bluuebunny/crossref_metadata_2025 huggingface dataset:
Serum C24 Bile Acids in the Developing Human Fetus
Authors: Courillon Florence , Gerhardt Marie-Françoise , Myara Anne , Daffos Fernand , Forestier François , Trivin François
Published: April 2003

The C24 bile acids (BA) in the serum of 22 healthy human fetuses between weeks 20 and 37 of gestation were determined by capillary GC-MS. Fetal blood samples were taken in utero from the umbilical cord monitored by echography. There was no correlation between total bile acids (TBA) and gestational age. The TBA concentration was 5.14 ± 2.13 µM. Primary BA (cholic acid and chenodeoxycholic acid) were the main BA (66.78 ± 13.47%) with chenodeoxycholic acid being the main one. There were low concentrations of secondary BA (deoxycholic acid and lithocholic acid) (10.28 ± 7.85%), which formed by intestinal bacterial 7α-dehydroxylation of primary BA in the adult, despite the germ-free gut. The tertiary BA (ursodeoxycholic acid) was also detected (12.06 ± 9.64%). There was 6α-hydroxylation of chenodeoxycholic acid and of lithocholic acid to produce hyocholic acid and hyodeoxycholic acid respectively. Two 1β-hydroxylated BA were detected at different times of gestation. Cholic acid was rarely found in the 6α- and 1β-hydroxylated forms. These additional hydroxylations could help to protect the fetal liver against the accumulation of cytotoxic bile acids at a time when other detoxification pathways are poorly developed. Traces of unsaturated bile acids like 3β-hydroxy-5-cholenoic acid were detected, showing that 27-hydroxylation of cholesterol does occur.
Effect of Phenobarbital on Bilirubin Metabolism in Rat Brain
Authors: Hansen Thor Willy Ruud , Tommarello Steve
Published: April 2003

Bilirubin is metabolized by brain mitochondrial membranes. This activity increases with postnatal age, is higher in glia than in neurons, and is subject to genetic variability. The rates of oxidation are such that this mechanism probably contributes meaningfully to clearance of bilirubin from brain. Phenobarbital is a well-known inducer of bilirubin-metabolizing enzymes in the liver. Previous incomplete data had suggested that phenobarbital treatment might also affect bilirubin metabolism in brain. We studied the clearance of bilirubin from brain (branch 1) as well as the oxidation of bilirubin by brain mitochondrial membranes (branch 2) following pretreatment of young adult SPRD rats with phenobarbital 75 mg/kg i.p. daily for 7 days; controls received solvent only. On day 8, rats in branch 1 (n = 8 in both phenobarbital-treated and control groups) were anesthetized and 50 mg/kg bilirubin was infused i.v. over 5 min. Rats were sacrificed after 60 min and brain bilirubin determined by acid chloroform extraction. In branch 2 (n = 7 in both groups) rats were sacrificed with i.p. pentobarbital, brains were homogenized in 0.32 M sucrose and mitochondria separated out by differential centrifugation. The mitochondrial membrane suspension was added to a 10-µmol/l bilirubin solution, and the rate of bilirubin oxidation was measured at 440 nm. As expected following phenobarbital treatment, serum bilirubin was slightly lower in phenobarbital-treated vs. control rats [126 ± 32 vs. 140 ± 21 µmol/l (mean ± SD); p = 0.3]. Brain bilirubin values were also lower in the phenobarbital-treated rats (0.44 ± 0.06 vs. 0.52 ± 0.08 nmol/g, p = 0.044). As the lower brain bilirubin values in phenobarbital-treated rats could be due entirely to lower serum bilirubin values, we compared the brain:serum bilirubin ratios in the two groups. These were not different (0.0063 ± 0.0016 vs. 0.0064 ± 0011). The rate of bilirubin oxidation was significantly lower in phenobarbital-treated vs. control rats (256 ± 10 vs. 286 ± 26 pmol/min/mg protein, p = 0.023). We conclude that phenobarbital inhibits bilirubin metabolism in brain. However, albeit statistically significant, the difference is small and may not be biologically meaningful. Thus, pretreatment with phenobarbital had no effect on overall brain bilirubin clearance rate. We speculate that phenobarbital treatment may be neither helpful nor harmful relative to the neurotoxic effects of bilirubin in infants with already established jaundice.
A Single Dose of Antenatal Betamethasone Enhances Isoprenaline and Prostaglandin E2-Induced Relaxation of Preterm Ovine Pulmonary Arteries
Authors: Gao Yuansheng , Tolsa Jean-Francois , Shen Hai , Raj J.Usha
Published: April 2003

