbances that lead to metabolic syndrome in children and adults. Additionally, IUGR severely affects short- and long-term fetal brain development and brain function (including motor, cognitive and executive function) and neurobehavior, especially neuropsychology. This review details the adverse effects of IUGR on fetal brain development and discusses intervention strategies.

  10. Respiratory sinus arrhythmia in growth restricted fetuses with normal Doppler hemodynamic indices.

    PubMed

    Arias-Ortega, R; Echeverría, J C; Guzmán-Huerta, M; Camargo-Marín, L; Gaitán-González, M J; Borboa-Olivares, H; Portilla-Islas, E; Camal-Ugarte, S; Vargas-García, C; Ortiz, M R; González-Camarena, R

    2016-02-01

    The autonomic behavior of growth-restricted fetuses at different evolving hemodynamic stages has not been fully elicited. To analyze the respiratory sinus arrhythmia (RSA) of growth-restricted fetuses that despite this severe condition show normal Doppler hemodynamics. 10 growth-restricted fetuses (FGR group) with normal arterial pulsatility indices (umbilical, uterine, middle cerebral, ductus venosus and aortic isthmus), and 10 healthy fetuses (Control group), 32-37weeks of gestation. B-mode ultrasound images for visualizing fetal breathing movements (FBM) or breathing akinesis (FBA), and the simultaneous RR-interval time series from maternal abdominal ECG recordings were obtained. The root-mean-square of successive differences of RR-intervals (RMSSD) was considered as a RSA-related parameter among the instantaneous amplitude of the high-frequency component (AMPHF) and its corresponding instantaneous frequency (IFHF), both computed by using empirical mode decomposition. Mean fetal heart-periods and RSA-related parameters were assessed during episodes of FBM and FBA in 30s length windows. FGR and Control groups presented RSA-related fluctuations during FBM and FBA. Also, both groups showed significant higher (p<0.001) values for the mean heart-period, RMSSD and AMPHF during FBM. No-significant differences (p>0.05) were found for the IFHF regardless of breathing activity (FBM vs. FBA). Growth-restricted fetuses without evident hemodynamic compromise exhibit a preserved autonomic cardiovascular regulation, characterized by higher values of RSA and mean heart-period in the presence of FBM. This physiological response reflects a compensatory strategy that may contribute to preserve blood flow redistribution to vital organs. Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

  11. 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. © 2015 The Royal Australian and New Zealand College of Obstetricians and Gynaecologists.

  12. Misoprostol versus Foley catheter insertion for induction of labor in pregnancies affected by fetal growth restriction.

    PubMed

    Chavakula, Pearlin R; Benjamin, Santosh J; Abraham, Anuja; Londhe, Vaibhav; Jeyaseelan, Visalakshi; Mathews, Jiji E

    2015-05-01

    To compare 25μg of vaginal misoprostol with a Foley catheter for induction of labor (IOL) for fetal growth restriction. A randomized controlled trial was conducted in a tertiary center in South India. Women with fetal growth restriction (n=100) were randomized to be induced with three doses of vaginal misoprostol (25μg) every 6hours or with an intracervical Foley catheter, inserted 12hours before rupture of membranes, and oxytocin if needed. The primary outcome was uterine tachysystole with fetal cardiotocography abnormalities. Secondary outcomes pertained to effectiveness, complications, and patient satisfaction. One woman in the misoprostol group and none in the Foley catheter group had uterine tachysystole. The duration of labor from IOL to delivery was similar in both groups (P=0.416). More women in the misoprostol group had a vaginal delivery within 12hours (26.1% versus 5.6%; P=0.005). Women induced with misoprostol were less likely to deliver by lower-segment cesarean delivery (15.2% versus 29.6%; P=0.168) and to require oxytocin augmentation (60.9% versus 85.2%; P=0.007). Complications were few in both group. Few women had uterine tachysystole with cardiotocography abnormalities. Vaginal misoprostol at 25μg was more effective than a Foley catheter for IOL in fetal growth restriction. Clinical Trials Registry India:CTRI/2014/02/004411. Copyright © 2015 International Federation of Gynecology and Obstetrics. Published by Elsevier Ireland Ltd. All rights reserved.

  13. 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

  14. 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

  15. 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

  16. Impaired Angiogenic Potential of Human Placental Mesenchymal Stromal Cells in Intrauterine Growth Restriction.

    PubMed

    Mandò, Chiara; Razini, Paola; Novielli, Chiara; Anelli, Gaia Maria; Belicchi, Marzia; Erratico, Silvia; Banfi, Stefania; Meregalli, Mirella; Tavelli, Alessandro; Baccarin, Marco; Rolfo, Alessandro; Motta, Silvia; Torrente, Yvan; Cetin, Irene

    2016-04-01

    Human placental mesenchymal stromal cells (pMSCs) have never been investigated in intrauterine growth restriction (IUGR). We characterized cells isolated from placental membranes and the basal disc of six IUGR and five physiological placentas. Cell viability and proliferation were assessed every 7 days during a 6-week culture. Expression of hematopoietic, stem, endothelial, and mesenchymal markers was evaluated by flow cytometry. We characterized the multipotency of pMSCs and the expression of genes involved in mitochondrial content and function. Cell viability was high in all samples, and proliferation rate was lower in IUGR compared with control cells. All samples presented a starting heterogeneous population, shifting during culture toward homogeneity for mesenchymal markers and occurring earlier in IUGR than in controls. In vitro multipotency of IUGR-derived pMSCs was restricted because their capacity for adipocyte differentiation was increased, whereas their ability to differentiate toward endothelial cell lineage was decreased. Mitochondrial content and function were higher in IUGR pMSCs than controls, possibly indicating a shift from anaerobic to aerobic metabolism, with the loss of the metabolic characteristics that are typical of undifferentiated multipotent cells. This study demonstrates that the loss of endothelial differentiation potential and the increase of adipogenic ability are likely to play a significant role in the vicious cycle of abnormal placental development in intrauterine growth restriction (IUGR). This is the first observation of a potential role for placental mesenchymal stromal cells in intrauterine growth restriction, thus leading to new perspectives for the treatment of IUGR. ©AlphaMed Press.

  17. 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.

  18. Early Onset Intrauterine Growth Restriction in a Mouse Model of Gestational Hypercholesterolemia and Atherosclerosis

    PubMed Central

    Busso, Dolores; Mascareño, Lilian; Salas, Francisca; Berkowitz, Loni; Santander, Nicolás; Quiroz, Alonso; Amigo, Ludwig; Valdés, Gloria; Rigotti, Attilio

    2014-01-01

    The susceptibility to develop atherosclerosis is increased by intrauterine growth restriction and prenatal exposure to maternal hypercholesterolemia. Here, we studied whether mouse gestational hypercholesterolemia and atherosclerosis affected fetal development and growth at different stages of gestation. Female LDLR KO mice fed a proatherogenic, high cholesterol (HC) diet for 3 weeks before conception and during pregnancy exhibited a significant increase in non-HDL cholesterol and developed atherosclerosis. At embryonic days 12.5 (E12.5), E15.5, and E18.5, maternal gestational hypercholesterolemia and atherosclerosis were associated to a 22–24% reduction in male and female fetal weight without alterations in fetal number/litter or morphology nor placental weight or structure. Feeding the HC diet exclusively at the periconceptional period did not alter fetal growth, suggesting that maternal hypercholesterolemia affected fetal weight only after implantation. Vitamin E supplementation (1,000 UI of α-tocopherol/kg) of HC-fed females did not change the mean weight of E18.5 fetuses but reduced the percentage of fetuses exhibiting body weights below the 10th percentile of weight (HC: 90% vs. HC/VitE: 68%). In conclusion, our results showed that maternal gestational hypercholesterolemia and atherosclerosis in mice were associated to early onset fetal growth restriction and that dietary vitamin E supplementation had a beneficial impact on this condition. PMID:25295255

  19. Early onset intrauterine growth restriction in a mouse model of gestational hypercholesterolemia and atherosclerosis.

    PubMed

    Busso, Dolores; Mascareño, Lilian; Salas, Francisca; Berkowitz, Loni; Santander, Nicolás; Quiroz, Alonso; Amigo, Ludwig; Valdés, Gloria; Rigotti, Attilio

    2014-01-01

    The susceptibility to develop atherosclerosis is increased by intrauterine growth restriction and prenatal exposure to maternal hypercholesterolemia. Here, we studied whether mouse gestational hypercholesterolemia and atherosclerosis affected fetal development and growth at different stages of gestation. Female LDLR KO mice fed a proatherogenic, high cholesterol (HC) diet for 3 weeks before conception and during pregnancy exhibited a significant increase in non-HDL cholesterol and developed atherosclerosis. At embryonic days 12.5 (E12.5), E15.5, and E18.5, maternal gestational hypercholesterolemia and atherosclerosis were associated to a 22-24% reduction in male and female fetal weight without alterations in fetal number/litter or morphology nor placental weight or structure. Feeding the HC diet exclusively at the periconceptional period did not alter fetal growth, suggesting that maternal hypercholesterolemia affected fetal weight only after implantation. Vitamin E supplementation (1,000 UI of α-tocopherol/kg) of HC-fed females did not change the mean weight of E18.5 fetuses but reduced the percentage of fetuses exhibiting body weights below the 10th percentile of weight (HC: 90% vs. HC/VitE: 68%). In conclusion, our results showed that maternal gestational hypercholesterolemia and atherosclerosis in mice were associated to early onset fetal growth restriction and that dietary vitamin E supplementation had a beneficial impact on this condition.

  20. Insulin-like growth factor 1 receptor regulates hypothermia during calorie restriction.

    PubMed

    Cintron-Colon, Rigo; Sanchez-Alavez, Manuel; Nguyen, William; Mori, Simone; Gonzalez-Rivera, Ruben; Lien, Tiffany; Bartfai, Tamas; Aïd, Saba; François, Jean-Christophe; Holzenberger, Martin; Conti, Bruno

    2017-09-05

    When food resources are scarce, endothermic animals can lower core body temperature (Tb). This phenomenon is believed to be part of an adaptive mechanism that may have evolved to conserve energy until more food becomes available. Here, we found in the mouse that the insulin-like growth factor 1 receptor (IGF-1R) controls this response in the central nervous system. Pharmacological or genetic inhibition of IGF-1R enhanced the reduction of temperature and of energy expenditure during calorie restriction. Full blockade of IGF-1R affected female and male mice similarly. In contrast, genetic IGF-1R dosage was effective only in females, where it also induced transient and estrus-specific hypothermia in animals fed ad libitum. These effects were regulated in the brain, as only central, not peripheral, pharmacological activation of IGF-1R prevented hypothermia during calorie restriction. Targeted IGF-1R knockout selectively in forebrain neurons revealed that IGF signaling also modulates calorie restriction-dependent Tb regulation in regions rostral of the canonical hypothalamic nuclei involved in controlling body temperature. In aggregate, these data identify central IGF-1R as a mediator of the integration of nutrient and temperature homeostasis. They also show that calorie restriction, IGF-1R signaling, and body temperature, three of the main regulators of metabolism, aging, and longevity, are components of the same pathway.

  1. The role of epidermal growth factor receptor (EGFR) signaling in SARS coronavirus-induced pulmonary fibrosis.

    PubMed

    Venkataraman, Thiagarajan; Frieman, Matthew B

    2017-07-01

    Many survivors of the 2003 outbreak of severe acute respiratory syndrome (SARS) developed residual pulmonary fibrosis with increased severity seen in older patients. Autopsies of patients that died from SARS also showed fibrosis to varying extents. Pulmonary fibrosis can be occasionally seen as a consequence to several respiratory viral infections but is much more common after a SARS coronavirus (SARS-CoV) infection. Given the threat of future outbreaks of severe coronavirus disease, including Middle East respiratory syndrome (MERS), it is important to understand the mechanisms responsible for pulmonary fibrosis, so as to support the development of therapeutic countermeasures and mitigate sequelae of infection. In this article, we summarize pulmonary fibrotic changes observed after a SARS-CoV infection, discuss the extent to which other respiratory viruses induce fibrosis, describe available animal models to study the development of SARS-CoV induced fibrosis and review evidence that pulmonary fibrosis is caused by a hyperactive host response to lung injury mediated by epidermal growth factor receptor (EGFR) signaling. We summarize work from our group and others indicating that inhibiting EGFR signaling may prevent an excessive fibrotic response to SARS-CoV and other respiratory viral infections and propose directions for future research. Copyright © 2017 Elsevier B.V. All rights reserved.

  2. 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.

  3. Influence of intrauterine growth restriction on airway development in fetal and postnatal sheep.

    PubMed

    Wignarajah, Dharshini; Cock, Megan L; Pinkerton, Kent E; Harding, Richard

    2002-06-01

    Epidemiologic studies suggest that intrauterine growth restriction (IUGR) can lead to impaired lung function, yet little information exists on the effects of IUGR on airway development. Our objectives were to characterize morphometrically effects of IUGR on airway structure in the fetus and to determine whether alterations persist into postnatal life. We used two groups of sheep, each with appropriate controls; a fetal group was subjected to IUGR by restriction of placental function from 120 to 140 d (term approximately 147 d), and a postnatal group, killed 8 wk after birth, was subjected to IUGR from 120 d to birth at term. In both fetuses and postnatal lambs, IUGR did not alter lung weight relative to body weight. In IUGR fetuses, the luminal areas and basement membrane perimeters of the trachea and larger bronchi (generations 0-8, trachea = 0) were smaller than in controls. Airway wall areas, relative to basement membrane perimeters, were reduced in IUGR fetuses compared with controls, largely due to reduced areas of cartilage and epithelium. At 8 wk after birth, there were no significant differences in airway dimensions between IUGR and control lambs. However, the number of profiles of bronchial submucosal glands, relative to basement membrane perimeters, was lower in IUGR lambs than in controls and the area of epithelial mucin was increased. We conclude that restriction of fetal growth during late gestation impairs the growth of bronchial walls that could affect airway compliance in the immediate postnatal period. Although airway growth deficits are reversed by 8 wk, alterations in mucus elements persist.

  4. Genetic, metabolic and endocrine aspect of intrauterine growth restriction: an update.

    PubMed

    Sharma, Deepak; Sharma, Pradeep; Shastri, Sweta

    2017-10-01

    Intrauterine growth restriction (IUGR) is defined as growth of fetus below its in-utero growth potential. Small for gestational age (SGA) is defined as newborn with birth weight less than 10th centile as per the gestational age, sex and race. There exists major difference between IUGR and SGA. IUGR infants have multiple short-term and long-term complications and IUGR is a silent cause of various morbidities and mortalities in these infants. IUGR/SGA is usually end results of maternal, placental, fetal and genetic causes. With the advance of molecular biology, the list genetic cause of IUGR is increasing and these genetic causes include maternal, placental and fetal genes. Several metabolic and endocrinal causes are also responsible to cause IUGR. In this review, we will try to cover genetic, metabolic and endocrinal factors that are responsible for IUGR.

  5. Restrictive pulmonary function is more prevalent in patients with ankylosing spondylitis than in matched population controls and is associated with impaired spinal mobility: a comparative study

    PubMed Central

    2012-01-01

    Introduction Pulmonary involvement is a known manifestation in patients with ankylosing spondylitis (AS). However, previous studies have been based on small samples and the reported prevalence and associations with typical clinical features vary. The purpose of this study was to compare pulmonary function (PF) in patients with AS and population controls, and to study associations between PF and disease related variables, cardio-respiratory fitness and demographic variables in patients with AS. Methods In a cross-sectional controlled study, 147 AS patients and 121 controls underwent examinations, including demographic variables, laboratory (C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)) and clinical measures (disease activity (AS disease activity score, ASDAS), physical function (Bath ankylosing spondylitis functional index, BASFI), spinal mobility (Bath ankylosing spondylitis metrology index, BASMI), chest expansion, cardio-respiratory fitness (peak oxygen uptake, VO2peak) and pulmonary function test (PFT) (spirometry)). Cumulative probability plots were used to visualize associations between the ASDAS and BASMI scores and the corresponding forced vital capacity (FVC%, percentage of predicted value controlled for the influence of confounding factors) score for each patient. Univariate ANCOVAs were performed to explore group differences in PF adjusting for relevant variables, and a multiple regression model was used to estimate the explanatory power of independent variables (demographic, disease related, VO2peak) on restrictive ventilatory impairment (FVC%). Results AS patients showed significantly lower PF values compared with controls, and significantly more patients were categorized with restrictive pattern (18% vs. 0%, P < 0.001). Cumulative probability plots showed significant associations between spinal mobility measures (BASMI) and FVC% for individual patients. BASMI, chest expansion and male gender contributed significantly and independently

  6. Restrictive pulmonary function is more prevalent in patients with ankylosing spondylitis than in matched population controls and is associated with impaired spinal mobility: a comparative study.

    PubMed

    Berdal, Gunnhild; Halvorsen, Silje; van der Heijde, Désirée; Mowe, Morten; Dagfinrud, Hanne

    2012-01-25

    Pulmonary involvement is a known manifestation in patients with ankylosing spondylitis (AS). However, previous studies have been based on small samples and the reported prevalence and associations with typical clinical features vary. The purpose of this study was to compare pulmonary function (PF) in patients with AS and population controls, and to study associations between PF and disease related variables, cardio-respiratory fitness and demographic variables in patients with AS. In a cross-sectional controlled study, 147 AS patients and 121 controls underwent examinations, including demographic variables, laboratory (C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)) and clinical measures (disease activity (AS disease activity score, ASDAS), physical function (Bath ankylosing spondylitis functional index, BASFI), spinal mobility (Bath ankylosing spondylitis metrology index, BASMI), chest expansion, cardio-respiratory fitness (peak oxygen uptake, VO(2peak) and pulmonary function test (PFT) (spirometry)). Cumulative probability plots were used to visualize associations between the ASDAS and BASMI scores and the corresponding forced vital capacity (FVC%, percentage of predicted value controlled for the influence of confounding factors) score for each patient. Univariate ANCOVAs were performed to explore group differences in PF adjusting for relevant variables, and a multiple regression model was used to estimate the explanatory power of independent variables (demographic, disease related, VO(2peak) on restrictive ventilatory impairment (FVC%). AS patients showed significantly lower PF values compared with controls, and significantly more patients were categorized with restrictive pattern (18% vs. 0%, P < 0.001). Cumulative probability plots showed significant associations between spinal mobility measures (BASMI) and FVC% for individual patients. BASMI, chest expansion and male gender contributed significantly and independently in a multiple regression

  7. The timing of "catch-up growth" affects metabolism and appetite regulation in male rats born with intrauterine growth restriction.

    PubMed

    Coupé, Bérengère; Grit, Isabelle; Darmaun, Dominique; Parnet, Patricia

    2009-09-01

    Epidemiological studies demonstrated a relationship between low birth weight mainly caused by intrauterine growth restriction (IUGR) and adult metabolic disorders. The concept of metabolic programming centers on the idea that nutritional and hormonal status during the key period of development determines the long-term control of energy balance by programming future feeding behavior and energy expenditure. The present study examined the consequence of early or late "catch-up growth" after IUGR on feeding behavior and metabolic cues of male offspring of rat dams exposed to protein restriction during gestation and/or lactation. Our results suggest that early catch-up growth may be favorable for fasting metabolic parameters at weaning, as no differences were observed on plasma leptin, triglyceride, glucose, and insulin levels compared with controls. In contrast, if pups remained malnourished until weaning, low insulin concentration was detected and was accompanied by hyperphagia associated with a large increase in hypothalamic NPY and AgRP mRNA expression. At adult age, on a regular chow diet, only the meal structure was modified by fetal programming. The two IUGR groups demonstrated a reduced meal duration that enhanced the speed of food ingestion and consequently increased the rest period associated to the satiety state without changes in the hypothalamic expression of appetite neuropeptides. Our findings demonstrate that in IUGR, regardless of postnatal growth magnitude, metabolic programming occurred in utero and was responsible for both feeding behavior alteration and postprandial higher insulin level in adults. Additionally, catch-up growth immediately after early malnutrition could be a key point for the programming of postprandial hyperleptinemia.

  8. 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.

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

    PubMed Central

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

    2015-01-01

    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

  10. The association between low 50 g glucose challenge test result and fetal growth restriction.

    PubMed

    Melamed, Nir; Hiersch, Liran; Peled, Yoav; Hod, Moshe; Wiznitzer, Arnon; Yogev, Yariv

    2013-07-01

    To determine whether a low-GCT result is predictive of low birthweight and to identify the lower GCT threshold for prediction of fetal growth restriction. A retrospective cohort study of 12,899 women who underwent a GCT (24-28 weeks). Women with a low-GCT result (<10th percentile (70 mg/dL) were compared to women with normal-GCT result (70-140 mg/dL). ROC analysis was used to determine the optimal lower GCT threshold for the prediction of growth restriction. Women in the low GCT had significant lower rates of cesarean delivery (18.7% versus 22.5%), shoulder dystocia (0.0% versus 0.3%), mean birthweight (3096 ± 576 versus 3163 ± 545) and birthweight percentile (49.1 ± 27.0 versus 53.1 ± 26.7) and significant higher rates of birthweight <2500 g (11.3% versus 8.5%), below the 10th percentile (8.3% versus 6.5%) and 3rd percentile (2.3% versus 1.4%). Low GCT was independently associated with an increased risk for birthweight <2500 g (OR = 1.6, 1.2-2.0), birthweight <10th percentile (OR = 1.3, 1.1-1.6), birthweight <3rd percentile (OR = 1.7, 1.2-2.5) and neonatal hypoglycemia (OR = 1.4, 1.02-2.0). The optimal GCT threshold for the prediction of birthweight <10th percentile was 88.5 mg/dL (sensitivity 48.5%, specificity 58.1%). Low-GCT result is independently associated with low birthweight and can be used in combination with additional factors for the prediction of fetal growth restriction.

  11. A uniform management approach to optimize outcome in fetal growth restriction.

    PubMed

    Seravalli, Viola; Baschat, Ahmet A

    2015-06-01

    A uniform approach to the diagnosis and management of fetal growth restriction (FGR) consistently produces better outcome, prevention of unanticipated stillbirth, and appropriate timing of delivery. Early-onset and late-onset FGR represent two distinct clinical phenotypes of placental dysfunction. Management challenges in early-onset FGR revolve around prematurity and coexisting maternal hypertensive disease, whereas in late-onset disease failure of diagnosis or surveillance leading to unanticipated stillbirth is the primary issue. Identifying the surveillance tests that have the highest predictive accuracy for fetal acidemia and establishing the appropriate monitoring interval to detect fetal deterioration is a high priority. Copyright © 2015 Elsevier Inc. All rights reserved.

  12. Defect of hepatocyte growth factor production by fibroblasts in human pulmonary emphysema.

    PubMed

    Plantier, Laurent; Marchand-Adam, Sylvain; Marchal-Sommé, Joëlle; Lesèche, Guy; Fournier, Michel; Dehoux, Monique; Aubier, Michel; Crestani, Bruno

    2005-04-01

    Pulmonary emphysema results from an excessive degradation of lung parenchyma associated with a failure of alveolar repair. Secretion by pulmonary fibroblasts of hepatocyte growth factor (HGF) and keratinocyte growth factor (KGF) is crucial to an effective epithelial repair after lung injury. We hypothesized that abnormal HGF or KGF secretion by pulmonary fibroblasts could play a role in the development of emphysema. We measured in vitro production of HGF and KGF by human fibroblasts cultured from emphysematous and normal lung samples. HGF and KGF production was quantified at basal state and after stimulation. Intracellular content of HGF was lower in emphysema (1.52 pg/mug, range of 0.15-7.40 pg/mug) than in control fibroblasts (14.16 pg/mug, range of 2.50-47.62 pg/mug; P = 0.047). HGF production by emphysema fibroblasts (19.3 pg/mug protein, range of 10.4-39.2 pg/mug) was lower than that of controls at baseline (57.5 pg/mug, range of 20.4-116 pg/mug; P = 0.019) and after stimulation with interleukin-1beta or prostaglandin E(2). Neither retinoic acids (all-trans and 9-cis) nor N-acetylcysteine could reverse this abnormality. KGF production by emphysema fibroblasts (5.3 pg/mug, range of 2.2-9.3 pg/mug) was similar to that of controls at baseline (2.6 pg/mug, range of 1-6.1 pg/mug; P = 0.14) but could not be stimulated with interleukin-1beta. A decreased secretion of HGF by pulmonary fibroblasts could contribute to the insufficient alveolar repair in pulmonary emphysema.

  13. [Two cases of severe cutaneous vasculitis with thrombocytopenia associated with hepatic cirrhosis: autoimmune and infective-inflammatory component with endothelial lesion and restrictive pulmonary pattern in one case].

    PubMed

    de Andrade Júnior, D R; Warth, M do P; Morrone, L F; Calich, I; de Andrade, D R

    1992-01-01

    Two clinical cases of female patients with hepatic cirrhosis and autoimmune multisystemic involvement with infectious intercurrent are reported. Case 1 presented infective endocarditis and erysipelas on the left thigh. In the course of the clinical picture a cutaneous vasculitis developed in the same place together with autoimmune thrombocytopenia, leukopenia and pulmonary restrictive picture with inflammatory pattern. There are also elevate immune complexes and complement consumption. Case 2 presented erysipelas on the left thigh cutaneous vasculitis and complement consumption. In Case 1 the infective endocarditis was treated with antibiotic therapy during 4 weeks followed by 1 mg/kg corticoid (Prednisone) with thrombocytopenia and leukopenia reversion. Case 2 presented an improvement with antibiotic only. The relation between chronic liver diseases and systemic autoimmune phenomena is commented, special attention being paid to the cutaneous, hematological and pulmonary affection.

  14. Restricted regions of enhanced growth of Antarctic krill in the circumpolar Southern Ocean.

    PubMed

    Murphy, Eugene J; Thorpe, Sally E; Tarling, Geraint A; Watkins, Jonathan L; Fielding, Sophie; Underwood, Philip

    2017-07-31

    Food webs in high-latitude oceans are dominated by relatively few species. Future ocean and sea-ice changes affecting the distribution of such species will impact the structure and functioning of whole ecosystems. Antarctic krill (Euphausia superba) is a key species in Southern Ocean food webs, but there is little understanding of the factors influencing its success throughout much of the ocean. The capacity of a habitat to maintain growth will be crucial and here we use an empirical relationship of growth rate to assess seasonal spatial variability. Over much of the ocean, potential for growth is limited, with three restricted oceanic regions where seasonal conditions permit high growth rates, and only a few areas around the Scotia Sea and Antarctic Peninsula suitable for growth of the largest krill (>60 mm). Our study demonstrates that projections of impacts of future change need to account for spatial and seasonal variability of key ecological processes within ocean ecosystems.

  15. The effect of iron and zinc dietary restriction of pregnant rats on physical growth of litters.

    PubMed

    Shahbazi, M; Naghdi, N; Tahmasebi, S; Sheikh, M; Namvar Asl, N; Kazemnejad, A

    2009-06-01

    Evidence suggests that micronutrient deficiencies may be associated with problems in early growth. Iron (Fe) and Zinc (Zn) deficiency (D) are prevalent during gestation in low-income countries. For pregnant dams, adequate amount of these micronutrients are needed in the diet to ensure the capacity for increased physical growth. In this study, the role of Fe and Zn dietary restriction of pregnant rats on physical growth of litters was investigated. Pregnant rats after to mating were divided to three groups. Control group fed a standard diet and a FeD group fed a diet deficient in Fe and a ZnD group fed a diet deficient in Zn. All the diets were exposed during the last third of pregnancy. The results showed serum Fe and Zn concentration after to exert dietary compared to before to exert dietary in FeD and ZnD groups was significant. There was a significant difference in the physical growth indexes (body weight, body length, tail length, and head length) between FeD and ZnD groups compared to the Control group, but a significant difference in head width and brain weight between FeD and ZnD groups compared to the Control group was not seen. The results of this study suggest that adequate Fe and Zn affect the physical growth of litters.

  16. 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

  17. Salt restriction inhibits renal growth and stabilizes injury in rats with established renal disease.

    PubMed

    Dworkin, L D; Benstein, J A; Tolbert, E; Feiner, H D

    1996-03-01

    Salt restriction inhibits renal growth and stabilizes injury in rats with established renal disease. Male Munich-Wistar rats that underwent right nephrectomy and segmental infarction of two thirds of the left kidney were fed standard chow for 4 wk and then randomly assigned to ingest standard or low-salt chow for an additional 4 wk. Four wk after ablation, rats had systemic hypertension, proteinuria, and glomerular sclerosis. The prevalence of sclerosis, protein excretion rate, and glomerular volume increased between the fourth and eighth week in rats that were fed standard chow, however, in rats that were fed low-salt chow, the increase in glomerular volume and development of further glomerular sclerosis was prevented whereas the protein excretion rate actually declined. Micropuncture studies performed 8 wk after ablation revealed that the glomerular hydraulic pressure was elevated in remnant kidneys and was not affected by salt restriction. This study demonstrates that dietary salt restriction can prevent further glomerular injury and reduce proteinuria even when instituted in rats with established renal disease. These findings are also consistent with the hypothesis that glomerular hypertrophy promotes injury in this model of hypertension and progressive renal disease.

  18. 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

  19. Oxygen flux reduces Cux1 positive neurons and cortical growth in a gestational rodent model of growth restriction.

    PubMed

    Fletcher, Elaine; Wade, Jean; Georgala, Petrina A; Gillespie, Trudi L; Price, David J; Pilley, Elizabeth; Becher, Julie-Clare

    2017-03-01

    The mammalian cerebral cortex forms in an inside-out manner, establishing deep cortical layers before superficial layers and is regulated by transcription factors which influence cell differentiation. Preterm birth interrupts the trajectory of normal neurodevelopment and adverse perinatal exposures have been implicated in cortical injury. We hypothesise that growth restriction (GR) and fluctuating hyperoxia (ΔO2) impair cortical laminar development. Sprague-Dawley rats received 18% (non-restricted, NR) or 9% (growth restricted, GR) protein diet from E15-P7. Litters were reared in air or fluctuating hyperoxia (circa 10kPa) from P0 to P7. Cortical laminae were stained and measured. Neuronal subtypes were quantified using immunofluorescence for subtype-specific transcription factors (Satb2, Cux1, Ctip2, Tbr1). ΔO2 did not affect brain weight at P7 but reduced cortical thickness in both NR (p<0.05) and GR groups (p<0.001). ΔO2 resulted in superficial cortical thinning in both groups and in the deep layers of GR pups (p<0.001). Cell density was preserved. ΔO2 did not affect proportions of callosal, corticothalamic and corticospinal neurons but resulted in a reduction of neurons expressing Cux1 (p<0.01) implicated in dendritic branching and synapse formation. Postnatal ΔO2, a modifiable factor in neonatal care, impairs cortical development in a rodent model with preferential disadvantage to superficial neurons. Copyright © 2016 Elsevier GmbH. All rights reserved.

  20. 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

  1. Carbohydrate Restriction, Prostate Cancer Growth, and the Insulin-Like Growth Factor Axis

    PubMed Central

    Freedland, Stephen J.; Mavropoulos, John; Wang, Amy; Darshan, Medha; Demark-Wahnefried, Wendy; Aronson, William J.; Cohen, Pinchas; Hwang, David; Peterson, Bercedis; Fields, Timothy; Pizzo, Salvatore V.; Isaacs, William B.

    2012-01-01

    BACKGROUND Recent evidence suggests carbohydrate intake may influence prostate cancer biology. We tested whether a no-carbohydrate ketogenic diet (NCKD) would delay prostate cancer growth relative to Western and low-fat diets in a xenograft model. METHODS Seventy-five male SCID mice were fed a NCKD (84% fat–0% carbohydrate–16% protein kcal), low-fat (12% fat–72% carbohydrate–16% protein kcal), or Western diet (40% fat–44% carbohydrate–16% protein kcal). Low-fat mice were fed ad libitum and the other arms fed via a modified-paired feeding protocol. After 24 days, all mice were injected with LAPC-4 cells and sacrificed when tumors approached 1,000 mm3. RESULTS Despite consuming equal calories, NCKD-fed mice lost weight (up to 15% body weight) relative to low-fat and Western diet-fed mice and required additional kcal to equalize body weight. Fifty-one days after injection, NCKD mice tumor volumes were 33% smaller than Western mice (rank-sum, P = 0.009). There were no differences in tumor volume between low-fat and NCKD mice. Dietary treatment was significantly associated with survival (log-rank, P = 0.006), with the longest survival among the NCKD mice, followed by the low-fat mice. Serum IGFBP-3 was highest and IGF-1:IGFBP-3 ratio was lowest among NCKD mice while serum insulin and IGF-1 levels were highest in Western mice. NCKD mice had significantly decreased hepatic fatty infiltration relative to the other arms. CONCLUSIONS In this xenograft model, despite consuming more calories, NCKD-fed mice had significantly reduced tumor growth and prolonged survival relative to Western mice and was associated with favorable changes in serum insulin and IGF axis hormones relative to low-fat or Western diet. PMID:17999389

  2. Parenteral administration of L-arginine prevents fetal growth restriction in undernourished ewes.

    PubMed

    Lassala, Arantzatzu; Bazer, Fuller W; Cudd, Timothy A; Datta, Sujay; Keisler, Duane H; Satterfield, M Carey; Spencer, Thomas E; Wu, Guoyao

    2010-07-01

    Intrauterine growth restriction (IUGR) is a major health problem worldwide that currently lacks an effective therapeutic solution. This study was conducted with an ovine IUGR model to test the hypothesis that parenteral administration of l-arginine (Arg) is effective in enhancing fetal growth. Beginning on d 28 of gestation, ewes were fed a diet providing 100% (control-fed) or 50% (underfed) of NRC-recommended nutrient requirements. Between d 60 of gestation and parturition, underfed ewes received i.v. infusions of saline or 155 micromol Arg-HCl/kg body weight 3 times daily, whereas control-fed ewes received only saline. The birth weights of lambs from saline-infused underfed ewes were 23% lower (P < 0.01) than those of lambs from control-fed dams. Administration of Arg to underfed ewes increased (P < 0.01) concentrations of Arg (69%), ornithine (55%), proline (29%), methionine (37%), leucine (36%), isoleucine (35%), cysteine (19%), and FFA (43%) in maternal serum, decreased maternal circulating levels of ammonia (18%) and triglycerides (32%), and enhanced birth weights of lambs by 21% compared with saline-infused underfed ewes. There was no difference in birth weights of lambs between the control-fed and the Arg-infused underfed ewes. These novel results indicate that parenteral administration of Arg to underfed ewes prevented fetal growth restriction and provide support for its clinical use to ameliorate IUGR in humans. The findings also lay a new framework for studying cellular and molecular mechanisms responsible for the beneficial effects of Arg in regulating conceptus growth and development.

  3. Parenteral Administration of l-Arginine Prevents Fetal Growth Restriction in Undernourished Ewes12

    PubMed Central

    Lassala, Arantzatzu; Bazer, Fuller W.; Cudd, Timothy A.; Datta, Sujay; Keisler, Duane H.; Satterfield, M. Carey; Spencer, Thomas E.; Wu, Guoyao

    2010-01-01

    Intrauterine growth restriction (IUGR) is a major health problem worldwide that currently lacks an effective therapeutic solution. This study was conducted with an ovine IUGR model to test the hypothesis that parenteral administration of l-arginine (Arg) is effective in enhancing fetal growth. Beginning on d 28 of gestation, ewes were fed a diet providing 100% (control-fed) or 50% (underfed) of NRC-recommended nutrient requirements. Between d 60 of gestation and parturition, underfed ewes received i.v. infusions of saline or 155 μmol Arg-HCl/kg body weight 3 times daily, whereas control-fed ewes received only saline. The birth weights of lambs from saline-infused underfed ewes were 23% lower (P < 0.01) than those of lambs from control-fed dams. Administration of Arg to underfed ewes increased (P < 0.01) concentrations of Arg (69%), ornithine (55%), proline (29%), methionine (37%), leucine (36%), isoleucine (35%), cysteine (19%), and FFA (43%) in maternal serum, decreased maternal circulating levels of ammonia (18%) and triglycerides (32%), and enhanced birth weights of lambs by 21% compared with saline-infused underfed ewes. There was no difference in birth weights of lambs between the control-fed and the Arg-infused underfed ewes. These novel results indicate that parenteral administration of Arg to underfed ewes prevented fetal growth restriction and provide support for its clinical use to ameliorate IUGR in humans. The findings also lay a new framework for studying cellular and molecular mechanisms responsible for the beneficial effects of Arg in regulating conceptus growth and development. PMID:20505020

  4. Influence of gestational maternal feed restriction on growth performance and meat quality of rabbit offsprings.

    PubMed

    Goliomytis, M; Skoupa, E-P; Konga, A; Symeon, G K; Charismiadou, M A; Deligeorgis, S G

    2016-01-01

    The purpose of the present study was to evaluate the effect of feed restriction during pregnancy on reproductive performance of rabbit does and growth performance and meat quality of their offspring. A total of 26 primiparous non lactating does were equally divided into two treatment groups: the control group (C, n=13) that was fed ad libitum throughout gestation and the feed restricted group (R, n=13) that was fed to 75% of maintenance energy requirements from the 7(th) to the 26(th) day of gestation. Rabbit offsprings were weaned at 35 days of age and grown until the 72 days of age when they were slaughtered for meat quality assessment. Meat quality traits measured were pH(24), colour (L*, a*, b*), percentage of released water, cook loss, shear values and intramuscular fat. At kindling, R does produced smaller litter weights compared with those of does from group C, 447.8 and 591.4 g, respectively, and smaller individual kit birth weights, 56.2 and 71.5 g, respectively (P0.05). Performance and meat quality characteristics of fattening rabbits at 72 days of age were not influenced by gestational feed restriction of their mothers (P>0.05). Taking into consideration that, simultaneous gestation and lactation in rabbit does may be simulated by gestational feed restriction, results of the present study suggest that lactating does can support a simultaneous gestation without any adverse effect on the offsprings' quantitative and qualitative performance at the expense of increased mortality rates at parturition and until weaning.

  5. Urbanization and the problem of restricting the growth of very large cities.

    PubMed

    Bialkovskaia, V; Novikov, V

    1983-10-01

    This article discusses the problem of preventing the excessive growth of very large cities to the detriment of the development of smaller urban settlements in the USSR. The increase in size of the urban population throughout the entire USSR is mainly connected with the increase in the number of city dwellers. In 1960 and 1970 the number of largest cities in the USSR increased, along with a share of the nation's population living in these large cities. The low natural increase in population of very large cities creates a high demand for labor power which must come from the population of other cities. In 1970-1980, Moscow, one of the largest millionaire cities, had the lowest population growth rate of all major USSR cities (113.7%). The growth of Moscow and other very large cities in the last few years has been due to the mechanical increase in population and the increase in area. The analysis of Moscow's pattern of population growth over time focuses on changes in the level of availability of social and everyday services. The prewar period is characterized by a reserve of labor resources, the highest growth in industry and science, but a low overall population dynamic in the city. In the postwar period there was a significant decline in the annual increase of all indicators; this was a period of strong social development of the city. The period between 1966 and 1980 shows a further slowdown in the growth rate of city forming branches by an accelerated development of municipal service branches. The demand for measures to restrict the growth of very large Soviet cities depends on: 1) the reorientation of the development of the economic base, 2) the restructuring of their economy, and 3) the siting of various types of production of goods and services. Developing the specialization of the urban economy consists of planned development of the production of goods and services based on the use of available resources.

  6. 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. © 2014 Society for Endocrinology.

  7. The consequences of fetal growth restriction on brain structure and neurodevelopmental outcome.

    PubMed

    Miller, Suzanne L; Huppi, Petra S; Mallard, Carina

    2016-02-15

    Fetal growth restriction (FGR) is a significant complication of pregnancy describing a fetus that does not grow to full potential due to pathological compromise. FGR affects 3-9% of pregnancies in high-income countries, and is a leading cause of perinatal mortality and morbidity. Placental insufficiency is the principal cause of FGR, resulting in chronic fetal hypoxia. This hypoxia induces a fetal adaptive response of cardiac output redistribution to favour vital organs, including the brain, and is in consequence called brain sparing. Despite this, it is now apparent that brain sparing does not ensure normal brain development in growth-restricted fetuses. In this review we have brought together available evidence from human and experimental animal studies to describe the complex changes in brain structure and function that occur as a consequence of FGR. In both humans and animals, neurodevelopmental outcomes are influenced by the timing of the onset of FGR, the severity of FGR, and gestational age at delivery. FGR is broadly associated with reduced total brain volume and altered cortical volume and structure, decreased total number of cells and myelination deficits. Brain connectivity is also impaired, evidenced by neuronal migration deficits, reduced dendritic processes, and less efficient networks with decreased long-range connections. Subsequent to these structural alterations, short- and long-term functional consequences have been described in school children who had FGR, most commonly including problems in motor skills, cognition, memory and neuropsychological dysfunctions. © 2015 The Authors. The Journal of Physiology © 2015 The Physiological Society.

  8. Growth hormone-releasing hormone disruption extends lifespan and regulates response to caloric restriction in mice

    PubMed Central

    Sun, Liou Y; Spong, Adam; Swindell, William R; Fang, Yimin; Hill, Cristal; Huber, Joshua A; Boehm, Jacob D; Westbrook, Reyhan; Salvatori, Roberto; Bartke, Andrzej

    2013-01-01

    We examine the impact of targeted disruption of growth hormone-releasing hormone (GHRH) in mice on longevity and the putative mechanisms of delayed aging. GHRH knockout mice are remarkably long-lived, exhibiting major shifts in the expression of genes related to xenobiotic detoxification, stress resistance, and insulin signaling. These mutant mice also have increased adiponectin levels and alterations in glucose homeostasis consistent with the removal of the counter-insulin effects of growth hormone. While these effects overlap with those of caloric restriction, we show that the effects of caloric restriction (CR) and the GHRH mutation are additive, with lifespan of GHRH-KO mutants further increased by CR. We conclude that GHRH-KO mice feature perturbations in a network of signaling pathways related to stress resistance, metabolic control and inflammation, and therefore provide a new model that can be used to explore links between GHRH repression, downregulation of the somatotropic axis, and extended longevity. DOI: http://dx.doi.org/10.7554/eLife.01098.001 PMID:24175087

  9. Effect of intra-uterine growth restriction on long-term fertility in boars.

    PubMed

    Lin, Yan; Cheng, Xu; Sutovsky, Peter; Wu, De; Che, Lian-Qiang; Fang, Zheng-Feng; Xu, Sheng-Yu; Ren, Bo; Dong, Hong-Jun

    2015-08-21

    The present study assessed the effect of birthweight on reproductive performance, including a possible mechanism, in male pigs. Ten newborn male piglets, including five normal birthweight (NBW) piglets and five intra-uterine growth restricted (IUGR) piglets, were used in the study. All piglets were weaned on Day 28 and fed the same diet during the experiment (10 months). Average daily weight gain, feed intake and the feed conversion ratio were higher in NBW than IUGR piglets. Similarly, testis volume and the number of Leydig and Sertoli cells in the distal portion of the testes were higher in NBW than IUGR piglets (P < 0.05). Semen volume (P < 0.05) and the total number of spermatozoa per ejaculate (P = 0.08) were lower in IUGR boars. Testosterone concentrations on Day 141 and prostaglandin E2 concentrations on Days 82 and 141 were higher in IUGR than NBW boars (P < 0.05). The malondialdehyde content of seminal plasma was higher in IUGR boars, whereas sperm glutathione peroxidase activity was lower in IUGR versus NBW boars (P < 0.05). Expression of DNA methyltransferase (Dnmt) genes Dnmt1, Dnmt3a, histone-lysine N-methyltransferase (Suv39h2), and lysine (K)-specific demethylase Kdm4a was upregulated in testes from IUGR boars. These findings suggest that growth restriction affects sperm production via reproductive organ development and epigenetic regulation.

  10. Can anomalies of fetal brain circulation be useful in the management of growth restricted fetuses?

    PubMed

    Hernandez-Andrade, Edgar; Serralde, Jesus Andres Benavides; Cruz-Martinez, Rogelio

    2012-02-01

    Assessment of the fetal cerebral circulation provides important information on the hemodynamic changes associated with chronic hypoxia and intrauterine growth restriction. Despite the incorporation of new US parameters, the landmark for the fetal brain hemodynamic evaluation is still the middle cerebral artery. However, new vascular territories, such as the anterior and posterior cerebral arteries, might provide additional information on the onset of the brain sparing effect. The fractional moving blood volume estimation and three-dimensional power Doppler ultrasound indices are new techniques that seem to be promising in identifying cases at earlier stages of vascular deterioration; still, they are not available for clinical application and more information is needed on the reproducibility and advantages of three-dimensional power Doppler ultrasound blood flow indices. In the past, the brain sparing effect was considered as a protective mechanism; however, recent information challenges this concept. There is growing evidence of an association between brain sparing effect and increased risk of abnormal neurodevelopment after birth. Even in mild late-onset intrauterine growth restriction affected fetuses with normal umbilical artery blood flow, increased cerebral blood perfusion can be associated with a substantial risk of abnormal neuroadaptation and neurodevelopment during childhood.

  11. Intrauterine growth restriction does not alter response of protein synthesis to feeding in newborn pigs.

    PubMed

    Davis, T A; Fiorotto, M L; Burrin, D G; Pond, W G; Nguyen, H V

    1997-05-01

    This study aimed to determine the effect of intrauterine growth restriction (IUGR) on the acute response of tissue protein synthesis to feeding in newborn pigs. Newborn pigs of sows fed either control or protein-restricted diets throughout gestation were designated C or IUGR, respectively. Both groups were either fasted for 9 h after birth or fed hourly 30 ml colostrum/kg body wt for 2.75 h after a 6-h fast. Fractional rates of tissue protein synthesis (Ks) were measured in vivo with a flooding dose of L-[4-3H]phenylalanine. Birth weight was reduced by 33% in IUGR pigs. IUGR had no effect on Ks in skeletal muscles, heart, liver, jejunum, or pancreas. Feeding stimulated tissue Ks similarly in C and IUGR pigs. Fasting plasma insulin concentrations and their rise with feeding were unaffected by IUGR. Plasma insulin-like growth factor I (IGF-I) concentrations were reduced by 42% in IUGR pigs and were not altered by feeding in either IUGR or C pigs. There were positive nonlinear relationships between tissue Ks and circulating concentrations of insulin. The results indicate that, in newborn pigs, tissue Ks are unaffected by IUGR, despite reduced plasma IGF-I concentrations. The efficiency with which nutrients stimulate tissue Ks is also not altered by IUGR, perhaps because the rise in plasma insulin concentrations with feeding is unaffected by IUGR.

  12. New computerized fetal heart rate analysis for surveillance of intrauterine growth restriction.

    PubMed

    Huhn, E A; Lobmaier, S; Fischer, T; Schneider, R; Bauer, A; Schneider, K T; Schmidt, G

    2011-05-01

    Decreased fetal heart rate variability is associated with higher perinatal morbidity and mortality in intrauterine growth restriction (IUGR). This study used a new method [phase-rectified signal averaging (PRSA)] to calculate acceleration- and deceleration-related fluctuations of the fetal heart rate. Cardiotocograms from 74 growth-restricted and 161 normal fetuses were included. Both groups were matched for gestational age. The transformed PRSA signal was quantified by the acceleration-related parameter-averaged acceleration capacity (AAC) and compared to the standard short-term variation (STV). Mann-Whitney test and receiver operator characteristic (ROC) curves were used for statistical analysis. For AAC, the median values of the IUGR group and control group were 1.97 bpm [interquartile range (IQR): 1.66-2.23] and 2.49 bpm (IQR: 2.24-2.72), respectively. For STV, these values were 5.44 ms (IQR: 4.49-7.38) and 7.79 ms (IQR: 6.35-9.66), respectively. The area under the ROC curve was 81.4% for AAC and 70.5% for STV. The results of AAC are in both groups comparable to STV. Longitudinal studies are needed to investigate the association of AAC with the clinical outcome of the newborn. Copyright © 2011 John Wiley & Sons, Ltd.

  13. Fetal growth restriction and the programming of heart growth and cardiac insulin-like growth factor 2 expression in the lamb

    PubMed Central

    Wang, Kimberley C W; Zhang, Lei; McMillen, I Caroline; Botting, Kimberley J; Duffield, Jaime A; Zhang, Song; Suter, Catherine M; Brooks, Doug A; Morrison, Janna L

    2011-01-01

    Abstract Reduced growth in fetal life together with accelerated growth in childhood, results in a ∼50% greater risk of coronary heart disease in adult life. It is unclear why changes in patterns of body and heart growth in early life can lead to an increased risk of cardiovascular disease in adulthood. We aimed to investigate the role of the insulin-like growth factors in heart growth in the growth-restricted fetus and lamb. Hearts were collected from control and placentally restricted (PR) fetuses at 137–144 days gestation and from average (ABW) and low (LBW) birth weight lambs at 21 days of age. We quantified cardiac mRNA expression of IGF-1, IGF-2 and their receptors, IGF-1R and IGF-2R, using real-time RT-PCR and protein expression of IGF-1R and IGF-2R using Western blotting. Combined bisulphite restriction analysis was used to assess DNA methylation in the differentially methylated region (DMR) of the IGF-2/H19 locus and of the IGF-2R gene. In PR fetal sheep, IGF-2, IGF-1R and IGF-2R mRNA expression was increased in the heart compared to controls. LBW lambs had a greater left ventricle weight relative to body weight as well as increased IGF-2 and IGF-2R mRNA expression in the heart, when compared to ABW lambs. No changes in the percentage of methylation of the DMRs of IGF-2/H19 or IGF-2R were found between PR and LBW when compared to their respective controls. In conclusion, a programmed increased in cardiac gene expression of IGF-2 and IGF-2R may represent an adaptive response to reduced substrate supply (e.g. glucose and/or oxygen) in order to maintain heart growth and may be the underlying cause for increased ventricular hypertrophy and the associated susceptibility of cardiomyocytes to ischaemic damage later in life. PMID:21807611

  14. Fetal growth restriction and the programming of heart growth and cardiac insulin-like growth factor 2 expression in the lamb.

    PubMed

    Wang, Kimberley C W; Zhang, Lei; McMillen, I Caroline; Botting, Kimberley J; Duffield, Jaime A; Zhang, Song; Suter, Catherine M; Brooks, Doug A; Morrison, Janna L

    2011-10-01

    Reduced growth in fetal life together with accelerated growth in childhood, results in a ~50% greater risk of coronary heart disease in adult life. It is unclear why changes in patterns of body and heart growth in early life can lead to an increased risk of cardiovascular disease in adulthood. We aimed to investigate the role of the insulin-like growth factors in heart growth in the growth-restricted fetus and lamb. Hearts were collected from control and placentally restricted (PR) fetuses at 137-144 days gestation and from average (ABW) and low (LBW) birth weight lambs at 21 days of age. We quantified cardiac mRNA expression of IGF-1, IGF-2 and their receptors, IGF-1R and IGF-2R, using real-time RT-PCR and protein expression of IGF-1R and IGF-2R using Western blotting. Combined bisulphite restriction analysis was used to assess DNA methylation in the differentially methylated region (DMR) of the IGF-2/H19 locus and of the IGF-2R gene. In PR fetal sheep, IGF-2, IGF-1R and IGF-2R mRNA expression was increased in the heart compared to controls. LBW lambs had a greater left ventricle weight relative to body weight as well as increased IGF-2 and IGF-2R mRNA expression in the heart, when compared to ABW lambs. No changes in the percentage of methylation of the DMRs of IGF-2/H19 or IGF-2R were found between PR and LBW when compared to their respective controls. In conclusion, a programmed increased in cardiac gene expression of IGF-2 and IGF-2R may represent an adaptive response to reduced substrate supply (e.g. glucose and/or oxygen) in order to maintain heart growth and may be the underlying cause for increased ventricular hypertrophy and the associated susceptibility of cardiomyocytes to ischaemic damage later in life.

  15. Intrauterine pulmonary hypertension impairs angiogenesis in vitro: role of vascular endothelial growth factor nitric oxide signaling.

    PubMed

    Gien, Jason; Seedorf, Gregory J; Balasubramaniam, Vivek; Markham, Neil; Abman, Steven H

    2007-12-01

    Mechanisms that impair angiogenesis in neonatal persistent pulmonary hypertension (PPHN) are poorly understood. To determine if PPHN alters fetal pulmonary artery endothelial cell (PAEC) phenotype and impairs growth and angiogenesis in vitro, and if altered vascular endothelial growth factor-nitric oxide (VEGF-NO) signaling contributes to this abnormal phenotype. Proximal PAECs were harvested from fetal sheep that had undergone partial ligation of the ductus arteriosus in utero (PPHN) and age-matched control animals. Growth and tube formation +/- VEGF and NO stimulation and inhibition were studied in normal and PPHN PAECs. Western blot analysis was performed for VEGF, VEGF receptor-2 (VEGF-R2), and endothelial NO synthase (eNOS) protein content. NO production with VEGF administration was measured in normal and PPHN PAECs. PPHN PAECs demonstrate decreased growth and tube formation in vitro. VEGF and eNOS protein expression were decreased in PPHN PAECs, whereas VEGF-R2 protein expression was not different. VEGF and NO increased PPHN PAEC growth and tube formation to values achieved in normal PAECs. VEGF inhibition decreased growth and tube formation in normal and PPHN PAECs. NOS inhibition decreased growth in normal and PPHN PAECs, but tube formation was only reduced in normal PAECs. NO reversed the inhibitory effects of VEGF-R2 inhibition on tube formation in normal and PPHN PAECs. VEGF increased NO production in normal and PPHN PAECs. PPHN in utero causes sustained impairment of PAEC phenotype in vitro, with reduced PAEC growth and tube formation and down-regulation of VEGF and eNOS protein. VEGF and NO enhanced growth and tube formation of PPHN PAECs.

  16. Catch-up growth following intra-uterine growth-restriction programmes an insulin-resistant phenotype in adipose tissue.

    PubMed

    Berends, L M; Fernandez-Twinn, D S; Martin-Gronert, M S; Cripps, R L; Ozanne, S E

    2013-08-01

    It is now widely accepted that the early-life nutritional environment is important in determining susceptibility to metabolic diseases. In particular, intra-uterine growth restriction followed by accelerated postnatal growth is associated with an increased risk of obesity, type-2 diabetes and other features of the metabolic syndrome. The mechanisms underlying these observations are not fully understood. Using a well-established maternal protein-restriction rodent model, our aim was to determine if exposure to mismatched nutrition in early-life programmes adipose tissue structure and function, and expression of key components of the insulin-signalling pathway. Offspring of dams fed a low-protein (8%) diet during pregnancy were suckled by control (20%)-fed dams to drive catch-up growth. This 'recuperated' group was compared with offspring of dams fed a 20% protein diet during pregnancy and lactation (control group). Epididymal adipose tissue from 22-day and 3-month-old control and recuperated male rats was studied using histological analysis. Expression and phosphorylation of insulin-signalling proteins and gene expression were assessed by western blotting and reverse-transcriptase PCR, respectively. Recuperated offspring at both ages had larger adipocytes (P<0.001). Fasting serum glucose, insulin and leptin levels were comparable between groups but increased with age. Recuperated offspring had reduced expression of IRS-1 (P<0.01) and PI3K p110β (P<0.001) in adipose tissue. In adult recuperated rats, Akt phosphorylation (P<0.01) and protein levels of Akt-2 (P<0.01) were also reduced. Messenger RNA expression levels of these proteins were not different, indicating a post-transcriptional effect. Early-life nutrition programmes alterations in adipocyte cell size and impairs the protein expression of several insulin-signalling proteins through post-transcriptional mechanisms. These indices may represent early markers of insulin resistance and metabolic disease risk.

  17. 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.

  18. Effects of restricted feeding of prepubertal ewe lambs on growth performance and mammary gland development.

    PubMed

    Villeneuve, L; Cinq-Mars, D; Lacasse, P

    2010-06-01

    The aim of this study was to determine the effects of restricted feeding before puberty on growth performance and mammary gland development in replacement ewe lambs. At weaning, 72 Dorset ewe lambs were assigned to one of the three diets: an ad libitum control diet with medium-quality forage (MQF; diet A-MQF); a restricted diet with the same forage as A, but less feed concentrate (diet R-MQF); or a high-quality forage (HQF) diet (diet F-HQF). The quantity of concentrate offered to the group R-MQF and F-HQF ewe lambs was adjusted to obtain 70% of the control ewe lambs' growth rate. The diets were offered for 75 days after weaning to cover the allometric phase of mammary gland development. During this period, average daily gain (ADG) was 223 and 229 g/day for groups R-MQF and F-HQF, respectively, compared to 305 g/day for group A-MQF (P < 0.0001). At the end of this period, 28 ewe lambs were slaughtered and their mammary gland was collected. Parenchymal fresh tissue weight tended to be higher for groups R-MQF and F-HQF compared to group A-MQF (P = 0.09). Stroma weight was greater (P < 0.05) for the group A-MQF ewe lambs than for those in the other treatments. Total DNA and total protein in parenchymal tissue tended to be greater for groups R-MQF and F-HQF (P = 0.09 and P = 0.07, respectively). Dry fat-free tissue was greater for groups R-MQF and F-HQF (P < 0.05). The remaining ewe lambs were fed the same haylage and barley diet until their first lambing. During this period, compensatory growth was observed. ADG was greater (P < 0.01) for groups R-MQF and F-HQF than for group A-MQF, and feed conversion was improved (P < 0.01) for groups R-MQF and F-HQF compared with the control, whereas the dry matter intake was similar for all groups. Live body weight, loin eye depth and backfat depth at breeding and around lambing were similar for all groups. The results of this study suggest that restricted feeding before puberty improves mammary gland development without

  19. Endothelial injury in a transforming growth factor β-dependent mouse model of scleroderma induces pulmonary arterial hypertension.

    PubMed

    Derrett-Smith, Emma C; Dooley, Audrey; Gilbane, Adrian J; Trinder, Sarah L; Khan, Korsa; Baliga, Reshma; Holmes, Alan M; Hobbs, Adrian J; Abraham, David; Denton, Christopher P

    2013-11-01

    To delineate the constitutive pulmonary vascular phenotype of the TβRIIΔk-fib mouse model of scleroderma, and to selectively induce pulmonary endothelial cell injury using vascular endothelial growth factor (VEGF) inhibition to develop a model with features characteristic of pulmonary arterial hypertension (PAH). The TβRIIΔk-fib mouse strain expresses a kinase-deficient transforming growth factor β (TGFβ) receptor type II driven by a fibroblast-specific promoter, leading to ligand-dependent up-regulation of TGFβ signaling, and replicates key fibrotic features of scleroderma. Structural, biochemical, and functional assessments of pulmonary vessels, including in vivo hemodynamic studies, were performed before and following VEGF inhibition, which induced pulmonary endothelial cell apoptosis. These assessments included biochemical analysis of the TGFβ and VEGF signaling axes in tissue sections and explanted smooth muscle cells. In the TβRIIΔk-fib mouse strain, a constitutive pulmonary vasculopathy with medial thickening, a perivascular proliferating chronic inflammatory cell infiltrate, and mildly elevated pulmonary artery pressure resembled the well-described chronic hypoxia model of pulmonary hypertension. Following administration of SU5416, the pulmonary vascular phenotype was more florid, with pulmonary arteriolar luminal obliteration by apoptosis-resistant proliferating endothelial cells. These changes resulted in right ventricular hypertrophy, confirming hemodynamically significant PAH. Altered expression of TGFβ and VEGF ligand and receptor was consistent with a scleroderma phenotype. In this study, we replicated key features of systemic sclerosis-related PAH in a mouse model. Our results suggest that pulmonary endothelial cell injury in a genetically susceptible mouse strain triggers this complication and support the underlying role of functional interplay between TGFβ and VEGF, which provides insight into the pathogenesis of this disease. Copyright

  20. Improvement of pulmonary function in children with early-onset scoliosis using magnetic growth rods.

    PubMed

    Yoon, Wai Weng; Sedra, Fady; Shah, Suken; Wallis, Colin; Muntoni, Francesco; Noordeen, Hilali

    2014-07-01

    Case series. To determine whether there is improvement in pulmonary function in children with early-onset scoliosis (EOS) using magnetic growth rods (MGRs). EOS deformities have large impacts on lung function and volumes. Deterioration of pulmonary function in scoliosis is multifactorial, including severity, location of apex vertebra, and medical comorbidities. MGR insertion has benefits including reduction in operative procedures with repeated anesthetics, cost-effectiveness, and minimizing surgical and psychological distress. Pulmonary function tests provide objective and quantitative information about functional impairment caused by scoliosis. This is the first study that observes the MGR lengthening and changes in pulmonary function during a minimum period of 2.2 years. Six cases of EOS secondary to neuromuscular disease were identified. Mean age at diagnosis was 2.8 year (2.1-4.9 yr), mean age at surgery was 7.5 year (5-10 yr), and mean follow-up was 2.5 year (2.2-2.8 yr). Pulmonary function test (forced vital capacity [FVC] + forced expired volume in 1 second [FEV1] both % predicted) was measured before and after insertion of MGR and at every lengthening clinic subsequently for a minimum 2 years. Coronal and sagittal Cobb angles were measured pre- and postoperatively as were length extension of growth rods. All except 1 patient had dual MGRs inserted (the other had a single rod). Lengthening was commenced and data was collected at 6-month intervals. Average correction was 34° ± 18° and 36° ± 15° for coronal and sagittal Cobb angles, respectively. Mean lengthening achieved was 24.9 mm. Mean improvement in postoperative FVC and FEV1 was 14.1% and 17.2%, respectively. There was significant difference between the median preoperative and postoperative Cobb angle, P = 0.028. This study demonstrates early intervention using MGR in patients with EOS is associated with significant improvement in postoperative pulmonary function tests; and significant improvement

  1. Growth of the pulmonary autograft after the Ross operation in childhood.

    PubMed

    Simon, P; Aschauer, C; Moidl, R; Marx, M; Keznickl, F P; Eigenbauer, E; Wolner, E; Wollenek, G

    2001-02-01

    Excellent hemodynamic performance has been demonstrated after aortic valve replacement using the autologous pulmonary valve as described by D. Ross. However, in the pediatric population there is concern in regard to growth of the autograft and late dilatation in the systemic circulation. Since 1991, 30 children (mean age, 11.3+/-3.1 years) had aortic valve replacement with the pulmonary autograft as a root replacement. All children had yearly clinical and echocardiographic follow-up. There were no perioperative deaths; one child died late in a car accident. At the last follow-up (mean follow-up, 4.3+/-2.6 years), all patients were in NYHA class I. There was one early reoperation, in which the autograft had to be reconstructed due to a leaflet perforation. There were no major valve related events. All children showed normal somatic growth. The annulus diameter increased significantly from 18+/-2 at surgery to 20+/-3.5 mm at the latest follow-up (P<0.004). The sinus also increased significantly in diameter from 29+/-4 at surgery to 34+/-2 mm at the last follow-up (P<0.001). This increase in autograft size, both for the annulus and the sinus, paralleled the increase in body surface area with no evidence for unproportional dilatation. Hemodynamic measurements demonstrated physiological peak gradients of 6.8+/-2.9 mmHg and no or trivial aortic insufficiency in 95% of this rapidly growing patient population. These data demonstrate growth of the pulmonary autograft parallel to somatic growth without undue dilatation in the systemic circulation. The hemodynamics are excellent with regard to physiological gradients and no increase in aortic insufficiency.

  2. 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.

  3. Serious foetal growth restriction is associated with reduced proportions of natural killer cells in decidua basalis.

    PubMed

    Eide, Irina P; Rolfseng, Toril; Isaksen, Christina V; Mecsei, Reidun; Roald, Borghild; Lydersen, Stian; Salvesen, Kjell A; Harsem, Nina K; Austgulen, Rigmor

    2006-03-01

    Extravillous trophoblasts are major participants in placental development and remodelling of spiral arteries. Trophoblast invasion is regulated by maternal immune cells, and abnormal leucocyte subpopulation composition has been reported in implantation failure. In pre-eclampsia (PE), with or without foetal growth restriction (FGR), superficial trophoblast invasion and insufficient remodelling of spiral arteries are common findings. In the present study, we have compared spiral artery remodelling and leucocyte composition in decidual tissue from 30 cases (PE=8, FGR=5, PE + FGR=17) and 31 controls. Six histological remodelling criteria were established, and each pregnancy obtained a remodelling score. Numbers of natural killer (NK) cells (CD56+), T cells (CD3+) and activated (CD25+ or CD69+) leucocytes were determined and related to total leucocyte (CD45+) numbers in serial sections. Cases demonstrated significantly impaired spiral artery remodelling, inappropriate placental growth and reduced NK cell proportions, as compared to controls (P=0.02, P<0.001 and P=0.01, respectively). Reduced NK cell proportion was primarily found in pregnancies complicated by FGR, with or without PE, and a significant positive correlation was observed between NK cell proportion, trophoblast infiltration and placental growth. Our in vivo observations support the hypothesized association between NK cells, impaired placental development and pathogenesis of PE/FGR.

  4. Shared and disparate components of the pathophysiologies of fetal growth restriction and preeclampsia.

    PubMed

    Ness, Roberta B; Sibai, Baha M

    2006-07-01

    Intrauterine growth restriction (IUGR) and preeclampsia differ in their association with maternal disease but share a similar placental pathology. Moreover, mothers who have had pregnancies complicated by preeclampsia or IUGR are at elevated later-life cardiovascular risk. Why, then, do some women develop IUGR and others develop preeclampsia? In this clinical opinion, based on a review of the literature, we hypothesize that both women experiencing preeclampsia and IUGR enter pregnancy with some degree of endothelial dysfunction, a lesion that predisposes to shallow placentation. In our opinion, preeclampsia develops when abnormal placentation, through the mediator of elevated circulating cytokines, interacts with maternal metabolic syndrome, comprised of adiposity, insulin resistance/hyperglycemia, hyperlipidemia, and coagulopathy. IUGR develops in the absence of antenatal metabolic syndrome. Among these women, the baby is affected by shallow placentation but the mother does not develop clinically apparent disease. This conceptualization provides a testable framework for future etiologic studies of preeclampsia and IUGR.

  5. 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.

  6. Brain metabolite alterations in infants born preterm with intrauterine growth restriction: association with structural changes and neurodevelopmental outcome.

    PubMed

    Simões, Rui V; Muñoz-Moreno, Emma; Cruz-Lemini, Mónica; Eixarch, Elisenda; Bargalló, Núria; Sanz-Cortés, Magdalena; Gratacós, Eduard

    2017-01-01

    Intrauterine growth restriction and premature birth represent 2 independent problems that may occur simultaneously and contribute to impaired neurodevelopment. The objective of the study was to assess changes in the frontal lobe metabolic profiles of 1 year old intrauterine growth restriction infants born prematurely and adequate-for-gestational-age controls, both premature and term adequate for gestational age and their association with brain structural and biophysical parameters and neurodevelopmental outcome at 2 years. A total of 26 prematurely born intrauterine growth restriction infants (birthweight <10th centile for gestational age), 22 prematurely born but adequate for gestational age controls, and 26 term adequate-for-gestational-age infants underwent brain magnetic resonance imaging and magnetic resonance spectroscopy at 1 year of age during natural sleep, on a 3 Tesla scanner. All brain T1-weighted and diffusion-weighted images were acquired along with short echo time single-voxel proton spectra from the frontal lobe. Magnetic resonance imaging/magnetic resonance spectroscopy data were processed to derive structural, biophysical, and metabolic information, respectively. Neurodevelopment was evaluated at 2 years of age using the Bayley Scales 3rd edition, assessing cognitive, language, motor, socioemotional, and adaptive behavior. Prematurely born intrauterine growth restriction infants had slightly smaller brain volumes and increased frontal lobe white matter mean diffusivity compared with both prematurely born but adequate for gestational age and term adequate for gestational age controls. Frontal lobe N-acetylaspartate levels were significantly lower in prematurely born intrauterine growth restriction than in prematurely born but adequate for gestational age infants but increased in prematurely born but adequate for gestational age compared with term adequate-for-gestational-age infants. The prematurely born intrauterine growth restriction group also

  7. Cardiovascular transition to extrauterine life in growth-restricted neonates: relationship with prenatal Doppler findings.

    PubMed

    Turan, Sifa; Turan, Ozhan M; Salim, Mubadda; Berg, Christoph; Gembruch, Ulrich; Harman, Christopher R; Baschat, Ahmet A

    2013-01-01

    Cardiovascular status in fetal growth restriction (FGR) can be classified by the severity of individual Doppler abnormalities (early and late) or by the rate of clinical progression. We tested the hypothesis that aspects of the fetal cardiovascular status in FGR affect neonatal cardiovascular findings. FGR cases [abdominal circumference <5th percentile and an elevated umbilical (MCA) artery (UA) pulsatility index] had UA, middle cerebral artery and ductus venosus (DV) Doppler. Positive UA end-diastolic velocity and/or a low MCA pulsatility index denoted early and absent/reversed UA end-diastolic velocity, whereas an increased DV pulsatility index for veins denoted late responses. The rate of progression was classified into mild, progressive and severe. After delivery, shunt dynamics and blood flow across the patent ductus arteriosus (PDA), foramen ovale and atriaventricular valves, myocardial contractility and pharmacologic pressor requirement were noted at neonatal echocardiography. These findings were related to prenatal Doppler parameters. In 94 patients, only individual Doppler parameters related to neonatal echocardiographic findings. Absent/reversed UA DV significantly predicted PDA with right to left shunt (p = 0.016). The pressor need for cardiovascular instability was observed in neonates with abnormal prenatal DV Doppler and with lower birth weights delivered at earlier gestational age (p < 0.0001 for both). Pressor need was significantly related to neonatal death (Nagelkerke R² = 0.35, p = 0.002). A markedly abnormal UA Doppler predisposes growth-restricted neonates to persistence of fetal circulation associated with right to left shunting. Abnormal venous Doppler is a risk factor for cardiovascular instability which in turn significantly contributes to neonatal mortality. Further clarification of the neonatal cardiovascular transition may be helpful in guiding early neonatal assessment and management. Copyright © 2012 S. Karger AG, Basel.

  8. Growth restriction, leptin, and the programming of adult behavior in mice.

    PubMed

    Meyer, Lauritz R; Zhu, Vivian; Miller, Alise; Roghair, Robert D

    2014-12-15

    Prematurity and neonatal growth restriction (GR) are risk factors for autism and attention deficit hyperactivity disorder (ADHD). Leptin production is suppressed during periods of undernutrition, and we have shown that isolated neonatal leptin deficiency leads to adult hyperactivity while neonatal leptin supplementation normalizes the brain morphology of GR mice. We hypothesized that neonatal leptin would prevent the development of GR-associated behavioral abnormalities. From postnatal day 4-14, C57BL/6 mice were randomized to daily injections of saline or leptin (80ng/g), and GR was identified by a weanling weight below the tenth percentile. The behavioral phenotypes of GR and control mice were assessed beginning at 4 months. Within the tripartite chamber, GR mice had significantly impaired social interaction. Baseline escape times from the Barnes maze were faster for GR mice (65+/-6s vs 87+/-7s for controls, p<0.05), but GR mice exhibited regression in their escape times on days 2 and 3 (56% regressed vs 22% of control saline mice, p<0.05). Compared to controls, GR mice entered the open arms of the elevated plus maze more often and stayed there longer (72+/-10s vs 36+/-5s, p<0.01). Neonatal leptin supplementation normalized the behavior of GR mice across all behavioral assays. In conclusion, GR alters the social interactions, learning and activity of mice, and supplementation with the neurotrophic hormone leptin mitigates these effects. We speculate neonatal leptin deficiency may contribute to the adverse neurodevelopmental outcomes associated with postnatal growth restriction, and postnatal leptin therapy may be protective.

  9. 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

  10. 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

  11. Puerarin affects bone biomarkers in the serum of rats with intrauterine growth restriction.

    PubMed

    Chen, Juncao; Chen, Pingyang; Qi, Huaxue; Huang, Danhong

    2016-04-01

    To investigate serum bone biomarkers in rats with intrauterine growth restriction (IUGR) in order to determine the effects of puerarin on bone metabolism. A rat model of IUGR was induced using a low protein diet during pregnancy. The offspring were given puerarin or an identical volume of saline via subcutaneous abdominal injection. All rats were studied at 1, 3, and 8 weeks of age. Serum biomarkers of bone formation, including insulin-like growth factor-1 (IGF-1), bone-specific alkaline phosphatase (BALP), osteocalcin (OC), osteoprotegerin (OPG), receptor-activator of nuclear factor-κB Iigand (RANKL), as well as blood levels of calcium and phosphorus were measured. Serum BALP, OPG, IGF-1, and OC levels, as well as the OPG/RANKL ratio, were lower in the IUGR group compared with the control group at 1 week of age (P = 0.024, 0.011, 0.014, 0.004, and 0.002, respectively). At 3 weeks of age, the serum BALP and OC levels were higher in the protein-restricted group compared with the control group (P = 0.003 and 0.001, respectively). A comparison between the IUGR plus puerarin intervention group and the IUGR group revealed differences in the levels of BALP and IGF-1 at 3 weeks of age (P = 0.008 and 0.003, respectively). In addition, serum OPG and OC levels and the OPG/RANKL ratio were higher at 8 weeks of age (P = 0.044, 0.007, and 0.016, respectively). No differences in serum calcium and phosphorus levels were observed among the three groups. Our study demonstrates that the bone microenvironment of the fetus can be altered by a low protein maternal diet and that puerarin can reverse these effects. These results indicate that the nutritional environment plays an important role in early skeletal development and that the bone turnover of IUGR rats can be altered by puerarin treatment.

  12. Maternal and fetal risk factors affecting perinatal mortality in early and late fetal growth restriction.

    PubMed

    Demirci, Oya; Selçuk, Selçuk; Kumru, Pınar; Asoğlu, Mehmet Reşit; Mahmutoğlu, Didar; Boza, Barış; Türkyılmaz, Gürcan; Bütün, Zafer; Arısoy, Resul; Tandoğan, Bülent

    2015-12-01

    To determine the factors which affect the perinatal deaths in early and late fetal growth restriction (FGR) fetuses using threshold of estimated fetal weight (EFW) < 5(th) percentile. This retrospective study included singleton 271 FGR fetuses, defined as an EFW < 5(th) percentile. All fetuses considered as growth restrictions were confirmed by birth weight. Fetuses with multiple pregnancy, congenital malformation, chromosomal abnormality, and premature rupture of membrane were excluded. Samples were grouped in early and late FGR. Early FGR fetuses was classified as gestational age at birth ≤ 34 weeks and late FGR was classified as gestational age at birth > 34 weeks. Factors which affect the perinatal deaths were analyzed descriptively in early and late FGR. The perinatal mortality was calculated by adding the number of stillbirths and neonatal deaths. The study included 86 early and 185 late FGR fetuses, 31 resulted in perinatal deaths, 28 perinatal deaths were in early FGR, and three perinatal deaths were in late FGR. Perinatal deaths occurred more commonly in early FGR fetuses with an EFW < 3(rd) percentile. Prior stillbirth, preeclampsia, the degree of increasing vascular impedance of umbilical artery(UA) and uterine artery (UtA) showed significant correlation with perinatal death in early FGR. All three perinatal deaths in late FGR occurred in fetuses with EFW < 3(rd) percentile and severe oligohydramnios. Also, placental abruption and perinatal death was found significantly higher in increased vascular impedance of UtAs whatever the umbilical artery Doppler. Only EFW < 3(rd) percentile and severe olgohydramnios seem to be contributing factors affecting perinatal death in late FGR in comparison with early FGR. Copyright © 2015. Published by Elsevier B.V.

  13. Renal and extrarenal mechanisms of perinatal programming after intrauterine growth restriction.

    PubMed

    Dötsch, Jörg

    2009-04-01

    The concept of fetal programming of disease in later life after intrauterine growth restriction (IUGR) has opened a potential new perspective on the treatment and prevention of arterial hypertension. Numerous large studies have recently confirmed the relationship between low birth weight and raised blood pressure. Hyperalimentation after birth appears to add to the risk of higher blood pressure later in life. However, there is still a controversy and clear intervention studies have not yet been possible. Therefore, the gain of knowledge about the underlying mechanisms of fetal programming is of utmost importance.Two major groups of mechanisms may be identified: renal and extrarenal mechanisms. Renal mechanisms include the reduction of nephron number, which is encountered in patients and animals with low birth weight. According to the so-called Brenner hypothesis, this may lead to increased arterial blood pressure. Another important renal system is the renin-angiotensin-aldosterone system, which appears to be more active on a number of levels in low birth weight individuals. Finally, there is the conversion of cortisol to inactive cortisone by the 11beta-hydroxysteroid dehydrogenase in distal tubule cells, which is reduced after intrauterine growth restriction. This enables a more powerful activation of mineralocorticoid receptors by cortisol. Extrarenal mechanisms include alterations in vascular structure (primary and secondary), increased activity of the sympathetic nerve system, and maybe most interestingly, an impairment of endothelial function. The latter is at least partially caused by an inactivation of nitric oxide by an excess of free oxygen radicals. In summary, mechanisms of fetal programming are only in the process of being revealed, and research has to focus on finding the key mechanism that might allow for successful intervention.

  14. Epigenetic regulation of insulin-like growth factor signaling: A novel insight into the pathophysiology of neonatal pulmonary hypertension.

    PubMed

    Madonna, Rosalinda; De Caterina, Raffaele; Geng, Yong-Jian

    2015-10-01

    Burdened by high morbidity and mortality, neonatal pulmonary hypertension (PH) is a life-threatening pathophysiological condition that progressively elevates the mean pulmonary artery pressure (PAP) and pulmonary vascular resistance (PVR). Pulmonary vascular remodeling and vasoconstriction are recognized pathophysiological features of the disease. Neonatal PH is a serious pathological condition in which persistent PH of the newborn causes hypoxemia and right-to-left extrapulmonary shunting of blood flow, leading to right heart failure and serious life-threatening complications. Recently, the role of growth factors in the pathogenesis of neonatal PH has attracted much attention. Here we provide an update on the ongoing research regarding the epigenetic regulation of the insulin growth factor (IGF)-1/IGF-1 receptor pathway, with insight into the potential regulatory role such regulation in the pathogenesis of neonatal PH.

  15. 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

  16. Fetal window of vulnerability to airborne polycyclic aromatic hydrocarbons on proportional intrauterine growth restriction.

    PubMed

    Choi, Hyunok; Wang, Lu; Lin, Xihong; Spengler, John D; Perera, Frederica P

    2012-01-01

    Although the entire duration of fetal development is generally considered a highly susceptible period, it is of public health interest to determine a narrower window of heightened vulnerability to polycyclic aromatic hydrocarbons (PAHs) in humans. We posited that exposure to PAHs during the first trimester impairs fetal growth more severely than a similar level of exposure during the subsequent trimesters. In a group of healthy, non-smoking pregnant women with no known risks of adverse birth outcomes, personal exposure to eight airborne PAHs was monitored once during the second trimester for the entire cohort (n = 344), and once each trimester within a subset (n = 77). Both air monitoring and self-reported PAH exposure data were used in order to statistically estimate PAH exposure during the entire gestational period for each individual newborn. One natural-log unit increase in prenatal exposure to the eight summed PAHs during the first trimester was associated with the largest decrement in the Fetal Growth Ratio (FGR) (-3%, 95% Confidence Interval (CI), -5 to -0%), birthweight (-105 g, 95% CI, -188 to -22 g), and birth length (-0.78 cm, 95% CI, -1.30 to -0.26 cm), compared to the unit effects of PAHs during the subsequent trimesters, after accounting for confounders. Furthermore, a unit exposure during the first trimester was associated with the largest elevation in Cephalization Index (head to weight ratio) (3 μm/g, 95% CI, 1 to 5 μm/g). PAH exposure was not associated with evidence of asymmetric growth restriction in this cohort. PAH exposure appears to exert the greatest adverse effect on fetal growth during the first trimester. The present data support the need for the protection of pregnant women and the embryo/fetus, particularly during the earliest stage of pregnancy.

  17. 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

    2014-12-05

    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.

  18. Phenotypic and molecular characterization of intrauterine fetal growth restriction in interspecies sheep pregnancy.

    PubMed

    Chávez-García, A; Vázquez-Martínez, E R; Murcia, C; Rodríguez, A; Cerbón, M; Mejía, O

    2015-10-01

    Interspecies pregnancies between closely related species are usually performed in livestock to obtain improved and enriched offspring. Indeed, different hybrids have been obtained for research purposes since many years ago, and the maternal-fetal interactions have been studied as a possible strategy for species preservation. The aim of this study was to characterize by physiological and molecular approaches the interspecies pregnancy between bighorn sheep () and domestic sheep (). Hybrids were obtained by artificial insemination; the blood pressure and protein urine levels were measured during the last two-thirds of gestation. After parturition, offspring and placentas were weighed and measured and cotyledons were counted and weighed and their surface area determined. Plasma samples were obtained between wk 8 and 21 of gestation to assess progesterone (P4), vascular endothelial growth factor (VEGF), and placental growth factor (PlGF) levels and cell-free RNA was isolated during the same period to assess hypoxia-inducible factor-1 α (α) gene expression. Hybrid and normal pregnancies were analyzed using physiological and molecular parameters during the last two-thirds of gestation (wk 8-21). The results show that during the measurement period, ewes with a hybrid pregnancy presented normal blood pressure and no alteration in urinary protein content. However, compared with sheep with a normal pregnancy, those with a hybrid pregnancy had a decrease in fetal and placental growth as well as in the cotyledonary surface area. Furthermore, in the hybrid group, there was placental insufficiency, characterized by a decrease in P4 production, as well as indications of endothelial dysfunction, characterized an increase in plasma levels of VEGF and PlGF as well as in plasma gene expression of α. Overall, the results indicate that hybrids of and presented intrauterine growth restriction, essentially due to altered endothelial function and chronic placental insufficiency

  19. No association of chronic obstructive pulmonary disease with abdominal aortic aneurysm growth.

    PubMed

    Takagi, Hisato; Umemoto, Takuya

    2016-11-01

    Chronic obstructive pulmonary disease (COPD) is independently and positively associated with abdominal aortic aneurysm (AAA) presence. The aim of the present article was to determine whether COPD is associated with AAA growth. We reviewed currently available studies with a systematic literature search and meta-analytic estimate. Databases including MEDLINE and EMBASE were searched through July 2015 using Web-based search engines (PubMed and OVID). Studies considered for inclusion met the following criteria: the study population was AAA patients with and without COPD; and outcomes included data regarding AAA growth. For each study, growth rates in both the COPD and non-COPD groups were used to generate standardized mean differences (SMDs) and 95 % confidence intervals (CIs). Of 614 potentially relevant publications screened initially, we identified 10 eligible studies including data on a total of 2663 AAA patients. None of them demonstrated a statistically significant (positive or negative) association of COPD with AAA growth rates. A pooled analysis demonstrated that COPD is not associated with AAA growth rates (SMD, 0.04; 95 % CI, -0.07 to 0.15; p = 0.50). There was no evidence of significant publication bias. In conclusion, we found that COPD is not associated with AAA growth. Further investigations would be required to elucidate why COPD is not associated with AAA growth despite its positive association with AAA presence.

  20. Pulmonary synovial sarcoma with polypoid endobronchial growth: a case report, immunohistochemical and cytogenetic study.

    PubMed

    Niwa, Hideki; Masuda, Shinji; Kobayashi, Chikashi; Oda, Yoshinao

    2004-08-01

    A rare case of primary pulmonary synovial sarcoma with polypoid endobronchial growth in a 42-year-old Japanese woman is described. Left upper sleeve lobectomy was performed for the polypoid tumor measuring 2.5 cm in the left major bronchus and the patient was treated with adjuvant chemotherapy. Three years later, a recurrent tumor was discovered. Microscopically, this tumor was characterized by a proliferation of oval to spindle-shaped cells arranged in sheets and fascicles and covered by the thin normal bronchial epithelium. Immunohistochemically, tumor cells were positive for vimentin, and focally positive for pancytokeratin recognized by AE1/AE3, cytokeratin 7 and epithelial membrane antigen. A chimera gene, SYT-SSX1, was detected. Recently, primary pulmonary synovial sarcoma is an increasingly recognized clinical entity; however, most of these tumors present as a parenchymal mass. The present case is a unique example of primary synovial sarcoma of endobronchial polypoid type. This case suggests that pulmonary synovial sarcoma might originate from bronchial submucosal stromal tissue.

  1. Effect of feed restriction on intake of Moringa oleifera and Leucaena leucocephala and growth performance of rabbits.

    PubMed

    Santos-Ricalde, R; Gutiérrez-Ruiz, E; Novelo-Ucan, W; Martinez-Romero, P; Segura-Correa, J

    2017-08-13

    Two experiments were conducted to evaluate the effect of feed restriction on intake of Moringa oleifera (MO) or Leucaena leucocephala (LL) and growth of rabbits. In experiment one, 45 rabbits (male and female) weighing 1.18 ± 0.15 kg were used. They were randomly distributed to three feed restriction treatments (20, 30, and 40%) with 15 rabbits each (9 females and 6 males) and they were offered M. oleifera (MO) ad libitum. In experiment two, 45 growing male rabbits weighing 0.63 ± 0.113 kg were used. They were randomly assigned to 0, 20, and 30% feed restriction diets, and they have free access to L. leucocephala (LL). Intake of MO increased (P < 0.05) conforming feed restriction increased (40.6, 52.9, and 55.2 g/day of MO for 20, 30, and 40%, respectively). Daily liveweight gain and feed conversion did not differ (P > 0.05), and economic efficiency was similar among treatments. Consumption of LL increased (P < 0.05) in rabbits under the 30% restriction treatment in comparison to that of rabbits restricted 20% (46.0 and 44.4 g/day, respectively). Total feed intake (LL + feed) was highest in 20% restricted rabbits (108.0, 100.8, and 93.2 g/day for 20, 30, and 0%, respectively). Daily liveweight gain and feed conversion were not affected by feed restriction (P > 0.05). Economic efficiency improved twice in feed-restricted rabbits (2.0 and 2.3 for 20 and 30%, respectively) in contrast to that of the control 0% group (1.1). The results suggest that rabbits restricted up to 30% and supplemented with either MO or LL did not affect growth performance and reduced feed cost.

  2. [Role of connective tissue growth factor on pulmonary artery remodeling in rats exposed to smoke].

    PubMed

    Tian, Feng; Xu, Yong-Jian; Zhang, Zhen-Xiang; Fan, Xin-Lei; Hu, Jing

    2007-12-01

    To explore the role of connective tissue growth factor (CTGF) on pulmonary artery remodeling induced by smoke exposure in rats. Thirty-five male Wistar rats were randomly assigned into a control group (A group), a smoke exposure one month group (B group), a smoke exposure and high dose CTGF antisense oligonucleotide (ASON) one month group (C group), a smoke exposure and low dose CTGF ASON one month group (D group), a smoke exposure two month group (E group), a smoke exposure and high dose CTGF ASON two month group (F group), and a smoke exposure and low dose CTGF ASON two month group (G group). Pulmonary artery remodeling was observed by hematoxylin-eosin staining, and the CTGF mRNA expressions of pulmonary arteries were evaluated by RT-PCR. Immunohistochemistry methods were performed to determine CTGF protein expression in pulmonary artery smooth muscle. The difference between the groups was analyzed. (1) The pulmonary artery WA% of the seven groups were respectively (28.6 +/- 1.2)%, (42.5 +/- 2.3)%, (33.7 +/- 1.8)%, (42.1 +/- 2.4)%, (49.6 +/- 2.1)%, (34.3 +/- 1.9)% and (38.4 +/- 2.0)%. There was significant difference between B group and C group (q = 5.09, P < 0.01). Compared to E group, there were significant decreases in F group and G group (q = 8.15, 3.75, all P < 0.05). (2) The CTGF protein expressions (A value) of pulmonary artery smooth muscle were respectively 0.098 +/- 0.015, 0.159 +/- 0.023, 0.118 +/- 0.017, 0.153 +/- 0.022, 0.406 +/- 0.036, 0.109 +/- 0.012 and 0.146 +/- 0.024. There was significant difference between B group and C group (q = 3.26, P < 0.05). Compared to E group, there were significant decreases in F group and G group (q = 67.08, 18.09, all P < 0.01). (3) The CTGF mRNA expressions (A(CTGF)/A(beta-actin)) of pulmonary artery were respectively 0.051 +/- 0.010, 0.823 +/- 0.096, 0.216 +/- 0.056, 0.810 +/- 0.085, 2.452 +/- 0.267, 0.207 +/- 0.062 and 0.509 +/- 0.067. There was significant difference between B group and C group (q = 53.50, P

  3. 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. Copyright © 2015 the American Physiological Society.

  4. Utero-placental perfusion Doppler indices in growth restricted fetuses: effect of sildenafil citrate.

    PubMed

    El-Sayed, Mohamed Adel; Saleh, Said Abdel-Aty; Maher, Mohammad Ahmed; Khidre, Asmaa Mohamed

    2017-03-27

    To assess efficacy and tolerability of sildenafil citrate on utero-placental blood flow and fetal growth in pregnancies complicated by fetal growth restriction (FGR). From March 2015, a randomized controlled trial of 54 patients at 24 weeks or more complicated by FGR and abnormal Doppler indices were randomly allocated 1:1 into an intervention arm (receive sildenafil citrate, 50 mg) or a control arm (receive placebo). The primary outcomes were changes occurred in the Doppler parameters 2 h following drug administration. Baseline characteristics were similar between groups. Significant difference was observed in the Delta uterine and umbilical Doppler indices among sildenafil group as compared to placebo group (p < 0.001). Middle cerebral Doppler indices, however, decreased significantly after sildenafil, which could be the result of shifting more blood to improve the utero-placental perfusion. No difference regarding Delta cerebro-placental ratio among both groups (p = 0.979). Sildenafil was also associated with pregnancy prolongation (p = .0001), increased gestational age at delivery (p = .004), improved neonatal weight (p = .0001), and less admission to neonatal intensive care unit (p = .03). No adverse effects reported in both treatment arms. Sildenafil citrate, by its vasodilator effect, can improve utero-placental blood flow in pregnancies complicated by FGR and abnormal Doppler. gov Registry: NCT02362399.

  5. 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. © The Author(s) 2015.

  6. Dietary interventions for fetal growth restriction - therapeutic potential of dietary nitrate supplementation in pregnancy.

    PubMed

    Cottrell, Elizabeth; Tropea, Teresa; Ormesher, Laura; Greenwood, Susan; Wareing, Mark; Johnstone, Edward; Myers, Jenny; Sibley, Colin

    2017-08-01

    Fetal growth restriction (FGR) affects around 5% of pregnancies and is associated with significant short- and long-term adverse outcomes. A number of factors can increase the risk of FGR, one of which is poor maternal diet. In terms of pathology, both clinically and in many experimental models of FGR, impaired uteroplacental vascular function is implicated, leading to a reduction in the delivery of oxygen and nutrients to the developing fetus. Whilst mechanisms underpinning impaired uteroplacental vascular function are not fully understood, interventions aimed at enhancing nitric oxide (NO) bioavailability remain a key area of interest in obstetric research. In addition to endogenous NO production from the amino acid l-arginine, via nitric oxide synthase (NOS) enzymes, research in recent years has established that significant NO can be derived from dietary nitrate, via the 'alternative NO pathway'. Dietary nitrate, abundant in green leafy vegetables and beetroot, can increase NO bioactivity, conferring beneficial effects on cardiovascular function and blood flow. Given the beneficial effects of dietary nitrate supplementation to date in non-pregnant humans and animals, current investigations aim to assess the therapeutic potential of this approach in pregnancy to enhance NO bioactivity, improve uteroplacental vascular function and increase fetal growth. © 2017 The Authors. The Journal of Physiology © 2017 The Physiological Society.

  7. [Complications due to malnutrition and intrauterine growth restriction in preterm newborns].