β-Adrenergic agonists and prostaglandin E2 (PGE2) play an important role in perinatal pulmonary circulation. We have determined the effect of antenatal glucocorticoid treatment on isoprenaline- and PGE2-mediated relaxation of pulmonary arteries of newborn preterm lambs. Ovine fetuses (121 days of gestation; term = 150 days) received a single intramuscular dose of betamethasone (0.5 mg/kg) or saline. Fifteen hours after the injection, the lambs were delivered, ventilated for 3 h, and sacrificed. The fourth-generation pulmonary arteries were dissected and cut into rings for study. In endothelin-1-preconstricted vessels, isoprenaline, PGE2, and forskolin (an activator of adenylyl cyclase) induced greater relaxations of pulmonary arteries of betamethasone-treated lambs than those of controls. 8-Bromo-cyclic adenosine monophosphate, a cell membrane permeable analogue of cyclic adenosine monophosphate, caused similar relaxation of all vessels. When stimulated with isoprenaline and PGE2, the adenylyl cyclase activity of crude membrane preparations of pulmonary arteries treated with betamethasone was greater than that of controls. These results show that single-dose antenatal betamethasone treatment enhances relaxation of pulmonary arteries of preterm lambs induced by isoprenaline and PGE2 and that an enhanced adenylyl cyclase activity contributes to the effect of betamethasone on pulmonary arteries of preterm lambs.
Differential Developmental Effects of Acute Hypoxia on the Rabbit Atrioventricular Conduction Axis
Authors: Wright Stanley B. , Hewett Kenneth W. , Case Christopher L. , McKay Christine A. , Gillette Paul C.
Published: April 2003

The differential developmental effects of hypoxia on antegrade fast and slow and retrograde conduction through the atrioventricular junction are unknown. This study describes the effects of hypoxia on fast and slow antegrade atrioventricular node, infra-Hisian and retrograde conduction in immature and mature hearts during premature pacing protocols in excise, perfused adult and neonatal rabbits. The results are: (1) antegrade conduction delay through the atrioventricular node is the same developmentally, but delay through the His-Purkinje system is greater in adults; (2) hypoxia reduces the extra delay in the His-Purkinje system in adults; (3) fast atrioventricular node conduction is more sensitive to hypoxia in neonates than in adults, and slow atrioventricular node conduction is more sensitive to hypoxia in adults than in neonates, and (4) retrograde atrioventricular node conduction is more resistant to hypoxia in neonates than in adults.
Growth Hormone, Insulin-Like Growth Factor-I and Insulin-Like Growth Factor Binding Protein-3 Are Regulated Differently in Small-for-Gestational-Age and Appropriate-for-Gestational-Age Neonates
Authors: Cance-Rouzaud A. , Laborie S. , Bieth E. , Tricoire J. , Rolland M. , Grandjean H. , Rochiccioli P. , Tauber M.
Published: April 2003

Growth hormone (GH), insulin-like growth factor-I (IGF-I) and IGF-binding protein-3 (IGFBP-3) were measured in 90 neonates during the first 5 days of life. Twenty-six small-for-gestational-age (SGA) neonates were compared with 64 appropriate-for-gestational-age (AGA) neonates. There were no differences in nutritional status between the 2 groups. Mean GH levels were significantly higher in the SGA group (53.4 ± 30.8 vs. 39.9 ± 23.3 µg/l; p < 0.05). In both groups GH levels correlated with birth weight (expressed as SDS) but not with gestational age. IGF-I levels were significantly lower in SGA neonates (6.6 ± 4.0 vs. 11.7 ± 8.2 ng/ml; p < 0.01). In SGA neonates with short stature, IGF-I levels were lower and GH levels were higher than in normal stature SGA neonates. IGFBP-3 levels were significantly lower in SGA neonates than in AGA neonates (0.72 ± 0.40 vs. 0.98 ± 0.43 µg/l; p < 0.01). IGF-I and IGFBP-3 correlated with gestational age in AGA but not in SGA neonates and there was no correlation with birth weight in either group. Our data provide evidence for a graduation in the severity of impact of fetal ‘malnutrition’ on the somatotropic axis and on intrauterine growth. The most severe state (SGA with short stature) was associated with a GH-resistance syndrome, characterized by very low IGF-I levels and high GH levels.
Effect of L-Aspartate on the Ventilatory Response to Hypoxia in Sedated Newborn Piglets
Authors: Navarro Hugo , Suguihara Cleide , Soliz Amed , Hehre Dorothy , Huang Jian , Bancalari Eduardo
Published: April 2003