    PubMed

    Arteaga-Mancera, Mayra Patricia; Rendón-Macías, Mario Enrique; Iglesias-Leboreiro, José; Bernárdez-Zapata, Isabel; Ortiz-Maldonado, Francisco

    2014-01-01

    To analyze neonatal complications in preterm infants with or without previous diagnosis of intrauterine growth restriction (IUGR) and malnutrition at birth. We integrated four preterm cohorts: IUGR and malnourished at birth (n = 24), IUGR without malnutrition (n = 22), without IUGR and malnourished (n = 43), and with proper weight without IUGR (n = 224). Nutritional status was determined by weighted index adjusted for weeks of gestation and fetal ultrasound IUGR. Apgar, type of resuscitation, neonatal morbidities, and hospital days of stay were analyzed at birth. Malnutrition was observed more frequently in infants with preeclamptic or eclamptic mothers, or in multiple pregnancies. There were no differences in birth conditions between groups. There were more complications in cohorts of infants with IUGR, but even more if they had malnutrition as well. Infants with IUGR adjusted for gestational age had more days of hospital stay, without differences regarding their nutritional status. In preterm infants, important growth impairments at birth (malnutrition) after being diagnosed with IUGR increase the likelihood of neonatal complications.

  8. Effect of corticosteroids on cardiac function in growth-restricted fetuses.

    PubMed

    Pedersen, L H; Mogra, R; Hyett, J

    2016-08-01

    To determine the acute effects of corticosteroids on the cardiovascular system in growth-restricted fetuses. This was a prospective cohort study conducted at a tertiary hospital between January 2011 and October 2013. Fetal cardiovascular function in fetuses with intrauterine growth restriction (IUGR) was assessed immediately before and 24 h after the first dose of betamethasone, administered in routine management of IUGR. Fetal arterial and venous Dopplers were assessed. Fetal cardiac function was evaluated by tissue Doppler echocardiography, with the assessment of both left and right ventricular function by calculating myocardial performance index (MPI') and E':A' ratios. Values were compared before and after exposure. Seventeen patients were included at a mean gestational age of 34 + 1 (range, 29 + 1 to 37 + 4) weeks. Fifteen fetuses were below the 5(th) percentile and two were below the 10(th) percentile for estimated fetal weight and abdominal circumference and all had no interval growth during a 2-week period. There was a decrease in right MPI' (from 0.56 to 0.47; P = 0.007) after corticosteroid exposure but no change in left MPI' (from 0.49 to 0.48). Right MPI' was higher than left MPI' before exposure (0.56 vs 0.49, respectively; P = 0.001), but not after exposure (P = 0.55). There was no change in left or right ventricular E':A' ratios and no difference was detected in umbilical artery, middle cerebral artery or ductus venosus pulsatility index following administration of corticosteroids. Corticosteroids altered right-sided, but not left-sided, tissue Doppler MPI' in IUGR fetuses, with no detectable change in arterial or venous Doppler pulsatility indices. Before exposure, the mean right MPI' was higher than the left. However, after exposure, there was no difference, suggesting that corticosteroids may reverse the negative effect of IUGR on fetal heart function. Large prospective studies with a larger sample size are needed to

  9. Impaired Cerebellar Maturation, Growth Restriction, and Circulating Insulin-Like Growth Factor 1 in Preterm Rabbit Pups.

    PubMed

    Sveinsdóttir, Kristbjörg; Länsberg, John-Kalle; Sveinsdóttir, Snjólaug; Garwicz, Martin; Ohlsson, Lennart; Hellström, Ann; Smith, Lois; Gram, Magnus; Ley, David

    2017-10-04

    Cerebellar growth is impeded following very preterm birth in human infants and the observed reduction in cerebellar volume is associated with neurodevelopmental impairment. Decreased levels of circulating insulin-like growth factor 1 (IGF-1) are associated with decreased cerebellar volume. The relationship between preterm birth, circulating IGF-1, and key cell populations supporting cerebellar proliferation is unknown. The aim of this study was to evaluate the effect of preterm birth on postnatal growth, circulating IGF-1, and cerebellar maturation in a preterm rabbit pup model. Preterm rabbit pups (PT) were delivered by cesarean section at day 29 of gestation, cared for in closed incubators with humidified air, and gavage fed with formula. Control term pups (T) delivered by spontaneous vaginal delivery at day 32 of gestation were housed and fed by their lactating doe. In vivo perfusion-fixation for immunohistochemical evaluation of cerebellar proliferation, cell maturation, and apoptosis was performed at repeated time points in PT and T pups. Results show that the mean weight of the pups and circulating IGF-1 protein levels were lower in the PT group at all time points (p < 0.05) than in the T group. Postnatal weight development correlated with circulating IGF-1 (r2 = 0.89) independently of gestational age at birth and postnatal age. The proliferative (Ki-67-positive) portion of the external granular layer (EGL) was decreased in the PT group at postnatal day 2 (P2) compared to in the T group (p = 0.01). Purkinje cells exhibited decreased calbindin staining at P0 (p = 0.003), P2 (p = 0.004), and P5 (p = 0.04) in the PT group compared to in the T group. Staining for sonic hedgehog was positive in neuronal EGL progenitors and Purkinje cells at early time points but was restricted to a well-defined Purkinje cell monolayer at later time points. Preterm birth in rabbit pups is associated with lower circulating levels of IGF-1, decreased postnatal growth, and decreased

  10. Growth and development of house sparrows (Passer domesticus) in response to chronic food restriction throughout the nestling period.

    PubMed

    Killpack, Tess L; Karasov, William H

    2012-06-01

    Birds have evolved phenotypic plasticity in growth and developmental patterns in order to respond to fluctuating environmental conditions and to mitigate the impact of poor feeding on fitness. Chronic food shortage can occur during chick development in the wild, and the responses of altricial birds have not been thoroughly studied. House sparrow (Passer domesticus) nestlings were raised in the laboratory on age-specific meal sizes (controls) or meal sizes 25% less than age-specific amounts (food-restricted) and analyzed at 6, 9 and 12 days post-hatch for differences in growth and development. Food-restricted birds had significantly reduced body mass and body temperature, but skeletal growth was maintained with respect to controls. Muscle mass was significantly reduced and muscle water content was slightly, though not significantly, higher in food-restricted birds, which may reflect slight developmental immaturity. Assimilation organ masses, summed enzymatic capacity of the intestine and lipid content of the liver were significantly reduced in food-restricted birds. Findings from this study indicate that altricial birds experiencing chronic, moderate food restriction throughout the nestling period may allocate resources to structural growth through energy-saving reductions in mass of assimilation organs and body temperature.

  11. 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

  12. Fibroblast growth factor 2 is required for epithelial recovery, but not for pulmonary fibrosis, in response to bleomycin.

    PubMed

    Guzy, Robert D; Stoilov, Ivan; Elton, Timothy J; Mecham, Robert P; Ornitz, David M

    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.

  13. 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

  14. CXCR4-mediated osteosarcoma growth and pulmonary metastasis is promoted by mesenchymal stem cells through VEGF.

    PubMed

    Zhang, Peng; Dong, Ling; Yan, Kang; Long, Hua; Yang, Tong-Tao; Dong, Ming-Qing; Zhou, Yong; Fan, Qing-Yu; Ma, Bao-An

    2013-10-01

    Chemokines and chemokine receptor 4 (CXCR4) play an important role in metastasis. CXCR4 is also expressed in the human osteosarcoma cell line 9607-F5M2 (F5M2), which has a high tumorigenic ability and potential for spontaneous pulmonary metastasis. Mesenchymal stem cells (MSCs) contribute to the formation of the tumor stroma and promote metastasis. However, mechanisms underlying the promotion of osteosarcoma growth and pulmonary metastasis by MSCs are still elusive. Our study co-injected the human MSCs and F5M2 cells into the caudal vein of nude mice. The total number of tumor nodules per lung was significantly increased in the F5M2+MSC group compared to the other groups (control, F5M2 cells alone and MSCs alone) at week six. Moreover, a high number of Dil-labeled MSCs was present also at the osteosarcoma metastasis sites in the lung. Using Transwell assays, we found that F5M2 cells migrate towards MSCs, while the CXCR4 inhibitor AMD3100 decreased the migration potential of F5M2 cells towards MSCs. Furthermore, upon treatment with F5M2-conditioned medium, MSCs expressed and secreted higher levels of VEGF as determined by immunohistochemistry, western blotting and ELISA, respectively. Importantly, co-cultured with F5M2 cells, MSCs expressed and secreted higher VEGF levels, while AMD3100 dramatically decreased the VEGF secretion by MSCs. However, CXCR4 expression on F5M2 cells was not significantly increased in the co-culture system. Additionally, VEGF increased the proliferation of both MSCs and F5M2 cells. These findings suggest that CXCR4-mediated osteosarcoma growth and pulmonary metastasis are promoted by MSCs through VEGF.

  15. 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

  16. 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.

  17. The effect of caloric restriction interventions on growth hormone secretion in nonobese men and women.

    PubMed

    Redman, Leanne M; Veldhuis, Johannes D; Rood, Jennifer; Smith, Steven R; Williamson, Donald; Ravussin, Eric

    2010-02-01

    Lifespan in rodents is prolonged by caloric restriction (CR) and by mutations affecting the somatotropic axis. It is not known if CR can alter the age-associated decline in growth hormone (GH), insulin-like growth factor (IGF)-1 and GH secretion. To evaluate the effect of CR on GH secretory dynamics; forty-three young (36.8 +/- 1.0 years), overweight (BMI 27.8 +/- 0.7) men (n = 20) and women (n = 23) were randomized into four groups; control = 100% of energy requirements; CR = 25% caloric restriction; CR + EX = 12.5% CR + 12.5% increase in energy expenditure by structured exercise; LCD = low calorie diet until 15% weight reduction followed by weight maintenance. At baseline and after 6 months, body composition (DXA), abdominal visceral fat (CT) 11 h GH secretion (blood sampling every 10 min for 11 h; 21:00-08:00 hours) and deconvolution analysis were measured. After 6 months, weight (control: -1 +/- 1%, CR: -10 +/- 1%, CR + EX: -10 +/- 1%, LCD: -14 +/- 1%), fat mass (control: -2 +/- 3%, CR: -24 +/- 3%, CR + EX: -25 +/- 3%, LCD: -31 +/- 2%) and visceral fat (control: -2 +/- 4%, CR: -28 +/- 4%, CR + EX: -27 +/- 3%, LCD: -36 +/- 2%) were significantly (P < 0.001) reduced in the three intervention groups compared to control. Mean 11 h GH concentrations were not changed in CR or control but increased in CR + EX (P < 0.0001) and LCD (P < 0.0001) because of increased secretory burst mass (CR + EX: 34 +/- 13%, LCD: 27 +/- 22%, P < 0.05) and amplitude (CR + EX: 34 +/- 14%, LCD: 30 +/- 20%, P < 0.05) but not to changes in secretory burst frequency or GH half-life. Fasting ghrelin was significantly increased from baseline in all three intervention groups; however, total IGF-1 concentrations were increased only in CR + EX (10 +/- 7%, P < 0.05) and LCD (19 +/- 4%, P < 0.001). A 25% CR diet for 6 months does not change GH, GH secretion or IGF-1 in nonobese men and women.

  18. Relationship between arterial and venous Doppler and perinatal outcome in fetal growth restriction.

    PubMed

    Baschat, A A; Gembruch, U; Reiss, I; Gortner, L; Weiner, C P; Harman, C R

    2000-10-01

    The aim of this investigation was to assess the relationship between abnormal arterial and venous Doppler findings and perinatal outcome in fetuses with intrauterine growth restriction (IUGR). Doppler velocimetry of the umbilical artery (UA), middle cerebral artery (MCA), inferior vena cava (IVC), ductus venosus (DV) and free umbilical vein was performed in 121 IUGR fetuses with a UA pulsatility index (PI) > 2 SD above the gestational age mean and subsequent birth weight < 10th centile for gestational age. Groups based on the last Doppler exam were: 1 = abnormal UA-PI only (n = 42, 34.7%), 2 = MCA-PI > 2 SD below the gestational age mean (= 'brain sparing') in addition to abnormal UA-PI (n = 29, 24.0%), 3 = DV or IVC peak velocity index (PVIV) > 2 SD above the gestational age mean and/or pulsatile UV flow (n = 50, 41.3%). Z-scores (delta indices) were calculated for Doppler indices. Perinatal mortality, respiratory distress (RDS), bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), necrotizing enterocolitis (NEC), circulatory failure and umbilical artery blood gases were recorded. Absence or reversal of umbilical artery end-diastolic flow was observed in 4 (9.5%) of fetuses in group 1, 10 (34.5%) fetuses in group 2 and 41 (82%) fetuses in group 3. A low middle cerebral artery pulsatility index was found in 39 (78%) fetuses in group 3. Multiple regression analysis with gestational age at delivery, delta indices and cord artery blood gas as independent parameters and individual perinatal outcomes as dependent variables was performed. In this analysis the association was strongest with gestational age for each complication. There were no significant differences in Apgar scores between groups. At delivery, 'brain sparing' was associated with hypoxemia and abnormal venous flows with acidemia. Perinatal mortality was highest in group 3 and stillbirth was only observed when venous flow was abnormal. All postpartum complications were more frequent in

  19. [Intrauterine growth restriction: endocrinological perspective. Update of the 2007 version (Arch Argent Pediatr 2007;105(1):71-73)].

    PubMed

    2017-06-01

    Most children born with low weight or intrauterine growth restriction develop catch-up growth that allows them to reach a final height according to their genetic target height. However, in about 15% of children this growth is insufficient. In both, children who have adequate compensatory growth and therefore normal height and children who remain low in childhood, it is necessary to take into account that if puberty starts early, the final height could be compromised. Timely and appropriate intervention could improve it. Control of body weight is also important, as an excessive gain in childhood is associated with metabolic complications in adolescence and adult life. Sociedad Argentina de Pediatría.

  20. [Effect of positive nutritional support strategy on extrauterine growth restriction in preterm infants].

    PubMed

    Wang, Xue-Min; Zhu, Yan-Ping; Wang, Li

    2013-12-01

    To investigate the effects of positive nutritional support in the early stage after birth on the nutritional status during hospitalization and extrauterine growth restriction (EUGR) in preterm infants. There were two groups of preterm infants. Group A (n=99) was given the previous nutritional program, while group B (n=101) was given positive nutritional support. The nutritional intake, growth rate and EUGR incidence were compared between the two groups. Compared with group A, group B had significantly higher enteral calorie intake and total calorie intake within one week after birth. Additionally, the age of first feeding, time of regaining birth weight, duration of intravenous nutrition, time to full enteral feeding, and length of hospital stay in group B were all shorter than in group A. Group B also had less physiological weight loss than group A. Among the preterm infants with a gestational age less than 32 weeks, group B had faster increases in body weight, head circumference, and body length and a lower incidence of EUGR compared with group A. Among the preterm infants with a gestational age not less than 32 weeks, group B had faster increases in body weight and a lower incidence of EUGR (evaluated based on body weight and head circumference) compared with group A. During hospitalization, group B had significantly lower incidence of feeding intolerance, necrotizing enterocolitis, and sepsis than group A. Positive nutritional support strategy, applied in preterm infants early after birth, can effectively improve their nutritional status during hospitalization and reduce the incidence of EUGR without increasing the incidence of related complications during hospitalization.

  1. 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.

  2. Myocardial macronutrient transporter adaptations in the adult pregestational female intrauterine and postnatal growth-restricted offspring

    PubMed Central

    Abbasi, Afshan; Thamotharan, Manikkavasagar; Shin, Bo-Chul; Jordan, Maria C.; Roos, Kenneth P.; Stahl, Andreas

    2012-01-01

    Associations between exponential childhood growth superimposed on low birth weight and adult onset cardiovascular disease with glucose intolerance/type 2 diabetes mellitus exist in epidemiological investigations. To determine the metabolic adaptations that guard against myocardial failure on subsequent exposure to hypoxia, we compared with controls (CON), the effect of intrauterine (IUGR), postnatal (PNGR), and intrauterine and postnatal (IPGR) calorie and growth restriction (n = 6/group) on myocardial macronutrient transporter (fatty acid and glucose) -mediated uptake in pregestational young female adult rat offspring. A higher myocardial FAT/CD36 protein expression in IUGR, PNGR, and IPGR, with higher FATP1 in IUGR, FATP6 in PNGR, FABP-c in PNGR and IPGR, and no change in GLUT4 of all groups was observed. These adaptive macronutrient transporter protein changes were associated with no change in myocardial [3H]bromopalmitate accumulation but a diminution in 2-deoxy-[14C]glucose uptake. Examination of the sarcolemmal subfraction revealed higher basal concentrations of FAT/CD36 in PNGR and FATP1 and GLUT4 in IUGR, PNGR, and IPGR vs. CON. Exogenous insulin uniformly further enhanced sarcolemmal association of these macronutrient transporter proteins above that of basal, with the exception of insulin resistance of FATP1 and GLUT4 in IUGR and FAT/CD36 in PNGR. The basal sarcolemmal macronutrient transporter adaptations proved protective against subsequent chronic hypoxic exposure (7 days) only in IUGR and PNGR, with notable deterioration in IPGR and CON of the echocardiographic ejection fraction. We conclude that the IUGR and PNGR pregestational adult female offspring displayed a resistance to insulin-induced translocation of FATP1, GLUT4, or FAT/CD36 to the myocardial sarcolemma due to preexistent higher basal concentrations. This basal adaptation of myocardial macronutrient transporters ensured adequate fatty acid uptake, thereby proving protective against chronic

  3. Myocardial macronutrient transporter adaptations in the adult pregestational female intrauterine and postnatal growth-restricted offspring.

    PubMed

    Abbasi, Afshan; Thamotharan, Manikkavasagar; Shin, Bo-Chul; Jordan, Maria C; Roos, Kenneth P; Stahl, Andreas; Devaskar, Sherin U

    2012-06-01

    Associations between exponential childhood growth superimposed on low birth weight and adult onset cardiovascular disease with glucose intolerance/type 2 diabetes mellitus exist in epidemiological investigations. To determine the metabolic adaptations that guard against myocardial failure on subsequent exposure to hypoxia, we compared with controls (CON), the effect of intrauterine (IUGR), postnatal (PNGR), and intrauterine and postnatal (IPGR) calorie and growth restriction (n = 6/group) on myocardial macronutrient transporter (fatty acid and glucose) -mediated uptake in pregestational young female adult rat offspring. A higher myocardial FAT/CD36 protein expression in IUGR, PNGR, and IPGR, with higher FATP1 in IUGR, FATP6 in PNGR, FABP-c in PNGR and IPGR, and no change in GLUT4 of all groups was observed. These adaptive macronutrient transporter protein changes were associated with no change in myocardial [(3)H]bromopalmitate accumulation but a diminution in 2-deoxy-[(14)C]glucose uptake. Examination of the sarcolemmal subfraction revealed higher basal concentrations of FAT/CD36 in PNGR and FATP1 and GLUT4 in IUGR, PNGR, and IPGR vs. CON. Exogenous insulin uniformly further enhanced sarcolemmal association of these macronutrient transporter proteins above that of basal, with the exception of insulin resistance of FATP1 and GLUT4 in IUGR and FAT/CD36 in PNGR. The basal sarcolemmal macronutrient transporter adaptations proved protective against subsequent chronic hypoxic exposure (7 days) only in IUGR and PNGR, with notable deterioration in IPGR and CON of the echocardiographic ejection fraction. We conclude that the IUGR and PNGR pregestational adult female offspring displayed a resistance to insulin-induced translocation of FATP1, GLUT4, or FAT/CD36 to the myocardial sarcolemma due to preexistent higher basal concentrations. This basal adaptation of myocardial macronutrient transporters ensured adequate fatty acid uptake, thereby proving protective against

  4. 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

  5. First-trimester adiponectin and subsequent development of preeclampsia or fetal growth restriction.

    PubMed

    Valdés, Enrique R; Lattes, Karinna A; Muñoz, Hernán S; Barja, Pilar Y; Papapietro, Karin V

    2011-01-01

    The evidence regarding the utility of assessing first-trimester adiponectin (ApN) serum levels in early prediction of preeclampsia (PE) and fetal growth restriction (FGR) is contradictory. This study aims to determine the role of maternal serum ApN levels as an early predictor of PE and FGR. A prospective case-control study among a pregnant population who attended their 11- to 14-week ultrasound scan at the University of Chile's Clinical Hospital's Fetal Medicine Unit. We included patients who developed PE or FGR (10 cases per group) and 35 healthy controls. We determined ApN levels in blood samples from these 55 patients using a commercial ELISA kit and assessed the relationship of ApN levels with variables like development of PE, FGR, weight at birth and maternal BMI. There were no significant differences among first-trimester ApN serum levels in the groups. Average concentrations were 8, 6.8 and 10.8 ng/ml for the control, PE and FGR groups, respectively. In our study, maternal serum ApN levels were not useful in predicting subsequent development of PE and FGR. However, maternal serum ApN concentration adjusted by BMI was significantly higher during the first trimester in women who later developed FGR. Copyright © 2011 S. Karger AG, Basel.

  6. Suspected Fetal Growth Restriction at 37 Weeks: A Comparison of Doppler and Placental Pathology

    PubMed Central

    Millington, Karmaine A.; Ibekwe, Tochi O.; Ural, Serdar H.

    2017-01-01

    Objective. Our objective was determining if abnormal Doppler evaluation had a higher prevalence of placental pathology compared to normal Doppler in suspected fetal growth restriction (FGR) of cases delivered at 37 weeks. Study Design. This retrospective cohort study of suspected FGR singletons with antenatal Doppler evaluation delivered at 37 weeks had a primary outcome of the prevalence of placental pathology related to FGR. Significance was defined as p ≤ 0.05. Results. Of 100 pregnancies 46 and 54 were in the abnormal and normal Doppler cohorts, respectively. Placental pathology was more prevalent with any abnormal Doppler, 84.8% versus 55.6%, odds ratio (OR) 4.46, 95% confidence interval (CI): 1.55, 13.22, and p = 0.002. Abnormal middle cerebral artery (MCA) Doppler had a higher prevalence: 96.2% versus 54.8%, OR 20.7, 95% CI: 2.54, 447.1, and p < 0.001. Conclusion. Abnormal Doppler was associated with more placental pathology in comparison to normal Doppler in fetuses with suspected FGR. Abnormal MCA Doppler had the strongest association. PMID:28409154

  7. Cysteinylation of maternal plasma albumin and its association with intrauterine growth restriction.

    PubMed

    Bar-Or, David; Heyborne, Kent D; Bar-Or, Raphael; Rael, Leonard T; Winkler, James V; Navot, Daniel

    2005-03-01

    We investigated cysteinylation of maternal plasma albumin in an observational study of intrauterine growth restriction (IUGR). High-risk pregnancies and uteroplacental insufficiency (UPI) have been associated with elevated levels of homocysteine, and, in oxidizing environments, homocysteine is converted to cysteine, resulting in cysteinylation of proteins. The study population included pregnancies with IUGR (n = 12) and uncomplicated pregnancies as controls (n = 8). In all cases, cysteinylation of maternal plasma albumin was measured in a blinded fashion using liquid chromatography coupled with electrospray ionization mass spectrometry. Markedly elevated maternal plasma levels of cysteinylated albumin were detected in pregnancies with IUGR (44.7 +/- 14.8% of total albumin) compared to those in normal pregnancies (20.9 +/- 6.1%). As a result, native albumin decreased from 52.5 +/- 6.5% of total albumin in normal pregnancies to 30.1 +/- 13.3% in IUGR pregnancies. We hypothesize that sustained oxidative stress present in UPI is reflected by high levels of maternal cysteinylated albumin and may be a factor in the etiology of IUGR. Results of this preliminary study suggest that measurement of maternal plasma cysteinylated albumin may be useful for monitoring pregnancies associated with UPI and for detection of IUGR. Copyright 2005 John Wiley & Sons, Ltd.

  8. 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.

  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. Intestinal proteomics in pig models of necrotising enterocolitis, short bowel syndrome and intrauterine growth restriction.

    PubMed

    Jiang, Pingping; Sangild, Per Torp

    2014-10-01

    Necrotising enterocolitis (NEC), short bowel syndrome (SBS) and intrauterine growth restriction (IUGR) are three conditions associated with intestinal dysfunction in newborn infants, particularly those born preterm. Piglet (Sus scrofa) models have recently been developed for NEC, SBS and IUGR, and tissue proteomic analyses have identified unknown pathways and new prognostic disease markers. Intestinal HSPs, iron metabolism proteins and proteins related to amino acid (e.g. arginine) and glucose metabolism are consistently affected by NEC progression and some of these proteins are also affected by SBS and IUGR. Parallel changes in some plasma and urinary proteins (e.g. haptoglobin, globulins, complement proteins, fatty acid binding proteins) may mirror the intestinal responses and pave the way to biomarker discovery. Explorative non-targeted proteomics provides ideas about the cellular pathways involved in intestinal adaptation during the critical neonatal period. Proteomics, combined with other -omic techniques, helps to get a more holistic picture of intestinal adaptation during NEC, SBS and IUGR. Explorative -omic research methods also have limitations and cannot replace, but only supplement, classical hypothesis-driven research that investigate disease mechanisms using a single or few endpoints.

  11. Early onset of fatty liver in growth restricted rat fetuses and newborns

    PubMed Central

    Yamada, Makiko; Wolfe, Diana; Han, Guang; French, Samuel W.; Ross, Michael G.; Desai, Mina

    2011-01-01

    Intrauterine growth restricted (IUGR) newborns have increased risk of adult metabolic syndrome, including fatty liver. However, it is unclear whether the fatty liver development is “programmed” or secondary to the accompanying obesity. In this study, we examined hepatic lipid accumulation and lipid-regulatory factors (sterol regulatory element-binding protein-1c and fatty acid synthase) in IUGR and Control fetal (embryonic day 20; e20) and newborn (postnatal day 1; p1) rat pups. Notably, despite of in utero undernutrition state, IUGR fetuses demonstrated ‘fatty liver’ with upregulation of these lipogenic indices at as early as e20. Both IUGR and Control newborns exhibited the same extent of massive increase in hepatic lipid content whereas IUGR newborns continued to exhibit upregulated lipogenic indices. The persistent upregulation of the lipogenic indices in fetal and newborn IUGR suggests that fatty liver is gestationally programmed. Our study suggested that IUGR offspring were born with an altered metabolic life strategy of increased fuel/lipid storage which could be a distinct metabolic pathway of the thrifty phenotype. PMID:22103455

  12. NLRP3 Deficiency Improves Angiotensin II-Induced Hypertension But Not Fetal Growth Restriction During Pregnancy.

    PubMed

    Shirasuna, Koumei; Karasawa, Tadayoshi; Usui, Fumitake; Kobayashi, Motoi; Komada, Tadanori; Kimura, Hiroaki; Kawashima, Akira; Ohkuchi, Akihide; Taniguchi, Shun'ichiro; Takahashi, Masafumi

    2015-11-01

    Preeclampsia is a pregnancy-specific syndrome characterized by elevated blood pressure, proteinuria, and intrauterine growth restriction (IUGR). Although sterile inflammation appears to be involved, its pathogenesis remains unclear. Recent evidence indicates that sterile inflammation is mediated through the nucleotide-binding oligomerization domain-like receptor family pyrin domain-containing 3 (NLRP3) inflammasomes, composed of NLRP3, apoptosis-associated speck-like protein containing a caspase recruitment domain (ASC), and caspase-1. Here we investigated the role of the NLRP3 inflammasomes in the pathogenesis of preeclampsia using Nlrp3(-/-) and Asc(-/-) (Nlrp3 and Asc deficient) pregnant mice. During pregnancy in mice, continuous infusion of high-dose angiotensin II (AngII) induced hypertension, proteinuria, and IUGR, whereas infusion of low-dose AngII caused hypertension alone. AngII-induced hypertension was prevented in Nlrp3(-/-) mice but not in Asc(-/-), indicating that NLRP3 contributes to gestational hypertension independently of ASC-mediated inflammasomes. Although NLRP3 deficiency had no effect on IUGR, it restored the IL-6 up-regulation in the placenta and kidney of AngII-infused mice. Furthermore, treatment with hydralazine prevented the development of gestational hypertension but not IUGR or IL-6 expression in the placenta and kidney. These findings demonstrate that NLRP3 contributes to the development of gestational hypertension independently of the inflammasomes and that IUGR and kidney injury can occur independent of blood pressure elevation during pregnancy.

  13. Quantification of mechanical dyssynchrony in growth restricted fetuses and normal controls using speckle tracking echocardiography (STE).

    PubMed

    Krause, Kristina; Möllers, Mareike; Hammer, Kerstin; Falkenberg, Maria Karina; Möllmann, Ute; Görlich, Dennis; Klockenbusch, Walter; Schmitz, Ralf

    2017-10-26

    To evaluate longitudinal mechanical dyssynchrony in normally grown fetuses by speckle tracking echocardiography (STE) and to compare longitudinal mechanical dyssynchrony in fetal growth restriction (FGR) with normal controls. A prospective study was performed on 30 FGR and 62 normally grown fetuses, including 30 controls matched by gestational age, using STE and a transversal four-chamber view. Data analysis was carried out with a high frame rate of about 175 frames/s. Dyssynchrony was analyzed offline with QLab 9 (Philips Medical Systems, Andover, MA, USA) as time differences between peaks in strain of both ventricles and the septum. Inter- and intraventricular and intraseptal dyssynchrony were obtained and inter- and intraobserver reliability was analyzed. Longitudinal mechanical dyssynchrony was feasible in all cases, with high inter- and intraobserver reliability. Levels of inter- and intraventricular dyssynchrony were higher in the FGR than in the control group. Speckle tracking echocardiography (STE) is a reliable technique for cardiac function assessment in the fetal heart. Interventricular dyssynchrony could be a potential parameter for early detection of subclinical myocardial dysfunction before other parameters demand intervention. The future clinical role of longitudinal mechanical dyssynchrony needs to be verified in larger studies and with a technique customized for prenatal echocardiography.

  14. [Intelligence level and structure in school age children with fetal growth restriction].

    PubMed

    Ma, Jian; Ma, Hong-Wei; Tian, Xiao-Bo; Liu, Fang

    2009-10-01

    To study the intelligence level and structure in school age children with fetal growth restriction (FGR). The intelligence levels were tested by the Wechsler Children Scales of Intelligence (C-WISC) in 54 children with FGR and in 84 normal children. The full intelligence quotient (FIQ), verbal IQ (VIQ) and performance IQ (PIQ) in the FGR group were 105.9+/-10.3, 112.4+/-11.2 and 97.1+/-10.6 respectively, and they all were in a normal range. But the PIQ was significantly lower than that in the control group (104.8+/-10.5; p<0.001), and the picture arrangement and the decipher subtest scores were significantly lower than those in the control group (p<0.01). The scores of perception/organization and memory/attention factors in the FGR group were 99.8+/-11.1 and 116.3+/-14.4, respectively, which were inferior to those in the control group (104.6+/-11.5 and 113.4+/-14.5 respectively; p<0.05). The total intelligence level of children with FGR is normal, but there are imbalances in the intelligence structure and dysfunctions in performance ability related to right cerebral hemisphere. Performance trainings should be done from the infancy in children with FGR.

  15. Uterine artery Doppler longitudinal changes in pregnancies complicated with intrauterine growth restriction without preeclampsia.

    PubMed

    Contro, Elena; Cha, Dong Hyun; De Maggio, Irene; Ismail, Sara Yasmin; Falcone, Veronica; Gabrielli, Sandro; Farina, Antonio

    2014-12-01

    The objective of this article is to evaluate the longitudinal changes in uterine artery Doppler pulsatility index (UtA-PI) in pregnancies complicated with early onset intrauterine growth restriction (IUGR). Case-control study comparing UtA-PI from 20 to 34 weeks gestation in pregnancies affected by IUGR at 20 to 28 weeks and confirmed at delivery (cases), matched with 1000 controls. Multivariable analyses were used to estimate the UtA-PI as a function of both gestational age and IUGR severity. Finally, bootstrapping technique was used to internally validate the models. We retrospectively retrieved 53 cases and 1000 controls. Regression line having log10 UtA-PI as dependent variable was a function of both gestational age and IUGR. UtA-PI decreased with gestational age in both groups. In IUGR group, UtA-PI was higher from 20 weeks onward and the difference with controls increased with gestational age. In fact, at 20 weeks, the UtA-PI ratio between cases and controls was 1.84, but at 30 weeks it rose to 2.05. Finally, the weight at delivery in the IUGR group was also inversely correlated with the UtA-PI values. We presented a reliable multivariable statistical model to evaluate the temporal changes of UtA-PI values as a function of both gestational age and IUGR. © 2014 John Wiley & Sons, Ltd.

  16. Early onset of fatty liver in growth-restricted rat fetuses and newborns.

    PubMed

    Yamada, Makiko; Wolfe, Diana; Han, Guang; French, Samuel W; Ross, Michael G; Desai, Mina

    2011-12-01

    Intrauterine growth-restricted (IUGR) newborns have increased risk of adult metabolic syndrome, including fatty liver. However, it is unclear whether the fatty liver development is "programmed" or secondary to the accompanying obesity. In this study, we examined hepatic lipid accumulation and lipid-regulatory factors (sterol regulatory element-binding protein-1c and fatty acid synthase) in IUGR and Control fetal (embryonic day 20; e20) and newborn (postnatal day 1; p1) rat pups. Notably, despite of in utero undernutrition state, IUGR fetuses demonstrated "fatty liver" with upregulation of these lipogenic indices at as early as e20. Both IUGR and Control newborns exhibited the same extent of massive increase in hepatic lipid content, whereas IUGR newborns continued to exhibit upregulated lipogenic indices. The persistent upregulation of the lipogenic indices in fetal and newborn IUGR suggests that fatty liver is gestationally programmed. Our study suggested that IUGR offspring were born with an altered metabolic life strategy of increased fuel/lipid storage which could be a distinct metabolic pathway of the thrifty phenotype.

  17. Management of Very Early-onset Fetal Growth Restriction: Results from 92 Consecutive Cases.

    PubMed

    Hoellen, Friederike; Beckmann, Annika; Banz-Jansen, Constanze; Weichert, Jan; Rody, Achim; Bohlmann, Michael K

    2016-01-01

    To evaluate management of early-onset intrauterine growth restriction (IUGR) and to define outcome according to obstetric setting. During an 11-year period (2000-2011), data of patients presenting with IUGR and preterm delivery of less than 30 weeks of gestation at a tertiary perinatal center were retrospectively reviewed. A total of 92 pregnancies were investigated. Delivery was indicated for fetal reasons in 38 out of 92 patients. Sixteen children of our cohort died within one year post partum, out of which eight had suffered from severe early-onset IUGR causing iatrogenic preterm delivery. Concerning the fetal outcome, gestational age at delivery and antenatal exposure to corticosteroids were found to be crucial. In some cases, respiratory distress syndrome prophylaxis and a "wait and see" approach to management in favor of a prolongation of the pregnancy might be favorable. Randomized prospective trials in early-onset IUGR with threatened preterm deliveries are needed in order to define guidelines for an individually tailored management of early-onset preterm infants. Copyright © 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.

  18. Sex and intrauterine growth restriction modify brain neurotransmitters profile of newborn piglets.

    PubMed

    Vázquez-Gómez, M; Valent, D; García-Contreras, C; Arroyo, L; Óvilo, C; Isabel, B; Bassols, A; González-Bulnes, A

    2016-12-01

    The current study aimed to determine, using a swine model of intrauterine growth restriction (IUGR), whether short- and long-term neurological deficiencies and interactive dysfunctions of Low Birth-Weight (LBW) offspring might be related to altered pattern of neurotransmitters. Hence, we compared the quantities of different neurotransmitters (catecholamines and indoleamines), which were determined by HPLC, at brain structures related to the limbic system (hippocampus and amygdala) in 14 LBW and 10 Normal Body-Weight (NBW) newborn piglets. The results showed, firstly, significant effects of sex on the NBW newborns, with females having higher dopamine (DA) concentrations than males. The IUGR processes affected DA metabolism, with LBW piglets having lower concentrations of noradrenaline at the hippocampus and higher concentrations of the DA metabolites, homovanillic acid (HVA), at both the hippocampus and the amygdala than NBW neonates. The effects of IUGR were modulated by sex; there were no significant differences between LBW and NBW females, but LBW males had higher HVA concentration at the amygdala and higher concentration of 5-hydroxyindoleacetic acid, the serotonin metabolite, at the hippocampus than NBW males. In conclusion, the present study shows that IUGR is mainly related to changes, modulated by sex, in the concentrations of catecholamine neurotransmitters, which are related to adaptation to physical activity and to essential cognitive functions such as learning, memory, reward-motivated behavior and stress.

  19. Receptor Polymorphism Restricts Contact-Dependent Growth Inhibition to Members of the Same Species

    PubMed Central

    Ruhe, Zachary C.; Wallace, Adam B.; Low, David A.; Hayes, Christopher S.

    2013-01-01

    ABSTRACT Bacteria that express contact-dependent growth inhibition (CDI) systems outcompete siblings that lack immunity, suggesting that CDI mediates intercellular competition. To further explore the role of CDI in competition, we determined the target cell range of the CDIEC93 system from Escherichia coli EC93. The CdiAEC93 effector protein recognizes the widely conserved BamA protein as a receptor, yet E. coli EC93 does not inhibit other enterobacterial species. The predicted membrane topology of BamA indicates that three of its extracellular loops vary considerably between species, suggesting that loop heterogeneity may control CDI specificity. Consistent with this hypothesis, other enterobacteria are sensitized to CDIEC93 upon the expression of E. coli bamA and E. coli cells become CDIEC93 resistant when bamA is replaced with alleles from other species. Our data indicate that BamA loops 6 and 7 form the CdiAEC93-binding epitope and their variation between species restricts CDIEC93 target cell selection. Although BamA loops 6 and 7 vary dramatically between species, these regions are identical in hundreds of E. coli strains, suggesting that BamAEcoli and CdiAEC93 play a role in self-nonself discrimination. PMID:23882017

  20. Differential Effects of Intrauterine Growth Restriction on the Regional Neurochemical Profile of the Developing Rat Brain.

    PubMed

    Maliszewski-Hall, Anne M; Alexander, Michelle; Tkáč, Ivan; Öz, Gülin; Rao, Raghavendra

    2017-01-01

    Intrauterine growth restricted (IUGR) infants are at increased risk for neurodevelopmental deficits that suggest the hippocampus and cerebral cortex may be particularly vulnerable. Evaluate regional neurochemical profiles in IUGR and normally grown (NG) 7-day old rat pups using in vivo (1)H magnetic resonance (MR) spectroscopy at 9.4 T. IUGR was induced via bilateral uterine artery ligation at gestational day 19 in pregnant Sprague-Dawley dams. MR spectra were obtained from the cerebral cortex, hippocampus and striatum at P7 in IUGR (N = 12) and NG (N = 13) rats. In the cortex, IUGR resulted in lower concentrations of phosphocreatine, glutathione, taurine, total choline, total creatine (P < 0.01) and [glutamate]/[glutamine] ratio (P < 0.05). Lower taurine concentrations were observed in the hippocampus (P < 0.01) and striatum (P < 0.05). IUGR differentially affects the neurochemical profile of the P7 rat brain regions. Persistent neurochemical changes may lead to cortex-based long-term neurodevelopmental deficits in human IUGR infants.

  1. Levels of neopterin and C-reactive protein in pregnant women with fetal growth restriction.

    PubMed

    Erkenekli, K; Keskin, U; Uysal, B; Kurt, Y G; Sadir, S; Çayci, T; Ergün, A; Erkaya, S; Danişman, N; Uygur, D

    2015-04-01

    The aim of this study was to evaluate whether pregnant women with fetal growth restriction (FGR) have higher plasma neopterin and C-reactive protein (CRP) concentrations compared with those with uncomplicated pregnancy. A total of 34 pregnant women with FGR and 62 patients with uncomplicated pregnancy were included. Neopterin and CRP levels were measured at the time of diagnosis. The primary outcome of this study was to compare the neopterin and CRP levels in pregnant women with FGR and those with uncomplicated pregnancies. The secondary outcome of our study was to evaluate the correlation between fetal birth weight and maternal neopterin levels. The serum neopterin levels were significantly elevated in pregnant women with FGR (22.71 ± 7.70 vs 19.15 ± 8.32). However, CRP was not elevated in pregnant women with FGR (7.47 ± 7.59 vs 5.29 ± 3.58). These findings support the hypothesis that pregnancy with FGR is associated with a marked increase in macrophage activation and the natural immune system.

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

    PubMed

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

    2016-03-01

    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.

  3. Differences in cortical development assessed by fetal MRI in late-onset intrauterine growth restriction.

    PubMed

    Egaña-Ugrinovic, Gabriela; Sanz-Cortes, Magdalena; Figueras, Francesc; Bargalló, Nuria; Gratacós, Eduard

    2013-08-01

    The objective of the study was to evaluate cortical development parameters by magnetic resonance imaging (MRI) in late-onset intrauterine growth-restricted (IUGR) fetuses and normally grown fetuses. A total of 52 IUGR and 50 control fetuses were imaged using a 3T MRI scanner at 37 weeks of gestational age. T2 half-Fourier acquisition single-shot turbo spin-echo anatomical acquisitions were obtained in 3 planes. Cortical sulcation (fissures depth corrected by biparietal diameter), brain volumetry, and asymmetry indices were assessed by means of manual delineation and compared between cases and controls. Late-onset IUGR fetuses had significantly deeper measurements in the left insula (late-onset IUGR: 0.293 vs control: 0.267; P = .02) and right insula (0.379 vs 0.318; P < .01) and the left cingulate fissure (0.096 vs 0.087; P = .03) and significantly lower intracranial (441.25 cm(3) vs 515.82 cm(3); P < .01), brain (276.47 cm(3) vs 312.07 cm(3); P < .01), and left opercular volumes (2.52 cm(3) vs 3.02 cm(3); P < .01). IUGR fetuses showed significantly higher right insular asymmetry indices. Late-onset IUGR fetuses had a different pattern of cortical development assessed by MRI, supporting the existence of in utero brain reorganization. Cortical development could be useful to define fetal brain imaging-phenotypes characteristic of IUGR. Copyright © 2013 Mosby, Inc. All rights reserved.

  4. Blood folic acid, vitamin B12, and homocysteine levels in pregnant women with fetal growth restriction.

    PubMed

    Jiang, H L; Cao, L Q; Chen, H Y

    2016-12-19

    Deficiencies in nutrients such as folic acid and vitamin B12 may play a role in fetal growth restriction (FGR). However, whether folic acid, vitamin B12, or homocysteine is associated with FGR in Chinese populations remains unclear. This study investigated the relationship between these nutrient deficiencies and FGR in pregnant Chinese women. We selected 116 mother and infant pairs, and categorized the neonates into the FGR, appropriate for gestational age, and large for gestational age groups. Birth weight, body length, head circumference, body mass index (BMI), and Rohrer's body index of the newborns were measured. Serum folic acid, vitamin B12, and homocysteine levels were measured in mothers during the first three days of their hospital stay. Results showed that the FGR group exhibited reduced folic acid and vitamin B12 levels and elevated homocysteine levels than those in the other two groups. Folic acid and vitamin B12 levels were positively correlated with birth weight, head circumference, and BMI, whereas homocysteine level was negatively correlated with these variables. The FGR ratio in the folic acid and vitamin B12 deficiency group was higher than that in the sufficiency group (χ(2) = 4.717 and 4.437, P = 0.029 and 0.035, respectively). In addition, elevated homocysteine was associated with FGR (χ(2) = 5.366, P = 0.021). In conclusion, we found that folic acid and vitamin B12 deficiency was associated with elevated homocysteine levels, which may increase susceptibility to FGR.

  5. 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

  6. Intrauterine Growth Restriction Impairs Small Intestinal Mucosal Immunity in Neonatal Piglets

    PubMed Central

    Dong, Li; Zhong, Xiang; Ahmad, Hussain; Li, Wei; Wang, Yuanxiao; Zhang, Lili

    2014-01-01

    Intrauterine growth restriction (IUGR) is a very common problem in both piglet and human neonate populations. We hypothesized that IUGR neonates have impaired intestinal mucosal immunity from birth. Using neonatal piglets as IUGR models, immune organ weights, the weight and length of the small intestine (SI), intestinal morphology, intraepithelial immune cell numbers, levels of cytokines and immunoglobulins, and the relative gene expression of cytokines in the SI were investigated. IUGR neonatal piglets were observed to have lower absolute immune organ weight and SI length, decreased relative weights of the thymus, spleen, mesenteric lymph node, and thinner but longer SIs. Damaged and jagged villi, shorter microvilli, presence of autophagosomes, swelled mitochondria, and decreased villus surface areas were also found in the SIs of IUGR neonatal piglets. We also found a smaller number of epithelial goblet cells and lymphocytes in the SIs of IUGR neonates. In addition, we detected reduced levels of the cytokines TNF-α and IFN-γ and decreased gene expression of cytokines in IUGR neonates. In conclusion, IUGR was shown to impair the mucosal immunity of the SI in neonatal piglets, and the ileum was the major site of impairment. PMID:24710659

  7. 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

  8. In Utero Programming of Later Adiposity: The Role of Fetal Growth Restriction

    PubMed Central

    Sarr, Ousseynou; Yang, Kaiping; Regnault, Timothy R. H.

    2012-01-01

    Intrauterine growth restriction (IUGR) is strongly associated with obesity in adult life. The mechanisms contributing to the onset of IUGR-associated adult obesity have been studied in animal models and humans, where changes in fetal adipose tissue development, hormone levels and epigenome have been identified as principal areas of alteration leading to later life obesity. Following an adverse in utero development, IUGR fetuses display increased lipogenic and adipogenic capacity in adipocytes, hypoleptinemia, altered glucocorticoid signalling, and chromatin remodelling, which subsequently all contribute to an increased later life obesity risk. Data suggest that many of these changes result from an enhanced activity of the adipose master transcription factor regulator, peroxisome proliferator-activated receptor-γ (PPARγ) and its coregulators, increased lipogenic fatty acid synthase (FAS) expression and activity, and upregulation of glycolysis in fetal adipose tissue. Increased expression of fetal hypothalamic neuropeptide Y (NPY), altered hypothalamic leptin receptor expression and partitioning, reduced adipose noradrenergic sympathetic innervations, enhanced adipose glucocorticoid action, and modifications in methylation status in the promoter of hepatic and adipose adipogenic and lipogenic genes in the fetus also contribute to obesity following IUGR. Therefore, interventions that inhibit these fetal developmental changes will be beneficial for modulation of adult body fat accumulation. PMID:23251802

  9. Phase-rectified signal averaging as a new method for surveillance of growth restricted fetuses.

    PubMed

    Lobmaier, S M; Huhn, E A; Pildner von Steinburg, S; Müller, A; Schuster, T; Ortiz, J U; Schmidt, G; Schneider, K T

    2012-12-01

    This study aims to compare average acceleration capacity (AAC), a new parameter to assess the dynamic capacity of the fetal autonomous nervous system, and short term variation (STV) in fetuses affected by intrauterine growth restriction (IUGR) and healthy fetuses. A prospective observational study was performed, including 39 women with IUGR singleton pregnancies (estimated fetal weight <10th percentile and umbilical artery resistance index >95th percentile) and 43 healthy control pregnancies matched according to gestational age at recording. Ultrasound biometries and Doppler examination were performed for identification of IUGR and control fetuses, with subsequent analysis of fetal heart rate, resulting in STV and AAC. Follow-up for IUGR and control pregnancies was done, with perinatal outcome variables recorded. AAC [IUGR mean value 2.0 bpm (interquartile range = 1.6-2.1), control 2.7 bpm (2.6-3.0)] differentiates better than STV [IUGR 7.4 ms (5.3-8.9), control 10.9 ms (9.2-12.7)] between IUGR and control. The area under the curve for AAC is 97 % [95% CI = (0.95-1.0)], for STV 85 % (CI = 0.76-0.93; p < 0.01). Positive predictive value for STV is 77% and negative predictive value is 81%. For AAC both positive and negative predictive values are 90%. AAC shows an improvement to discriminate between normal and compromised fetuses at a single moment in time, in comparison with STV.