L-Aspartate (L-ASP) acts as an excitatory amino acid neurotransmitter at the synapses of brain stem respiratory neurons. In order to determine the effect of L-ASP on the neonatal ventilatory response to hypoxia, 9 control piglets [age 4.3 ± (SD) 0.9 days, weight 1.9 ± 0.5 kg] and 9 L-ASP-treated animals [age 5.0 ± (SD) 1.4 days, weight 2.1 ± 0.7 kg] were studied. Minute ventilation, oxygen consumption, arterial blood pressure, and blood gases were measured in sedated piglets while spontaneously breathing room air and during 1, 5, and 10 min of hypoxia (O2 concentration in inspired gas 0.10). Measurements were obtained before and 60 min after the administration of L-ASP (580 mg/kg i.v. over 1 h) or 5% dextrose solution. In the control animals, the ventilatory response to hypoxia was similar before and after dextrose infusion. In contrast, a significant and sustained increase in ventilation was observed at 1, 5, and 10 min of hypoxia after the administration of L-ASP. Changes in oxygen consumption, heart rate, arterial blood pressure, pH, and arterial O2 tension with hypoxia were similar before and after the L-ASP infusion, while the arterial CO2 tension decreased significantly during hypoxia after the administration of L-ASP. These data suggest that the excitatory amino acid L-ASP is an important mediator of the hypoxic hyperventilation in the neonate. We speculate that the administration of exogenous L-ASP modifies the balance of central nervous system neurotransmitters during hypoxia, resulting in predominance of excitatory neurotransmission.
Postnatal Development of Urea Synthesis Capacity in Preterm Infants with Intrauterine Growth Retardation
Authors: Boehm G. , Teichmann B. , Jung K. , Moro G.
Published: April 2003

The postnatal development of the urea-synthesizing capacity was studied in 21 preterm infants with intrauterine growth retardation (IUGR) and compared with results found in 12 infants without IUGR as controls. The urea-synthesizing capacity was estimated by the ratio Q of 15N abundance of ammonia and urea in 6-hour urine samples collected after enteral administration of 3 mg [15N]H4Cl/kg body weight. The measurements were performed on the first day when a protein intake of 3.0–3.5 g/kg/day and an energy intake of 120 kcal/kg/day were tolerated (study day 1: postnatal 14–21 days) and on the day of discharge from the hospital (study day 2: postnatal age 39–56 days). The group of infants with IUGR was subdivided in one group of infants who developed catch-up growth (n = 12) and one group who did not demonstrate catch-up growth (n = 9). On study day 1, the Q values of the IUGR infants without catch-up growth were significantly higher than those of the IUGR infants with catch-up growth (13.4 ± 2.3 vs. 9.2 ± 2.2) or of the control infants without IUGR. During the time period from study day 1 to study day 2 the Q values of the IUGR infants with catch-up growth decreased significantly (9.2 ± 2.2 vs. 4.8 ± 2.0; p < 0.001) and were in the range of the control infants without IUGR. In contrast, the Q values of the IUGR infants without catch-up growth did not significantly change during the study period (13.4 ± 2.3 vs. 11.3 ± 2.8; p = 0.097). On both study days there was a significant correlation between the Q values and the degree of IUGR (study day 1: r = 0.652, p < 0.01; study day 2: r = 0.842, p < 0.001). The data indicate that the urea-synthesizing capacity of preterm infants increases during early postnatal life and that severe IUGR may impair this development. Metabolic investigations using urea as marker for evaluation of optimal quantity or quality of dietary proteins should carefully be interpreted when infants with severe IUGR are studied.
Biotin Plasma Levels of theHuman Fetus
Authors: Mantagos S. , Malamitsi-Puchner A. , Antsaklis A. , Livaniou E. , Evangelatos G. , Ithakissios D.S.
Published: April 2003