  10. Effects of a restricted fetal growth environment on human kidney morphology, cell apoptosis and gene expression.

    PubMed

    Wang, Yan-Ping; Chen, Xu; Zhang, Zhi-Kun; Cui, Hong-Yan; Wang, Peng; Wang, Yue

    2015-12-01

    Kidney development is key to the onset of hypertension and cardiovascular diseases in adults, and in the fetal stage will be impaired by a lack of nutrients in utero in animal models. However, few human studies have been performed. Kidney samples from fetuses in a fetal growth restriction (FGR) environment were collected and the morphological characteristics were observed. Potentially molecular mechanisms were explored by analyzing apoptosis and kidney-development related gene expression. The results indicated that no malformations were observed in the kidney samples of the FGR group, but the mean kidney weight and volume were significantly decreased. Moreover, the ratio of apoptotic cells and Bax-positive cells was increased and the ratio of Bcl-2-positive cells was decreased in the FGR group, indicating potential apoptosis induction under an in utero FGR environment. Finally, aberrant expression of renin and angiotensinogen indicated potential kidney functional abnormalities in the FGR group. Our study suggested increased apoptosis and decreased renin and angiotensinogen expression during human kidney development in an FGR environment. The current results will be helpful to further explore the molecular mechanism of FGR and facilitate future studies of hypertension and cardiovascular diseases and the establishment of preventive methods. © The Author(s) 2014.

  11. 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.

  12. Suspected Fetal Growth Restriction at 37 Weeks: A Comparison of Doppler and Placental Pathology.

    PubMed

    Curtin, William M; Millington, Karmaine A; Ibekwe, Tochi O; Ural, Serdar H

    2017-01-01

    Objective. Our objective was determining if abnormal Doppler evaluation had a higher prevalence of placental pathology compared to normal Doppler in suspected fetal growth restriction (FGR) of cases delivered at 37 weeks. Study Design. This retrospective cohort study of suspected FGR singletons with antenatal Doppler evaluation delivered at 37 weeks had a primary outcome of the prevalence of placental pathology related to FGR. Significance was defined as p ≤ 0.05. Results. Of 100 pregnancies 46 and 54 were in the abnormal and normal Doppler cohorts, respectively. Placental pathology was more prevalent with any abnormal Doppler, 84.8% versus 55.6%, odds ratio (OR) 4.46, 95% confidence interval (CI): 1.55, 13.22, and p = 0.002. Abnormal middle cerebral artery (MCA) Doppler had a higher prevalence: 96.2% versus 54.8%, OR 20.7, 95% CI: 2.54, 447.1, and p < 0.001. Conclusion. Abnormal Doppler was associated with more placental pathology in comparison to normal Doppler in fetuses with suspected FGR. Abnormal MCA Doppler had the strongest association.

  13. Ultrasound predictors of mortality in monochorionic twins with selective intrauterine growth restriction.

    PubMed

    Ishii, K; Murakoshi, T; Hayashi, S; Saito, M; Sago, H; Takahashi, Y; Sumie, M; Nakata, M; Matsushita, M; Shinno, T; Naruse, H; Torii, Y

    2011-01-01

    The aim of this study was to evaluate the use of ultrasound assessment to predict risk of mortality in expectantly managed monochorionic twin fetuses with selective intrauterine growth restriction (sIUGR). This was a retrospective study of 101 monochorionic twin pregnancies diagnosed with sIUGR before 26 weeks of gestation. All patients were under expectant management during the observation period. At the initial evaluation, the presence or absence of each of the following abnormalities was documented: oligohydramnios; stuck twin phenomenon; severe IUGR < 3(rd) centile of estimated fetal weight; abnormal Doppler in the umbilical artery; and polyhydramnios in the larger twin. The relationships between these ultrasound findings and mortality of sIUGR fetuses were evaluated using multiple logistic regression analysis. Of 101 sIUGR twins, 22 (21.8%) fetuses suffered intrauterine demise and nine (8.9%) suffered neonatal death; 70 (69.3%) survived the neonatal period. Multiple logistic regression analysis revealed that the stuck twin phenomenon (odds ratio (OR): 14.5; 95% CI: 2.2-93.2; P = 0.006) and constantly absent diastolic flow in the umbilical artery (OR: 29.4; 95% CI: 3.3-264.0; P = 0.003) were significant risk factors for mortality. Not only abnormal Doppler flow in the umbilical artery but also severe oligohydramnios should be recognized as important indicators for mortality in monochorionic twins with sIUGR.

  14. Increased hepatic glucose production in fetal sheep with intrauterine growth restriction is not suppressed by insulin.

    PubMed

    Thorn, Stephanie R; Brown, Laura D; Rozance, Paul J; Hay, William W; Friedman, Jacob E

    2013-01-01

    Intrauterine growth restriction (IUGR) increases the risk for metabolic disease and diabetes, although the developmental origins of this remain unclear. We measured glucose metabolism during basal and insulin clamp periods in a fetal sheep model of placental insufficiency and IUGR. Compared with control fetuses (CON), fetuses with IUGR had increased basal glucose production rates and hepatic PEPCK and glucose-6-phosphatase expression, which were not suppressed by insulin. In contrast, insulin significantly increased peripheral glucose utilization rates in CON and IUGR fetuses. Insulin robustly activated AKT, GSK3β, and forkhead box class O (FOXO)1 in CON and IUGR fetal livers. IUGR livers, however, had increased basal FOXO1 phosphorylation, nuclear FOXO1 expression, and Jun NH(2)-terminal kinase activation during hyperinsulinemia. Expression of peroxisome proliferator-activated receptor γ coactivator 1α and hepatocyte nuclear factor-4α were increased in IUGR livers during basal and insulin periods. Cortisol and norepinephrine concentrations were positively correlated with glucose production rates. Isolated IUGR hepatocytes maintained increased glucose production in culture. In summary, fetal sheep with IUGR have increased hepatic glucose production, which is not suppressed by insulin despite insulin sensitivity for peripheral glucose utilization. These data are consistent with a novel mechanism involving persistent transcriptional activation in the liver that seems to be unique in the fetus with IUGR.

  15. Intrauterine Growth Restriction and the Fetal Programming of the Hedonic Response to Sweet Taste in Newborn Infants

    PubMed Central

    Ayres, Caroline; Agranonik, Marilyn; Portella, André Krumel; Filion, Françoise; Johnston, Celeste C.; Silveira, Patrícia Pelufo

    2012-01-01

    Intrauterine growth restriction is associated with increased risk for adult metabolic syndrome and cardiovascular disease, which seems to be related to altered food preferences in these individuals later in life. In this study, we sought to understand whether intrauterine growth leads to fetal programming of the hedonic responses to sweet. Sixteen 1-day-old preterm infants received 24% sucrose solution or water and the taste reactivity was filmed and analyzed. Spearman correlation demonstrated a positive correlation between fetal growth and the hedonic response to the sweet solution in the first 15 seconds after the offer (r = 0.864, P = 0.001), without correlation when the solution given is water (r = 0.314, P = 0.455). In fact, the more intense the intrauterine growth restriction, the lower the frequency of the hedonic response observed. IUGR is strongly correlated with the hedonic response to a sweet solution in the first day of life in preterm infants. This is the first evidence in humans to demonstrate that the hedonic response to sweet taste is programmed very early during the fetal life by the degree of intrauterine growth. The altered hedonic response at birth and subsequent differential food preference may contribute to the increased risk of obesity and related disorders in adulthood in intrauterine growth-restricted individuals. PMID:22851979

  16. Implementation of a Nutrition Program Reduced Post-Discharge Growth Restriction in Thai Very Low Birth Weight Preterm Infants

    PubMed Central

    Japakasetr, Suchada; Sirikulchayanonta, Chutima; Suthutvoravut, Umaporn; Chindavijak, Busba; Kagawa, Masaharu; Nokdee, Somjai

    2016-01-01

    Very low birth weight (VLBW) preterm infants are vulnerable to growth restriction after discharge due to cumulative protein and energy deficits during their hospital stay and early post-discharge period. The current study evaluated the effectiveness of the preterm infant, post-discharge nutrition (PIN) program to reduce post-discharge growth restriction in Thai VLBW preterm infants. A prospective, non-randomized interventional cohort study was undertaken to assess the growth of 22 VLBW preterm infants who received the PIN program and compared them with 22 VLBW preterm infants who received conventional nutrition services. Infant’s growth was recorded monthly until the infants reached six months’ corrected age (6-moCA). Intervention infants had significantly greater body weights (p = 0.013) and head circumferences (p = 0.009). Also, a greater proportion of the intervention group recovered their weight to the standard weight at 4-moCA (p = 0.027) and at 6-moCA (p = 0.007) and their head circumference to the standard head circumference at 6-moCA (p = 0.004) compared to their historical comparison counterparts. Enlistment in the PIN program thus resulted in significantly reduced post-discharge growth restriction in VLBW preterm infants. Further research on longer term effects of the program on infant’s growth and development is warranted. PMID:27999313

  17. Intrauterine growth restriction and the fetal programming of the hedonic response to sweet taste in newborn infants.

    PubMed

    Ayres, Caroline; Agranonik, Marilyn; Portella, André Krumel; Filion, Françoise; Johnston, Celeste C; Silveira, Patrícia Pelufo

    2012-01-01

    Intrauterine growth restriction is associated with increased risk for adult metabolic syndrome and cardiovascular disease, which seems to be related to altered food preferences in these individuals later in life. In this study, we sought to understand whether intrauterine growth leads to fetal programming of the hedonic responses to sweet. Sixteen 1-day-old preterm infants received 24% sucrose solution or water and the taste reactivity was filmed and analyzed. Spearman correlation demonstrated a positive correlation between fetal growth and the hedonic response to the sweet solution in the first 15 seconds after the offer (r = 0.864, P = 0.001), without correlation when the solution given is water (r = 0.314, P = 0.455). In fact, the more intense the intrauterine growth restriction, the lower the frequency of the hedonic response observed. IUGR is strongly correlated with the hedonic response to a sweet solution in the first day of life in preterm infants. This is the first evidence in humans to demonstrate that the hedonic response to sweet taste is programmed very early during the fetal life by the degree of intrauterine growth. The altered hedonic response at birth and subsequent differential food preference may contribute to the increased risk of obesity and related disorders in adulthood in intrauterine growth-restricted individuals.

  18. Implementation of a Nutrition Program Reduced Post-Discharge Growth Restriction in Thai Very Low Birth Weight Preterm Infants.

    PubMed

    Japakasetr, Suchada; Sirikulchayanonta, Chutima; Suthutvoravut, Umaporn; Chindavijak, Busba; Kagawa, Masaharu; Nokdee, Somjai

    2016-12-17

    Very low birth weight (VLBW) preterm infants are vulnerable to growth restriction after discharge due to cumulative protein and energy deficits during their hospital stay and early post-discharge period. The current study evaluated the effectiveness of the preterm infant, post-discharge nutrition (PIN) program to reduce post-discharge growth restriction in Thai VLBW preterm infants. A prospective, non-randomized interventional cohort study was undertaken to assess the growth of 22 VLBW preterm infants who received the PIN program and compared them with 22 VLBW preterm infants who received conventional nutrition services. Infant's growth was recorded monthly until the infants reached six months' corrected age (6-moCA). Intervention infants had significantly greater body weights (p = 0.013) and head circumferences (p = 0.009). Also, a greater proportion of the intervention group recovered their weight to the standard weight at 4-moCA (p = 0.027) and at 6-moCA (p = 0.007) and their head circumference to the standard head circumference at 6-moCA (p = 0.004) compared to their historical comparison counterparts. Enlistment in the PIN program thus resulted in significantly reduced post-discharge growth restriction in VLBW preterm infants. Further research on longer term effects of the program on infant's growth and development is warranted.

  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. Chromosomal Microarray Analysis in Fetuses with Growth Restriction and Normal Karyotype: A Systematic Review and Meta-Analysis.

    PubMed

    Borrell, Antoni; Grande, Maribel; Pauta, Montse; Rodriguez-Revenga, Laia; Figueras, Francesc

    2017-09-09

    To perform a systematic review of the literature and a meta-analysis to estimate the incremental yield of chromosomal microarray analysis (CMA) over karyotyping in fetal growth restriction (FGR). This was a systematic review conducted in accordance with the PRISMA criteria. All articles identified in PubMed, Ovid Medline, and ISI Web of Knowledge (Web of Science) from January 2009 to November 2016 describing pathogenic copy number variants (CNVs) in fetuses with growth restriction were included. Case reports were excluded. Risk differences were pooled to estimate the overall and stratified CMA incremental yield. Ten studies with full data available met the inclusion criteria for analysis. Combined data from these studies revealed a 4% (95% confidence interval [CI] 1-6%) incremental yield of CMA over karyotyping in nonmalformed growth-restricted fetuses, and a 10% (95% CI 6-14%) incremental yield in FGR when associated with fetal malformations. The most frequently found pathogenic CNVs were 22q11.2 duplication, Xp22.3 deletion, and 7q11.23 deletion (Williams-Beuren syndrome), particularly in isolated FGR. The use of genomic CMA provides a 4% incremental yield of detecting pathogenic CNVs in fetuses with isolated growth restriction and normal karyotype. © 2017 S. Karger AG, Basel.

  1. 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…

  2. Gender-specific early postnatal catch-up growth after intrauterine growth retardation by food restriction in swine with obesity/leptin resistance.

    PubMed

    Gonzalez-Bulnes, A; Ovilo, C; Lopez-Bote, C J; Astiz, S; Ayuso, M; Perez-Solana, M L; Sanchez-Sanchez, R; Torres-Rovira, L

    2012-08-01

    The effects of undernutrition during pregnancy on prenatal and postnatal development of the offspring were evaluated in sows with obesity/leptin resistance. Females were fed, from day 35 of pregnancy onwards, a diet fulfilling either 100% (group control, n=10) or 50% of the nutritional requirements (group underfed, n=10). In the control group, maternal body weight increased during pregnancy (P<0.05) while it decreased or remained steady in the underfed group. At days 75 and 100 of gestation, plasma triglycerides were lower but urea levels were higher in restricted than in control sows (P<0.05 for both). Assessment of the offspring indicated that the trunk diameter was always smaller in the restricted group (P<0.01 at day 50, P<0.005 at days 75 and 100 and P<0.0001 at birth) while head measurements were similar through pregnancy, although smaller in the restricted than in the control group at birth (P<0.05). Newborns from restricted sows were also lighter than offspring from control females (P<0.01) and had higher incidence of growth retardation (P<0.01). Afterwards, during lactation, early postnatal growth in restricted piglets was modulated by gender. At weaning, males from restricted sows were still lighter than their control counterparts (P<0.05), while females from control and underfed sows were similar. Thus, the current study indicates a gender-related differential effect in the growth patterns of the piglets, with females from restricted sows evidencing catch-up growth to neutralise prenatal retardation and reaching similar development than control counterparts.

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

    PubMed

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

    2015-01-01

    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. 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). 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. Our data suggest that targeting the metabolic characteristics of neuroblastoma could open a new front in supporting standard therapy regimens. Therefore, we propose

  4. 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

  5. Effects of Female Dietary Restriction in a Rabbit Growth Line During Rearing on Reproductive Performance and Embryo Quality.

    PubMed

    Naturil-Alfonso, C; Lavara, R; Vicente, J S; Marco-Jiménez, F

    2016-02-01

    Maternal diet prior to mating has an effect on reproductive performance. We analysed the effect of maternal dietary restriction during rearing on reproductive performance, the embryo development and foetal growth. Females were categorized in two groups: (i) does with ad libitum access to feed or (ii) restricted. Two experiments were performed: (i) after 1 month, receptive females from both experimental groups were artificially inseminated and the reproductive performance was recorded during three reproductive cycles; at the first insemination, the body weight and perirenal fat thickness were recorded, and (ii) females from both experimental groups were inseminated, and 24 h later, embryos were recovered and transferred to recipient females from a maternal line. Later, embryonic implantation was assessed at day 14 by laparoscopy and foetal growth was monitored by ultrasound examination. In experiment 1, no differences in kindling rate was found, but prolificacy was showed to be higher in ad libitum does, which also were heavier than restricted ones. In experiment 2, no differences among does either in body weight, in perirenal fat thickness or in reproductive performance (ovulation rate and embryo recovery rate) were related to differences in feed intake. However, despite similar embryonic implantation losses, embryos from restricted females demonstrated higher foetal and gestational losses. Embryos from restricted does presented lower foetal growth than embryos from ad libitum does. Therefore, our results demonstrated that nutrition before first conception in a rabbit line selected for growth rate may impact on the embryo and results in a disturbance in gestational losses and foetal growth over all reproductive life. © 2015 Blackwell Verlag GmbH.

  6. Lipid-restricted recognition of mycobacterial lipoglycans by human pulmonary surfactant protein A: a surface-plasmon-resonance study.

    PubMed Central

    Sidobre, Stéphane; Puzo, Germain; Rivière, Michel

    2002-01-01

    The human pulmonary surfactant protein A (hSP-A), a member of the mammalian collectin family, is thought to play a key defensive role against airborne invading pulmonary pathogens, among which is Mycobacterium tuberculosis, the aetiologic agent of tuberculosis. hSP-A has been shown to promote the uptake and the phagocytosis of pathogenic bacilli through the recognition and the binding of carbohydrate motifs on the invading pathogen surface. Recently we identified lipomannan and mannosylated lipoarabinomannan (ManLAM), two major mycobacterial cell-wall lipoglycans, as potential ligands for binding of hSP-A. We demonstrated that both the terminal mannose residues and the fatty acids are critical for binding, whereas the inner arabinosyl and mannosyl domains do not participate. In the present study we developed a surface-plasmon-resonance assay to analyse the molecular basis for the recognition of ManLAM by hSP-A and to try to define further the role of the lipidic aglycone moiety. Binding of ManLAM to immobilized hSP-A was consistent with the simplest one-to-one interaction model involving a single class of carbohydrate-binding site. This observation strongly suggests that the lipid moiety of ManLAM does not directly interact with hSP-A, but is rather responsible for the macromolecular organization of the lipoglycan, which may be necessary for efficient recognition of the terminal mannosyl epitopes. The indirect, structural role of the lipoglycan lipidic component is further supported by the complete lack of interaction with hSP-A in the presence of a low concentration of mild detergent. PMID:12071842

  7. 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.

  8. Pulmonary malformation in transgenic mice expressing human keratinocyte growth factor in the lung.

    PubMed Central

    Simonet, W S; DeRose, M L; Bucay, N; Nguyen, H Q; Wert, S E; Zhou, L; Ulich, T R; Thomason, A; Danilenko, D M; Whitsett, J A

    1995-01-01

    Expression of human keratinocyte growth factor (KGF/FGF-7) was directed to epithelial cells of the developing embryonic lung of transgenic mice disrupting normal pulmonary morphogenesis during the pseudoglandular stage of development. By embryonic day 15.5(E15.5), lungs of transgenic surfactant protein C (SP-C)-KGF mice resembled those of humans with pulmonary cystadenoma. Lungs were cystic, filling the thoracic cavity, and were composed of numerous dilated saccules lined with glycogen-containing columnar epithelial cells. The normal distribution of SP-C proprotein in the distal regions of respiratory tubules was disrupted. Columnar epithelial cells lining the papillary structures stained variably and weakly for this distal respiratory cell marker. Mesenchymal components were preserved in the transgenic mouse lungs, yet the architectural relationship of the epithelium to the mesenchyme was altered. SP-C-KGF transgenic mice failed to survive gestation to term, dying before E17.5. Culturing mouse fetal lung explants in the presence of recombinant human KGF also disrupted branching morphogenesis and resulted in similar cystic malformation of the lung. Thus, it appears that precise temporal and spatial expression of KGF is likely to play a crucial role in the control of branching morphogenesis during fetal lung development. Images Fig. 1 Fig. 2 Fig. 3 PMID:8618921

  9. Insulin-like growth factor I stimulates elastin synthesis by bovine pulmonary arterial smooth muscle cells.

    PubMed

    Badesch, D B; Lee, P D; Parks, W C; Stenmark, K R

    1989-04-14

    Insulin-like growth factor I stimulates mitogenesis in smooth muscle cells, and upregulates elastin synthesis in embryonic aortic tissue. Increased smooth muscle elastin synthesis may play an important role in vascular remodeling in chronic pulmonary hypertension. Therefore, we studied the effect of IGF-I on elastin and total protein synthesis by pulmonary arterial smooth muscle cells in vitro. Tropoelastin synthesis was measured by enzyme immunoassay, and total protein synthesis was measured by [3H]-leucine incorporation. In addition, the steady-state levels of tropoelastin mRNA were determined by slot blot hybridization. Incubation of confluent cultures with various concentrations of IGF-I resulted in a dose-dependent stimulation of elastin synthesis, with a 2.4-fold increase over control levels at 1000 ng/ml of IGF. The increase in elastin synthesis was reflected by a stimulation of the steady-state levels of tropoelastin mRNA. We conclude that IGF-I has potent elastogenic effects on vascular smooth muscle cells, and speculate that it may contribute to vascular wall remodeling in chronic hypertension.

  10. Evaluation of broiler growth velocity and acceleration in relation to pulmonary hypertension syndrome.

    PubMed

    Roush, W B; Wideman, R F

    2000-02-01

    An evaluation was made of the relationship between individual daily growth patterns and susceptibility of broiler chickens to pulmonary hypertension syndrome (PHS). In the first experiment, 46 male broilers were weighed for each of 50 d, during which time 13 developed PHS. Three temporal phases (0 to 15, 16 to 35, and 36 to 50 d) of broiler growth velocity and acceleration were examined. Correlation dimensions and Lyapunov exponents suggested evidence of chaos in growth velocity and acceleration, but the absence of detectable differences between broilers in the normal and PHS categories led us to reject the hypotheses that growth is more chaotic in normal broilers than in broilers susceptible to PHS. Growth velocity and acceleration values for mean and SD were statistically evaluated as response variables for each growth phase. Mean values for velocity during the third phase were different between broilers in the normal and PHS categories (velocity: 68.8 vs 48.9 g/d, P = 0.03, respectively) and (acceleration: 0.3 vs -1.4 g/d2, P = 0.07, respectively). The third phase SD (reflecting oscillation for velocity and acceleration) was greater for normal than for PHS birds (velocity: 26.1 vs 21.3 g/d, P = 0.13, respectively; acceleration: 39.7 vs 28.2 g/d2, P = 0.03, respectively). The hypothesis was accepted that normal birds have greater oscillations in growth velocity and acceleration than birds susceptible to PHS. A general regression neural network (GRNN) with genetic adaptive calibration was trained to predict PHS based on individual growth phases and their combinations. Data representing the first, first two, and all three phases of growth were determined to have potential for computerized diagnostic weighing. With the GRNN, birds in all three data sets were successfully classified (100%) with or without PHS. A third hypothesis, therefore, was accepted that artificial neural networks could be used to distinguish the difference between normal broilers and those

  11. Maternal zinc restriction affects postnatal growth and glucose homeostasis in rat offspring differently depending upon adequacy of their nutrient intake.

    PubMed

    Jou, Ming-Yu; Lönnerdal, Bo; Philipps, Anthony F

    2012-03-01

    We have previously investigated effects of moderate maternal zinc (Zn) restriction on growth and glucose homeostasis in offspring, but interaction between maternal Zn restriction and postnatal nutrition have not been studied. Weight and serum Zn were lower in ZnD-IN than in ZnC-IN rats at wk 3, but ZnD-AN and ZnD-EN rats had greater weights than respective controls and higher insulin-like growth factor-1 (ZnD-AN) and leptin levels (ZnD-EN). Subsequently, both ZnD-AN and ZnD-EN pups were insulin resistant, and had evidence of elevated serum leptin and depressed insulin receptor phosphorylation with gender-specific differences up to 15 weeks. Maternal Zn restriction interacted with postnatal nutritional status, resulting in divergent effects on weight gain and insulin resistance. Interaction between potential effects of fetal Zn restriction and food availability postnatally may be one factor responsible for later metabolic derangements. Rats were fed Zn restricted (ZnD, 7 μg/g) or control (ZnC, 25 μg/g) diets ad libitum from 3 wk pre-conception to 3 wk post-parturition. Postnatally, litters were culled to 13 (IN, inadequate nutrition), 7 (AN, adequate nutrition), and 4 (EN, excess nutrition) pups/dam, respectively, and nursed by their original mothers. Postweaning, pups were fed rodent diet ad libitum. Tests to assess insulin resistance were performed subsequently.

  12. Vascular remodeling in primary pulmonary hypertension. Potential role for transforming growth factor-beta.

    PubMed Central

    Botney, M. D.; Bahadori, L.; Gold, L. I.

    1994-01-01

    Active exogenous transforming growth factor-beta s (TGF-beta s) are potent modulators of extracellular matrix synthesis in cell culture and stimulate matrix synthesis in wounds and other remodeling tissues. The role of endogenous TGF-beta s in remodeling tissues is less well defined. Vascular remodeling in the pulmonary arteries of patients with primary pulmonary hypertension is characterized, in part, by abnormal deposition of immunohistochemically detectable procollagen, thereby identifying actively remodeling vessels. We used this marker of active matrix synthesis to begin defining the in vivo role of TGF-beta in the complex milieu of actively remodeling tissues. Immunohistochemistry using isoform-specific anti-TGF-beta antibodies was performed to determine whether TGF-beta was present in actively remodeling hypertensive pulmonary arteries 20 to 500 microns in diameter. Intense, cell-associated TGF-beta 3 immunoreactivity was observed in the media and neointima of these hypertensive muscular arteries. Immunostaining was present, but less intense, in normal arteries of comparable size. TGF-beta 2 immunoreactivity was observed in normal vessels and was increased slightly in hypertensive vessels, in a pattern resembling TGF-beta 3 immunoreactivity. No staining was associated with the adventitia. TGF-beta 1 immunostaining was either faint or absent in both normal and hypertensive vessels. Comparison of procollagen and TGF-beta localization demonstrated that TGF-beta 2 and TGF-beta 3 colocalized at all sites of procollagen synthesis. However, TGF-beta was observed in vessels, or vascular compartments, where there was no procollagen synthesis. Procollagen immunoreactivity was not present in normal vessels that showed immunoreactivity for TGF-beta 2 and TGF-beta 3. These observations suggest: a) the stimulation of procollagen synthesis by TGF-beta in vivo is more complex than suggested by in vitro studies and b) a potential role for TGF-beta 2 or TGF-beta 3, but not

  13. Inhibitory effects of simvastatin on platelet-derived growth factor signaling in pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension.

    PubMed

    Ikeda, Tetsuya; Nakamura, Kazufumi; Akagi, Satoshi; Kusano, Kengo Fukushima; Matsubara, Hiromi; Fujio, Hideki; Ogawa, Aiko; Miura, Aya; Miura, Daiji; Oto, Takahiro; Yamanaka, Ryutaro; Otsuka, Fumio; Date, Hiroshi; Ohe, Tohru; Ito, Hiroshi

    2010-01-01

    Idiopathic pulmonary arterial hypertension (IPAH) is a progressive disease characterized by inappropriate increase of pulmonary artery smooth muscle cells (PASMCs) leading to occlusion of pulmonary arterioles. Inhibition of platelet-derived growth factor (PDGF) signaling is starting to garner attention as a targeted therapy for IPAH. We assessed the inhibitory effects of simvastatin, a 3-hydroxy-3-methylglutanyl coenzyme A reductase inhibitor, on PDGF-induced proliferation and migration of PASMCs obtained from 6 patients with IPAH who underwent lung transplantation. PDGF stimulation caused a significantly higher growth rate of PASMCs from patients with IPAH than that of normal control PASMCs as assessed by (3)H-thymidine incorporation. Simvastatin (0.1 micromol/L) significantly inhibited PDGF-induced cell proliferation of PASMCs from patients with IPAH but did not inhibit proliferation of normal control cells at the same concentration. Western blot analysis revealed that simvastatin significantly increased the expression of cell cycle inhibitor p27. PDGF significantly increased the migration distance of IPAH-PASMCs compared with that of normal PASMCs, and simvastatin (1 micromol/L) significantly inhibited PDGF-induced migration. Immunofluorescence staining revealed that simvastatin (1 micromol/L) inhibited translocation of Rho A from the cytoplasm to membrane and disorganized actin fibers in PASMCs from patients with IPAH. In conclusion, simvastatin had inhibitory effects on inappropriate PDGF signaling in PASMCs from patients with IPAH.

  14. Short-term dietary phosphate restriction up-regulates ileal fibroblast growth factor 15 gene expression in mice

    PubMed Central

    Nakahashi, Otoki; Yamamoto, Hironori; Tanaka, Sarasa; Kozai, Mina; Takei, Yuichiro; Masuda, Masashi; Kaneko, Ichiro; Taketani, Yutaka; Iwano, Masayuki; Miyamoto, Ken-ichi; Takeda, Eiji

    2014-01-01

    Members of the fibroblast growth factor (FGF) 19 subfamily, including FGF23, FGF15/19, and FGF21, have a role as endocrine factors which influence the metabolism of inorganic phosphate (Pi) and vitamin D, bile acid, and energy. It has been reported that dietary Pi regulates circulating FGF23. In this study, the short-term effects of dietary Pi restriction on the expression of FGF19 subfamily members in mice were analyzed. An initial analysis confirmed plasma FGF23 levels positively correlated with the amount of dietary Pi. On the other hand, ileal Fgf15 gene expression, but not hepatic Fgf21 gene expression, was up-regulated by dietary Pi restriction. In addition, we observed the increase of plasma 1,25-dihydroxyvitamin D [1,25(OH)2D] levels by dietary Pi restriction, and the up-regulation of ileal Fgf15 mRNA expression by 1,25(OH)2D3 and vitamin D receptor (VDR). Importantly, dietary Pi restriction-induced Fgf15 gene expression was prevented in VDR-knockout mice. Furthermore, diurnal variations of plasma triglyceride concentrations and hepatic mRNA expression of the bile acid synthesis enzyme Cyp7a1 as one of Fgf15 negative target genes was influenced by dietary Pi restriction. These results suggest that dietary Pi restriction up-regulates ileal Fgf15 gene expression through 1,25(OH)2D3 and VDR, and may affect hepatic bile acid homeostasis. PMID:24688219

  15. The effects of sildenafil citrate on feto?placental development and haemodynamics in a rabbit model of intrauterine growth restriction.

    PubMed

    López-Tello, Jorge; Arias-Álvarez, María; Jiménez-Martínez, Maria-Ángeles; Barbero-Fernández, Alicia; García-García, Rosa María; Rodríguez, María; Lorenzo, Pedro L; Torres-Rovira, Laura; Astiz, Susana; González-Bulnes, Antonio; Rebollar, Pilar G

    2016-05-23

    The present study evaluated the effectiveness of sildenafil citrate (SC) to improve placental and fetal growth in a diet-induced rabbit model of intrauterine growth restriction (IUGR). Pregnant rabbits were fed either ad libitum (Group C) or restricted to 50% of dietary requirements (Group R) or restricted and treated with SC (Group SC). The treatment with SC improved placental development by increasing vascularity and vessel hypertrophy in the decidua. The assessment of feto-placental haemodynamics showed higher resistance and pulsatility indices at the middle cerebral artery (MCA) in fetuses treated with SC when compared with Group R, which had increased systolic peak and time-averaged mean velocities at the MCA. Furthermore, fetuses in the SC group had significantly higher biparietal and thoracic diameters and longer crown-rump lengths than fetuses in Group R. Hence, the SC group had a reduced IUGR rate and a higher kit size at birth compared with Group R. In conclusion, SC may provide potential benefits in pregnancies with placental insufficiency and IUGR, partially counteracting the negative effects of food restriction on placental development and fetal growth. However, the present study also found evidence of a possible blood overflow in the brain that warrants further investigation.

  16. Are intrauterine growth restriction and preterm birth associated with dental caries?

    PubMed

    Saraiva, Maria C D; Bettiol, Heliosa; Barbieri, Marco A; Silva, Antonio A

    2007-10-01

    To assess the association between two intrauterine growth restriction (IUGR) surrogates - IUGR [small for gestational age birth (SGA) and fetal growth restriction (FGR)] and preterm birth with dental caries. Data from the Third National Health and Nutritional Examination Survey (1988-1994) were used, including 2- to 5.9-year-old singletons (n = 3189). Dental caries was defined as presence of any teeth with dental caries (treated or untreated) and also as presence of at least two teeth with dental caries. Exposure variables were preterm birth (<37 gestational weeks), FGR, and SGA. Covariates included were poverty, race/ethnicity, age, sex, sucrose intake, environmental tobacco smoking, dental visits, education of head of household, breastfeeding, and use of baby bottle. Separate statistical analyses were conducted for IUGR and for preterm birth through the estimation of prevalence ratio (PR), taking complex sampling design into consideration and adjusting for confounders. Sensitivity analysis was conducted including and excluding 2-year-old children and also with the two definitions of dental caries. In general, the inclusion of 2-year-old children and the case definition of presence of any teeth with dental caries biased the results toward the null, but with no major changes in the results. In bivariate analysis, SGA and FGR birth were both negatively but not significantly associated with dental caries while a significant positive association was found for preterm birth. Sensitivity analysis showed that the PR for preterm in bivariate analysis varied from 1.65 (95% CI 1.14-2.40) to 1.84 (95% CI 1.19-2.83). After adjusting for confounders, the PR for preterm birth varied from 1.38 (95% CI 1.00-1.89) to 1.64 (95% CI 1.22-2.20). After adjustment, the PR for SGA varied from 0.79 (95% CI 0.56-101) to 0.66 (95% CI 0.33-0.96). For children from 3 to 5.9 years old, the adjusted PR for FGR using the category 'none' as reference were mild (PR 1.10; 95% CI 0

  17. MCT8 expression in human fetal cerebral cortex is reduced in severe intrauterine growth restriction.

    PubMed

    Chan, Shiao Y; Hancox, Laura A; Martín-Santos, Azucena; Loubière, Laurence S; Walter, Merlin N M; González, Ana-Maria; Cox, Phillip M; Logan, Ann; McCabe, Christopher J; Franklyn, Jayne A; Kilby, Mark D

    2014-02-01

    The importance of the thyroid hormone (TH) transporter, monocarboxylate transporter 8 (MCT8), to human neurodevelopment is highlighted by findings of severe global neurological impairment in subjects with MCT8 (SLC16A2) mutations. Intrauterine growth restriction (IUGR), usually due to uteroplacental failure, is associated with milder neurodevelopmental deficits, which have been partly attributed to dysregulated TH action in utero secondary to reduced circulating fetal TH concentrations and decreased cerebral thyroid hormone receptor expression. We postulate that altered MCT8 expression is implicated in this pathophysiology; therefore, in this study, we sought to quantify changes in cortical MCT8 expression with IUGR. First, MCT8 immunohistochemistry was performed on occipital and parietal cerebral cortex sections obtained from appropriately grown for gestational age (AGA) human fetuses between 19 weeks of gestation and term. Secondly, MCT8 immunostaining in the occipital cortex of stillborn IUGR human fetuses at 24-28 weeks of gestation was objectively compared with that in the occipital cortex of gestationally matched AGA fetuses. Fetuses demonstrated widespread MCT8 expression in neurons within the cortical plate and subplate, in the ventricular and subventricular zones, in the epithelium of the choroid plexus and ependyma, and in microvessel wall. When complicated by IUGR, fetuses showed a significant fivefold reduction in the percentage area of cortical plate immunostained for MCT8 compared with AGA fetuses (P<0.05), but there was no significant difference in the proportion of subplate microvessels immunostained. Cortical MCT8 expression was negatively correlated with the severity of IUGR indicated by the brain:liver weight ratios (r(2)=0.28; P<0.05) at post-mortem. Our results support the hypothesis that a reduction in MCT8 expression in the IUGR fetal brain could further compromise TH-dependent brain development.

  18. MCT8 expression in human fetal cerebral cortex is reduced in severe intrauterine growth restriction

    PubMed Central

    Chan, Shiao Y; Hancox, Laura A; Martín-Santos, Azucena; Loubière, Laurence S; Walter, Merlin N M; González, Ana-Maria; Cox, Phillip M; Logan, Ann; McCabe, Christopher J; Franklyn, Jayne A; Kilby, Mark D

    2014-01-01

    The importance of the thyroid hormone (TH) transporter, monocarboxylate transporter 8 (MCT8), to human neurodevelopment is highlighted by findings of severe global neurological impairment in subjects with MCT8 (SLC16A2) mutations. Intrauterine growth restriction (IUGR), usually due to uteroplacental failure, is associated with milder neurodevelopmental deficits, which have been partly attributed to dysregulated TH action in utero secondary to reduced circulating fetal TH concentrations and decreased cerebral thyroid hormone receptor expression. We postulate that altered MCT8 expression is implicated in this pathophysiology; therefore, in this study, we sought to quantify changes in cortical MCT8 expression with IUGR. First, MCT8 immunohistochemistry was performed on occipital and parietal cerebral cortex sections obtained from appropriately grown for gestational age (AGA) human fetuses between 19 weeks of gestation and term. Secondly, MCT8 immunostaining in the occipital cortex of stillborn IUGR human fetuses at 24–28 weeks of gestation was objectively compared with that in the occipital cortex of gestationally matched AGA fetuses. Fetuses demonstrated widespread MCT8 expression in neurons within the cortical plate and subplate, in the ventricular and subventricular zones, in the epithelium of the choroid plexus and ependyma, and in microvessel wall. When complicated by IUGR, fetuses showed a significant fivefold reduction in the percentage area of cortical plate immunostained for MCT8 compared with AGA fetuses (P<0.05), but there was no significant difference in the proportion of subplate microvessels immunostained. Cortical MCT8 expression was negatively correlated with the severity of IUGR indicated by the brain:liver weight ratios (r2=0.28; P<0.05) at post-mortem. Our results support the hypothesis that a reduction in MCT8 expression in the IUGR fetal brain could further compromise TH-dependent brain development. PMID:24204008

  19. Expression of thyroid hormone transporters in the human placenta and changes associated with intrauterine growth restriction.

    PubMed

    Loubière, L S; Vasilopoulou, E; Bulmer, J N; Taylor, P M; Stieger, B; Verrey, F; McCabe, C J; Franklyn, J A; Kilby, M D; Chan, S-Y

    2010-04-01

    Thyroid hormones (TH) are important for the development of the human fetus and placenta from very early gestation. The transplacental passage of TH from mother to fetus and the supply of TH into trophoblasts require the expression of placental TH plasma membrane transporters. We describe the ontogeny of the TH transporters MCT8, MCT10, LAT1, LAT2, OATP1A2 and OATP4A1 in a large series (n = 110) of normal human placentae across gestation and describe their expression changes with intrauterine fetal growth restriction (IUGR n = 22). Quantitative RT-PCR revealed that all the mRNAs encoding TH transporters are expressed in human placenta from 6 weeks gestation and throughout pregnancy. MCT8, MCT10, OATP1A2 and LAT1 mRNA expression increased with gestation. OATP4A1 and CD98 (LATs obligatory associated protein) mRNA expression reached a nadir in mid-gestation before increasing towards term. LAT2 mRNA expression did not alter throughout gestation. Immunohistochemistry localised MCT10 and OATP1A2 to villous cytotrophoblasts and syncytiotrophoblasts, and extravillous trophoblasts while OATP4A1 was preferentially expressed in the villous syncytiotrophoblasts. Whilst MCT8 protein expression was increased, MCT10 mRNA expression was decreased in placentae from IUGR pregnancies delivered in the early 3rd trimester compared to age matched appropriately grown for gestational age controls. No significant change was found in the mRNA expression of the other transporters with IUGR. In conclusion, several TH transporters are present in the human placenta from early 1st trimester with varying patterns of expression throughout gestation. Their coordinated effects may regulate both transplacental TH passage and TH supply to trophoblasts, which are critical for the normal development of the fetus and placenta. Increased MCT8 and decreased MCT10 expression within placentae of pregnancies complicated by IUGR may contribute to aberrant development of the fetoplacental unit.

  20. Monocarboxylate transporter 8 expression in the human placenta: the effects of severe intrauterine growth restriction.

    PubMed

    Chan, S-Y; Franklyn, J A; Pemberton, H N; Bulmer, J N; Visser, T J; McCabe, C J; Kilby, M D

    2006-06-01

    Thyroid hormones (THs) are essential for normal fetal development, with even mild perturbation in maternal thyroid status in early pregnancy being associated with neurodevelopmental delay in children. Transplacental transfer of maternal THs is critical, with increasing evidence suggesting a role for 3,3',5-tri-iodothyronine (T3) in development and function of the placenta itself, as well as in development of the central nervous and other organ systems. Intrauterine growth restriction (IUGR) is associated with fetal hypothyroxinaemia, a factor that may contribute to neurodevelopmental delay. The recent description of monocarboxylate transporter 8 (MCT8) as a powerful and specific TH membrane transporter, and the association of MCT8 mutations with profound neurodevelopmental delay, led us to explore MCT8 expression in placenta. We describe the expression of MCT8 in normal human placenta throughout gestation, and in normal third-trimester placenta compared with that associated with IUGR using quantitative reverse transcriptase PCR. MCT8 mRNA was detected in placenta from early first trimester, with a significant increase with advancing gestation (P=0.007). In the early third trimester, MCT8 mRNA was increased in IUGR placenta compared with normal samples matched for gestational age (P<0.05), but there was no difference between IUGR and normal placenta in the late third trimester. Western immunoblotting findings in IUGR and normal placentae were in accord with mRNA data. MCT8 immunostaining was demonstrated in villous cytotrophoblast and syncytiotrophoblast as well as extravillous trophoblast cells from the first trimester onwards with increasingly widespread immunoreactivity seen with advancing gestation. In conclusion, expression of MCT8 in placenta from early gestation is compatible with an important role in TH transport during fetal development and a specific role in placental development. Altered expression in placenta associated with IUGR may reflect a

  1. Lactobacillus rhamnosus GG suspected infection in a newborn with intrauterine growth restriction.

    PubMed

    Sadowska-Krawczenko, I; Paprzycka, M; Korbal, P; Wiatrzyk, A; Krysztopa-Grzybowska, K; Polak, M; Czajka, U; Lutyńska, A

    2014-12-01

    A disseminated Lactobacillus rhamnosus GG ATCC 53103 infection was suspected in a 6 day-old newborn with intrauterine growth restriction (IUGR) symptoms, treated empirically with antibiotics and given L. rhamnosus GG with the aim of preventing antibiotic-associated gastrointestinal complications. The level of C-reactive protein on day 5 compared with day 2 was increased in spite of negative urine and cerebrospinal fluid cultures. The blood sampled on day 6 was found to be positive for lactobacilli, and the isolate was pre-identified as L. rhamnosus or Lactobacillus casei on day 11. The strain identity was then verified as L. rhamnosus GG through PCR and 16S rRNA sequencing. Genotyping with the rep-PCR and AFLP methods confirmed the 100% genetic similarity for both the strain isolated from patient blood and the probiotic product. The newborn became touch-sensitive, cried a lot, had worsening laboratory test results, and increased inflammation parameters, but no fever was observed. After a further 9 days of antibiotic therapy, blood cultures became negative, and laboratory tests improved on day 25. The patient was discharged from the hospital after 27 days. IUGR with a possible link to L. rhamnosus GG bacteraemia might be a new potential risk group, beside patients with organ failure, immunocompromised status and dysfunctional gut barrier mechanisms, for which safe use of probiotics needs careful attention. Universally accepted or improved guidelines for the safer administration of probiotics in risk groups are urgently needed. This report should not discourage the use of probiotics, but should highlight the need for their careful use in IUGR patients.

  2. Pregnancy outcome and placental findings in pregnancies complicated by fetal growth restriction with and without preeclampsia.

    PubMed

    Kovo, Michal; Schreiber, Letizia; Elyashiv, Osnat; Ben-Haroush, Avi; Abraham, Golan; Bar, Jacob

    2015-03-01

    To compare pregnancy outcome and placental pathology in pregnancies complicated by fetal growth restriction (FGR) with and without preeclampsia. Labor, fetal/neonatal outcome, and placental pathology parameters from neonates with a birth weight below the 10 th percentile (FGR), born between 24 and 42 weeks of gestation, were reviewed. Results were compared between pregnancies complicated with preeclampsia (hypertensive FGR [H-FGR]) to those without preeclampsia (normotensive FGR [N-FGR]). Composite neonatal outcome, defined as 1 or more of early complication (respiratory distress, necrotizing enterocolitis, sepsis, transfusion, ventilation, seizure, hypoxic-ischemic encephalopathy, phototherapy, or death), Apgar score ≤ 7 at 5 minutes, and days of hospitalization, were compared between the groups. Placental lesions, classified as lesions related to maternal vascular supply, lesions consistent with fetal thrombo-occlusive disease and inflammatory lesions, maternal inflammatory response, and fetal inflammatory response, were also compared. Women in the H-FGR group (n = 72) were older, with higher body mass index (BMI) and higher rate of preterm labor (<34 weeks) than in the N-FGR group (n = 270), P < .001 for all. Composite neonatal outcome was worse in the H-FGR than in the N-FGR group, 50% versus 15.5%, P < .001. Higher rate of maternal placental vascular lesions was detected in H-FGR compared with N-FGR, 82% versus 57.7%, P < .001. Using a stepwise logistic regression model, maternal BMI (1.13 odds ratio [OR], confidence interval [CI] 1.035-1.227, P = .006) and neonatal birth weight (0.996 OR, CI 0.995-0.998, P < .001) were independently associated with worse neonatal outcome. Worse neonatal outcome and more maternal placental vascular lesions in pregnancy complicated by FGR with preeclampsia versus FGR without preeclampsia suggest different pathophysiology in these entities. © The Author(s) 2014.

  3. Oxidatively modified LDL particles in the human placenta in early and late onset intrauterine growth restriction.

    PubMed

    Pecks, U; Rath, W; Caspers, R; Sosnowsky, K; Ziems, B; Thiesen, H-J; Maass, N; Huppertz, B

    2013-12-01

    Reduced serum LDL concentrations have been observed in pregnancies complicated by intrauterine growth restriction (IUGR) as compared to healthy pregnant women. Since increased oxidative stress has been suggested to play a major role in IUGR we now hypothesized that the lower LDL concentrations are accompanied by an accumulation of oxidized LDLs in the placenta. Fifteen placentas of near term and preterm born IUGR, and a gestational age matched control group (CTRL n = 15) were analyzed. Placental minimal modified LDL and fully oxidized LDL particles were measured by ELISA, and by immunohistochemistry, and were related to maternal and fetal serum lipid profiles. We found fully oxidized LDL but not minimal modified LDL being increased in the preterm subgroup of IUGR (n = 10) as compared to preterm CTRL (n = 10; p < 0.05). An increased staining intensity of trophoblasts in preterm IUGR subjects as compared to preterm CTRL has been confirmed by immunohistochemistry (p < 0.05). No difference could be found between the term groups (n = 5 each). Correlation analysis revealed an inverse relationship of maternal LDL (ρ = −0.49, p = 0.03) and fetal HDL cholesterol (ρ = −0.46, p = 0.04) with placental fully oxidized LDL particle concentration within preterms. IUGR is a heterogeneous entity. Different pathomechanisms seem to underlie the disease in preterm and term subjects with oxidation of LDL within the placenta possibly taking place in preterm IUGRs. We conclude that the reduced maternal LDL cholesterol concentration in IUGR pregnancies is attributed to increased accumulation of oxidized LDL particles within the placenta at least in early onset IUGR

  4. 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). Copyright © 2014 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  5. Maternal tissue blood flow and oxygen saturation in pre-eclampsia and intrauterine growth restriction.

    PubMed

    Karanam, V L; Page, N M; Anim-Nyame, N

    2014-07-01

    To investigate the hypothesis that impaired maternal tissue perfusion occurs in pre-eclampsia and intrauterine growth restriction (IUGR) and this correlates with maternal tissue oxygenation. Strain gauge plethysmography was used to compare maternal calf blood flow during the third trimester in 16 women with pre-eclampsia, 6 women with IUGR and 16 normal pregnant controls. A Mediaid iPOX pulse oximeter was used to measure maternal tissue oxygenation in the three groups and these were compared with tissue blood flow. Maternal tissue blood flow was significantly reduced in pre-eclampsia compared to the two other groups (p=0.003). Blood flow was significantly reduced in pre-eclampsia compared to IUGR (p=0.03). However there was no difference in blood flow between normal pregnancy and IUGR groups (p=0.76). No significant difference was noted in maternal tissue oxygenation between the normal pregnancy, pre-eclampsia and IUGR groups (mean±S.E.M. [97.13±0.4, 96.69±0.33, 97.83±0.47 respectively], p=0.26). No correlation was noted between blood flow and tissue oxygenation in the three groups of women. We have demonstrated that reduced maternal resting tissue blood flow present in women with pre-eclampsia is not seen in women with IUGR and the reduction in blood flow in pre-eclampsia is not associated with changes in maternal tissue oxygenation. Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.

  6. The influence of maternal Lewis, Secretor and ABO(H) blood groups on fetal growth restriction.

    PubMed

    Clark, P; Greer, I A

    2011-12-01

    Fetal growth restriction (FGR) is associated with thrombosis of the placenta and an increased risk of subsequent vascular disease in the mother and fetus. The products of interactions between ABO(H), Lewis and Secretor genes are also associated with thrombosis and vascular disease risk. A prospective case-control study of mothers with a severe FGR pregnancy (cases, n = 128; controls, n = 288) was performed to determine whether FGR is associated with particular maternal blood groups. No association with ABO(H) status was observed, but FGR was more common in maternal secretors (odds ratio [OR] 1.70, 95% confidence interval [CI] 1.08-2.69) and consequently in those mothers expressing Le(b) on their red cells (OR 1.80, 95% CI 1.15-2.83), with a reduced risk in non-secretors and those expressing Le(a). Given the association between blood groups and both activated protein C resistance (APCR) and von Willebrand factor (VWF) levels, post hoc pilot studies on first-trimester APCR and VWF antigen levels and blood group genotypes were performed. No relationship with Lewis or Secretor was observed. Despite this, lower first-trimester VWF levels were observed in pregnancies subsequently complicated by FGR.  This is the first study reporting a relationship between maternal Secretor/Lewis status and FGR. A link between blood groups and FGR is plausible, as both are associated with cardiovascular disease. We observed no relationship between Lewis/Secretor status and VWF or APCR, but this should be confirmed in a larger study. Thus, the mechanism whereby Secretor and/or Lewis influences FGR is unknown. © 2011 International Society on Thrombosis and Haemostasis.

  7. Sleep: A Window Into Autonomic Control in Children Born Preterm and Growth Restricted.

    PubMed

    Yiallourou, Stephanie R; Wallace, Euan M; Whatley, Christie; Odoi, Alexsandria; Hollis, Samantha; Weichard, Aidan J; Muthusamy, Jayan Shivanandhan; Varma, Suraj; Cameron, James; Narayan, Om; Horne, Rosemary S C

    2017-05-01

    Preterm birth and fetal growth restriction (FGR) are both associated with risk of hypertension in adulthood. Mechanisms leading to this pathology are unclear. In children aged 5-12 years, who were born preterm and FGR, we used sleep as a tool to assess autonomic control with assessment of cardiovascular structure and function. Eighteen children born preterm and FGR, 15 children born preterm with appropriate birth weights for gestational age (AGA), and 20 AGA term-born children were studied. Children underwent overnight polysomnography with the addition of continuous noninvasive blood pressure (Finometer™). Spectral measures of heart rate variability (HRV), blood pressure variability (BPV), and baroreflex sensitivity were assessed and overnight urinary catecholamine levels measured. Echocardiographic studies (Vivid7, GE Healthcare) were performed and vascular compliance assessed (Miller Instruments™). Statistical comparisons were adjusted for age and body size. Compared to term children, preterm AGA children had increased high frequency HRV (p < .05) and BPV (p < .05) during sleep, reflecting increased parasympathetic activation and blood pressure changes related to respiration. Preterm FGR children had smaller left ventricular lengths, ascending aorta, and left ventricular outflow tract diameter (p < .05 for all) and vascular compliance was positively correlated with gestational age (r2 = 0.93, p < .05). FGR combined with preterm birth did not alter autonomic control but altered heart structure in children. In contrast, preterm birth alone altered autonomic control but had no change in heart structure. These changes in children born preterm and FGR may contribute, in part, to increased risk of cardiovascular disease later in life but by different mechanisms.

  8. A computational model of the fetal circulation to quantify blood redistribution in intrauterine growth restriction.

    PubMed

    Garcia-Canadilla, Patricia; Rudenick, Paula A; Crispi, Fatima; Cruz-Lemini, Monica; Palau, Georgina; Camara, Oscar; Gratacos, Eduard; Bijnens, Bart H; Bijens, Bart H

    2014-06-01

    Intrauterine growth restriction (IUGR) due to placental insufficiency is associated with blood flow redistribution in order to maintain delivery of oxygenated blood to the brain. Given that, in the fetus the aortic isthmus (AoI) is a key arterial connection between the cerebral and placental circulations, quantifying AoI blood flow has been proposed to assess this brain sparing effect in clinical practice. While numerous clinical studies have studied this parameter, fundamental understanding of its determinant factors and its quantitative relation with other aspects of haemodynamic remodeling has been limited. Computational models of the cardiovascular circulation have been proposed for exactly this purpose since they allow both for studying the contributions from isolated parameters as well as estimating properties that cannot be directly assessed from clinical measurements. Therefore, a computational model of the fetal circulation was developed, including the key elements related to fetal blood redistribution and using measured cardiac outflow profiles to allow personalization. The model was first calibrated using patient-specific Doppler data from a healthy fetus. Next, in order to understand the contributions of the main parameters determining blood redistribution, AoI and middle cerebral artery (MCA) flow changes were studied by variation of cerebral and peripheral-placental resistances. Finally, to study how this affects an individual fetus, the model was fitted to three IUGR cases with different degrees of severity. In conclusion, the proposed computational model provides a good approximation to assess blood flow changes in the fetal circulation. The results support that while MCA flow is mainly determined by a fall in brain resistance, the AoI is influenced by a balance between increased peripheral-placental and decreased cerebral resistances. Personalizing the model allows for quantifying the balance between cerebral and peripheral-placental remodeling

  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.

  10. Umbilical venous pressure is unaltered by severe, early-onset growth restriction.

    PubMed

    Weiner, C P

    1997-01-01

    To determine whether severe, early-onset intrauterine growth restriction (IUGR) is associated with abnormal umbilical venous pressure (UVP) secondary to increased placental impedance. 42 singleton fetuses underwent fetal blood sampling from the umbilical vein during evaluation for severe, early-onset IUGR (diagnosed < 32 weeks or symmetrical IUGR diagnosed at any time in gestation). IUGR was confirmed at delivery. The UVP was measured with a solid-state transducer and corrected for amniotic fluid pressure. The ultimate cause of IUGR assigned was based on the antenatal laboratory and postnatal findings. Seven fetuses had a chromosome abnormality, 4 congenital viral infection, 8 miscellaneous causes and 23, by exclusion, uteroplacental (UP) dysfunction. Procedures complicated by fetal bradycardia were excluded because bradycardia raises the UVP. The mean gestation was 31.4 weeks (range 23-38). The umbilical artery resistance index (UA RI) was significantly higher in fetuses with IUGR secondary to either UP dysfunction or a chromosome abnormality compared to the remaining categories of IUGR. The UVP fell outside the 95% confidence interval in only 3 fetuses - 2 with aneuploidy (a 1:7 translocation with a normal UA RI and a mosaic trisomy 21), and 1 with UP dysfunction. The UVP rose with advancing gestation independent of the underlying cause of IUGR. There was an inverse relationship between UVP and the UA RI independent of gestation (r2 = 0.08, p < 0.05). There was an inverse relationship between the UA RI and both the UV pH and PO2 in the fetuses with UP dysfunction. However, there was no relationship between the UVP and either UVpH, UVPCO2, or UVpO2. These findings indicate that placental impedance has little clinically relevant impact on the UVP.

  11. Association of Reported Trimester-Specific Smoking Cessation and Fetal Growth Restriction

    PubMed Central

    Blatt, Kaitlin; Moore, Elizabeth; Chen, Aimin; Van Hook, James; DeFranco, Emily A.

    2016-01-01

    Objective To assess the association of reported smoking cessation at various time points during pregnancy with fetal growth restriction (FGR). Methods This was a population-based retrospective cohort study of singleton nonanomalous live births using Ohio birth certificates, 2006–2012. Outcomes of women who reported smoking only in the 3 months before conception and women who reported smoking through the first, second, or third trimester were compared to a referent group of nonsmokers. Multivariate logistic regression assessed the association between smoking cessation at various times in pregnancy and FGR less than the 10th and 5th percentiles. Results Of 927,424 births analyzed, 75% did not smoke. Of smokers, 24% smoked preconception only, 10% quit after the 1st trimester, 4% quit after the 2nd trimester, and 59% smoked throughout pregnancy. The rate of FGR less than the 10th and 5th percentiles among non-smokers was 8.1% and 3.6%, respectively. Although smoking only in the preconception period did not significantly increase FGR risk, smoking in any trimester did. The adjOR(95%CI) for FGR less than the 10th and 5th percentiles, respectively, of cessation after the 1st trimester was 1.19(1.13,1.24) and 1.25(1.17,1.33), and 1.67(1.57,1.78) and 1.83(1.68,1.99) for cessation after the second trimester. Women who reported smoking throughout pregnancy had the highest risks of FGR, 2.26 (2.22,2.31) and 2.44(2.37,2.51), after accounting for the influence of race, low socioeconomic status, and medical comorbidities. Conclusions Smoking of any duration during pregnancy is associated with an increased risk of FGR, with decreasing risk the earlier that cessation occurs. Smoking cessation programs should focus on the benefit of quitting as early in pregnancy as possible. PMID:26000517

  12. 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. Copyright © 2016 the American Physiological Society.

  13. A Computational Model of the Fetal Circulation to Quantify Blood Redistribution in Intrauterine Growth Restriction

    PubMed Central

    Garcia-Canadilla, Patricia; Rudenick, Paula A.; Crispi, Fatima; Cruz-Lemini, Monica; Palau, Georgina; Camara, Oscar; Gratacos, Eduard; Bijens, Bart H.

    2014-01-01

    Intrauterine growth restriction (IUGR) due to placental insufficiency is associated with blood flow redistribution in order to maintain delivery of oxygenated blood to the brain. Given that, in the fetus the aortic isthmus (AoI) is a key arterial connection between the cerebral and placental circulations, quantifying AoI blood flow has been proposed to assess this brain sparing effect in clinical practice. While numerous clinical studies have studied this parameter, fundamental understanding of its determinant factors and its quantitative relation with other aspects of haemodynamic remodeling has been limited. Computational models of the cardiovascular circulation have been proposed for exactly this purpose since they allow both for studying the contributions from isolated parameters as well as estimating properties that cannot be directly assessed from clinical measurements. Therefore, a computational model of the fetal circulation was developed, including the key elements related to fetal blood redistribution and using measured cardiac outflow profiles to allow personalization. The model was first calibrated using patient-specific Doppler data from a healthy fetus. Next, in order to understand the contributions of the main parameters determining blood redistribution, AoI and middle cerebral artery (MCA) flow changes were studied by variation of cerebral and peripheral-placental resistances. Finally, to study how this affects an individual fetus, the model was fitted to three IUGR cases with different degrees of severity. In conclusion, the proposed computational model provides a good approximation to assess blood flow changes in the fetal circulation. The results support that while MCA flow is mainly determined by a fall in brain resistance, the AoI is influenced by a balance between increased peripheral-placental and decreased cerebral resistances. Personalizing the model allows for quantifying the balance between cerebral and peripheral-placental remodeling

  14. Postnatal resveratrol supplementation improves cardiovascular function in male and female intrauterine growth restricted offspring.

    PubMed

    Shah, Amin; Quon, Anita; Morton, Jude S; Davidge, Sandra T

    2017-01-01

    Intrauterine growth restriction (IUGR) may predispose offspring to an increased susceptibility of developing cardiovascular disease (CVD) in adult life. The window of opportunity to treat later life CVD programmed in fetal life is critical. The aim of this study was to identify the effect of resveratrol treatment of IUGR offspring at a time of known CV dysfunction. Sprague-Dawley male and female rat offspring who experienced normoxia (21% O2; control) or hypoxia (11% O2; IUGR) in utero were fed a high-fat (HF) diet (3-21 weeks of age) or a HF diet (3-21 weeks of age) supplemented with resveratrol from 13 to 21 weeks of age. At 21 weeks of age, echocardiographic data showed that male IUGR offspring had mild in vivo diastolic dysfunction, whereas female IUGR offspring had early signs of cardiac diastolic dysfunction that was not altered by resveratrol treatment. Notably, male and female IUGR offspring demonstrated equal susceptibility to ex vivo cardiac dysfunction recovery after ischemia/reperfusion (I/R) injury and this was improved by resveratrol treatment, independent of sex. Resveratrol increased cardiac phospho-adenosine monophosphate kinase (p-AMPK) levels in only female IUGR offspring. IUGR or resveratrol did not alter cardiac superoxide levels. However, in male offspring, an overall effect of IUGR in reducing cardiac catalase levels was observed that was not altered by resveratrol. Interestingly, in only female IUGR offspring, resveratrol significantly increased cardiac superoxide dismutase (SOD) 2 levels. In conclusion, resveratrol treatment of adult IUGR offspring, at the time of known CV dysfunction, improved cardiac function recovery in both sexes and the mechanisms involved were partially sex-specific. © 2017 The Authors. Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society.

  15. Antenatal taurine supplementation for improving brain ultrastructure in fetal rats with intrauterine growth restriction.

    PubMed

    Liu, J; Liu, L; Chen, H

    2011-05-05

    Changes in brain ultrastructure of fetal rats with intrauterine growth restriction (IUGR) were explored and the effects of antenatal taurine supplementation on their brain ultrastructure were determined. Fifteen pregnant rats were randomly divided into three groups: control group, IUGR model group and IUGR group given antenatal taurine supplements. Taurine was added to the diet of the taurine group at a dose of 300 mg/kg/d from 12 days after conception until natural delivery. Transmission electron microscopy was used to observe ultrastructural changes in the brains of the newborn rats. At the same time, brain cellular apoptosis was detected using TUNEL, and the changes in protein expression of neuron specific enolase and glial fibrillary acidic protein were analyzed using immunohistochemistry. The results showed that: 1) The average body weight and cerebral weight were significantly lower in the IUGR group than in the control group (p<0.01) and both of them were less so after taurine was supplemented (p<0.01). 2) Transmission electron microscopy revealed that brain cortex structures were sparse IUGR rats, showing many scattered apoptotic cells, decreased numbers of synapses, lower glial cell proliferation, and fewer neurons, more sparsely arranged, while these factors were significantly improved with taurine supplementation. 3) The results of TUNEL showed that the counts of apoptotic brain cells in IUGR groups were significantly increased from those in control groups and that taurine could significantly decrease brain cell apoptosis (p<0.001). 4) The results of immunohistochemistry showed that antenatal taurine-supplementation could significantly increase the counts of neuron specific enolase and glial fibrillary acidic protein immunoreactive cells in fetal rats with IUGR (p<0.001). It can be concluded that it IUGR has a significant detrimental influence on the development of fetal rat brains, and antenatal supplement of taurine can significantly improve the IUGR

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

    PubMed Central

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

    2015-01-01

    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

  17. Fetal Echocardiography and Pulsed-wave Doppler Ultrasound in a Rabbit Model of Intrauterine Growth Restriction

    PubMed Central

    Hodges, Ryan; Endo, Masayuki; La Gerche, Andre; Eixarch, Elisenda; DeKoninck, Philip; Ferferieva, Vessilina; D'hooge, Jan; Wallace, Euan M.; Deprest, Jan

    2013-01-01

    Fetal intrauterine growth restriction (IUGR) results in abnormal cardiac function that is apparent antenatally due to advances in fetoplacental Doppler ultrasound and fetal echocardiography. Increasingly, these imaging modalities are being employed clinically to examine cardiac function and assess wellbeing in utero, thereby guiding timing of birth decisions. Here, we used a rabbit model of IUGR that allows analysis of cardiac function in a clinically relevant way. Using isoflurane induced anesthesia, IUGR is surgically created at gestational age day 25 by performing a laparotomy, exposing the bicornuate uterus and then ligating 40-50% of uteroplacental vessels supplying each gestational sac in a single uterine horn. The other horn in the rabbit bicornuate uterus serves as internal control fetuses. Then, after recovery at gestational age day 30 (full term), the same rabbit undergoes examination of fetal cardiac function. Anesthesia is induced with ketamine and xylazine intramuscularly, then maintained by a continuous intravenous infusion of ketamine and xylazine to minimize iatrogenic effects on fetal cardiac function. A repeat laparotomy is performed to expose each gestational sac and a microultrasound examination (VisualSonics VEVO 2100) of fetal cardiac function is performed. Placental insufficiency is evident by a raised pulsatility index or an absent or reversed end diastolic flow of the umbilical artery Doppler waveform. The ductus venosus and middle cerebral artery Doppler is then examined. Fetal echocardiography is performed by recording B mode, M mode and flow velocity waveforms in lateral and apical views. Offline calculations determine standard M-mode cardiac variables, tricuspid and mitral annular plane systolic excursion, speckle tracking and strain analysis, modified myocardial performance index and vascular flow velocity waveforms of interest. This small animal model of IUGR therefore affords examination of in utero cardiac function that is

  18. Metabolomics Reveals Metabolic Alterations by Intrauterine Growth Restriction in the Fetal Rabbit Brain

    PubMed Central

    van Vliet, Erwin; Eixarch, Elisenda; Illa, Miriam; Arbat-Plana, Ariadna; González-Tendero, Anna; Hogberg, Helena T.; Zhao, Liang; Hartung, Thomas; Gratacos, Eduard

    2013-01-01

    Background Intrauterine Growth Restriction (IUGR) due to placental insufficiency occurs in 5–10% of pregnancies and is a major risk factor for abnormal neurodevelopment. The perinatal diagnosis of IUGR related abnormal neurodevelopment represents a major challenge in fetal medicine. The development of clinical biomarkers is considered a promising approach, but requires the identification of biochemical/molecular alterations by IUGR in the fetal brain. This targeted metabolomics study in a rabbit IUGR model aimed to obtain mechanistic insight into the effects of IUGR on the fetal brain and identify metabolite candidates for biomarker development. Methodology/Principal Findings At gestation day 25, IUGR was induced in two New Zealand rabbits by 40–50% uteroplacental vessel ligation in one horn and the contralateral horn was used as control. At day 30, fetuses were delivered by Cesarian section, weighed and brains collected for metabolomics analysis. Results showed that IUGR fetuses had a significantly lower birth and brain weight compared to controls. Metabolomics analysis using liquid chromatography-quadrupole time-of-flight mass spectrometry (LC-QTOF-MS) and database matching identified 78 metabolites. Comparison of metabolite intensities using a t-test demonstrated that 18 metabolites were significantly different between control and IUGR brain tissue, including neurotransmitters/peptides, amino acids, fatty acids, energy metabolism intermediates and oxidative stress metabolites. Principle component and hierarchical cluster analysis showed cluster formations that clearly separated control from IUGR brain tissue samples, revealing the potential to develop predictive biomarkers. Moreover birth weight and metabolite intensity correlations indicated that the extent of alterations was dependent on the severity of IUGR. Conclusions IUGR leads to metabolic alterations in the fetal rabbit brain, involving neuronal viability, energy metabolism, amino acid levels, fatty

  19. Placental corticotropin-releasing hormone (CRH), spontaneous preterm birth, and fetal growth restriction: a prospective investigation.

    PubMed

    Wadhwa, Pathik D; Garite, Thomas J; Porto, Manuel; Glynn, Laura; Chicz-DeMet, Aleksandra; Dunkel-Schetter, Christine; Sandman, Curt A

    2004-10-01

    Recent advances in the physiology of human pregnancy have implicated placental corticotropin-releasing hormone (CRH) as one of the primary endocrine mediators of parturition and possibly also of fetal development. The aim of this study was (1) to prospectively assess the relationship of maternal plasma concentrations of CRH in the early third trimester of gestation with two prematurity-related outcomes-spontaneous preterm birth (PTB), and small-for-gestational age birth (SGA), and (2) to determine whether the effects of CRH on each of these outcomes are independent from those of other established obstetric risk factors. In a sample of 232 women with a singleton, intrauterine pregnancy, maternal plasma was collected at 33 weeks' gestation and CRH concentrations were determined by radioimmunoassay. Each pregnancy was dated on the basis of last menstrual period and early ultrasonography. Parity, obstetric risk conditions for prematurity, mode of delivery, and birth outcomes were abstracted from the medical record. After adjusting for the effects of established obstetric risk factors, elevated CRH levels at 33 weeks' gestation were significantly associated with a 3.3-fold increase in the adjusted relative risk (RR) for spontaneous preterm birth and with a 3.6-fold increase in the adjusted relative risk for fetal growth restriction. Women who delivered postterm had significantly lower CRH levels in the early third trimester than those who delivered at term. When outcomes were stratified by gestational length and birth weight, the lowest CRH levels at 33 weeks' gestation were associated with the term non-SGA births, intermediate and approximately equal CRH levels were associated with the preterm non-SGA and term SGA births, and the highest CRH levels were associated with the preterm SGA births. For deliveries occurring after 33 weeks' gestation (the time of CRH sampling in this study), our findings support the notion that in humans placental CRH may play an impending

  20. Automated volumetric segmentation method for growth consistency of nonsolid pulmonary nodules in high-resolution CT

    NASA Astrophysics Data System (ADS)

    Browder, William A.; Reeves, Anthony P.; Apananosovich, Tatiyana V.; Cham, Matthew D.; Yankelevitz, David F.; Henschke, Claudia I.

    2007-03-01

    There is widespread clinical interest in the study of pulmonary nodules for early diagnosis of lung cancer. These nodules can be broadly classified into one of three types, solid, nonsolid and part-solid. Solid nodules have been extensively studied, while little research has focused on the characterization of nonsolid and part-solid nodules. Nonsolid nodules have an appearance in high-resolution CT consisting of voxels only slightly more dense than that of the surrounding lung parenchyma. For the solid nodule, robust techniques are available to estimate growth rate and this is commonly used to distinguish benign from malignant. For the nonsolid types, these techniques are less well developed. In this research, we propose an automated volumetric segmentation method for nonsolid nodules that accurately determines a nonsolid nodule's growth rate. Our method starts with an initial noise-filtering stage in the parenchyma region. Each voxel is then classified into one of three tissue types; lung parenchyma, nonsolid and solid. Removal of vessel attachments to the lesion is achieved with the use of a filter that focuses on vessel characteristics. Our results indicate that the automated method is more consistent than the radiologist with a median growth consistency of 1.87 compared to 3.12 for the radiologist on a database of 25 cases.

  1. Effects of basic fibroblast growth factor and cyclin D1 on cigarette smoke-induced pulmonary vascular remodeling in rats.

    PubMed

    Zhou, Sijing; Li, Min; Zeng, Daxiong; Sun, Gengyun; Zhou, Junsheng; Wang, Ran

    2015-01-01

    Cigarette smoking may contribute to pulmonary hypertension in chronic obstructive pulmonary disease by resulting in pulmonary vascular remodeling that involves pulmonary artery smooth muscle cell proliferation. This study investigated the effects of basic fibroblast growth factor (bFGF) and cyclin D1 on the pulmonary vascular remodeling in smoking-exposed rats. Twenty-four male Wistar rats were randomly divided into four groups. Three tobacco-exposed groups were exposed to the smoke produced by 20 cigarettes for 60 min, twice a day for two, four or eight weeks, and the control group were exposed to fresh air. The expression of bFGF and cyclin D1 in the pulmonary arterial smooth muscle cells were determined using immunohistochemistry. Quantitative polymerase chain reaction was conducted to determine the expression levels of bFGF and cyclin D1 mRNA. In addition, the expression of bFGF and cyclin D1 proteins was evaluated by western blotting. The expression of bFGF and cyclin D1 at the mRNA and protein levels was shown to increase with the duration of smoke exposure (P<0.05). The correlation analysis indicated the expression of bFGF and cyclin D1 was positively associated with the pulmonary vessel wall thickness. The expression of bFGF was positively associated with that of cyclin D1. Collectively, the data demonstrated that the upregulation of bFGF and cyclin D1 occurred in rats subjected to smoke exposure, which may be associated with the abnormal proliferation of the smooth muscle cells in the pulmonary arteries.

  2. A review of methionine dependency and the role of methionine restriction in cancer growth control and life-span extension.

    PubMed

    Cavuoto, Paul; Fenech, Michael F

    2012-10-01

    Methionine is an essential amino acid with many key roles in mammalian metabolism such as protein synthesis, methylation of DNA and polyamine synthesis. Restriction of methionine may be an important strategy in cancer growth control particularly in cancers that exhibit dependence on methionine for survival and proliferation. Methionine dependence in cancer may be due to one or a combination of deletions, polymorphisms or alterations in expression of genes in the methionine de novo and salvage pathways. Cancer cells with these defects are unable to regenerate methionine via these pathways. Defects in the metabolism of folate may also contribute to the methionine dependence phenotype in cancer. Selective killing of methionine dependent cancer cells in co-culture with normal cells has been demonstrated using culture media deficient in methionine. Several animal studies utilizing a methionine restricted diet have reported inhibition of cancer growth and extension of a healthy life-span. In humans, vegan diets, which can be low in methionine, may prove to be a useful nutritional strategy in cancer growth control. The development of methioninase which depletes circulating levels of methionine may be another useful strategy in limiting cancer growth. The application of nutritional methionine restriction and methioninase in combination with chemotherapeutic regimens is the current focus of clinical studies. Copyright © 2012 Elsevier Ltd. All rights reserved.

  3. D-lactate increases pulmonary apoptosis by restricting phosphorylation of bad and eNOS in a rat model of hemorrhagic shock.

    PubMed

    Jaskille, Amín; Alam, Hasan B; Rhee, Peter; Hanes, William; Kirkpatrick, John R; Koustova, Elena

    2004-08-01

    Resuscitation with racemic lactated Ringer's solution (containing equal amounts of D and L isomers of lactate) has been shown to induce pulmonary apoptosis. Substitution of DL-isomer lactate with ketone bodies (beta-hydroxybutyrate, BHB), sodium pyruvate, or L-isomer of lactate decrease this injury without changing the energy status of the tissues or the expression of apoptotic genes. These modified solutions however alter the function of apoptotic proteins through an unknown mechanism. We postulated that DL-LR induces apoptosis by restricting the phosphorylation of key apoptotic proteins. Male Sprague Dawley rats (n = 30, 5/group) were subjected to a three stage, volume-controlled hemorrhage and randomized to the following groups. 1) No hemorrhage (Sham); 2) Hemorrhage and no resuscitation (NR); 3) Resuscitation with 3x shed blood volume of racemic LR (DL-LR); 4) Resuscitation with 3x shed blood volume of LR containing only the L-isomer of lactate (L-LR); 5) Resuscitation with 3s shed blood volume of pyruvate Ringer's (PR); 6) Resuscitation with 3s shed blood volume of ketone Ringer's (KR). The modified Ringer's solutions were identical to racemic LR except for equimolar substitution of DL-lactate for L-lactate, pyruvate and BHB respectively. Lung tissue was obtained 2 hours later and subjected to Western Blotting. The levels of Akt, Bad, and eNOS (total and phosphorylated) proteins were measured. Finally, the expression of gene coding for protein 14-3-3 was measured using RT-PCR. Resuscitation with DL-LR caused a significant (p < 0.05) increase in the total Bad and a decrease in phosphorylated Bad protein expression in the lung. It also caused an increase in the phosphorylated Akt levels and a decrease in gene coding for protein 14-3-3. These changes were consistent with signaling imbalances that favor apoptosis. Modified LR solutions, on the other hand, did not cause these alterations. Phosphorylation pattern of eNOS supported the involvement of PI3K/Akt pathway

  4. 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

  5. Contingent versus routine third-trimester screening for late fetal growth restriction.

    PubMed

    Triunfo, S; Crovetto, F; Scazzocchio, E; Parra-Saavedra, M; Gratacos, E; Figueras, F

    2016-01-01

    To evaluate the use of third-trimester ultrasound screening for late fetal growth restriction (FGR) on a contingent basis, according to risk accrued in the second trimester, in an unselected population. Maternal characteristics, fetal biometry and second-trimester uterine artery (UtA) Doppler were included in logistic regression analysis to estimate risk for late FGR (birth weight < 3(rd) percentile, or 3(rd) -10(th) percentile plus abnormal cerebroplacental ratio or UtA Doppler, with delivery ≥ 34 weeks). Based on the second-trimester risk, strategies for performing contingent third-trimester ultrasound examinations in 10%, 25% or 50% of the cohort were tested against a strategy of routine ultrasound scanning in the entire population at 32 + 0 to 33 + 6 weeks. Models were constructed based on 1393 patients and validated in 1303 patients, including 73 (5.2%) and 82 late FGR (6.3%) cases, respectively. At the second-trimester scan, the a-posteriori second-trimester risk (a-posteriori first-trimester risk (baseline a-priori risk and mean arterial blood pressure) combined with second-trimester abdominal circumference and UtA Doppler) yielded an area under the receiver-operating characteristics curve (AUC) of 0.81 (95% CI, 0.74-0.87) (detection rate (DR), 43.1% for a 10% false-positive rate (FPR)). The combination of a-posteriori second-trimester risk plus third-trimester estimated fetal weight (full model) yielded an AUC of 0.92 (95% CI, 0.88-0.96) (DR, 74% for a 10% FPR). Subjecting 10%, 25% or 50% of the study population to third-trimester ultrasound, based on a-posteriori second-trimester risk, gave AUCs of 0.81 (95% CI, 0.75-0.88), 0.84 (95% CI, 0.78-0.91) and 0.89 (95% CI, 0.84-0.94), respectively. Only the 50% contingent model proved statistically equivalent to performing routine third-trimester ultrasound scans (AUC, 0.92 (95% CI, 0.88-0.96), P = 0.11). A strategy of selecting 50% of the study population to undergo third

  6. Fetal Growth Restriction with Brain Sparing: Neurocognitive and Behavioral Outcomes at 12 Years of Age.

    PubMed

    Beukers, Fenny; Aarnoudse-Moens, Cornelieke S H; van Weissenbruch, Mirjam M; Ganzevoort, Wessel; van Goudoever, Johannes B; van Wassenaer-Leemhuis, Aleid G

    2017-09-01

    To study neurocognitive functions and behavior in children with a history of fetal growth restriction (FGR) with brain sparing. We hypothesized that children with FGR would have poorer outcomes on these domains. Subjects were 12-year-old children with a history of FGR born to mothers with severe early-onset hypertensive pregnancy disorders (n = 96) compared with a normal functioning full term comparison group with a birth weight ≥2500 g (n = 32). Outcome measures were neurocognitive outcomes (ie, intelligence quotient, executive function, attention) and behavior. For the FGR group, the mean ratio of the pulsatility index for the umbilical artery/middle cerebral artery (UC-ratio = severity of brain sparing) was 1.42 ± 0.69. The mean gestational age was 31-6/7  ± 2-2/7 weeks. The mean birth weight was 1341  ± 454 g, and the mean birth weight ratio 0.68 ± 0.12. Neurocognitive outcomes were comparable between groups. Parents of children with FGR reported more social problems (mean T-score 56.6 ± 7.7; comparison 52.3 ± 4.3, P < .001, effect size = 1, 95% CI 0.52-1.46) and attention problems (mean T-score 57.3 ± 6.9; comparison 53.6 ± 4.2, P = .004, effect size = 0.88, 95% CI 0.42-1.33). UC-ratio was not associated with any of the outcomes, but low parental education and lower birth weight ratio were. In this prospective follow-up study of 12-year-old children with a history of FGR and confirmed brain sparing, neurocognitive functions were comparable with the comparison group, but parent-reported social and attention problem scores were increased. Copyright © 2017 Elsevier Inc. All rights reserved.

  7. MR Imaging Measurements of Altered Placental Oxygenation in Pregnancies Complicated by Fetal Growth Restriction.

    PubMed

    Ingram, Emma; Morris, David; Naish, Josephine; Myers, Jenny; Johnstone, Edward

    2017-07-14

    Purpose To evaluate oxygen-enhanced and blood oxygen level-dependent (BOLD) magnetic resonance (MR) imaging parameters in normal pregnancies and those complicated by fetal growth restriction (FGR). Materials and Methods This case-control study was approved by the local research ethics committee. Informed consent was obtained from all subjects. From October 2010 to October 2015, 28 women with uncomplicated pregnancies (individualized birthweight ratio [IBR] >20th percentile and delivery >37 weeks) and 23 with pregnancies complicated by FGR (IBR <5th percentile and abnormal Doppler ultrasonography [US] studies) underwent MR imaging. Differences in placental longitudinal R1 (1/T1) and transverse R2* (1/T2*) were quantified, with subjects breathing either air or oxygen. The difference in R1 (ΔR1) after hyperoxia was converted to change in partial pressure of oxygen (ΔPo2). Data were acquired prospectively, with retrospective interpretation of group differences (unpaired t tests). Diagnostic models were developed by using logistic regression analysis with gestational age as a covariate. Results The mean baseline R1 and R2* for normal pregnancies (R1: 0.59 sec(-1), 95% confidence interval [CI]: 0.58 sec(-1), 0.60 sec(-1); R2*: 17 sec(-1), 95% CI: 14 sec(-1), 20 sec(-1)) were significantly different from those of pregnancies complicated by FGR (R1: 0.63 sec(-1), 95% CI: 0.62 sec(-1), 0.65 sec(-1); R2*: 26 sec(-1), 95% CI: 22 sec(-1), 32 sec(-1)) (P < .0001). The ΔR1 showed a significant negative association with gestational age (P < .0001) in the combined cohort, with the FGR group having a ΔR1 that was generally 61.5% lower than that in the normal pregnancy group (P = .003). The area under the receiver operating characteristic curve for the differentiation between pregnancy complicated by FGR and normal pregnancy by using ΔPo2, baseline R1, and baseline R2* was 0.91 (95% CI: 0.82, 0.99). Conclusion R1, R2*, and ΔPo2 were significantly different between normal

  8. Altered transmission of maternal angiotensin II receptor haplotypes in fetal growth restriction.

    PubMed

    Tower, Clare; Chappell, Sally; Acharya, Meera; Crane, Richard; Szolin, Stephanie; Symonds, Lyneth; Chevins, Helen; Kalsheker, Noor; Baker, Philip; Morgan, Linda

    2006-02-01

    Fetal growth restriction (FGR) predisposes to significant short- and long-term health problems. Epidemiological studies have suggested a role for inherited factors in its pathogenesis. The angiotensin II receptor genes, AGTR1 and AGTR2, are candidate genes because they mediate processes that are important for placentation. This study investigated AGTR1 and AGTR2 haplotypes and genotypes in FGR. A total of 107 families (father, mother, and baby) with FGR, and 101 families with normal pregnancies were genotyped at five sites in AGTR1 and six sites across AGTR2. All of the participants were white western Europeans. FGR was identified antenatally by ultrasound scans and confirmed postnatally by correcting the birth weight centile for gestation, infant sex, maternal height, weight, and parity. Fetal genes were investigated using transmission disequilibrium testing (TDT), and a case-control comparison of maternal haplotypes was conducted. FGR was associated with maternal (but not paternal) transmission of the AGTR1 haplotype (GenBank AF245699.1) g.4955T, g.5052T, g.5245C, g.5612A, and haplotype g.4955T, g.5052T, g.5245T, g.5612A. Haplotype g.4955A, g.5052G, g.5245T, g.5612G was undertransmitted (P = 0.002). TDT of the AGTR1 genotype showed undertransmission of maternal AGTR1 genotypes g.4955T>A (odds ratio (OR), 0.34 (95% confidence interval (CI), 0.14-0.86); P = 0.02), g.5052T>G (OR, 0.18 (0.06-0.48); P<0.001), and g.5612A>G (OR, 0.21 (0.08-0.55); P < 0.001) in FGR. There were no differences in maternal haplotype frequencies between normal pregnancy and FGR for AGTR1 or AGTR2 (P > 0.10). This is the first study to show distortion of transmission of maternal AGTR1 haplotypes in FGR, which suggests that this gene plays a role in FGR. In particular, maternal-fetal gene sharing may be an important factor. 2006 Wiley-Liss, Inc.

  9. 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.

  10. Growth hormone abolishes beneficial effects of calorie restriction in long-lived Ames dwarf mice.

    PubMed

    Gesing, Adam; Al-Regaiey, Khalid A; Bartke, Andrzej; Masternak, Michal M

    2014-10-01

    Disruption of the growth hormone (GH) axis promotes longevity and delays aging. In contrast, GH over-expression may lead to accelerated aging and shorter life. Calorie restriction (CR) improves insulin sensitivity and may extend lifespan. Long-lived Ames dwarf (df/df) mice have additional extension of longevity when subjected to 30% CR. The aim of the study was to assess effects of CR or GH replacement therapy separately and as a combined (CR+GH) treatment in GH-deficient df/df and normal mice, on selected metabolic parameters (e.g., insulin, glucose, cholesterol), insulin signaling components (e.g., insulin receptor [IR] β-subunit, phosphorylated form of IR [IR pY1158], protein kinase C ζ/λ [p-PKCζ/λ] and mTOR [p-mTOR]), transcription factor p-CREB, and components of the mitogen-activated protein kinase (MAPK) signaling (p-ERK1/2, p-p38), responsible for cell proliferation, differentiation and survival. CR decreased plasma levels of insulin, glucose, cholesterol and leptin, and increased hepatic IR β-subunit and IR pY1158 levels as well as IR, IRS-1 and GLUT-2 gene expression compared to ad libitum feeding, showing a significant beneficial diet intervention effect. Moreover, hepatic protein levels of p-PKCζ/λ, p-mTOR and p-p38 decreased, and p-CREB increased in CR mice. On the contrary, GH increased levels of glucose, cholesterol and leptin in plasma, and p-mTOR or p-p38 in livers, and decreased plasma adiponectin and hepatic IR β-subunit compared to saline treatment. There were no GH effects on adiponectin in N mice. Moreover, GH replacement therapy did not affect IR, IRS-1 and GLUT-2 gene expression. GH treatment abolishes the beneficial effects of CR; it may suggest an important role of GH-IGF1 axis in mediating the CR action. Suppressed somatotrophic signaling seems to predominate over GH replacement therapy in the context of the examined parameters and signaling pathways.

  11. 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

  12. Placental pulsatility index: a new, more sensitive parameter for predicting adverse outcome in pregnancies suspected of fetal growth restriction.

    PubMed

    Gudmundsson, Saemundur; Flo, Kari; Ghosh, Gisela; Wilsgaard, Tom; Acharya, Ganesh

    2017-02-01

    The pulsatility indices of the umbilical and uterine arteries are used as the surrogate measures of utero-placental perfusion. Combining the two might simplify the evaluation of total placental vascular impedance, possibly improve prediction of adverse outcomes, and help identify pregnancies with suspected fetal growth restriction that need more intense surveillance. Umbilical and uterine blood flow velocities were recorded using pulsed-wave Doppler in a longitudinal study of 53 low-risk pregnancies (248 observations) during 20-40 weeks of gestation. Pulsatility indices was calculated for each of these vessels. A new placental pulsatility index was constructed as: (umbilical artery pulsatility index + mean of the left and right uterine artery pulsatility indices)/2, and mean +2 SD defined as abnormal. Gestational age-specific reference percentiles were calculated for the second half of pregnancy and related to values obtained from 340 pregnancies with suspected intra-uterine growth restriction to test its ability to predict adverse pregnancy outcome. The placental pulsatility index was closely associated with gestational age and decreased with advancing gestation in normal pregnancy. The placental pulsatility index had a higher sensitivity and comparable specificity in predicting adverse outcome in pregnancies suspected of intra-uterine fetal growth restriction when compared with conventional umbilical and uterine artery pulsatility indices. The new placental pulsatility index, reflecting placental vascular impedance on both the fetal and maternal side of placenta, improves prediction of adverse outcome in pregnancies suspected of intra-uterine fetal growth restriction. © 2017 Nordic Federation of Societies of Obstetrics and Gynecology.

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

    PubMed

    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 a 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 paper 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.

  14. Restriction of placental and fetal growth in sheep alters fetal blood pressure responses to angiotensin II and captopril

    PubMed Central

    Edwards, L J; Simonetta, G; Owens, J A; Robinson, J S; McMillen, I C

    1999-01-01

    We have measured arterial blood pressure between 115 and 145 days gestation in normally grown fetal sheep (control group; n = 16) and in fetal sheep in which growth was restricted by experimental restriction of placental growth and development (PR group; n = 13). There was no significant difference in the mean gestational arterial blood pressure between the PR (42.7 ± 2.6 mmHg) and control groups (37.7 ± 2.3 mmHg). Mean arterial blood pressure and arterial PO2 were significantly correlated in control animals (r = 0.53, P < 0.05, n = 16), but not in the PR group.There were no changes in mean arterial blood pressure in either the PR or control groups in response to captopril (7.5 μg captopril min−1; PR group n = 7, control group n = 6) between 115 and 125 days gestation. After 135 days gestation, there was a significant decrease (P < 0.05) in the fetal arterial blood pressure in the PR group but not in the control group during the captopril infusion (15 μg captopril min−1; PR group n = 7, control group n = 6).There was a significant effect (F = 14.75; P < 0.001) of increasing doses of angiotensin II on fetal diastolic blood pressure in the PR and control groups. The effects of angiotensin II were different (F = 8.67; P < 0.05) in the PR and control groups at both gestational age ranges.These data indicate that arterial blood pressure may be maintained by different mechanisms in growth restricted fetuses and normally grown counterparts and suggests a role for the fetal renin-angiotensin system in the maintenance of blood pressure in growth restricted fetuses. PMID:10066914

  15. MicroRNA-326 Regulates Profibrotic Functions of Transforming Growth Factor-β in Pulmonary Fibrosis

    PubMed Central

    Das, Sudipta; Kumar, Manish; Negi, Vinny; Pattnaik, Bijay; Prakash, Y. S.; Agrawal, Anurag

    2014-01-01

    Idiopathic pulmonary fibrosis (IPF) is a fatal disorder resulting from the progressive remodeling of lungs, with no known effective treatment. Although transforming growth factor (TGF)-β has a well-established role in lung fibrosis, clinical experience with neutralizing antibodies to TGF-β has been disappointing, and strategies to directly suppress TGF-β1 secretion are needed. In this study we used a combination of in silico, in vitro, and in vivo approaches to identify microRNAs involved in TGF-β1 regulation and to validate the role of miR-326 in pulmonary fibrosis.We show that hsa-miR-326 regulates TGF-β1 expression and that hsa-miR-326 levels are inversely correlated to TGF-β1 protein levels in multiple human cell lines. The increase in TGF-β1 expression during the progression of bleomycin-induced lung fibrosis in mice was associated with loss of mmu-miR-326. Restoration of mmu-miR-326 levels by intranasal delivery of miR-326 mimics was sufficient to inhibit TGF-β1 expression and attenuate the fibrotic response. Moreover, human IPF lung specimens had markedly diminished miR-326 expression as compared with nonfibrotic lungs. Additional targets of miR-326 controlling TGF-β signaling and fibrosis-related pathways were identified, and miR-326 was found to down-regulate profibrotic genes, such as Ets1, Smad3, and matrix metalloproteinase 9, whereas it up-regulates antifibrotic genes, such as Smad7. Our results suggest for the first time that miR-326 plays a key role in regulating TGF-β1 expression and other profibrotic genes and could be useful in developing better therapeutic strategies for alleviating lung fibrosis. PMID:24279830

  16. 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

  17. 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

  18. Postnatal growth velocity modulates alterations of proteins involved in metabolism and neuronal plasticity in neonatal hypothalamus in rats born with intrauterine growth restriction.