Biotin is an important vitamin for cellular function and growth and, therefore, essential for fetal development. The fetus is exclusively dependent on maternal biotin supply. Since biotin is not produced within the body, maternal biotin levels depend on dietary intake. In order to investigate the biotin status of the human fetus, we measured the plasma biotin levels in 15 pregnant women and their fetuses who underwent amniocentesis and fetal blood sampling at 18–24 weeks of gestation for prenatal diagnosis of thalassemia. Maternal biotin was found to be 131 ± (SD) 102 ng/l and fetal biotin 784 ± 327 ng/l (p < 0.0001). Our findings are indicative of an active transport mechanism of biotin through the placenta in favor of the fetus.
Gestational Age-Dependent Reference Values for Iron and Selected Proteins of Iron Metabolism in Serum of Premature Human Neonates
Authors: Lackmann Gerd M. , Schnieder Carsten , Bohner Jürgen
Published: April 2003

The diagnosis and treatment of fetal and neonatal diseases requires knowledge of gestational age-dependent reference ranges for most laboratory values. It was the aim of the present study to establish reference values for serum iron, transferrin, ferritin and ceruloplasmin concentrations in premature neonates, thereby paying attention to the possible changes with gestational age. Blood samples were taken from 100 premature neonates within the first hour of life. Total serum iron, transferrin, ferritin and ceruloplasmin concentrations were determined, transferrin saturation was calculated. Newborns who developed a presumed oxygen radical disease of prematurity were excluded from the study (n = 37), because previous investigations could demonstrate significantly lower serum transferrin and ceruloplasmin concentrations in prematures suffering one of these disorders. Related to gestational age, only serum transferrin concentration showed a statistically significant increase and correlation (r = 0.47; p < 0.0001) with rising age. Although statistically not significant, even serum ferritin concentration increased with rising age of the neonates. None of the investigated laboratory values correlated with birth weight. Only ferritin showed a slight, but statistically not significant increase with higher body mass. We conclude that gestational age-dependent changes of serum transferrin levels must be considered in the judgement of fetal and neonatal diseases, whereas total serum iron and ceruloplasmin concentrations remain rather constant at least during the last weeks of gestation.
Effect of Cyclosporine A on the Gastrointestinal Absorption of Acyclovir in Neonatal and Adult Rats
Authors: Mizuno Nobuyasu , Takagi Chie , Yamamoto Noriko , Takahashi Koichi
Published: April 2003

The effect of cyclosporine A (CyA) on the pharmacokinetics of acyclovir in neonatal and adult rats was studied. CyA at 25 and 50 mg/kg for 2-week-old and adult rats, respectively, given as a subcutaneous injection, reduced growth of the 2-week-old rats and inhibited growth of adult rats. The plasma concentration of acyclovir after intravenous administration (20 mg/kg) to neonatal CyA-treated rats increased and the total body clearance decreased compared with the neonatal controls. The bioavailabilities of acyclovir for neonatal control and CyA-treated rats after oral administration were significantly different at 15.6 and 22.0%, respectively, but those for the adult control and CyA-treated rats were the same at 15.6 and 14.0%, respectively. Experiments using the everted sac method showed that the amount of acyclovir transferred was higher in neonatal CyA-treated rats than the controls, but there was no difference in adult rats. A good relationship was observed between the bioavailabilities (in vivo) and cumulative transferred amounts (in vitro) in CyA-treated and control rats. Lactase activity in the brush border membrane of the intestine in the neonatal CyA-treated rats was significantly higher than in the controls. These results suggest that the gastrointestinal maturation of CyA-treated neonates is suppressed, resulting in increased bioavailability of acyclovir, while the gastrointestinal absorption of acyclovir does not differ between adult CyA-treated and control rats.
Impact of Protein Deprivation on Protein and DNA Synthesis in the Developing Rat Pancreas
Authors: Ip Wan F. , Beharry Satti , Durie Peter R.
Published: April 2003