    PubMed

    Alexandre-Gouabau, Marie-Cécile F; Bailly, Emilie; Moyon, Thomas L; Grit, Isabelle C; Coupé, Bérengère; Le Drean, Gwenola; Rogniaux, Hélène J; Parnet, Patricia

    2012-02-01

    Intrauterine growth restriction (IUGR) due to maternal protein restriction is associated in rats with an alteration in hypothalamic centers involved in feeding behaviour. In order to gain insight into the mechanism of perinatal maternal undernutrition in the brain, we used proteomics approach to identify hypothalamic proteins that are altered in their expression following protein restriction in utero. We used an animal model in which restriction of the protein intake of pregnant rats (8% vs. 20%) produces IUGR pups which were randomized to a nursing regimen leading to either rapid or slow catch-up growth. We identified several proteins which allowed, by multivariate analysis, a very good discrimination of the three groups according to their perinatal nutrition. These proteins were related to energy-sensing pathways (Eno 1, E(2)PDH, Acot 1 and Fabp5), redox status (Bcs 1L, PrdX3 and 14-3-3 protein) or amino acid pathway (Acy1) as well as neurodevelopment (DRPs, MAP2, Snca). In addition, the differential expressions of several key proteins suggested possible shunts towards ketone-body metabolism and lipid oxidation, providing the energy and carbon skeletons necessary to lipogenesis. Our results show that maternal protein deprivation during pregnancy only (IUGR with rapid catch-up growth) or pregnancy and lactation (IUGR with slow postnatal growth) modulates numerous metabolic pathways resulting in alterations of hypothalamic energy supply. As several of these pathways are involved in signalling, it remains to be determined whether hypothalamic proteome adaptation of IUGR rats in response to different postnatal growth rates could also interfere with cerebral plasticity or neuronal maturation.

  19. Basic fibroblast growth factor activates β-catenin/RhoA signaling in pulmonary fibroblasts with chronic obstructive pulmonary disease in rats.

    PubMed

    Ge, Zhengxing; Li, Bo; Zhou, Xun; Yang, Yi; Zhang, Jun

    2016-12-01

    Chronic obstructive pulmonary disease (COPD) is featured by aberrant extracellular matrix (ECM) deposition. Trigger of the β-catenin/RhoA pathway has been involved in aberrant ECM deposition in several diseases. We investigated WNT signaling activation in primary pulmonary fibroblasts of rats with and without COPD and the function of WNT signaling in pulmonary fibroblast. We evaluated the expression of WNT signaling and the role of β-catenin, using MRC-5 fibroblasts and primary lung fibroblasts of rats with and without COPD. Lung fibroblasts highly expressed mRNA of genes associated with WNT signaling. Treatment of MRC-5 fibroblasts using basic fibroblast growth factor (bFGF), a composition of the mucus in COPD patients, enhanced β-catenin, Wnt5a and RhoA expression. The expression in β-catenin, Wnt5a and RhoA induced by bFGF was higher in fibroblasts of rats with COPD than without COPD, whereas the basal expression was similar. bFGF also activated transcriptionally active and increased total β-catenin protein expression. Moreover, bFGF enhanced the expression of α-sm-actin and fibronectin, which was abrogated by β-catenin, Wnt5a and RhoA-specific adenovirus siRNA. The induction of active β-catenin and then fibronectin turnover in response to bFGF were markedly increased in pulmonary fibroblasts from rat with COPD. β-Catenin/RhoA pathway results in ECM deposition in lung fibroblasts and myofibroblasts differentiation. β-catenin/RhoA signaling induced by bFGF is promoted in lung fibroblasts from rats with COPD. The study indicated a crucial role of the WNT signaling in mediating fibroblast morphology and function in COPD.

  20. Prostaglandin F(2alpha) receptor signaling facilitates bleomycin-induced pulmonary fibrosis independently of transforming growth factor-beta.

    PubMed

    Oga, Toru; Matsuoka, Toshiyuki; Yao, Chengcan; Nonomura, Kimiko; Kitaoka, Shiho; Sakata, Daiji; Kita, Yoshihiro; Tanizawa, Kiminobu; Taguchi, Yoshio; Chin, Kazuo; Mishima, Michiaki; Shimizu, Takao; Narumiya, Shuh

    2009-12-01

    Idiopathic pulmonary fibrosis (IPF) is a progressive disease characterized by fibroblast proliferation and excess deposition of collagen and other extracellular matrix (ECM) proteins, which lead to distorted lung architecture and function. Given that anti-inflammatory or immunosuppressive therapy currently used for IPF does not improve disease progression therapies targeted to blocking the mechanisms of fibrogenesis are needed. Although transforming growth factor-beta (TGF-beta) functions are crucial in fibrosis, antagonizing this pathway in bleomycin-induced pulmonary fibrosis, an animal model of IPF, does not prevent fibrosis completely, indicating an additional pathway also has a key role in fibrogenesis. Given that the loss of cytosolic phospholipase A(2) (cPLA(2)) suppresses bleomycin-induced pulmonary fibrosis, we examined the roles of prostaglandins using mice lacking each prostoaglandin receptor. Here we show that loss of prostaglandin F (PGF) receptor (FP) selectively attenuates pulmonary fibrosis while maintaining similar levels of alveolar inflammation and TGF-beta stimulation as compared to wild-type (WT) mice, and that FP deficiency and inhibition of TGF-beta signaling additively decrease fibrosis. Furthermore, PGF(2alpha) is abundant in bronchoalveolar lavage fluid (BALF) of subjects with IPF and stimulates proliferation and collagen production of lung fibroblasts via FP, independently of TGF-beta. These findings show that PGF(2alpha)-FP signaling facilitates pulmonary fibrosis independently of TGF-beta and suggests this signaling pathway as a therapeutic target for IPF.

  1. Novel therapeutic approach for pulmonary emphysema using gelatin microspheres releasing basic fibroblast growth factor in a canine model.

    PubMed

    Chang, Sung Soo; Yokomise, Hiroyasu; Matsuura, Natsumi; Gotoh, Masashi; Tabata, Yasuhiko

    2014-08-01

    The prognosis of patients with emphysema is poor as there is no truly effective treatment. Our previous study showed that the alveolar space was smaller and the microvessel density was higher in a canine emphysema model after the intrapulmonary arterial administration of gelatin microspheres slowly releasing basic fibroblast growth factor (bFGF-GMS). In the present study, we evaluated the functional effect of injecting bFGF-GMS via the pulmonary artery in this canine pulmonary emphysema model. Using the porcine pancreatic elastase (PPE)-induced total emphysema model, we approximated the value of lung compliance with a Power Lab System, and performed blood gas analysis in a control group, a total emphysema group, and a bFGF group in which bFGF-GMS were injected toward the whole pulmonary artery via the femoral vein. Each group comprised five dogs. Lung compliance was higher in the total emphysema group than in the control group (p = 0.031), and the bFGF group showed no significant improvement of lung compliance vs. the total emphysema group (p = 0.112). PaO2 (partial pressure of oxygen in arterial blood) was improved by administering bFGF-GMS in the total emphysema model (p = 0.027). In the canine total emphysema model, blood gas parameters were improved by the whole pulmonary arterial administration of bFGF-GMS. This method has the potential to be an effective novel therapy for pulmonary emphysema.

  2. Smooth Muscle Insulin-Like Growth Factor-1 Mediates Hypoxia-Induced Pulmonary Hypertension in Neonatal Mice.

    PubMed

    Sun, Miranda; Ramchandran, Ramaswamy; Chen, Jiwang; Yang, Qiwei; Raj, J Usha

    2016-12-01

    Insulin-like growth factor (IGF)-1 is a potent mitogen of vascular smooth muscle cells (SMCs), but its role in pulmonary vascular remodeling associated with pulmonary hypertension (PH) is not clear. In an earlier study, we implicated IGF-1 in the pathogenesis of hypoxia-induced PH in neonatal mice. In this study, we hypothesized that hypoxia-induced up-regulation of IGF-1 in vascular smooth muscle is directly responsible for pulmonary vascular remodeling and PH. We studied neonatal and adult mice with smooth muscle-specific deletion of IGF-1 and also used an inhibitor of IGF-1 receptor (IGF-1R), OSI-906, in neonatal mice. We found that, in neonatal mice, SMC-specific deletion of IGF-1 or IGF-1R inhibition with OSI-906 attenuated hypoxia-induced pulmonary vascular remodeling in small arteries, right ventricular hypertrophy, and right ventricular systolic pressure. Pulmonary arterial SMCs from IGF-1-deleted mice or after OSI-906 treatment exhibited reduced proliferative potential. However, in adult mice, smooth muscle-specific deletion of IGF-1 had no effect on hypoxia-induced PH. Our data suggest that vascular smooth muscle-derived IGF-1 plays a critical role in hypoxia-induced PH in neonatal mice but not in adult mice. We speculate that the IGF-1/IGF-1R axis is important in pathogenesis of PH in the developing lung and may be amenable to therapeutic manipulation in this age group.

  3. Pulmonary hypertension

    MedlinePlus

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

  4. Sildenafil citrate treatment enhances amino acid availability in the conceptus and fetal growth in an ovine model of intrauterine growth restriction.

    PubMed

    Satterfield, M Carey; Bazer, Fuller W; Spencer, Thomas E; Wu, Guoyao

    2010-02-01

    Adequate placental blood flow is essential for the optimal delivery of nutrients from mother to fetus for conceptus growth. Restricted fetal development results from pathophysiological and environmental factors that alter utero-placental blood flow, placental function, and, therefore, nutrient availability in the fetus. To test this hypothesis, 0, 75, or 150 mg/d sildenafil citrate (Viagra) was administered subcutaneously from d 28 to 115 of gestation to either nutrient-restricted [50% of NRC requirements) or adequately-fed ewes (100% of NRC requirements). On d 115, maternal, fetal, and placental tissues and fluids were collected. Concentrations of total amino acids and polyamines in uterine venous and arterial sera, amniotic and allantoic fluids, and fetal umbilical venous serum were lower (P < 0.05) in nutrient-restricted ewes than in adequately fed ewes, as were the ratios of total amino acids in fetal umbilical venous serum to uterine arterial serum. Sildenafil citrate dose-dependently increased (P < 0.05) total amino acids and polyamines in amniotic fluid, allantoic fluid, and fetal serum without affecting values in maternal serum. Fetal weight was lower (P < 0.05) in nutrient-restricted ewes on d 115. Sildenafil citrate treatment dose-dependently increased (P < 0.05) fetal weight in both nutrient-restricted and adequately fed ewes. This study supports the hypothesis that long-term sildenafil citrate treatment enhances fetal growth, at least in part, by increasing the availability of amino acids in the conceptus. These findings may lead to the clinical use of sildenafil citrate in human pregnancies suspected to be at risk for intrauterine fetal growth retardation.

  5. Growth performance, carcass characteristics, and the incidence of ascites in broilers in response to feed restriction and litter oiling.

    PubMed

    McGovern, R H; Feddes, J J; Robinson, F E; Hanson, J A

    1999-04-01

    The effect of feed restriction and the application of canola oil to broiler straw litter to contain respirable dust on growth performance, carcass traits, and the incidence of ascites was evaluated with 800 male broilers studied in two 6-wk periods. Two pens of birds were feed restricted. Two pens of birds received feed ad libitum for the 6-wk trial. One restricted and one ad libitum pen received biweekly addition of canola oil to the litter. At 6 wk of age, 30 birds from each pen were killed for determination of breast muscle, fat pad, and heart weights. All birds were scored for the incidence of ascites at processing. A cross sectional image of each heart was digitally recorded and, using image analysis, the right ventricular area (RVA), left ventricular area (LVA), and total heart area (HA) were determined. The right ventricular wall was removed and its weight was expressed as a percentage of total heart weight (PRVW). The 40-d BW was significantly greater in the ad libitum birds (2.07 kg) than in the feed-restricted birds (1.86 kg). The right ventricular weight (RVW) (1.69 and 1.92 g) and the RVA (0.35 and 0.40 cm2) were also significantly different between the two feeding treatments. The ascites score was significantly correlated to the RVW (r = 0.50) and RVA (r = 0.52). The RVA was also correlated to the RVW (r = 0.63). Oiling the litter did not result in differences in carcass characteristics. Litter oiling significantly reduced the RVA of the ad libitum birds (0.36 cm2) compared to the ad libitum birds that did not have oiled litter (0.44 cm2). Feed restriction reduced the incidence of ascites, but also reduced gain. Litter oiling in the feed-restricted groups reduced the RVA, but did not reduce mortality.

  6. Effects of nutrient restriction of bovine dams during early gestation on postnatal growth and regulation of plasma glucose.

    PubMed

    Long, N M; Prado-Cooper, M J; Krehbiel, C R; Wettemann, R P

    2010-10-01

    Angus x Hereford heifers (15 mo and AI to a single sire) were used to evaluate the effect of prenatal nutritional restriction on postnatal growth and regulation of glucose in plasma. Dams (d 32 of gestation) were stratified by BW and BCS and allotted to low [LN, 55% of NRC (1996) requirements, n = 7] or moderate nutrition [MN, 100% of NRC (1996) requirements, n = 7]. After 83 d of feeding, dams were commingled and received a diet in excess of requirements. Dams were allowed to calve naturally, and bull calves were castrated at birth. Dams and calves were maintained as a group until weaning, and calves were maintained as a group after weaning. Calves (15 mo of age) were adapted to a similar diet during 2 wk; catheters were placed in both jugular veins; and calves were confined in stalls. Two days later, calves were subjected to an intravenous glucose challenge and the next day to an insulin challenge. Dams had similar (P = 0.31) BW at the beginning of the experiment. At the end of restriction, LN dams weighed less (P ≤ 0.01) and had less BCS (P < 0.001) compared with MN dams. Length of gestation was not affected by prenatal nutritional treatment. Nutrient restriction during gestation did not influence birth weight or postnatal growth. Concentrations of glucose (P = 0.49) and insulin (P = 0.29) were not different in plasma of LN and MN calves before glucose infusion. Plasma concentrations of glucose, after intravenous administration of glucose, decreased more rapidly (P = 0.05) in LN compared with MN calves. Concentrations of glucose (P = 0.68) and insulin (P = 0.55) in plasma of LN and MN calves were similar after infusion of insulin. Nutritional restriction of dams during early gestation did not influence postnatal growth, but altered clearance of glucose after a bolus infusion of glucose.

  7. Stress-shielding, growth and remodeling of pulmonary artery reinforced with copolymer scaffold and transposed into aortic position.

    PubMed

    Nappi, Francesco; Carotenuto, Angelo Rosario; Di Vito, Donato; Spadaccio, Cristiano; Acar, Cristophe; Fraldi, Massimiliano

    2016-10-01

    Ross operation, i.e., the use of autologous pulmonary artery to replace diseased aortic valve, has been recently at the center of a vivid debate regarding its unjust underuse in the surgical practice. Keystone of the procedure regards the use of an autologous biologically available graft which would preserve the anticoagulative and tissue homeostatic functions normally exerted by the native leaflets and would harmoniously integrate in the vascular system, allowing for progressive somatic growth of aortic structures. With this respect, recently, some of the authors have successfully pioneered a large animal model of transposition of pulmonary artery in systemic pressure load in order to reproduce the clinical scenario in which this procedure might be applied and allow for the development and testing of different devices or techniques to improve the pulmonary autograft (PA) performance, by testing a bioresorbable mesh for PA reinforcement. In the present work, to support and supplement the in vivo animal experimentation, a mathematical model is developed in order to simulate the biomechanical changes in pulmonary artery subjected to systemic pressure load and reinforced with a combination of resorbable and auxetic synthetic materials. The positive biological effects on vessel wall remodeling, the regional somatic growth phenomena and prevention of dilatative degeneration have been analyzed. The theoretical outcomes show that a virtuous biomechanical cooperation between biological and synthetic materials takes place, stress-shielding guiding the physiological arterialization of vessel walls, consequently determining the overall success of the autograft system.

  8. Inhibition of PI3K by PX-866 Prevents Transforming Growth Factor-α–Induced Pulmonary Fibrosis

    PubMed Central

    Le Cras, Timothy D.; Korfhagen, Thomas R.; Davidson, Cynthia; Schmidt, Stephanie; Fenchel, Matthew; Ikegami, Machiko; Whitsett, Jeffrey A.; Hardie, William D.

    2010-01-01

    Transforming growth factor-α (TGFα) is a ligand for the epidermal growth factor receptor (EGFR). EGFR activation is associated with fibroproliferative processes in human lung disease and animal models of pulmonary fibrosis. EGFR signaling activates several intracellular signaling pathways including phosphatidylinositol 3′-kinase (PI3K). We previously showed that induction of lung-specific TGFα expression in transgenic mice caused progressive pulmonary fibrosis over a 4-week period. The increase in levels of phosphorylated Akt, detected after 1 day of doxycycline-induced TGFα expression, was blocked by treatment with the PI3K inhibitor, PX-866. Daily administration of PX-866 during TGFα induction prevented increases in lung collagen and airway resistance as well as decreases in lung compliance. Treatment of mice with oral PX-866 4 weeks after the induction of TGFα prevented additional weight loss and further increases in total collagen, and attenuated changes in pulmonary mechanics. These data show that PI3K is activated in TGFα/EGFR-mediated pulmonary fibrosis and support further studies to determine the role of PI3K activation in human lung fibrotic disease, which could be amenable to targeted therapy. PMID:20042669

  9. Hepatocyte Growth Factor Is Required for Mesenchymal Stromal Cell Protection Against Bleomycin-Induced Pulmonary Fibrosis

    PubMed Central

    Cahill, Emer F.; Kennelly, Helen; Carty, Fiona; Mahon, Bernard P.

    2016-01-01

    The incidence of idiopathic pulmonary fibrosis is on the rise and existing treatments have failed to halt or reverse disease progression. Mesenchymal stromal cells (MSCs) have potent cytoprotective effects, can promote tissue repair, and have demonstrated efficacy in a range of fibrotic lung diseases; however, the exact mechanisms of action remain to be elucidated. Chemical antagonists and short hairpin RNA knockdown were used to identify the mechanisms of action used by MSCs in promoting wound healing, proliferation, and inhibiting apoptosis. Using the bleomycin induced fibrosis model, the protective effects of early or late MSC administration were examined. The role for hepatocyte growth factor (HGF) in MSC protection against bleomycin lung injury was examined using HGF knockdown MSC. Terminal deoxynucleotidyl transferase (TdT) dUTP nick-end labeling assay was performed on ex vivo lung sections to examine the effects of MSC on apoptosis. MSC conditioned media (CM) enhanced wound closure and inhibited apoptosis of pulmonary cells in vitro. HGF was required for MSC CM enhancement of epithelial cell proliferation and inhibition of apoptosis. In contrast, MSC required COX-2 for CM to inhibit fibroblast proliferation. In a murine model, early administration of MSC protected against bleomycin induced lung fibrosis and correlated with reduced levels of the proinflammatory cytokine interleukin-1β, reduced levels of apoptosis, and significantly increased levels of HGF. These protective effects were in part mediated by MSC derived HGF as HGF knockdown MSC were unable to protect against fibrosis in vivo. These findings delineate the mechanisms of MSC protection in a preclinical model of fibrotic lung disease. Significance The mechanisms used by mesenchymal stromal cells (MSCs) in mediating protective effects in chronic models of lung disease are not understood and remain to be elucidated. These findings from in vitro studies highlight an important role for the MSC

  10. 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

  11. PRETERM BIRTH AND FETAL GROWTH RESTRICTION IN HIV-INFECTED BRAZILIAN PREGNANT WOMEN

    PubMed Central

    dos REIS, Helena Lucia Barroso; ARAUJO, Karina da Silva; RIBEIRO, Lilian Paula; da ROCHA, Daniel Ribeiro; ROSATO, Drielli Petri; PASSOS, Mauro Romero Leal; de VARGAS, Paulo Roberto Merçon

    2015-01-01

    Introduction: Maternal HIV infection and related co-morbidities may have two outstanding consequences to fetal health: mother-to-child transmission (MTCT) and adverse perinatal outcomes. After Brazilian success in reducing MTCT, the attention must now be diverted to the potentially increased risk for preterm birth (PTB) and intrauterine fetal growth restriction (IUGR). Objective: To determine the prevalence of PTB and IUGR in low income, antiretroviral users, publicly assisted, HIV-infected women and to verify its relation to the HIV infection stage. Patients and Methods: Out of 250 deliveries from HIV-infected mothers that delivered at a tertiary public university hospital in the city of Vitória, state of Espírito Santo, Southeastern Brazil, from November 2001 to May 2012, 74 single pregnancies were selected for study, with ultrasound validated gestational age (GA) and data on birth dimensions: fetal weight (FW), birth length (BL), head and abdominal circumferences (HC, AC). The data were extracted from clinical and pathological records, and the outcomes summarized as proportions of preterm birth (PTB, < 37 weeks), low birth weight (LBW, < 2500g) and small (SGA), adequate (AGA) and large (LGA) for GA, defined as having a value below, between or beyond the ±1.28 z/GA score, the usual clinical cut-off to demarcate the 10th and 90th percentiles. Results: PTB was observed in 17.5%, LBW in 20.2% and SGA FW, BL, HC and AC in 16.2%, 19.1%, 13.8%, and 17.4% respectively. The proportions in HIV-only and AIDS cases were: PTB: 5.9 versus 27.5%, LBW: 14.7% versus 25.0%, SGA BW: 17.6% versus 15.0%, BL: 6.0% versus 30.0%, HC: 9.0% versus 17.9%, and AC: 13.3% versus 21.2%; only SGA BL attained a significant difference. Out of 15 cases of LBW, eight (53.3%) were preterm only, four (26.7%) were SGA only, and three (20.0%) were both PTB and SGA cases. A concomitant presence of, at least, two SGA dimensions in the same fetus was frequent. Conclusions: The proportions of preterm

  12. Sex differences in the enhanced responsiveness to acute angiotensin II in growth-restricted rats: role of fasudil, a Rho kinase inhibitor

    PubMed Central

    Ojeda, Norma B.; Royals, Thomas P.

    2013-01-01

    This study tested the hypothesis that Rho kinase contributes to the enhanced pressor response to acute angiotensin II in intact male growth-restricted and gonadectomized female growth-restricted rats. Mean arterial pressure (MAP) and renal function were determined in conscious animals pretreated with enalapril (250 mg/l in drinking water) for 1 wk to block the endogenous renin-angiotensin system and normalize blood pressure (baseline). Blood pressure and renal hemodynamics did not differ at baseline. Acute Ang II (100 ng·kg−1·min−1) induced a greater increase in MAP and renal vascular resistance and enhanced reduction in glomerular filtration rate in intact male growth-restricted rats compared with intact male controls (P < 0.05). Cotreatment with the Rho kinase inhibitor fasudil (33 μg·kg−1·min−1) significantly attenuated these hemodynamic changes (P < 0.05), but it did not abolish the differential increase in blood pressure above baseline, suggesting that the impact of intrauterine growth restriction on blood pressure in intact male growth-restricted rats is independent of Rho kinase. Gonadectomy in conjunction with fasudil returned blood pressure back to baseline in male growth-restricted rats, and yet glomerular filtration rate remained significantly reduced (P < 0.05). Thus, these data suggest a role for enhanced renal sensitivity to acute Ang II in the developmental programming of hypertension in male growth-restricted rats. However, inhibition of Rho kinase had no effect on the basal or enhanced increase in blood pressure induced by acute Ang II in the gonadectomized female growth-restricted rat. Therefore, these studies suggest that Rho kinase inhibition exerts a sex-specific effect on blood pressure sensitivity to acute Ang II in growth-restricted rats. PMID:23344570

  13. Effects of induced placental and fetal growth restriction, size at birth and early neonatal growth on behavioural and brain structural lateralization in sheep.

    PubMed

    Hunter, Damien Seth; Hazel, Susan J; Kind, Karen L; Liu, Hong; Marini, Danila; Giles, Lynne C; De Blasio, Miles J; Owens, Julie A; Pitcher, Julia B; Gatford, Kathryn L

    2017-09-01

    Poor perinatal growth in humans results in asymmetrical grey matter loss in fetuses and infants and increased functional and behavioural asymmetry, but specific contributions of pre- and postnatal growth are unclear. We therefore compared strength and direction of lateralization in obstacle avoidance and maze exit preference tasks in offspring of placentally restricted (PR: 10M, 13F) and control (CON: 23M, 17F) sheep pregnancies at 18 and 40 weeks of age, and examined gross brain structure of the prefrontal cortex at 52 weeks of age (PR: 14M, 18F; CON: 23M, 25F). PR did not affect lateralization direction, but 40-week-old PR females had greater lateralization strength than CON (P = .021). Behavioural lateralization measures were not correlated with perinatal growth. PR did not alter brain morphology. In males, cross-sectional areas of the prefrontal cortex and left hemisphere correlated positively with skull width at birth, and white matter area correlated positively with neonatal growth rate of the skull (all P < .05). These studies reinforce the need to include progeny of both sexes in future studies of neurodevelopmental programming, and suggest that restricting in utero growth has relatively mild effects on gross brain structural or behavioural lateralization in sheep.

  14. Placental and fetal growth restriction, size at birth and neonatal growth alter cognitive function and behaviour in sheep in an age- and sex-specific manner.

    PubMed

    Hunter, Damien S; Hazel, Susan J; Kind, Karen L; Liu, Hong; Marini, Danila; Giles, Lynne C; De Blasio, Miles J; Owens, Julie A; Pitcher, Julia B; Gatford, Kathryn L

    2015-12-01

    Intrauterine growth restriction and slow neonatal growth in humans are each associated with poorer learning, memory and cognitive flexibility in childhood and adulthood. The relative contributions of pre- and post-natal growth to cognitive outcomes are unclear, however. We therefore compared performance in learning, memory and reversal tasks using a modified Y-maze at 18 and 40 weeks of age in offspring of placentally-restricted (PR: 10 M, 13 F) and control (23 M, 17 F) ovine pregnancies. We also investigated relationships between size at birth, neonatal growth rates and cognitive outcomes. PR had limited effects on cognitive outcomes, with PR males requiring more trials to solve the initial learning task than controls (P=0.037) but faster completion of reversal tasks in both sexes at 18 weeks of age. In males, neonatal growth rate correlated inversely with numbers of trials and total time required to solve memory tasks at 40 weeks of age. In females, bleat frequency in the first reversal task at 18 weeks of age correlated positively with birth weight (r=0.734, P<0.05) and neonatal growth rate (r=0.563, P<0.05). We conclude that PR induces limited effects on cognitive outcomes in sheep, with some evidence of impaired learning in males, but little effect on memory or cognitive flexibility in either sex. Rapid neonatal growth predicted improved memory task performance in males, suggesting that strategies to optimize neonatal growth may have long-term cognitive benefits but that these may be sex-specific.

  15. Artificial Neural Networks, and Evolutionary Algorithms as a systems biology approach to a data-base on fetal growth restriction.

    PubMed

    Street, Maria E; Buscema, Massimo; Smerieri, Arianna; Montanini, Luisa; Grossi, Enzo

    2013-12-01

    One of the specific aims of systems biology is to model and discover properties of cells, tissues and organisms functioning. A systems biology approach was undertaken to investigate possibly the entire system of intra-uterine growth we had available, to assess the variables of interest, discriminate those which were effectively related with appropriate or restricted intrauterine growth, and achieve an understanding of the systems in these two conditions. The Artificial Adaptive Systems, which include Artificial Neural Networks and Evolutionary Algorithms lead us to the first analyses. These analyses identified the importance of the biochemical variables IL-6, IGF-II and IGFBP-2 protein concentrations in placental lysates, and offered a new insight into placental markers of fetal growth within the IGF and cytokine systems, confirmed they had relationships and offered a critical assessment of studies previously performed. Copyright © 2013 Elsevier Ltd. All rights reserved.

  16. Elevated temperature restricts growth potential of the coral reef fish Acanthochromis polyacanthus

    NASA Astrophysics Data System (ADS)

    Munday, P. L.; Kingsford, M. J.; O'Callaghan, M.; Donelson, J. M.

    2008-12-01

    In order to test the effect of temperature variation on the growth of a common coral-reef fish, Acanthochromis polyacanthus, juveniles, sub-adults and adults were reared on either high or low food rations at temperatures corresponding to the long-term (14 year) minimum, average and maximum summer sea-surface temperatures (26, 28 and 31°C respectively) at Orpheus Island, Great Barrier Reef, Australia. Both temperature and food supply affected the growth of juvenile and adult A. polyacanthus. Individuals grew more on high food rations, but growth declined with increasing temperature. Importantly, at 31°C, the growth of juveniles and adults on the high food ration was nearly identical to growth on the low food ration. This indicates that the capacity for growth is severely limited at higher ocean temperatures that are predicted to become the average for Orpheus Island within the next 100 years as a result of rapid climate change.

  17. Frequency of Epidermal Growth Factor Receptor Mutation in Smokers with Lung Cancer Without Pulmonary Emphysema.

    PubMed

    Takeda, Kenichi; Yamasaki, Akira; Igishi, Tadashi; Kawasaki, Yuji; Ito-Nishii, Shizuka; Izumi, Hiroki; Sakamoto, Tomohiro; Touge, Hirokazu; Kodani, Masahiro; Makino, Haruhiko; Yanai, Masaaki; Tanaka, Natsumi; Matsumoto, Shingo; Araki, Kunio; Nakamura, Hiroshige; Shimizu, Eiji

    2017-02-01

    Chronic obstructive pulmonary disease is a smoking-related disease, and is categorized into the emphysema and airway dominant phenotypes. We examined the relationship between emphysematous changes and epidermal growth factor receptor (EGFR) mutation status in patients with lung adenocarcinoma. The medical records for 250 patients with lung adenocarcinoma were retrospectively reviewed. All patients were categorized into the emphysema or non-emphysema group. Wild-type EGFR was detected in 136 (54%) and mutant EGFR in 48 (19%). Emphysematous changes were observed in 87 (36%) patients. EGFR mutation was highly frequent in the non-emphysema group (p=0.0014). Multivariate logistic regression analysis showed that emphysema was an independent risk factor for reduced frequency of EGFR mutation (Odds Ratio=3.47, p=0.005). Our data showed a relationship between emphysematous changes and EGFR mutation status. There might be mutually exclusive genetic risk factors for carcinogenesis and development of emphysematous changes. Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.

  18. Effects of water restriction on growth performance, feed nutrient digestibility, carcass and meat traits of rabbits.

    PubMed

    Bovera, F; Lestingi, A; Piccolo, G; Iannaccone, F; Attia, Y A; Tateo, A

    2013-10-01

    The study investigates the effects of a post-weaning water restriction on performance, nutrient digestibility, carcass traits and meat quality of 84-day-old rabbits. A total of 1388 weaned rabbits (35 days) were randomly divided into two groups on the basis of BW and sex. The two groups were fed the same diets ad libitum both in the post-weaning (35 to 60 days) and fattening (61 to 84 days) periods. In the post-weaning period, one group (AL) also received drinking water ad libitum, whereas the other (WR) had a water restriction from 35 to 41 days 2 h/day; from 42 to 48 days 2.5 h/day; from 49 to 55 days 3 h/day; and from 56 to 60 days 4 h/day. During the fattening period, both groups had water-free access. Individual live weights and feed intake per cage were recorded weekly for 32 cages randomly chosen per group (64 rabbits) to calculate the BW gain, feed intake and feed conversion ratio (FCR). The apparent digestibility values of nutrients were measured using acid-insoluble ash. Carcass data were collected from 16 rabbits (8 males and 8 females) per group selected for similar final BW in both groups. Mortality from 35 to 60 days was higher in the AL group (10.1% v. 5.2%, for AL and WR, respectively, P < 0.0001). BW gain was higher for the AL group during both the post-weaning (+22.4%, P < 0.01) and the entire period (+7.5%, P < 0.05). Water restriction reduced feed intake both in the post-weaning (-17.4%, P < 0.0001) and in the entire period (-9.9%, P < 0.05). During the fattening period, FCR was lower for the WR group (5.15 v. 5.75 g/g, for WR and AL, respectively, P < 0.05). The apparent digestibilities of dry matter, organic matter, NDF, ADF and cellulose were greater in the restricted rabbits (+4.7%, +4.5%, +10.2%, +18.8% and +12.8%, P < 0.01, P < 0.01, P < 0.05, P < 0.01, P < 0.05, respectively). Perirenal and scapular fat percentages were higher in the AL rabbits (+30.7% and +116.6%, P < 0.01 and P < 0.001, respectively). Water restriction increased

  19. The microRNA bantam regulates a developmental transition in epithelial cells that restricts sensory dendrite growth.

    PubMed

    Jiang, Nan; Soba, Peter; Parker, Edward; Kim, Charles C; Parrish, Jay Z

    2014-07-01

    As animals grow, many early born structures grow by cell expansion rather than cell addition; thus growth of distinct structures must be coordinated to maintain proportionality. This phenomenon is particularly widespread in the nervous system, with dendrite arbors of many neurons expanding in concert with their substrate to sustain connectivity and maintain receptive field coverage as animals grow. After rapidly growing to establish body wall coverage, dendrites of Drosophila class IV dendrite arborization (C4da) neurons grow synchronously with their substrate, the body wall epithelium, providing a system to study how proportionality is maintained during animal growth. Here, we show that the microRNA bantam (ban) ensures coordinated growth of C4da dendrites and the epithelium through regulation of epithelial endoreplication, a modified cell cycle that entails genome amplification without cell division. In Drosophila larvae, epithelial endoreplication leads to progressive changes in dendrite-extracellular matrix (ECM) and dendrite-epithelium contacts, coupling dendrite/substrate expansion and restricting dendrite growth beyond established boundaries. Moreover, changes in epithelial expression of cell adhesion molecules, including the beta-integrin myospheroid (mys), accompany this developmental transition. Finally, endoreplication and the accompanying changes in epithelial mys expression are required to constrain late-stage dendrite growth and structural plasticity. Hence, modulating epithelium-ECM attachment probably influences substrate permissivity for dendrite growth and contributes to the dendrite-substrate coupling that ensures proportional expansion of the two cell types.

  20. 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. Copyright © 2014 Elsevier B.V. All rights reserved.

  1. Pregnant growth restricted female rats have bone gains during late gestation which contributes to second generation adolescent and adult offspring having normal bone health.

    PubMed

    Anevska, Kristina; Gallo, Linda A; Tran, Melanie; Jefferies, Andrew J; Wark, John D; Wlodek, Mary E; Romano, Tania

    2015-05-01

    Low birth weight, due to uteroplacental insufficiency, results in programmed bone deficits in the first generation (F1). These deficits may be passed onto subsequent generations. We characterized the effects of being born small on maternal bone health during pregnancy; and aimed to characterize the contribution of the maternal environment and germ line effects to bone health in F2 offspring from mothers born small. Bilateral uterine vessel ligation (or sham) surgery was performed on female F0 WKY rats on gestational day 18 (term 22days) to induce uteroplacental insufficiency and fetal growth restriction. Control and Restricted F1 female offspring were allocated to a non-pregnant or pregnant group. To generate F2 offspring, F1 females were allocated to either non-embryo or embryo transfer groups. Embryo transfer was performed on gestational day 1, where second generation (F2) embryos were gestated (donor-in-recipient) in either a Control (Control-in-Control, Restricted-in-Control) or Restricted (Control-in-Restricted, Restricted-in-Restricted) mother. Restricted F1 females were born 10-15% lighter than Controls. Restricted non-pregnant females had shorter femurs, reduced trabecular and cortical bone mineral contents, trabecular density and bone geometry measures determined by peripheral quantitative computed tomography (pQCT) compared to non-pregnant Controls. Pregnancy restored the bone deficits that were present in F1 Restricted females. F2 non-embryo transfer male and female offspring were born of normal weight, while F2 embryo transfer males and females gestated in a Control mother (Control-in-Control, Restricted-in-Control) were heavier at birth compared to offspring gestated in a Restricted mother (Restricted-in-Restricted, Control-in-Restricted). Male F2 Restricted embryo groups (Restricted-in-Control and Restricted-in-Restricted) had accelerated postnatal growth. There was no transmission of bone deficits present at 35days or 6months in F2 offspring. Embryo

  2. Chronically Increased Amino Acids Improve Insulin Secretion, Pancreatic Vascularity, and Islet Size in Growth-Restricted Fetal Sheep.

    PubMed

    Brown, Laura D; Davis, Melissa; Wai, Sandra; Wesolowski, Stephanie R; Hay, William W; Limesand, Sean W; Rozance, Paul J

    2016-10-01

    Placental insufficiency is associated with reduced supply of amino acids to the fetus and leads to intrauterine growth restriction (IUGR). IUGR fetuses are characterized by lower glucose-stimulated insulin secretion, smaller pancreatic islets with less β-cells, and impaired pancreatic vascularity. To test whether supplemental amino acids infused into the IUGR fetus could improve these complications of IUGR we used acute (hours) and chronic (11 d) direct fetal amino acid infusions into a sheep model of placental insufficiency and IUGR near the end of gestation. IUGR fetuses had attenuated acute amino acid-stimulated insulin secretion compared with control fetuses. These results were confirmed in isolated IUGR pancreatic islets. After the chronic fetal amino acid infusion, fetal glucose-stimulated insulin secretion and islet size were restored to control values. These changes were associated with normalization of fetal pancreatic vascularity and higher fetal pancreatic vascular endothelial growth factor A protein concentrations. These results demonstrate that decreased fetal amino acid supply contributes to the pathogenesis of pancreatic islet defects in IUGR. Moreover, the results show that pancreatic islets in IUGR fetuses retain their ability to respond to increased amino acids near the end of gestation after chronic fetal growth restriction.

  3. Amotl1 mediates sequestration of the Hippo effector Yap1 downstream of Fat4 to restrict heart growth

    PubMed Central

    Ragni, Chiara V.; Diguet, Nicolas; Le Garrec, Jean-François; Novotova, Marta; Resende, Tatiana P.; Pop, Sorin; Charon, Nicolas; Guillemot, Laurent; Kitasato, Lisa; Badouel, Caroline; Dufour, Alexandre; Olivo-Marin, Jean-Christophe; Trouvé, Alain; McNeill, Helen; Meilhac, Sigolène M

    2017-01-01

    Although in flies the atypical cadherin Fat is an upstream regulator of Hippo signalling, the closest mammalian homologue, Fat4, has been shown to regulate tissue polarity rather than growth. Here we show in the mouse heart that Fat4 modulates Hippo signalling to restrict growth. Fat4 mutant myocardium is thicker, with increased cardiomyocyte size and proliferation, and this is mediated by an upregulation of the transcriptional activity of Yap1, an effector of the Hippo pathway. Fat4 is not required for the canonical activation of Hippo kinases but it sequesters a partner of Yap1, Amotl1, out of the nucleus. The nuclear translocation of Amotl1 is accompanied by Yap1 to promote cardiomyocyte proliferation. We, therefore, identify Amotl1, which is not present in flies, as a mammalian intermediate for non-canonical Hippo signalling, downstream of Fat4. This work uncovers a mechanism for the restriction of heart growth at birth, a process which impedes the regenerative potential of the mammalian heart. PMID:28239148

  4. Polymorphonuclear Leukocytes Restrict Growth of Pseudomonas aeruginosa in the Lungs of Cystic Fibrosis Patients

    PubMed Central

    Kragh, Kasper N.; Alhede, Morten; Jensen, Peter Ø.; Moser, Claus; Scheike, Thomas; Jacobsen, Carsten S.; Seier Poulsen, Steen; Eickhardt-Sørensen, Steffen Robert; Trøstrup, Hannah; Christoffersen, Lars; Hougen, Hans-Petter; Rickelt, Lars F.; Kühl, Michael; Høiby, Niels

    2014-01-01

    Cystic fibrosis (CF) patients have increased susceptibility to chronic lung infections by Pseudomonas aeruginosa, but the ecophysiology within the CF lung during infections is poorly understood. The aim of this study was to elucidate the in vivo growth physiology of P. aeruginosa within lungs of chronically infected CF patients. A novel, quantitative peptide nucleic acid (PNA) fluorescence in situ hybridization (PNA-FISH)-based method was used to estimate the in vivo growth rates of P. aeruginosa directly in lung tissue samples from CF patients and the growth rates of P. aeruginosa in infected lungs in a mouse model. The growth rate of P. aeruginosa within CF lungs did not correlate with the dimensions of bacterial aggregates but showed an inverse correlation to the concentration of polymorphonuclear leukocytes (PMNs) surrounding the bacteria. A growth-limiting effect on P. aeruginosa by PMNs was also observed in vitro, where this limitation was alleviated in the presence of the alternative electron acceptor nitrate. The finding that P. aeruginosa growth patterns correlate with the number of surrounding PMNs points to a bacteriostatic effect by PMNs via their strong O2 consumption, which slows the growth of P. aeruginosa in infected CF lungs. In support of this, the growth of P. aeruginosa was significantly higher in the respiratory airways than in the conducting airways of mice. These results indicate a complex host-pathogen interaction in chronic P. aeruginosa infection of the CF lung whereby PMNs slow the growth of the bacteria and render them less susceptible to antibiotic treatment while enabling them to persist by anaerobic respiration. PMID:25114118

  5. The Mycobacterium tuberculosis Complex-Restricted Gene cfp32 Encodes an Expressed Protein That Is Detectable in Tuberculosis Patients and Is Positively Correlated with Pulmonary Interleukin-10

    PubMed Central

    Huard, Richard C.; Chitale, Sadhana; Leung, Mary; Lazzarini, Luiz Claudio Oliveira; Zhu, Hongxia; Shashkina, Elena; Laal, Suman; Conde, Marcus B.; Kritski, AfrÂnio L.; Belisle, John T.; Kreiswirth, Barry N.; Lapa e Silva, José Roberto; Ho, John L.

    2003-01-01

    Human tuberculosis (TB) is caused by the bacillus Mycobacterium tuberculosis, a subspecies of the M. tuberculosis complex (MTC) of mycobacteria. Postgenomic dissection of the M. tuberculosis proteome is ongoing and critical to furthering our understanding of factors mediating M. tuberculosis pathobiology. Towards this end, a 32-kDa putative glyoxalase in the culture filtrate (CF) of growing M. tuberculosis (originally annotated as Rv0577 and hereafter designated CFP32) was identified, cloned, and characterized. The cfp32 gene is MTC restricted, and the gene product is expressed ex vivo as determined by the respective Southern and Western blot testing of an assortment of mycobacteria. Moreover, the cfp32 gene sequence is conserved within the MTC, as no polymorphisms were found in the tested cfp32 PCR products upon sequence analysis. Western blotting of M. tuberculosis subcellular fractions localized CFP32 predominantly to the CF and cytosolic compartments. Data to support the in vivo expression of CFP32 were provided by the serum recognition of recombinant CFP32 in 32% of TB patients by enzyme-linked immunosorbent assay (ELISA) as well as the direct detection of CFP32 by ELISA in the induced sputum samples from 56% of pulmonary TB patients. Of greatest interest was the observation that, per sample, sputum CFP32 levels (a potential indicator of increasing bacterial burden) correlated with levels of expression in sputum of interleukin-10 (an immunosuppressive cytokine and a putative contributing factor to disease progression) but not levels of gamma interferon (a key cytokine in the protective immune response in TB), as measured by ELISA. Combined, these data suggest that CFP32 serves a necessary biological function(s) in tubercle bacilli and may contribute to the M. tuberculosis pathogenic mechanism. Overall, CFP32 is an attractive target for drug and vaccine design as well as new diagnostic strategies. PMID:14638775

  6. Intra-uterine growth restriction as a risk factor for hypertension in children six to 10 years old

    PubMed Central

    Zamecznik, Agata; Niewiadomska-Jarosik, Katarzyna; Zamojska, Justyna; Stańczyk, Jerzy; Wosiak, Agnieszka; Moll, Jadwiga

    2014-01-01

    Summary Introduction Intra-uterine growth restriction (IUGR) is present in about 3–10% of live-born newborns and it is as high as 20–30% in developing countries. Since the 1990s, it has been known that abnormalities during foetal growth may result in cardiovascular disease, including hypertension in adulthood. Methods This study evaluated blood pressure parameters (using ambulatory blood pressure monitoring) in children aged six to 10 years old, born as small for gestational age (SGA), and compared them to their healthy peers born as appropriate for gestational age (AGA). Results In the SGA group, an abnormal blood pressure level (prehypertension or hypertension) was present significantly more often than in the AGA group (50 vs 16%, p < 0.01). This relationship also occurred in association with the type of IUGR (asymmetric p < 0.01, symmetric p < 0.05). Conclusion In SGA children, abnormal blood pressure values occurred more frequently than in AGA children. PMID:24844552

  7. 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

  8. 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.

  9. Cord blood triglycerides are associated with IGF-I levels and contribute to the identification of growth-restricted neonates.

    PubMed

    Sifianou, Popi; Zisis, Dimitris

    2012-12-01

    The aim of this study was to investigate whether readily available laboratory tests may aid in the identification of growth-restricted neonates. Cord serum levels of 15 chemical analytes, including insulin-like growth factor I (IGF-I) and insulin-like growth factor binding protein 3 (IGFBP-3) were measured in newborns ≥36 weeks gestational age (GA). Based on the number of anthropometric indices (out of four) with values ≤25th centile for GA, the babies were allocated into three groups, i.e., Group(25)0, Group(25)1 and Group(25)2 corresponding to neonates with 0, 1 and 2 or more indices, respectively, that were ≤25th centile for GA. Furthermore, two composite variables were developed: A25 (Group(25)0 and Group(25)1) and B25 (Group(25)0 and Group(25)2). The data were evaluated by the Mann-Whitney test and multiple regression analyses. Cord serum triglycerides and total cholesterol levels were significantly higher in Group(25)2 compared to Group(25)0 (p values 0.004 and 0.0009, respectively). The triglycerides almost doubled the power of the variable B25 for predicting IGF-I levels and were found to have a highly significant, negative association with the IGF-I levels (p<0.0001). The IGF-I along with the IGFBP-3 levels explained almost one third of the variation of triglycerides. Cord serum triglycerides can assist in the identification of growth-restricted neonates. The novel finding of the association of triglycerides with IGF-I calls for further research as this can illuminate unknown aspects of the fetal lipid metabolism. Copyright © 2012 Elsevier Ltd. All rights reserved.

  10. Transforming growth factor-beta receptor-3 is associated with pulmonary emphysema.

    PubMed

    Hersh, Craig P; Hansel, Nadia N; Barnes, Kathleen C; Lomas, David A; Pillai, Sreekumar G; Coxson, Harvey O; Mathias, Rasika A; Rafaels, Nicholas M; Wise, Robert A; Connett, John E; Klanderman, Barbara J; Jacobson, Francine L; Gill, Ritu; Litonjua, Augusto A; Sparrow, David; Reilly, John J; Silverman, Edwin K

    2009-09-01

    Chronic obstructive pulmonary disease (COPD) is a heterogeneous syndrome, including emphysema and airway disease. Phenotypes defined on the basis of chest computed tomography (CT) may decrease disease heterogeneity and aid in the identification of candidate genes for COPD subtypes. To identify these genes, we performed genome-wide linkage analysis in extended pedigrees from the Boston Early-Onset COPD Study, stratified by emphysema status (defined by chest CT scans) of the probands, followed by genetic association analysis of positional candidate genes. A region on chromosome 1p showed strong evidence of linkage to lung function traits in families of emphysema-predominant probands in the stratified analysis (LOD score = 2.99 in families of emphysema-predominant probands versus 1.98 in all families). Association analysis in 949 individuals from 127 early-onset COPD pedigrees revealed association for COPD-related traits with an intronic single-nucleotide polymorphism (SNP) in transforming growth factor-beta receptor-3 (TGFBR3) (P = 0.005). This SNP was significantly associated with COPD affection status comparing 389 cases from the National Emphysema Treatment Trial to 472 control smokers (P = 0.04), and with FEV(1) (P = 0.004) and CT emphysema (P = 0.05) in 3,117 subjects from the International COPD Genetics Network. Gene-level replication of association with lung function was seen in 427 patients with COPD from the Lung Health Study. In conclusion, stratified linkage analysis followed by association testing identified TGFBR3 (betaglycan) as a potential susceptibility gene for COPD. Published human microarray and murine linkage studies have also demonstrated the importance of TGFBR3 in emphysema and lung function, and our group and others have previously found association of COPD-related traits with TGFB1, a ligand for TGFBR3.

  11. Connective Tissue Growth Factor Promotes Pulmonary Epithelial Cell Senescence and Is Associated with COPD Severity.

    PubMed

    Jang, Jun-Ho; Chand, Hitendra S; Bruse, Shannon; Doyle-Eisele, Melanie; Royer, Christopher; McDonald, Jacob; Qualls, Clifford; Klingelhutz, Aloysius J; Lin, Yong; Mallampalli, Rama; Tesfaigzi, Yohannes; Nyunoya, Toru

    2017-04-01

    The purpose of this study was to determine whether expression of connective tissue growth factor (CTGF) protein in chronic obstructive pulmonary disease (COPD) is consistent in humans and animal models of COPD and to investigate the role of this protein in lung epithelial cells. CTGF in lung epithelial cells of ex-smokers with COPD was compared with ex-smokers without COPD by immunofluorescence. A total of twenty C57Bl/6 mice and sixteen non-human primates (NHPs) were exposed to cigarette smoke (CS) for 4 weeks. Ten mice of these CS-exposed mice and eight of the CS-exposed NHPs were infected with H3N2 influenza A virus (IAV), while the remaining ten mice and eight NHPs were mock-infected with vehicle as control. Both mRNA and protein expression of CTGF in lung epithelial cells of mice and NHPs were determined. The effects of CTGF overexpression on cell proliferation, p16 protein, and senescence-associated β-galactosidase (SA-β-gal) activity were examined in cultured human bronchial epithelial cells (HBECs). In humans, CTGF expression increased with increasing COPD severity. We found that protein expression of CTGF was upregulated in lung epithelial cells in both mice and NHPs exposed to CS and infected with IAV compared to those exposed to CS only. When overexpressed in HBECs, CTGF accelerated cellular senescence accompanied by p16 accumulation. Both CTGF and p16 protein expression in lung epithelia are positively associated with the severity of COPD in ex-smokers. These findings show that CTGF is consistently expressed in epithelial cells of COPD lungs. By accelerating lung epithelial senescence, CTGF may block regeneration relative to epithelial cell loss and lead to emphysema.

  12. Fibroblast growth factor 23 and the antiproteinuric response to dietary sodium restriction during renin-angiotensin-aldosterone system blockade.

    PubMed

    Humalda, Jelmer K; Lambers Heerspink, Hiddo J; Kwakernaak, Arjan J; Slagman, Maartje C J; Waanders, Femke; Vervloet, Marc G; Ter Wee, Pieter M; Navis, Gerjan; de Borst, Martin H

    2015-02-01

    Residual proteinuria during renin-angiotensin-aldosterone system (RAAS) blockade is a major renal and cardiovascular risk factor in chronic kidney disease. Dietary sodium restriction potentiates the antiproteinuric effect of RAAS blockade, but residual proteinuria remains in many patients. Previous studies linked high fibroblast growth factor 23 (FGF-23) levels with volume overload; others linked higher serum phosphate levels with impaired RAAS-blockade efficacy. We hypothesized that FGF-23 reduces the capacity of dietary sodium restriction to potentiate RAAS blockade, impairing the antiproteinuric effect. Post hoc analysis of cohort data from a randomized crossover trial with two 6-week study periods comparing proteinuria after a regular-sodium diet with proteinuria after a low-sodium diet, both during background angiotensin-converting enzyme inhibition. 47 nondiabetic patients with CKD with residual proteinuria (median protein excretion, 1.9 [IQR, 0.8-3.1] g/d; mean age, 50±13 [SD] years; creatinine clearance, 69 [IQR, 50-110] mL/min). Plasma carboxy-terminal FGF-23 levels. Difference in residual proteinuria at the end of the regular-sodium versus low-sodium study period. Residual proteinuria during the low-sodium diet period adjusted for proteinuria during the regular-sodium diet period. Higher baseline FGF-23 level was associated with reduced antiproteinuric response to dietary sodium restriction (standardized β=-0.46; P=0.001; model R(2)=0.71). For every 100-RU/mL increase in FGF-23 level, the antiproteinuric response to dietary sodium restriction was reduced by 10.6%. Higher baseline FGF-23 level was a determinant of more residual proteinuria during the low-sodium diet (standardized β=0.27; P=0.003) in linear regression analysis adjusted for baseline proteinuria (model R(2)=0.71). There was no interaction with creatinine clearance (P interaction=0.5). Baseline FGF-23 level did not predict changes in systolic or diastolic blood pressure upon intensified

  13. Spontaneous intrauterine growth restriction due to increased litter size in the guinea pig programmes postnatal growth, appetite and adult body composition.

    PubMed

    Horton, D M; Saint, D A; Owens, J A; Kind, K L; Gatford, K L

    2016-10-01

    Intrauterine growth restriction (IUGR) and subsequent neonatal catch-up growth are implicated in the programming of increased appetite, adiposity and cardiometabolic diseases. Guinea pigs provide an alternate small animal model to rodents to investigate mechanisms underlying prenatal programming, being relatively precocial at birth, with smaller litter sizes and undergoing neonatal catch-up growth after IUGR. The current study, therefore, investigated postnatal consequences of spontaneous IUGR due to varying litter size in this species. Size at birth, neonatal, juvenile (post-weaning, 30-60 days) and adolescent (60-90 days) growth, juvenile and adolescent food intake, and body composition of young adults (120 days) were measured in 158 male and female guinea pigs from litter sizes of one to five pups. Compared with singleton pups, birth weight of pups from litters of five was reduced by 38%. Other birth size measures were reduced to lesser degrees with head dimensions being relatively conserved. Pups from larger litters had faster fractional neonatal growth and faster absolute and fractional juvenile growth rates (P<0.005 for all). Relationships of post-weaning growth, feed intakes and adult body composition with size at birth and neonatal growth rate were sex specific, with neonatal growth rates strongly and positively correlated with adiposity in males only. In conclusion, spontaneous IUGR due to large litter sizes in the guinea pig causes many of the programmed sequelae of IUGR reported in other species, including human. This may therefore be a useful model to investigate the mechanisms underpinning perinatal programming of hyperphagia, obesity and longer-term metabolic consequences.

  14. Knockdown of connective tissue growth factor by plasmid-based short hairpin RNA prevented pulmonary vascular remodeling in cigarette smoke-exposed rats.

    PubMed

    Wang, Ran; Xu, Yong-Jian; Liu, Xian-Sheng; Zeng, Da-Xiong; Xiang, Min

    2011-04-01

    Cigarette smoking may contribute to pulmonary hypertension in chronic obstructive pulmonary disease by resulting in pulmonary vascular remodeling that involves pulmonary artery smooth muscle cell proliferation. Connective tissue growth factor (CTGF) is a cysteine-rich peptide implicated in several biological processes such as cell proliferation, survival, and migration. This study investigated the potential role of CTGF in pulmonary vascular remodeling. We constructed a plasmid-based short hairpin RNA (shRNA) to knock down the expression of CTGF in primary cultured rat pulmonary artery smooth muscle cells (rPASMCs) and in rat lung vessels. Rat PASMCs were challenged with cigarette smoke extract (CSE). Rats were exposed to cigarette smoke for 3 months in the absence or in the presence of plasmid-based short hairpin RNA against CTGF which was administrated by tail vein injection. CTGFshRNA significantly prevented CTGF and cyclin D1 expression, arrested cell cycle at G0/G1 phase and suppressed cell proliferation in rPASMCs exposed to CSE. CTGFshRNA administration ameliorated pulmonary vascular remodeling, inhibited cigarette smoke-induced CTGF elevation and reversed the cyclin D1 increase in pulmonary vessels in rats. Collectively, our data demonstrated that plasmid-based shRNA against CTGF attenuated pulmonary vascular remodeling in cigarette smoke-exposed rats. Copyright © 2011 Elsevier Inc. All rights reserved.

  15. Alcohol-induced brain growth restrictions (microencephaly) were not affected by concurrent exposure to cocaine during the brain growth spurt.

    PubMed

    Chen, W J; Andersen, K H; West, J R

    1994-09-01

    The prevalence of concomitant use of alcohol and cocaine among drug abusers has raised concern about the possible increased risk of fetal damage. The aim of this study was to assess the interactive effects of alcohol and cocaine on lethality, somatic growth, and brain growth using an animal model system. Sprague-Dawley rat pups were used as subjects. They were randomly assigned to 1 of the 9 artificially reared groups which varied with respect to the combination treatments of cocaine (0, 40, or 60 mg/kg) and alcohol (0, 3.3, or 4.5 g/kg). All artificially reared pups were given daily cocaine and alcohol treatments during a major part of the brain growth spurt period (postnatal days 4-9). An additional group of suckled control animals raised by their natural dams was included to control for artificial rearing. The results are summarized as follows: 1) Drug-induced lethality was higher in cocaine-treated groups when compared with non-cocaine-treated groups, and the concurrent administration of high doses of alcohol and cocaine significantly increased the mortality rate. 2) Somatic growth, in terms of body weight, was not affected by alcohol, cocaine, or the combination of both drugs using the artificial rearing technique. 3) Alcohol exposure during this brain growth spurt period significantly reduced whole brain weight, as well as forebrain, cerebellum, and brain stem weights. 4) In contrast to alcohol, cocaine failed to exert a detrimental effect on brain weight measures during this early postnatal period.(ABSTRACT TRUNCATED AT 250 WORDS)

  16. Salinity stiffens the epidermal cell walls of salt-stressed maize leaves: is the epidermis growth-restricting?

    PubMed

    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.

  17. 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

  18. 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

  19. Is middle cerebral artery Doppler related to neonatal and 2-year infant outcome in early fetal growth restriction?

    PubMed

    Stampalija, Tamara; Arabin, Birgit; Wolf, Hans; Bilardo, Caterina M; Lees, Christoph

    2017-05-01

    Reduced fetal middle cerebral artery Doppler impedance is associated with hypoxemia in fetal growth restriction. It remains unclear as to whether this finding could be useful in timing delivery, especially in the third trimester. In this regard there is a paucity of evidence from prospective studies. The aim of this study was to determine whether there is an association between middle cerebral artery Doppler impedance and its ratio with the umbilical artery in relation to neonatal and 2 year infant outcome in early fetal growth restriction (26(+0)-31(+6) weeks of gestation). Additionally we sought to explore which ratio is more informative for clinical use. This is a secondary analysis from the Trial of Randomized Umbilical and Fetal Flow in Europe, a prospective, multicenter, randomized management study on different antenatal monitoring strategies (ductus venosus Doppler changes and computerized cardiotocography short-term variation) in fetal growth restriction diagnosed between 26(+0) and 31(+6) weeks. We analyzed women with middle cerebral artery Doppler measurement at study entry and within 1 week before delivery and with complete postnatal follow-up (374 of 503). The primary outcome was survival without neurodevelopmental impairment at 2 years corrected for prematurity. Neonatal outcome was defined as survival until first discharge home without severe neonatal morbidity. Z-scores were calculated for middle cerebral artery pulsatility index and both umbilicocerebral and cerebroplacental ratios. Odds ratios of Doppler parameter Z-scores for neonatal and 2 year infant outcome were calculated by multivariable logistic regression analysis adjusted for gestational age and birthweight p50 ratio. Higher middle cerebral artery pulsatility index at inclusion but not within 1 week before delivery was associated with neonatal survival without severe morbidity (odds ratio, 1.24; 95% confidence interval, 1.02-1.52). Middle cerebral artery pulsatility index Z-score and

  20. Relationship between nutritionally-mediated placental growth restriction and fetal growth, body composition and endocrine status during late gestation in adolescent sheep.

    PubMed

    Wallace, J M; Bourke, D A; Aitken, R P; Palmer, R M; Da Silva, P; Cruickshank, M A

    2000-01-01

    The aim was to investigate the consequences of nutritionally-mediated placental growth restriction on fetal organ growth, conformation, body composition and endocrine status during late gestation. Embryos recovered from superovulated adult ewes inseminated by a single sire were transferred in singleton to the uterus of peripubertal adolescent recipients. Post-transfer, adolescent dams were offered a high (H) or moderate (M) level of a complete diet to promote rapid or moderate maternal growth rates, respectively (n=7 per group). After day 100 of gestation the feed intake of the M dams was adjusted weekly to maintain body condition score. Liveweight gain during the first 100 days of gestation was 301+/-24 and 90+/-4.6 g/day for the H and M groups, respectively. Maternal plasma concentrations of insulin, IGF-I and urea were significantly higher and non-esterified fatty acid concentrations significantly lower in H compared with M dams prior to slaughter on day 128 of gestation. At this stage of gestation, total placentome weight was 50 per cent lower in H compared with M groups (P< 0.001) and was associated with a 37 per cent reduction in fetal weight (P< 0.01). All variables of fetal conformation and absolute fetal organ weights, with the exception of the adrenal glands, were lower (P< 0. 05) in the fetuses from H intake dams. However, relative fetal organ weights expressed as g/kg fetal body weight, with the exception of the gut, were not influenced by maternal dietary intake. Furthermore, fetal weight but not maternal nutritional group were predictive of individual organ weight for all organs dissected. Together these results imply that growth restriction in the fetuses derived from H intake dams was largely symmetrical. Fetal plasma concentrations of insulin, IGF-I and glucose were attenuated (P< 0.05) in fetuses from H compared with M groups. The lower fetal body weight in the former group was associated with a reduction in absolute but not relative crude protein

  1. The maternal endocrine environment in the low-protein model of intra-uterine growth restriction.

    PubMed

    Fernandez-Twinn, D S; Ozanne, S E; Ekizoglou, S; Doherty, C; James, L; Gusterson, B; Hales, C N

    2003-10-01

    Many adult diseases, including type 2 diabetes, hypertension and cardiovascular disease, are related to low birth weight. The mechanistic basis of this relationship is not known. To investigate the role of fetal undernutrition, we used a rat model of maternal protein restriction in which dams were fed a diet containing 80 g protein/kg (v. 200 g/kg in the control group) throughout gestation and lactation. Offspring were born smaller than controls and in adulthood developed diabetes, hyperinsulinaemia and tissue insulin resistance. To determine possible mechanisms of fetal programming, circulating levels of several hormones were measured in maternal plasma at gestational days 14, 17 and 21 and fetal plasma at gestational day 21. Several differences were noted at day 14, when glucose concentrations in maternal and feto-placental blood were raised significantly (P=0.04 and P=0.0001 respectively); insulin levels in the low-protein (LP) dams were raised (P=0.04), prolactin levels were raised (P=0.047) and progesterone levels were reduced (P=0.02). Circulating 17beta-oestradiol in the LP dams was raised by 35 % over those of the controls from day 17 to day 21 (P=0.008). A significant decrease in maternal leptin levels (P=0.004) was observed at gestation on day 21. Neither oestradiol nor leptin levels were altered in the fetal circulation at day 21. Maternal and fetal corticosterone levels were comparable with control levels, suggesting that they do not initiate the programming effects in this model. Our present results suggest that maternal protein restriction imposes changes in maternal levels of glucose, insulin, prolactin, progesterone, oestradiol and leptin; these changes could influence the programming of eventual adult disease in the developing fetus.

  2. Maternal snoring during pregnancy is not associated with fetal growth restriction.

    PubMed

    Tauman, Riva; Sivan, Yakov; Katsav, Shlomit; Greenfeld, Michal; Many, Ariel

    2012-08-01

    A small number of studies have, thus far, evaluated the association between maternal snoring and fetal growth revealing conflicting results. No study has compared fetal growth between women with habitual snoring who snored before pregnancy and women with habitual snoring that started to snore during pregnancy. To examine the effect of maternal snoring on fetal outcome and to investigate the differences between "chronic snorers" and "new-onset snorers". Women of singleton, uncomplicated, full-term pregnancies completed a questionnaire. Obstetric and labor records were reviewed. Newborn records were reviewed for gestational age, birth weight, Apgar score and gender. 246 low risk women were studied. Mean BMI at the beginning of pregnancy was 22.3 ± 3.5 kg/m(2). 32% reported habitual snoring. Of those, 26% were chronic snorers and 74% were new-onset snorers. Neither significant difference in fetal growth was found between snorers and non-snorers nor between chronic snorers and new-onset snorers. Increased rate of nulliparous women was found in new-onset snorers compared with both chronic snorers and non-snorers (54 vs. 25 and 29% respectively; p = 0.001). In pregnant women with no apparent risk factors, maternal snoring does not affect fetal growth. No differences in maternal characteristics or fetal outcome were found between chronic snorers and new-onset snorers.

  3. Control of Parasitophorous Vacuole Expansion by LYST/Beige Restricts the Intracellular Growth of Leishmania amazonensis

    PubMed Central

    Kennedy, Kathleen A.; Ward, Diane M.; Kaplan, Jerry; Aderem, Alan; Andrews, Norma W.

    2008-01-01

    The intracellular protozoan Leishmania replicates in parasitophorous vacuoles (PV) that share many features with late endosomes/lysosomes. L. amazonensis PVs expand markedly during infections, but the impact of PV size on parasite intracellular survival is still unknown. Here we show that host cells infected with L. amazonensis upregulate transcription of LYST/Beige, which was previously shown to regulate lysosome size. Mutations in LYST/Beige caused further PV expansion and enhanced L. amazonensis replication. In contrast, LYST/Beige overexpression led to small PVs that did not sustain parasite growth. Treatment of LYST/Beige over-expressing cells with vacuolin-1 reversed this phenotype, expanding PVs and promoting parasite growth. The opposite was seen with E-64d, which reduced PV size in LYST-Beige mutant cells and inhibited L. amazonensis replication. Enlarged PVs appear to protect parasites from oxidative damage, since inhibition of nitric oxide synthase had no effect on L. amazonensis viability within large PVs, but enhanced their growth within LYST/Beige-induced small PVs. Thus, the upregulation of LYST/Beige in infected cells functions as a host innate response to limit parasite growth, by reducing PV volume and inhibiting intracellular survival. PMID:18927622

  4. Circulating Soluble Endoglin Levels in Pregnant Women in Cameroon and Malawi—Associations with Placental Malaria and Fetal Growth Restriction

    PubMed Central

    Leke, Rose G. F.; Leke, Robert J. I.; Gwanmesia, Philomina; Molyneux, Malcolm E.; Wallace, Diane Taylor; Rogerson, Stephen J.; Kain, Kevin C.

    2011-01-01

    Placental infections with Plasmodium falciparum are associated with fetal growth restriction resulting in low birth weight (LBW). The mechanisms that mediate these effects have yet to be completely described; however, they are likely to involve inflammatory processes and dysregulation of angiogenesis. Soluble endoglin (sEng), a soluble receptor of transforming growth factor (TGF)-β previously associated with preeclampsia in pregnant women and with severe malaria in children, regulates the immune system and influences angiogenesis. We hypothesized that sEng may play a role in development of LBW associated with placental malaria (PM). Plasma levels of sEng were measured in women (i) followed prospectively throughout pregnancy in Cameroon (n = 52), and (ii) in a case-control study at delivery in Malawi (n = 479). The relationships between sEng levels and gravidity, peripheral and placental parasitemia, gestational age, and adverse outcomes of PM including maternal anemia and LBW were determined. In the longitudinal cohort from Cameroon, 28 of 52 women (54%) experienced at least one malaria infection during pregnancy. In Malawi we enrolled two aparasitemic gravidity-matched controls for every case with PM. sEng levels varied over the course of gestation and were significantly higher in early and late gestation as compared to delivery (P<0.006 and P<0.0001, respectively). Circulating sEng levels were higher in primigravidae than multigravidae from both Cameroon and Malawi, irrespective of malarial infection status (p<0.046 and p<0.001, respectively). Peripheral parasitemia in Cameroonian women and PM in Malawian women were each associated with elevated sEng levels following correction for gestational age and gravidity (p = 0.006 and p = 0.033, respectively). Increased sEng was also associated with the delivery of LBW infants in primigravid Malawian women (p = 0.017); the association was with fetal growth restriction (p = 0.003) but not pre

  5. Assessment of in vivo fetal growth and placental vascular function in a novel intrauterine growth restriction model of progressive uterine artery occlusion in guinea pigs

    PubMed Central

    Herrera, Emilio A.; Alegría, René; Farias, Marcelo; Díaz‐López, Farah; Hernández, Cherie; Uauy, Ricardo; Regnault, Timothy R. H.; Casanello, Paola

    2016-01-01

    Key points Intrauterine growth restriction (IUGR) is associated with short‐ and long‐term detrimental cardiometabolic effects.Mice and rats are commonly used to assess IUGR, but differences in placental and fetal developmental physiology relative to those in humans highlight the need for alternative small animal IUGR models.We developed a guinea pig IUGR model by gradual occlusion of uterine arteries by ameroid constrictor implantation. In this model, reduced uterine blood flow was associated with IUGR, allowing in vivo assessment of fetal growth trajectory and umbilico‐placental vascular function in conscious animals.The intervention induces placental vascular dysfunction and remodelling, as well as altered fetal abdominal growth resulting in an asymmetric IUGR and preserved brain growth. Abstract Intra‐uterine growth restriction (IUGR) is associated with short and long‐term metabolic and cardiovascular alterations. Mice and rats have been extensively used to study the effects of IUGR, but there are notable differences in fetal and placental physiology relative to those of humans that argue for alternative animal models. This study proposes that gradual occlusion of uterine arteries from mid‐gestation in pregnant guinea pigs produces a novel model to better assess human IUGR. Fetal biometry and in vivo placental vascular function were followed by sonography and Doppler of control pregnant guinea pigs and sows submitted to surgical placement of ameroid constrictors in both uterine arteries (IUGR) at mid‐gestation (35 days). The ameroid constrictors induced a reduction in the fetal abdominal circumference growth rate (0.205 cm day−1) compared to control (0.241 cm day−1, P < 0.001) without affecting biparietal diameter growth. Umbilical artery pulsatility and resistance indexes at 10 and 20 days after surgery were significantly higher in IUGR animals than controls (P < 0.01). These effects were associated with a decrease in the relative

  6. Intraplacental gene therapy with Ad-IGF-1 corrects naturally occurring rabbit model of intrauterine growth restriction.

    PubMed

    Keswani, Sundeep G; Balaji, Swathi; Katz, Anna B; King, Alice; Omar, Khaled; Habli, Mounira; Klanke, Charles; Crombleholme, Timothy M

    2015-03-01

    Intrauterine growth restriction (IUGR) due to placental insufficiency is a leading cause of perinatal complications for which there is no effective prenatal therapy. We have previously demonstrated that intraplacental injection of adenovirus-mediated insulin-like growth factor-1 (Ad-IGF-1) corrects fetal weight in a murine IUGR model induced by mesenteric uterine artery branch ligation. This study investigated the effect of intraplacental Ad-IGF-1 gene therapy in a rabbit model of naturally occurring IUGR (runt) due to placental insufficiency, which is similar to the human IUGR condition with onset in the early third trimester, brain sparing, and a reduction in liver weight. Laparotomy was performed on New Zealand White rabbits on day 21 of 30 days of gestation and litters were divided into five groups: Control (first position)+phosphate-buffered saline (PBS), control+Ad-IGF-1, runt (third position)+PBS, runt+Ad-IGF-1, and runt+Ad-LacZ. The effect of IGF-1 gene therapy on fetal, placental, liver, heart, lung, and musculoskeletal weights of the growth-restricted pups was examined. Protein expression after gene transfer was seen along the maternal-fetal placenta interface (n=12) 48 hr after gene therapy. There was minimal gene transfer detected in the pups or maternal organs. At term, compared with the normally grown first-position control, the runted third-position pups demonstrated significantly lower fetal, placental, liver, lung, and musculoskeletal weights. The fetal, liver, and musculoskeletal weights were restored to normal by intraplacental Ad-IGF-1 gene therapy (p<0.01), with no change in the placental weight. Intraplacental gene therapy is a novel strategy for the treatment of IUGR caused by placental insufficiency that takes advantage of an organ that will be discarded at birth. Development of nonviral IGF-1 gene delivery using placenta-specific promoters can potentially minimize toxicity to the mother and fetus and facilitate clinical translation of

  7. First-trimester fetal growth restriction and the occurrence of miscarriage in rural Bangladesh: A prospective cohort study

    PubMed Central

    Rashid, Harunor; Ma, Enbo; Ferdous, Farzana; Ekström, Eva-Charlotte

    2017-01-01

    Fetal growth restriction in early pregnancy increases the risk of adverse pregnancy outcome, which has a significant social and psychological impact on women. There is limited information related to community-based study to evaluate early indicators related to miscarriage. The aim of this study is to examine the relationship between fetal growth restriction, measured by ultrasound crown-rump length (CRL), and subsequent occurrence of miscarriage in pregnant women in rural Bangladesh. The study was conducted within the Maternal and Infant Nutrition Interventions Trial in Matlab (MINIMat study), Bangladesh. A total of 4436 pregnant women were enrolled in the study when they were at less than 14 gestational weeks. The expected CRL was determined based on an established growth curve of gestational age and CRL, and deviation from this curve of CRL was expressed as a z-score. After identifying related covariates, the multiple Poisson regression model was used to determine the independent contribution from the CRL to miscarriage. A total of 3058 singleton pregnant women were included in analyses, with 92 miscarriages and 2966 continued pregnancies. The occurrence of miscarriages was significantly higher in the smaller categories of CRL z-score after adjustments for maternal age, parity, early pregnancy BMI, gestational age at CRL measurement and socioeconomic status (adjusted relative risk [95% confidence interval]: 1.03 [1.02–1.05] for less than -2 z-score). In a rural Bangladesh population, smaller than expected CRL for the gestational age was related to subsequent miscarriage. Ultrasound biometry information together with careful clinical assessment should provide much needed attention and care for pregnant women. PMID:28732073

  8. DNA Methylation-Independent Growth Restriction and Altered Developmental Programming in a Mouse Model of Preconception Male Alcohol Exposure.

    PubMed

    Chang, Richard C; Skiles, William M; Sarah, S Chronister; Wang, Haiqing; Sutton, Gabrielle I; Bedi, Yudhishtar S; Snyder, Matthew; Long, Charles R; Golding, Michael C

    2017-08-17

    The preconception environment is a significant modifier of dysgenesis and the development of environmentally-induced disease. To date, Fetal Alcohol Spectrum Disorders (FASDs) have been exclusively associated with maternal exposures, yet emerging evidence suggests male-inherited alterations in the developmental program of sperm may be relevant to the growth-restriction phenotypes of this condition. Using a mouse model of voluntary consumption, we find chronic preconception male ethanol exposure associates with fetal growth restriction, decreased placental efficiency, abnormalities in cholesterol trafficking, sex-specific alterations in the genetic pathways regulating hepatic fibrosis, and disruptions in the regulation of imprinted genes. Alterations in the DNA methylation profiles of imprinted loci have been identified in clinical studies of alcoholic sperm, suggesting the legacy of paternal drinking may transmit via heritable disruptions in the regulation of imprinted genes. However, the capacity of sperm-inherited changes in DNA methylation to broadly transmit environmentally-induced phenotypes remains unconfirmed. Using bisulphite mutagenesis and second-generation deep sequencing, we find no evidence to suggest that these phenotypes or any of the associated transcriptional changes are linked to alterations in the sperm-inherited DNA methylation profile. These observations are consistent with recent studies examining the male transmission of diet-induced phenotypes and emphasize the importance of epigenetic mechanisms of paternal inheritance beyond DNA methylation. This study challenges the singular importance of maternal alcohol exposures and suggests paternal alcohol abuse is a significant, yet overlooked epidemiological factor complicit in the genesis of alcohol-induced growth defects, and may provide mechanistic insight into the failure of FASD children to thrive postnatally.

  9. Verbal short-term memory span in children: long-term modality dependent effects of intrauterine growth restriction.

    PubMed

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

    2008-12-01

    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. This long-term, prospective design study examined modality-dependent verbal STM functions in children who were diagnosed at birth with IUGR (n = 138) and a control group (n = 64). Their STM skills were evaluated individually at 9 years of age with four conditions of the Visual-Aural Digit Span Test (VADS; Koppitz, 1981): auditory-oral, auditory-written, visuospatial-oral and visuospatial-written. Cognitive competence was evaluated with the short form of the Wechsler Intelligence Scales for Children--revised (WISC-R95; Wechsler, 1998). We found IUGR-related specific auditory-oral STM deficits (p < .036) in conjunction with two double dissociations: an auditory-visuospatial (p < .014) and an input-output processing distinction (p < .014). Cognitive competence had a significant effect on all four conditions; however, the effect of IUGR on the auditory-oral condition was not overridden by the effect of intelligence quotient (IQ). Intrauterine growth restriction affects global competence and inter-modality processing, as well as distinct auditory input processing related to verbal STM functions. The findings support a long-term relationship between prenatal aberrant head growth and auditory verbal STM deficits by the end of the first decade of life. Empirical, clinical and educational implications are presented.

  10. Local controlled intramyocardial delivery of platelet-derived growth factor improves postinfarction ventricular function without pulmonary toxicity.

    PubMed

    Hsieh, Patrick C H; MacGillivray, Catherine; Gannon, Joseph; Cruz, Francisco U; Lee, Richard T

    2006-08-15

    Local delivery methods can target therapies to specific tissues and potentially avoid toxicity to other organs. Platelet-derived growth factor can protect the myocardium, but it also plays an important role in promoting pulmonary hypertension. It is not known whether local myocardial delivery of platelet-derived growth factor during myocardial infarction (MI) can lead to sustained cardiac benefit without causing pulmonary hypertension. We performed a randomized and blinded experiment of 127 rats that survived experimental MI or sham surgery. We delivered platelet-derived growth factor (PDGF)-BB with self-assembling peptide nanofibers (NFs) to provide controlled release within the myocardium. There were 6 groups with n > or = 20 in each group: sham, sham+NF, sham+NF/PDGF, MI, MI+NF, and MI+NF/PDGF. Serial echocardiography from 1 day to 3 months showed significant improvement of ventricular fractional shortening, end-systolic dimension, and end-diastolic dimension with local PDGF delivery (P < 0.05 for MI+NF/PDGF versus MI or MI+NF). Catheterization at 4 months revealed improved ventricular function in the controlled delivery group (left ventricular end-diastolic pressure, cardiac index, +dP/dt, -dP/dt, and time constant of exponential decay all P < 0.05 for MI+NF/P versus MI or MI+NF). Infarcted myocardial volume was reduced by NF/PDGF therapy (34.0 +/- 13.3% in MI, 28.9 +/- 12.9% in MI+NF, and 12.0 +/- 5.8% in MI+NF/PDGF; P < 0.001). There was no evidence of pulmonary toxicity from the therapy, with no differences in right ventricular end-systolic pressure, right ventricular dP/dt, bromodeoxyuridine staining, or pulmonary artery medial wall thickness. Intramyocardial delivery of PDGF by self-assembling peptide NFs leads to long-term improvement in cardiac performance after experimental infarction without apparent pulmonary toxicity. Local myocardial protection may allow prevention of heart failure without systemic toxicity.

  11. Phosphorus restriction prevents parathyroid gland growth. High phosphorus directly stimulates PTH secretion in vitro.

    PubMed Central

    Slatopolsky, E; Finch, J; Denda, M; Ritter, C; Zhong, M; Dusso, A; MacDonald, P N; Brown, A J

    1996-01-01

    Dietary phosphorus (P) restriction is known to ameliorate secondary hyperparathyroidism in renal failure patients. In early renal failure, this effect may be mediated by an increase in 1,25-(OH)2D3, whereas in advanced renal failure, P restriction can act independent of changes in 1,25-(OH)2D3 and serum ionized calcium (ICa). In this study, we examined the effects of dietary P on serum PTH, PTH mRNA, and parathyroid gland (PTG) hyperplasia in uremic rats. Normal and uremic rats were maintained on a low (0.2%) or high (0.8%) P diet for 2 mo. PTG weight and serum PTH were similar in both groups of normal rats and in uremic rats fed the 0.2% P diet. In contrast, there were significant increases in serum PTH (130 +/- 25 vs. 35 +/- 3.5 pg/ml, P < 0.01), PTG weight (1.80 +/- 0.13 vs. 0.88 +/- 0.06 microg/gram of body weight, P < 0.01), and PTG DNA (1.63 +/- 0.24 vs. 0.94 +/- 0.07 microg DNA/gland, P < 0.01) in the uremic rats fed the 0.8% P diet as compared with uremic rats fed the 0.2% P diet. Serum ICa and 1,25-(OH)2D3 were not altered over this range of dietary P, suggesting a direct effect of P on PTG function. We tested this possibility in organ cultures of rat PTGs. While PTH secretion was acutely (30 min) regulated by medium calcium, the effects of medium P were not evident until 3 h. During a 6-h incubation, PTH accumulation was significantly greater in the 2.8 mM P medium than in the 0.2 mM P medium (1,706 +/- 215 vs. 1,033 +/- 209 pg/microg DNA, P < 0.02); the medium ICa was 1.25 mM in both conditions. Medium P did not alter PTH mRNA in this system, but cycloheximide (10 microg/ml) abolished the effect of P on PTH secretion. Thus, the effect of P is posttranscriptional, affecting PTH at a translational or posttranslational step. Collectively, these in vivo and in vitro results demonstrate a direct action of P on PTG function that is independent of ICa and 1,25-(OH)2D3. PMID:8647946

  12. Altered Cell Wall Plasticity Can Restrict Plant Growth under Ammonium Nutrition.

    PubMed

    Podgórska, Anna; Burian, Maria; Gieczewska, Katarzyna; Ostaszewska-Bugajska, Monika; Zebrowski, Jacek; Solecka, Danuta; Szal, Bożena

    2017-01-01

    Plants mainly utilize inorganic forms of nitrogen (N), such as nitrate (NO3(-)) and ammonium (NH4(+)). However, the composition of the N source is important, because excess of NH4(+) promotes morphological disorders. Plants cultured on NH4(+) as the sole N source exhibit serious growth inhibition, commonly referred to as "ammonium toxicity syndrome." NH4(+)-mediated suppression of growth may be attributable to both repression of cell elongation and reduction of cell division. The precondition for cell enlargement is the expansion of the cell wall, which requires the loosening of the cell wall polymers. Therefore, to understand how NH4(+) nutrition may trigger growth retardation in plants, properties of their cell walls were analyzed. We found that Arabidopsis thaliana using NH4(+) as the sole N source has smaller cells with relatively thicker cell walls. Moreover, cellulose, which is the main load-bearing polysaccharide revealed a denser assembly of microfibrils. Consequently, the leaf blade tissue showed elevated tensile strength and indicated higher cell wall stiffness. These changes might be related to changes in polysaccharide and ion content of cell walls. Further, NH4(+) toxicity was associated with altered activities of cell wall modifying proteins. The lower activity and/or expression of pectin hydrolyzing enzymes and expansins might limit cell wall expansion. Additionally, the higher activity of cell wall peroxidases can lead to higher cross-linking of cell wall polymers. Overall, the NH4(+)-mediated inhibition of growth is related to a more rigid cell wall structure, which limits expansion of cells. The changes in cell wall composition were also indicated by decreased expression of Feronia, a receptor-like kinase involved in the control of cell wall extension.

  13. Altered Cell Wall Plasticity Can Restrict Plant Growth under Ammonium Nutrition

    PubMed Central

    Podgórska, Anna; Burian, Maria; Gieczewska, Katarzyna; Ostaszewska-Bugajska, Monika; Zebrowski, Jacek; Solecka, Danuta; Szal, Bożena

    2017-01-01

    Plants mainly utilize inorganic forms of nitrogen (N), such as nitrate (NO3–) and ammonium (NH4+). However, the composition of the N source is important, because excess of NH4+ promotes morphological disorders. Plants cultured on NH4+ as the sole N source exhibit serious growth inhibition, commonly referred to as “ammonium toxicity syndrome.” NH4+-mediated suppression of growth may be attributable to both repression of cell elongation and reduction of cell division. The precondition for cell enlargement is the expansion of the cell wall, which requires the loosening of the cell wall polymers. Therefore, to understand how NH4+ nutrition may trigger growth retardation in plants, properties of their cell walls were analyzed. We found that Arabidopsis thaliana using NH4+ as the sole N source has smaller cells with relatively thicker cell walls. Moreover, cellulose, which is the main load-bearing polysaccharide revealed a denser assembly of microfibrils. Consequently, the leaf blade tissue showed elevated tensile strength and indicated higher cell wall stiffness. These changes might be related to changes in polysaccharide and ion content of cell walls. Further, NH4+ toxicity was associated with altered activities of cell wall modifying proteins. The lower activity and/or expression of pectin hydrolyzing enzymes and expansins might limit cell wall expansion. Additionally, the higher activity of cell wall peroxidases can lead to higher cross-linking of cell wall polymers. Overall, the NH4+-mediated inhibition of growth is related to a more rigid cell wall structure, which limits expansion of cells. The changes in cell wall composition were also indicated by decreased expression of Feronia, a receptor-like kinase involved in the control of cell wall extension. PMID:28848567

  14. 6B.06: CARDIAC AQP1 NITROSYLATION IN RESPONSE TO OSMOTIC STRESS INDUCED BY WATER RESTRICTION DURING POSTNATAL GROWTH.

    PubMed

    Netti, V; Iovane, A; Zotta, E; Fellet, A; Balaszczuk, A

    2015-06-01

    Aquaporin-1 (AQP1) is expressed in the heart and it has been reported to transport nitric oxide (NO), an important regulator of cardiac function. Our aim was to study AQP1 abundance and localization, NO synthase (NOS) activity and AQP1 nitrosylation in response to osmotic stress induced by water restriction during postnatal growth. Male Sprague-Dawley rats aged 25 and 50 days (n = 10) were divided in: R: water restriction 3 days; C: water ad libitum 3 days. NOS activity (14C-Arginine), AQP1 protein levels (Western Blot) and localization (immunohistochemistry) and AQP1 nitrosylation (colocalization of immunofluorescence signals of AQP1 and nitrosylated cysteine by confocal microscopy) were determined in cardiac tissue. We also evaluated the effects of NO donor sodium nitroprusside (SNP) on osmotic water permeability of cardiac membrane vesicles expressing AQP1 by stopped-flow spectrometry. Water restriction induced a dehydration state in both age groups. Cardiac AQP1 was localized in the endocardium and endothelium in both age groups in control animals. Water restriction did not change AQP1 abundance or localization in the 25-day-old R group; however, in the 50-day-old group, AQP1 protein levels were increased and immunohistochemistry showed its localization on cardiomyocyte plasma membrane after water restriction. Cardiac NOS activity was increased in the youngest R group but it did not change in the 50-day-old R group. AQP1 nitrosylation was increased in R25 group, whereas there are no significant differences in colocalization of fluorescent signals between C or R animals aged 50 days. On the other hand, cardiac membrane vesicles expressing AQP1 presented a high water permeability coefficient (Pf: 326+/-17 μm/s, n = 6) indicated water transport by aquaporins and pretreatment with SNP decreased water permeability (Pf: 102+/-4 μm/s, n = 5). Cardiac NO system and AQP1 abundance and localization during osmotic stress in vivo depend on postnatal age

  15. Cardiac hypertrophy and altered hemodynamic adaptation in growth-restricted preterm infants.

    PubMed

    Leipälä, Jaana A; Boldt, Talvikki; Turpeinen, Ursula; Vuolteenaho, Olli; Fellman, Vineta

    2003-06-01

    The objective was to elucidate hemodynamic adaptation in very low birth weight (<1500 g) infants after intrauterine growth retardation. 31 growth-retarded (SGA, birth weight <-2 SD) and 32 appropriate for gestational age (AGA, birth weight within +/- 1 SD range) infants were enrolled. In SGA infants, the diastolic diameters of the interventricular septum and the left ventricle were increased, and serum brain natriuretic peptide (BNP) was elevated. Left ventricular output (LVO) of the AGA infants increased from 150 +/- 28 to 283 +/- 82 mL/kg/min during the study (p < 0.01). The SGA infants had a higher initial LVO than the AGA infants (243 +/- 47 versus 150 +/- 28 mL/kg/min, p < 0.05), but did not show further LVO increase during the study period. Red cell (RCV) and blood (BV) volume were assessed by Hb subtype analysis, when packed donor red cells were transfused. RCV and BV did not differ between the groups initially, but RCV increased by 18% and BV by 29% in the AGA group during the first 3 d. On day 3, AGA infants had larger BV than the SGA infants (88 +/- 5 versus 73 +/- 12 mL/kg, p < 0.05). In conclusion, cardiac hypertrophy, elevated initial LVO and BNP of the SGA infants suggest increased cardiac workload after intrauterine growth retardation. Based on the BV and RCV data, blood volume regulation may also be impaired. The data suggest that SGA preterm infants may be exposed to an increased risk of circulatory failure during early adaptation.

  16. Sildenafil citrate increases fetal weight in a mouse model of fetal growth restriction with a normal vascular phenotype.

    PubMed

    Dilworth, Mark Robert; Andersson, Irene; Renshall, Lewis James; Cowley, Elizabeth; Baker, Philip; Greenwood, Susan; Sibley, Colin Peter; Wareing, Mark

    2013-01-01

    Fetal growth restriction (FGR) is defined as the inability of a fetus to achieve its genetic growth potential and is associated with a significantly increased risk of morbidity and mortality. Clinically, FGR is diagnosed as a fetus falling below the 5(th) centile of customised growth charts. Sildenafil citrate (SC, Viagra™), a potent and selective phosphodiesterase-5 inhibitor, corrects ex vivo placental vascular dysfunction in FGR, demonstrating potential as a therapy for this condition. However, many FGR cases present without an abnormal vascular phenotype, as assessed by Doppler measures of uterine/umbilical artery blood flow velocity. Thus, we hypothesized that SC would not increase fetal growth in a mouse model of FGR, the placental-specific Igf2 knockout mouse, which has altered placental exchange capacity but normal placental blood flow. Fetal weights were increased (by 8%) in P0 mice following maternal SC treatment (0.4 mg/ml) via drinking water. There was also a trend towards increased placental weight in treated P0 mice (P = 0.056). Additionally, 75% of the P0 fetal weights were below the 5(th) centile, the criterion used to define human FGR, of the non-treated WT fetal weights; this was reduced to 51% when dams were treated with SC. Umbilical artery and vein blood flow velocity measures confirmed the lack of an abnormal vascular phenotype in the P0 mouse; and were unaffected by SC treatment. (14)C-methylaminoisobutyric acid transfer (measured to assess effects on placental nutrient transporter activity) per g placenta was unaffected by SC, versus untreated, though total transfer was increased, commensurate with the trend towards larger placentas in this group. These data suggest that SC may improve fetal growth even in the absence of an abnormal placental blood flow, potentially affording use in multiple sub-populations of individuals presenting with FGR.

  17. Sildenafil Citrate Increases Fetal Weight in a Mouse Model of Fetal Growth Restriction with a Normal Vascular Phenotype

    PubMed Central

    Dilworth, Mark Robert; Andersson, Irene; Renshall, Lewis James; Cowley, Elizabeth; Baker, Philip; Greenwood, Susan; Sibley, Colin Peter; Wareing, Mark

    2013-01-01

    Fetal growth restriction (FGR) is defined as the inability of a fetus to achieve its genetic growth potential and is associated with a significantly increased risk of morbidity and mortality. Clinically, FGR is diagnosed as a fetus falling below the 5th centile of customised growth charts. Sildenafil citrate (SC, Viagra™), a potent and selective phosphodiesterase-5 inhibitor, corrects ex vivo placental vascular dysfunction in FGR, demonstrating potential as a therapy for this condition. However, many FGR cases present without an abnormal vascular phenotype, as assessed by Doppler measures of uterine/umbilical artery blood flow velocity. Thus, we hypothesized that SC would not increase fetal growth in a mouse model of FGR, the placental-specific Igf2 knockout mouse, which has altered placental exchange capacity but normal placental blood flow. Fetal weights were increased (by 8%) in P0 mice following maternal SC treatment (0.4 mg/ml) via drinking water. There was also a trend towards increased placental weight in treated P0 mice (P = 0.056). Additionally, 75% of the P0 fetal weights were below the 5th centile, the criterion used to define human FGR, of the non-treated WT fetal weights; this was reduced to 51% when dams were treated with SC. Umbilical artery and vein blood flow velocity measures confirmed the lack of an abnormal vascular phenotype in the P0 mouse; and were unaffected by SC treatment. 14C-methylaminoisobutyric acid transfer (measured to assess effects on placental nutrient transporter activity) per g placenta was unaffected by SC, versus untreated, though total transfer was increased, commensurate with the trend towards larger placentas in this group. These data suggest that SC may improve fetal growth even in the absence of an abnormal placental blood flow, potentially affording use in multiple sub-populations of individuals presenting with FGR. PMID:24204949

  18. Paracrine effects of bombesin/gastrin-releasing peptide and other growth factors on pulmonary neuroendocrine cells in vitro.

    PubMed

    Speirs, V; Bienkowski, E; Wong, V; Cutz, E

    1993-05-01

    Pulmonary neuroendocrine cells (PNEC) are numerous in the fetus where they have been implicated to have a role in fetal lung development. We assessed the effects of putative growth factors, gastrin releasing peptide (GRP), cholecystokinin (CCK), gastrin (GN), serotonin (5-HT), and epidermal growth factor (EGF), some of which are produced by PNEC, either alone or in combination, on cultured fetal rabbit PNEC from 20, 24, and 28 day fetuses. GRP increased the total protein of the cultures over a 7 day period in an age-dependent manner, with greatest effect in cultures from the 24 day fetus, no effect with the 28 day fetus, and an inhibitory effect on 20 day cultures. This was accompanied by an increase in PNEC, which could be blocked by treatment of the cultures with a monoclonal antibody to GRP (2A11). There was no increase in 3H-thymidine labeling of PNEC in GRP treated cultures but an increase in numbers of cells partially stained for 5-HT, suggesting the induction of a precursor cell. Other growth factors had neither an inhibitory nor a stimulatory effect either alone or in combination with GRP. Preliminary studies with 125I-GRP receptor localization suggests that the GRP receptor is mostly expressed on pulmonary fibroblasts, and less on epithelial cells, so that the role for GRP in fetal lung development, at least in the rabbit, is probably indirect, acting via a paracrine mechanism.

  19. Plant-mediated gene silencing restricts growth of the potato late blight pathogen Phytophthora infestans.

    PubMed

    Jahan, Sultana N; Åsman, Anna K M; Corcoran, Pádraic; Fogelqvist, Johan; Vetukuri, Ramesh R; Dixelius, Christina

    2015-05-01

    Phytophthora infestans is an oomycete that causes severe damage to potato, and is well known for its ability to evolve rapidly in order to overcome resistant potato varieties. An RNA silencing strategy was evaluated here to clarify if small interfering RNA homologous to selected genes in P. infestans could be targeted from the plant host to reduce the magnitude of the infection. As a proof-of-concept, a hairpin RNA (hp-RNA) construct using the GFP marker gene was designed and introduced in potato. At 72 hpi, a 55-fold reduction of the signal intensity of a corresponding GFP expressing P. infestans strain on leaf samples of transgenic plants, compared with wild-type potato, was detected. This suggests that an RNA interference construct in the potato host could be processed and target a transcript of the pathogen. Three genes important in the infection process of P. infestans, PiGPB1, PiCESA2, and PiPEC, together with PiGAPDH taking part in basic cell maintenance were subsequently tested using an analogous transgenic strategy. Out of these gene candidates, the hp-PiGPB1 targeting the G protein β-subunit (PiGPB1) important for pathogenicity resulted in most restricted disease progress. Further, Illumina sequencing of inoculated transgenic potato leaves revealed sRNAs of 24/25 nt size homologous to the PiGPB1 gene in the transgenic plants indicating post-transcriptional silencing of the target gene. The work demonstrates that a host-induced gene-silencing approach is functional against P. infestans but is highly dependent on target gene for a successful outcome. This finding broadens the arsenal of control strategies to this important plant disease.

  20. 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

  1. p38α MAPK regulates adult muscle stem cell fate by restricting progenitor proliferation during postnatal growth and repair.

    PubMed

    Brien, Patrick; Pugazhendhi, Dhamayanthi; Woodhouse, Samuel; Oxley, David; Pell, Jennifer M

    2013-08-01

    Stem cell function is essential for the maintenance of adult tissue homeostasis. Controlling the balance between self-renewal and differentiation is crucial to maintain a receptive satellite cell pool capable of responding to growth and regeneration cues. The mitogen-activated protein kinase p38α has been implicated in the regulation of these processes but its influence in adult muscle remains unknown. Using conditional satellite cell p38α knockout mice we have demonstrated that p38α restricts excess proliferation in the postnatal growth phase while promoting timely myoblast differentiation. Differentiation was still able to occur in the p38α-null satellite cells, however, but was delayed. An absence of p38α resulted in a postnatal growth defect along with the persistence of an increased reservoir of satellite cells into adulthood. This population was still capable of responding to cardiotoxin-induced injury, resulting in complete, albeit delayed, regeneration, with further enhancement of the satellite cell population. Increased p38γ phosphorylation accompanied the absence of p38α, and inhibition of p38γ ex vivo substantially decreased the myogenic defect. We have used genome-wide transcriptome analysis to characterize the changes in expression that occur between resting and regenerating muscle, and the influence p38α has on these expression profiles. This study provides novel evidence for the fundamental role of p38α in adult muscle homeostasis in vivo.

  2. 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.

  3. Overexpression of transforming growth factor-β1 in fetal monkey lung results in prenatal pulmonary fibrosis

    PubMed Central

    Tarantal, A.F.; Chen, H.; Shi, T.T.; Lu, C-H.; Fang, A.B.; Buckley, S.; Kolb, M.; Gauldie, J.; Warburton, D.; Shi, W.

    2011-01-01

    Altered transforming growth factor (TGF)-β expression levels have been linked to a variety of human respiratory diseases, including bronchopulmonary dysplasia and pulmonary fibrosis. However, a causative role for aberrant TGF-β in neonatal lung diseases has not been defined in primates. Exogenous and transient TGF-β1 overexpression in fetal monkey lung was achieved by transabdominal ultrasound-guided fetal intrapulmonary injection of adenoviral vector expressing TGF-β1 at the second or third trimester of pregnancy. The lungs were then harvested near term, and fixed for histology and immunohistochemistry. Lung hypoplasia was observed where TGF-β1 was overexpressed during the second trimester. The most clearly marked phenotype consisted of severe pulmonary and pleural fibrosis, which was independent of the gestational time point when TGF-β1 was overexpressed. Increased cell proliferation, particularly in α-smooth muscle actin-positive myofibroblasts, was detected within the fibrotic foci. But epithelium to mesenchyme transdifferentiation was not detected. Massive collagen fibres were deposited on the inner and outer sides of the pleural membrane, with an intact elastin layer in the middle. This induced fibrotic pathology persisted even after adenoviral-mediated TGF-β1 overexpression was no longer evident. Therefore, overexpression of TGF-β1 within developing fetal monkey lung results in severe and progressive fibrosis in lung parenchyma and pleural membrane, in addition to pulmonary hypoplasia. PMID:20351039

  4. 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.

  5. Sequential analysis of myofibroblast differentiation and transforming growth factor-β1/Smad pathway activation in murine pulmonary fibrosis.

    PubMed

    Usuki, Jiro; Matsuda, Kuniko; Azuma, Arata; Kudoh, Shoji; Gemma, Akihiko

    2012-01-01

    Myofibroblasts play a critical role in tissue fibrosis. However, the intracellular signaling pathways in myofibroblast differentiation are poorly understood. Here, we studied the relationship between transforming growth factor-β (TGF-β)/Smad pathway activation and myofibroblast differentiation in both in vivo and in vitro experiments. In murine bleomycin-induced pulmonary fibrosis, nuclear localization of phosphorylated Smad2/3 (p-Smad2/3) was observed in pulmonary fibrotic lesions 7 days after bleomycin injection, whereas α-smooth muscle actin (ASMA)-positive myofibroblasts appeared in the lesions at 14 days, when the cytoplasmic localization of p-Smad2/3 was observed. We also compared the effects of TGF-β1 on myofibroblast differentiation and on type I collagen expression in a murine lung fibroblast cell line (MLg2908). TGF-β1 induced rapid expression of p-Smad2/3 in nuclei, after which ASMA organization in the cytoplasm of fibroblasts was observed. However, TGF-β1 produced no effect on the quantity of ASMA, either in mRNA levels or protein levels, even after the phosphorylation of Smad2/3. In contrast, TGF-β1 upregulated the expression of type I collagen mRNA. These findings suggest that in pulmonary fibrosis the molecular mechanism of myofibroblast differentiation is complex and that the difference between ASMA expression and type I collagen expression is mediated by the TGF-β/Smad pathway.

  6. Pulmonary microvascular hyperpermeability and expression of vascular endothelial growth factor in smoke inhalation- and pneumonia-induced acute lung injury.

    PubMed

    Lange, Matthias; Hamahata, Atsumori; Traber, Daniel L; Connelly, Rhykka; Nakano, Yoshimitsu; Traber, Lillian D; Schmalstieg, Frank C; Herndon, David N; Enkhbaatar, Perenlei

    2012-11-01

    Acute lung injury (ALI) and sepsis are major contributors to the morbidity and mortality of critically ill patients. The current study was designed further evaluate the mechanism of pulmonary vascular hyperpermeability in sheep with these injuries. Sheep were randomized to a sham-injured control group (n=6) or ALI/sepsis group (n=7). The sheep in the ALI/sepsis group received inhalation injury followed by instillation of Pseudomonas aeruginosa into the lungs. These groups were monitored for 24 h. Additional sheep (n=16) received the injury and lung tissue was harvested at different time points to measure lung wet/dry weight ratio, vascular endothelial growth factor (VEGF) mRNA and protein expression as well as 3-nitrotyrosine protein expression in lung homogenates. The injury induced severe deterioration in pulmonary gas exchange, increases in lung lymph flow and protein content, and lung water content (P<0.01 each). These alterations were associated with elevated lung and plasma nitrite/nitrate concentrations, increased tracheal blood flow, and enhanced VEGF mRNA and protein expression in lung tissue as well as enhanced 3-nitrotyrosine protein expression (P<0.05 each). This study describes the time course of pulmonary microvascular hyperpermeability in a clinical relevant large animal model and may improve the experimental design of future studies. Copyright © 2012 Elsevier Ltd and ISBI. All rights reserved.

  7. A hypomorphic Cbx3 allele causes prenatal growth restriction and perinatal energy homeostasis defects.

    PubMed

    Aydin, Ebru; Kloos, Dick-Paul; Gay, Emmanuel; Jonker, Willem; Hu, Lijuan; Bullwinkel, Jorn; Brown, Jeremy P; Manukyan, Maria; Giera, Martin; Singh, Prim B; Fundele, Reinald

    2015-06-01

    Mammals have three HP1 protein isotypes HP1 beta (CBX1), HP1 alpha (CBX3) and HP1 alpha (CBX5) that are encoded by the corresponding genes Cbx1, Cbx3 and Cbx5. Recent work has shown that reduction of CBX3 protein in homozygotes for a hypomorphic allele (Cbx3hypo) causes a severe postnatal mortality with around 99 percent of the homozygotes dying before weaning. It is not known what the causes of the postnatal mortality are. Here we show that Cbx3hypo/hypo conceptuses are significantly reduced in size and the placentas exhibit a haplo-insufficiency. Late gestation Cbx3hypo/hypo placentas have reduced mRNA transcripts for genes involved in growth regulation, amino acid and glucose transport. Blood vessels within the Cbx3hypo/hypo placental labyrinth are narrower than wild-type. Newborn Cbx3hypo/hypo pups are hypoglycemic, the livers are depleted of glycogen reserves and there is almost complete loss of stored lipid in brown adipose tissue (BAT). There is a 10-fold reduction in expression of the BAT-specific Ucp1 gene, whose product is responsible for nonshivering themogenesis. We suggest that it is the small size of the Cbx3hypo/hypo neonates, a likely consequence of placental growth and transport defects, combined with a possible inability to thermoregulate that causes the severe postnatal mortality.

  8. Intrauterine growth restriction leads to a dysregulation of Wilms' tumour supressor gene 1 (WT1) and to early podocyte alterations.

    PubMed

    Menendez-Castro, Carlos; Hilgers, Karl F; Amann, Kerstin; Daniel, Christoph; Cordasic, Nada; Wachtveitl, Rainer; Fahlbusch, Fabian; Plank, Christian; Dötsch, Jörg; Rascher, Wolfgang; Hartner, Andrea

    2013-06-01

    Intrauterine growth restriction (IUGR) leads to low nephron number and higher incidence of renal disease. We hypothesized that IUGR induces early podocyte alterations based on a dysregulation of Wilms' tumour suppressor gene 1 (WT1), a key player of nephrogenesis and mediator of podocyte integrity. IUGR was induced in rats by maternal protein restriction during pregnancy. Kidneys were harvested from male offspring at Days 1 and 70 of life. qRT-PCR, immunohistochemistry and electron microscopy were performed in renal tissue. Albuminuria was assessed by enzyme-linked immunosorbent assay. At Day 70 of life, higher albuminuria and overt alterations of podocyte ultrastructure were detected in IUGR animals in spite of normal blood pressure. Moreover, we found increased glomerular immunoreactivity and expression of desmin, while synaptopodin and nephrin were decreased. Glomerular immunoreactivity and expression of WT1 were increased in IUGR animals at this time point with an altered expressional ratio of WT1 +KTS and -KTS isoforms. These changes of WT1 expression were already present at the time of birth. IUGR results in early podocyte damage possibly due to a dysregulation of WT1. We suggest that an imbalance of WT1 isoforms to the disadvantage of -KTS affects nephrogenesis in IUGR rats and that persistent dysregulation of WT1 results in a reduced ability to maintain podocyte integrity, rendering IUGR rats more susceptible for renal disease.

  9. Fetal growth restriction is related to placental levels of cadmium, lead and arsenic but not with antioxidant activities.

    PubMed

    Llanos, Miguel N; Ronco, Ana María

    2009-01-01

    The objectives of this study were: to measure some essential metals and toxicants in placentas of mothers delivering neonates with fetal growth restriction, and to establish potential associations between environmental adverse stimulus and antioxidant protective mechanisms. Placentas of 20 mothers delivering neonates with low birth weight (<2500g) and normal birth weight (>3000g) at term were collected. Placental concentration of zinc, mercury, selenium and arsenic were measured by Instrumental Neutron Activation Analysis (INAA), and iron, copper, cadmium and lead by Atomic Absorption Spectrometry (AAS). Total glutathione, lipid peroxidation, total antioxidant activity and antioxidant enzyme activities (superoxide dismutase and glutathione peroxidase) were determined spectrophotometrically. Results showed reduced iron levels and increased concentrations of cadmium, lead and arsenic in placentas of mothers delivering low birth weight neonates, but not differences in oxidative stress parameters or antioxidant enzymatic activities, suggesting a relationship between low birth weight and placental concentration of cadmium, arsenic and lead.

  10. Inhibition of placental ornithine decarboxylase by DL-alpha-difluoro-methyl ornithine causes fetal growth restriction in rat.

    PubMed

    Ishida, Makoto; Hiramatsu, Yuji; Masuyama, Hisashi; Mizutani, Yasushi; Kudo, Takafumi

    2002-02-08

    The roles of polyamines in intrauterine growth restriction (IUGR) is studied. The DL-alpha-difluoromethyl ornithine (DFMO), an irreversible inhibitor of ornithine decarboxylase (ODC) which is a rate limiting enzyme of polyamine synthesis was administrated to pregnant rats so that we obtained rat fetuses with IUGR. The changes of maternal nutrition, damage of the placenta, and the direct effect of DFMO on the fetus were examined in this IUGR model. Administration of DFMO did not induced changes of maternal nutrition except for triglyceride and the fetal metabolic state. But the placental weight, ODC activity, and DNA in the placenta were decreased significantly. The ODC activity in the total placenta decreased to less than 10% of that of the control. Depression of ODC activity in the placenta may be the major cause of IUGR induced by DFMO administration, and polyamines play important roles to carry pregnancy.

  11. How Are Child Restricted and Repetitive Behaviors Associated with Caregiver Stress Over Time? A Parallel Process Multilevel Growth Model.

    PubMed

    Harrop, Clare; McBee, Matthew; Boyd, Brian A

    2016-05-01

    The impact of raising a child with autism spectrum disorder (ASD) is frequently accompanied by elevated caregiver stress. Examining the variables that predict these elevated rates will help us understand how caregiver stress is impacted by and impacts child behaviors. This study explored how restricted and repetitive behaviors (RRBs) contributed concurrently and longitudinally to caregiver stress in a large sample of preschoolers with ASD using parallel process multilevel growth models. Results indicated that initial rates of and change in RRBs predicted fluctuations in caregiver stress over time. When caregivers reported increased child RRBs, this was mirrored by increases in caregiver stress. Our data support the importance of targeted treatments for RRBs as change in this domain may lead to improvements in caregiver wellbeing.

  12. Salidroside blocks the proliferation of pulmonary artery smooth muscle cells induced by platelet‑derived growth factor‑BB.

    PubMed

    Chen, Changgui; Tang, Yanhong; Deng, Wei; Huang, Congxin; Wu, Tianyi

    2014-08-01

    The proliferation of pulmonary artery smooth muscle cells (PASMCs) contributes to the development of pulmonary vascular remodeling, ultimately leading to pulmonary hypertension. In this study, the effects and molecular mechanisms of salidroside on the platelet‑derived growth factor (PDGF)‑BB‑induced proliferation of primary cultured rat PASMCs were investigated. The presented data demonstrated that salidroside significantly inhibited the proliferation and DNA synthesis of PASMCs induced by PDGF‑BB in a dose‑ and time‑dependent manner, without cell cytotoxicity. In accordance with these findings, salidroside blocked progression through G0/G1 to S phase of the cell cycle. The salidroside‑induced inhibition of the cell cycle was associated with the inhibition of cyclin D1, cyclin E, cyclin‑dependent kinase 2 (CDK2) and CDK4 mRNA expression, as well as an increase in the mRNA expression of p27 in PDGF‑BB‑stimulated PASMCs. Further experiments showed that the beneficial effect of salidroside on blocking the proliferation of PASMCs was associated with the suppression of the AKT/glycogen synthase kinase 3 β (GSK3β) signaling pathway, but did not involve the extracellular signal‑regulated kinase 1/2, p38 and c‑Jun‑N‑terminal kinase signaling pathways. These results indicate that salidroside suppresses PDGF‑BB‑induced PASMC proliferation through the AKT/GSK3β signaling pathway and suggests that it may be a feasible therapy for pulmonary vascular remodeling diseases.

  13. Infergen Stimulated Macrophages Restrict Mycobacterium tuberculosis Growth by Autophagy and Release of Nitric Oxide

    PubMed Central

    Pahari, Susanta; Khan, Nargis; Aqdas, Mohammad; Negi, Shikha; Kaur, Jagdeep; Agrewala, Javed N.

    2016-01-01

    IFN alfacon-1 (Infergen) is a synthetic form of Interferon (IFN)-α2b. Infergen has immunomodulatory activity and is effective against hepatitis C virus. However, the effect of Infergen (IFG) on Mycobacterium tuberculosis (Mtb) has not yet been reported. Therefore, for the first time, we have studied the influence of IFG in constraining the survival of Mtb in human macrophages. We observed that IFG significantly enhanced the maturation and activation of macrophages. Further, it substantially augmented the secretion of IL-6, nitric oxide (NO) and antigen uptake. Moreover, macrophages exhibited remarkably higher bactericidal activity, as evidenced by reduction in the Mtb growth. Infergen-mediated mechanism was different from the type-1 interferons; since it worked through the activation of NF-κB, phosphorylation of STAT-3 and Akt-PI3K that improved the bactericidal activity through autophagy and NO release. In future, IFG immunotherapy can be a novel strategy for treating patients and controlling TB. PMID:28000752

  14. Development of a fetal risk assessment score for the prediction of neonatal outcome in the growth-restricted fetus.

    PubMed

    Ott, William J

    2012-10-01

    To develop and analyze a fetal risk assessment score (FRAS) that incorporates fetal arterial and venous blood flow studies (BFS), amniotic fluid volume, the non-stress test (NST) and an estimated fetal weight to improve the ability of antenatal testing to identify fetuses at risk for poor perinatal outcome and compare it to the Biophysical Profile (BPP). The Perinatal data base of the author's institution was searched for all patients with singleton gestation with the diagnosis of intrauterine growth restriction, and who had both a biophysical profile (BPP) and fetal BFS (umbilical and middle cerebral artery, ductus venosus) within 4 days of delivery. Fetuses with major congenital abnormalities, chromosomal anomalies, or who delivered less than 25 weeks gestation were excluded. A FRAS score was developed by assigning numerical points for increasing abnormal arterial and venous BFS, and one point each for a non-reactive NST, oligohydramnios or if the fetus was small for gestational age. Recommendations for delivery were based on the clinical situation and the results of the Biophysical Profile (BPP); the FRAS score was not available to the attending physician. The FRAS was then compared to the BPP for the prediction of poor neonatal outcome (significant neonatal complications or prolonged hospital stay) using receiver operating characteristic (ROC) curve analysis and χ(2) analysis. Two hundred twenty-nine patients were included in the study. The results of the ROC analysis showed that the designed FRAS (area: 0.802) was slightly better than the BPP (area: 0.659) at predicting poor perinatal outcome in a group of growth-restricted fetuses. The study gives support to the hypothesis that combining biophysical tests with BFS will improve the identification of potential high-risk patients at increased risk for poor neonatal outcome, but prospective, randomized studies are needed to confirm this hypothesis.

  15. Food restriction in young Japanese quails: effects on growth, metabolism, plasma thyroid hormones and mRNA species in the thyroid hormone signalling pathway.

    PubMed

    Rønning, Bernt; Mortensen, Anne S; Moe, Børge; Chastel, Olivier; Arukwe, Augustine; Bech, Claus

    2009-10-01

    Young birds, in their post-natal growth period, may reduce their growth and metabolism when facing a food shortage. To examine how such responses can be mediated by endocrine-related factors, we exposed Japanese quail chicks to food restriction for either 2 days (age 6-8 days) or 5 days (age 6-11 days). We then measured growth and resting metabolic rate (RMR), and circulating 3,3',5-triiodo-l-thyronine (T3) and 3,5,3',5'-tetraiodothyronine (T4) levels as well as expression patterns of genes involved in growth (insulin-like growth factor-I: IGF-I) and thyroid hormone signalling (thyroid-stimulating hormone-beta: TSHbeta, type II iodothyronine deiodinase: D2, thyroid hormone receptors isoforms: TRalpha and TRbeta). The food-restricted chicks receiving a weight-maintenance diet showed reductions in structural growth and RMR. Plasma levels of both T3 and T4 were reduced in the food-restricted birds, and within the 5 days food-restricted group there was a positive correlation between RMR and T3. IGF-I mRNA showed significantly higher abundance in the liver of ad libitum fed birds at day 8 compared with food-restricted birds. In the brain, TSHbeta mRNA level tended to be lower in food-restricted quails on day 8 compared with controls. Furthermore, TRalpha expression was lower in the brain of food-restricted birds at day 8 compared with birds fed ad libitum. Interestingly, brain D2 mRNA was negatively correlated with plasma T3 levels, tending to increase with the length of food restriction. Overall, our results show that food restriction produced significant effects on circulating thyroid hormones and differentially affected mRNA species in the thyroid hormone signalling pathway. Thus, we conclude that the effects of food restriction observed on growth and metabolism were partly mediated by changes in the endocrine-related factors investigated.

  16. Neonatal Exendin-4 Reduces Growth, Fat Deposition and Glucose Tolerance during Treatment in the Intrauterine Growth-Restricted Lamb

    PubMed Central

    Mohammad, Saidatul N. B.; De Blasio, Miles J.; Harland, M. Lyn; Simmons, Rebecca A.; Owens, Julie A.

    2013-01-01

    Background IUGR increases the risk of type 2 diabetes mellitus (T2DM) in later life, due to reduced insulin sensitivity and impaired adaptation of insulin secretion. In IUGR rats, development of T2DM can be prevented by neonatal administration of the GLP-1 analogue exendin-4. We therefore investigated effects of neonatal exendin-4 administration on insulin action and β-cell mass and function in the IUGR neonate in the sheep, a species with a more developed pancreas at birth. Methods Twin IUGR lambs were injected s.c. daily with vehicle (IUGR+Veh, n = 8) or exendin-4 (1 nmol.kg-1, IUGR+Ex-4, n = 8), and singleton control lambs were injected with vehicle (CON, n = 7), from d 1 to 16 of age. Glucose-stimulated insulin secretion and insulin sensitivity were measured in vivo during treatment (d 12–14). Body composition, β-cell mass and in vitro insulin secretion of isolated pancreatic islets were measured at d 16. Principal Findings IUGR+Veh did not alter in vivo insulin secretion or insulin sensitivity or β-cell mass, but increased glucose-stimulated insulin secretion in vitro. Exendin-4 treatment of the IUGR lamb impaired glucose tolerance in vivo, reflecting reduced insulin sensitivity, and normalised glucose-stimulated insulin secretion in vitro. Exendin-4 also reduced neonatal growth and visceral fat accumulation in IUGR lambs, known risk factors for later T2DM. Conclusions Neonatal exendin-4 induces changes in IUGR lambs that might improve later insulin action. Whether these effects of exendin-4 lead to improved insulin action in adult life after IUGR in the sheep, as in the PR rat, requires further investigation. PMID:23424667

  17. The expression of growth-arrest genes in the liver and kidney of the protein-restricted rat fetus.

    PubMed

    Maloney, Christopher A; Lilley, Christina; Cruickshank, Morven; McKinnon, Caroline; Hay, Susan M; Rees, William D

    2005-07-01

    During fetal life, there are periods of rapid cell proliferation, which are uniquely sensitive to nutritional perturbation. Feeding the pregnant rat a protein-restricted diet alters the growth trajectory of major fetal organs such as the kidney. By day 21 of gestation, the ratio of kidney weight to total body weight is reduced in the fetuses of dams fed a protein-deficient diet. In contrast, the ratio of fetal liver weight to total body weight is unchanged. To investigate the mechanisms underlying this disproportionate change in organ growth in the low-protein group, cell proliferation and differentiation have been assessed in the liver and kidney. The steady-state levels of mRNA for the growth-arrest and DNA-damage gene gadd153/CHOP-10, CCAAT enhancer-binding proteins alpha and beta were unaffected by maternal diet in both fetal liver and kidney. The mRNA for alpha-fetoprotein, albumin and hepatic glucokinase were unchanged in the liver, suggesting that maternal protein deficiency does not alter the state of differentiation. The steady-state levels of the mRNA coding for the cyclin-dependent protein kinase inhibitors (p15(INK4a), p19(INK4d), p21(CIP1), p27(KIP1) and p57(KIP2)) were unchanged in the fetal livers but were significantly increased in the kidneys of fetuses from dams fed the low-protein diet. These results show that the asymmetrical growth of the kidney is associated with increases in mRNA for the Cip/Kip cyclin-dependent kinase inhibitors and that these may reflect specific lesions in organ development.

  18. 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.

  19. [Early diagnosis of intra-uterine growth restriction by ultrasonographic estimation of fetal weight].

    PubMed

    Martins, Maria Marta; Tedesco, José Júlio de Azevedo

    2005-01-01

    Aiming to reduce the perinatal and late morbidity and lethality through opportune prenatal intervention, this study proposed to sequentially evaluate the echographic fetal weight at the 25th and 27th weeks of gestation, establishing cut-off values for echographic fetal weight useful in the diagnosis of small-for-gestational-age at this gestation time, and developing a mathematical model able to recognize the probability of a newborn small-for- gestational-age. Eighty-five newborns were evaluated, 35 small and 50 adequate for gestational age. The mothers who underwent prenatal care at our Institution were healthy or presented chronic arterial hypertension as the only disease, no history of addictions, gemellarity or malformed fetuses. All mothers performed ultrasonographic exams at the 25th and 27th weeks for estimation of the fetal weight. The exams were able to detect the inadequate development of those fetuses small-for-gestational-age group. The cut-off values for echographic fetal weight were established as 775 grams and 1015 grams for the 25th and 27th weeks, respectively. A mathematical model was developed, capable of quantifying the probability of newborns exhibiting insufficient intra-uterine growth, being small-for-gestational-age.

  20. 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

  1. Intrauterine growth restriction affects hippocampal dual specificity phosphatase 5 gene expression and epigenetic characteristics

    PubMed Central

    Ke, Xingrao; McKnight, Robert A.; Caprau, Diana; O'Grady, Shannon; Fu, Qi; Yu, Xing; Callaway, Christopher W.; Albertine, Kurt H.

    2011-01-01

    Intrauterine growth retardation (IUGR) predisposes humans toward hippocampal morbidities, such as impaired learning and memory. Hippocampal dual specificity phosphatase 5 (DUSP5) may be involved in these morbidities because DUSP5 regulates extracellular signal-regulated kinase phosphorylation (Erk). In the rat, IUGR causes postnatal changes in hippocampal gene expression and epigenetic characteristics. However, the impact of IUGR upon hippocampal DUSP5 expression and epigenetic characteristics is not known. We therefore hypothesized that IUGR affects hippocampal 1) DUSP5 expression, DNA CpG methylation, and histone code, and 2) erk1/2 phosphorylation in a well-characterized rat model of IUGR. We found that IUGR significantly decreased DUSP5 expression in the day of life (DOL) 0 and 21 male rat, while decreasing only DUSP5 protein levels in the DOL21 female rat. Fluorescent in situ hybridization and immunohistochemistry analyses localized the changes in DUSP5 mRNA and protein, many of which occurred in the dentate gyrus. IUGR also caused sex-specific differences in DNA CpG methylation and histone code in two sites of the hippocampal DUSP5 gene, a 5′-flanking specificity protein-1 (SP1) site and exon 2. Finally, when IUGR decreased DUSP5 protein levels, Erk phosphorylation increased. We conclude that IUGR affects hippocampal DUSP5 expression and epigenetic characteristics in a sex-specific manner. PMID:21828247

  2. 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.

  3. Transforming growth factor-β evokes Ca2+ waves and enhances gene expression in human pulmonary fibroblasts.

    PubMed

    Mukherjee, Subhendu; Kolb, Martin R J; Duan, Fuqin; Janssen, Luke J

    2012-06-01

    Fibroblasts maintain the structural framework of animal tissue by synthesizing extracellular matrix molecules. Chronic lung diseases are characterized in part by changes in fibroblast numbers, properties, and more. Fibroblasts respond to a variety of growth factors, cytokines, and proinflammatory mediators. However, the signaling mechanisms behind these responses have not been fully explored. We sought to determine the role of Ca(2+) waves in transforming growth factor-β (TGF-β)-mediated gene expression in human pulmonary fibroblasts. Primary human pulmonary fibroblasts were cultured and treated with TGF-β and different blockers under various conditions. Cells were then loaded with the Ca(2+) indicator dye Oregon green, and Ca(2+) waves were monitored by confocal [Ca(2+)](i) fluorimetry. Real-time PCR was used to probe gene expression. TGF-β (1 nM) evoked recurring Ca(2+) waves. A 30-minute pretreatment of SD 208, a TGF-β receptor-1 kinase inhibitor, prevented Ca(2+) waves from being evoked by TGF-β. The removal of external Ca(2+) completely occluded TGF-β-evoked Ca(2+) waves. Cyclopiazonic acid, an inhibitor of the internal Ca(2+) pump, evoked a relatively slowly developing rise in Ca(2+) waves compared with the rapid changes evoked by TGF-β, but the baseline fluorescence was increased. Ryanodine (10(-5) M) also blocked TGF-β-mediated Ca(2+) wave activity. Real-time PCR showed that TGF-β rapidly and dramatically increased the gene expression of collagen A1 and fibronectin. This increase was blocked by ryanodine treatment and cyclopiazonic acid. We conclude that, in human pulmonary fibroblasts, TGF-β acts on ryanodine-sensitive channels, leading to Ca(2+) wave activity, which in turn amplifies extracellular matrix gene expression.

  4. RNAseq analysis of fast skeletal muscle in restriction-fed transgenic coho salmon (Oncorhynchus kisutch): an experimental model uncoupling the growth hormone and nutritional signals regulating growth.

    PubMed

    Garcia de la Serrana, Daniel; Devlin, Robert H; Johnston, Ian A

    2015-07-31

    Coho salmon (Oncorhynchus kisutch) transgenic for growth hormone (Gh) express Gh in multiple tissues which results in increased appetite and continuous high growth with satiation feeding. Restricting Gh-transgenics to the same lower ration (TR) as wild-type fish (WT) results in similar growth, but with the recruitment of fewer, larger diameter, muscle skeletal fibres to reach a given body size. In order to better understand the genetic mechanisms behind these different patterns of muscle growth and to investigate how the decoupling of Gh and nutritional signals affects gene regulation we used RNA-seq to compare the fast skeletal muscle transcriptome in TR and WT coho salmon. Illumina sequencing of individually barcoded libraries from 6 WT and 6 TR coho salmon yielded 704,550,985 paired end reads which were used to construct 323,115 contigs containing 19,093 unique genes of which >10,000 contained >90 % of the coding sequence. Transcripts coding for 31 genes required for myoblast fusion were identified with 22 significantly downregulated in TR relative to WT fish, including 10 (vaspa, cdh15, graf1, crk, crkl, dock1, trio, plekho1a, cdc42a and dock5) associated with signaling through the cell surface protein cadherin. Nineteen out of 44 (43 %) translation initiation factors and 14 of 47 (30 %) protein chaperones were upregulated in TR relative to WT fish. TR coho salmon showed increased growth hormone transcripts and gene expression associated with protein synthesis and folding than WT fish even though net rates of protein accretion were similar. The uncoupling of Gh and amino acid signals likely results in additional costs of transcription associated with protein turnover in TR fish. The predicted reduction in the ionic costs of homeostasis in TR fish associated with increased fibre size were shown to involve multiple pathways regulating myotube fusion, particularly cadherin signaling.

  5. The frontal cortex IGF system is down regulated in the term, intrauterine growth restricted fetal baboon.

    PubMed

    Xie, L; Antonow-Schlorke, I; Schwab, M; McDonald, T J; Nathanielsz, P W; Li, C

    2013-10-01

    The IGF system exerts systemic and local actions during development. We previously demonstrated that fetal cerebral cortical IGF1 is reduced at 0.5 gestation in our IUGR baboon nonhuman primate model. We hypothesized that by term protein expression of several key IGF system stimulatory peptide pathway components and downstream nutrient signaling effectors of IGF, mammalian target of rapamycin (mTOR) and S6, would decrease, indicating reduced cellular nutrient uptake and protein synthesis. We fed 7 control baboons ad libitum while 6 baboons ate a globally reduced diet (70% of feed eaten by controls) from 0.16 gestation through pregnancy that produces IUGR. Fetuses were removed at Cesarean section at 0.9 gestation. Frontal cortex sections were stained for IGFI, IGFII, IGFRI, IGFR2, IGFBP2, 3, 5 and 6, and mTOR and ribosomal protein S6 and double stained with NeuN a neuron-specific nuclear antigen. All proteins stained neuronal cytoplasm except IGFRI which showed only glial cell cytoplasmic and blood vessel staining. IUGR fetuses showed decreased frontal cortical immunoreactive IGFI, IGFII, IGFRI, IGFBP2, 5 and 6, and mTOR and S6 (p < 0.05). IGFBP3 increased (p < 0.05) and IGFR2 was unchanged (p > 0.05). There were no differences between male and female fetal brains. When fetal nutrient availability is decreased, IUGR down regulates the IGF system and its mTOR signaling pathway in the fetal frontal cortex coincident with slowed growth. These findings emphasize the importance of the local tissue IGF system in fetal primate brain development. © 2013.

  6. 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. © 2016 by the Society for Experimental Biology and Medicine.

  7. Autophagy restricts Chlamydia trachomatis growth in human macrophages via IFNG-inducible guanylate binding proteins.

    PubMed

    Al-Zeer, Munir A; Al-Younes, Hesham M; Lauster, Daniel; Abu Lubad, Mohammad; Meyer, Thomas F

    2013-01-01

    Interferon γ (IFNG) is a key host response regulator of intracellular pathogen replication, including that of Chlamydia spp The antichlamydial functions of IFNG manifest in a strictly host, cell-type and chlamydial strain dependent manner. It has been recently shown that the IFNG-inducible family of immunity-related GTPases (IRG) proteins plays a key role in the defense against nonhost adapted chlamydia strains in murine epithelial cells. In humans, IFN-inducible guanylate binding proteins (hGBPs) have been shown to potentiate the antichlamydial effect of IFNG; however, how hGBPs regulate this property of IFNG is unknown. In this study, we identified hGBP1/2 as important resistance factors against C. trachomatis infection in IFNG-stimulated human macrophages. Exogenous IFNG reduced chlamydial infectivity by 50 percent in wild-type cells, whereas shRNA hGBP1/2 knockdown macrophages fully supported chlamydial growth in the presence of exogenous IFNG. hGBP1/2 were recruited to bacterial inclusions in human macrophages upon stimulation with IFNG, which triggered rerouting of the typically nonfusogenic bacterial inclusions for lysosomal degradation. Inhibition of lysosomal activity and autophagy impaired the IFNG-mediated elimination of inclusions. Thus, hGBP1/2 are critical effectors of antichlamydial IFNG responses in human macrophages. Through their capacity to remodel classically nonfusogenic chlamydial inclusions and stimulate fusion with autophagosomes, hGBP1/2 disable a major chlamydial virulence mechanism and contribute to IFNG-mediated pathogen clearance.

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

    PubMed Central

    Zhang, Lin; Chen, Wei; Dai, Yuee

    2016-01-01

    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

  9. 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

  10. Increased lymphocyte micronucleus frequency in early pregnancy is associated prospectively with pre-eclampsia and/or intrauterine growth restriction

    PubMed Central

    Furness, D. L. F.; Dekker, G. A.; Hague, W. M; Khong, T. Y.; Fenech, M. F.

    2010-01-01

    Genome stability is essential for normal foetal growth and development. To date, genome stability in human lymphocytes has not been studied in relation to late pregnancy diseases, such as pre-eclampsia (PE) and intrauterine growth restriction (IUGR), which can be life-threatening to mother and baby and together affect >10% of pregnancies. We performed a prospective cohort study investigating the association of maternal chromosomal damage in mid-pregnancy (20 weeks gestation) with pregnancy outcomes. Chromosome damage was measured using the cytokinesis-block micronucleus cytome (CBMNcyt) assay in peripheral blood lymphocytes. The odds ratio for PE and/or IUGR in a mixed cohort of low- and high-risk pregnancies (N = 136) and a cohort of only high-risk pregnancies (N = 91) was 15.97 (P = 0.001) and 17.85 (P = 0.007), respectively, if the frequency of lymphocytes with micronuclei (MN) at 20 weeks gestation was greater than the mean + 2 SDs of the cohort. These results suggest that the presence of lymphocyte MN is significantly increased in women who develop PE and/or IUGR before the clinical signs or symptoms appear relative to women with normal pregnancy outcomes. The CBMNcyt assay may provide a new approach for the early detection of women at risk of developing these late pregnancy diseases and for biomonitoring the efficacy of interventions to reduce DNA damage, which may in turn ameliorate pregnancy outcome. PMID:20581221

  11. Quantitative 3D micro-CT imaging of the human feto-placental vasculature in intrauterine growth restriction.

    PubMed

    Langheinrich, A C; Vorman, S; Seidenstücker, J; Kampschulte, M; Bohle, R M; Wienhard, J; Zygmunt, M

    2008-11-01

    Placental vascular development matches fetal growth and development. Quantification of the feto-placental vasculature in placentas from pregnancies is complicated by intrauterine growth restriction (IUGR) revealed confounding results. Therefore, the feto-placental vascular volume in IUGR placentas was assessed by 3D micro-computed tomography (micro-CT). Placental probes from IUGR (n=24) and healthy control placentas (n=40) were perfused in situ with Microfil or BaSO(4) and randomly chosen samples were scanned by micro-CT. Using 3D images, we quantitated the feto-placental vascular volume fraction (VVF). A subanalysis was performed at three different levels, reaching from the chorionic plate artery (level A), to intermediate arteries (level B) and capillary system (level C). Results were complemented by histology. The significance of differences in vascular volume measurements was tested with analysis of variance [ANOVA]. Microfil perfused placentas showed a total vascular volume fraction of 20.5+/-0.9% in healthy controls. In contrast, the VVF decreased to 7.9+/-0.9% (p<0.001) in IUGR placentas. Significant differences were found between Microfil and BaSO(4) perfused placentas in the vascular volume fraction using micro-CT and histology. Micro-CT demonstrated localized concentric luminal encroachments in the intermediate arteries in placentas complicated by IUGR. Micro-CT imaging is feasible for quantitative analysis of the feto-placental vascular tree in healthy controls and pregnancies complicated by IUGR.

  12. 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.

  13. N-Acetylcysteine, a glutathione precursor, reverts vascular dysfunction and endothelial epigenetic programming in intrauterine growth restricted guinea pigs.

    PubMed

    Herrera, Emilio A; Cifuentes-Zúñiga, Francisca; Figueroa, Esteban; Villanueva, Cristian; Hernández, Cherie; Alegría, René; Arroyo-Jousse, Viviana; Peñaloza, Estefania; Farías, Marcelo; Uauy, Ricardo; Casanello, Paola; Krause, Bernardo J

    2017-02-15

    Intrauterine growth restriction (IUGR) is associated with vascular dysfunction, oxidative stress and signs of endothelial epigenetic programming of the umbilical vessels. There is no evidence that this epigenetic programming is occurring on systemic fetal arteries. In IUGR guinea pigs we studied the functional and epigenetic programming of endothelial nitric oxide synthase (eNOS) (Nos3 gene) in umbilical and systemic fetal arteries, addressing the role of oxidative stress in this process by maternal treatment with N-acetylcysteine (NAC) during the second half of gestation. The present study suggests that IUGR endothelial cells have common molecular markers of programming in umbilical and systemic arteries. Notably, maternal treatment with NAC restores fetal growth by increasing placental efficiency and reverting the functional and epigenetic programming of eNOS in arterial endothelium in IUGR guinea pigs. In humans, intrauterine growth restriction (IUGR) is associated with vascular dysfunction, oxidative stress and signs of endothelial programming in umbilical vessels. We aimed to determine the effects of maternal antioxidant treatment with N-acetylcysteine (NAC) on fetal endothelial function and endothelial nitric oxide synthase (eNOS) programming in IUGR guinea pigs. IUGR was induced by implanting ameroid constrictors on uterine arteries of pregnant guinea pigs at mid gestation, half of the sows receiving NAC in the drinking water (from day 34 until term). Fetal biometry and placental vascular resistance were followed by ultrasound throughout gestation. At term, umbilical arteries and fetal aortae were isolated to assess endothelial function by wire-myography. Primary cultures of endothelial cells (ECs) from fetal aorta, femoral and umbilical arteries were used to determine eNOS mRNA levels by quantitative PCR and analyse DNA methylation in the Nos3 promoter by pyrosequencing. Doppler ultrasound measurements showed that NAC reduced placental vascular resistance

  14. Fetal growth restriction and the risk of perinatal mortality-case studies from the multicentre PORTO study.

    PubMed

    Unterscheider, Julia; O'Donoghue, Keelin; Daly, Sean; Geary, Michael P; Kennelly, Mairead M; McAuliffe, Fionnuala M; Hunter, Alyson; Morrison, John J; Burke, Gerard; Dicker, Patrick; Tully, Elizabeth C; Malone, Fergal D

    2014-02-11

    Intrauterine growth restriction (IUGR) is the single largest contributing factor to perinatal mortality in non-anomalous fetuses. Advances in antenatal and neonatal critical care have resulted in a reduction in neonatal deaths over the past decades, while stillbirth rates have remained unchanged. Antenatal detection rates of fetal growth failure are low, and these pregnancies carry a high risk of perinatal death. The Prospective Observational Trial to Optimize Paediatric Health in IUGR (PORTO) Study recruited 1,200 ultrasound-dated singleton IUGR pregnancies, defined as EFW <10th centile, between 24+0 and 36+6 weeks gestation. All recruited fetuses underwent serial sonographic assessment of fetal weight and multi-vessel Doppler studies until birth. Perinatal outcomes were recorded for all pregnancies. Case records of the perinatal deaths from this prospectively recruited IUGR cohort were reviewed, their pregnancy details and outcome were analysed descriptively and compared to the entire cohort. Of 1,116 non-anomalous singleton infants with EFW <10th centile, 6 resulted in perinatal deaths including 3 stillbirths and 3 early neonatal deaths. Perinatal deaths occurred between 24+6 and 35+0 weeks gestation corresponding to birthweights ranging from 460 to 2260 grams. Perinatal deaths occurred more commonly in pregnancies with severe growth restriction (EFW <3rd centile) and associated abnormal Doppler findings resulting in earlier gestational ages at delivery and lower birthweights. All of the described pregnancies were complicated by either significant maternal comorbidities, e.g. hypertension, systemic lupus erythematosus (SLE) or diabetes, or poor obstetric histories, e.g. prior perinatal death, mid-trimester or recurrent pregnancy loss. Five of the 6 mortalities occurred in women of non-Irish ethnic backgrounds. All perinatal deaths showed abnormalities on placental histopathological evaluation. The PNMR in this cohort of prenatally identified IUGR cases was 5

  15. Intraplacental Gene Therapy with Ad-IGF-1 Corrects Naturally Occurring Rabbit Model of Intrauterine Growth Restriction

    PubMed Central

    Keswani, Sundeep G.; Balaji, Swathi; Katz, Anna B.; King, Alice; Omar, Khaled; Habli, Mo