The metabolic effects of protein malnutrition on growth and development of the exocrine pancreas are largely unknown. The aim of the present study was to evaluate the effects of protein malnutrition on pancreatic protein and DNA synthesis during postnatal development. Rat dams and their offspring were fed a protein-deficient diet (6% casein) or a control diet (25% casein) during gestation, lactation and after weaning. Pancreatic protein and DNA synthesis were measured in vitro at postnatal ages 1, 3, 10, 23, 36 and 60 days, by assessing [3H]leucine and [3H]thymidine incorporation in freshly isolated acini. Different patterns of protein synthesis were seen in the two groups. At birth, pancreatic protein synthesis was low in both control and malnourished animals. At day 3, protein synthesis in the control acini increased 10-fold while synthesis in acini of the malnourished animal group was only 50% of age-matched control values. No differences in protein synthesis were detected between the control and malnourished groups between 10 and 36 days of age. At 60 days (adulthood), acinar protein synthesis declined in the control-fed rats, but a significant increase was observed in the malnourished animals (p < 0.0005). At birth, DNA synthesis was high in the acini from both control and malnourished animals. The low-protein diet induced a slight reduction in DNA synthesis at day 3, without altering the general pattern during later stages of development. In conclusion, protein deprivation has variable effects on pancreatic protein and DNA synthesis at different stages of postnatal development. Furthermore, the mechanisms of control within acini appear to be intrinsically regulated.
Congenital Diaphragmatic Hernia
Authors: Thébaud B. , Mercier J.-C. , Dinh-Xuan A.T.
Published: April 2003

Congenital diaphragmatic hernia (CDH) is still an unsolved problem. A disease which was, for a long time, thought to be merely a hole in the diaphragm appears today to be an intriguing malformation with a poorly understood pathogenesis and a complex pathophysiology. CDH results in various degrees of pulmonary hypoplasia and severe persistent pulmonary hypertension of the newborn. Despite antenatal ultrasound diagnosis and continuous improvement in neonatal intensive care, these features could not be overcome, and the overall mortality rate in CDH is still reaching 50%. Experimental works during the past 20 years suggest that CDH is a disease of impaired lung development associated with, but not caused by, a structural defect of the diaphragm. Furthermore, there is increasing evidence that the lung in CDH is not only small but that there are numerous disorders (e.g. surfactant deficiency, decreased anti-oxidant activity, increased vascular reactivity with decreased nitric oxide and increased endothelin 1 activity, and left heart hypoplasia) which may be associated with impaired lung development. Although antenatal diagnosis of CDH is feasible by ultrasound, there is no reliable predictor of pulmonary hypoplasia, the main prognostic factor in CDH. Whilst modern therapeutic strategies such as high-frequency oscillatory ventilation, exogenous surfactant or inhaled nitric oxide may be beneficial in selected subjects, most newborns with hypoplastic lungs will not survive despite these postnatal therapies. Perhaps these newborns would benefit from antenatal treatment directed at altering lung growth early in utero to minimize pulmonary hypoplasia. Therefore, research is needed to elucidate the aetiology and pathogenesis of CDH. Knowledge about the cellular control of proliferation, differentiation and programmed cell death (apoptosis) in the organogenesis should clarify our understanding of these processes and allow us to develop drugs that stimulate lung growth or even correct the anatomical defect. Furthermore, early and reliable assessment of prognosis for fetuses with CDH at risk of death will become increasingly important in the identification of fetuses most likely to benefit from antenatal therapies and may eventually lead to decreased mortality.
The Effect of Recombinant TGFα, Human Milk, and Human Milk Macrophage Media on Gut Epithelial Proliferation Is Decreased in the Presence of a Neutralizing TGFα Antibody
Authors: Wagner Carol L. , Forsythe Donna W. , Wagner Mark T.
Published: April 2003

Objective: An in vitro model was devised to compare the relative effects of recombinant transforming growth factor-alpha (TGFα), aqueous human milk, and human milk macrophage (HMM) medium on human fetal small intestinal cell (FHs-74) proliferation. Methods: Recombinant TGFα at increasing concentrations (range 0.01–1,000 ng/ml media), the aqueous fraction of human milk (AHM), or HMM medium was added to FHs-74 cells in the presence or absence of a neutralizing TGFα antibody (1 µg/ml medium). At 24 h, cell proliferation was measured and expressed as percent control. The experimental variables were (1) activators of cell growth (TGFα, AHM, and HMM medium); (2) increasing concentrations of TGFα, and (3) neutralizing antibody to TGFα. The dependent variable for all experiments was cell proliferation. Results: Significant effects for growth stimulators and TGFα concentration as measured by cell proliferation were found. Specifically, there was a dose-dependent effect of TGFα on cell proliferation to the 5-ng/ml concentration, with a plateau reached in cell proliferation at higher concentrations. The stimulatory effect of TGFα was decreased in the presence of TGFα antibody (mean ± SD 22 ± 7.1% decline, p < 0.001). In the presence of TGFα antibody, there was a 25 ± 3.1% decline in HM-stimulated growth (p < 0.004), and a 27.6 ± 3.2% decline in HMM medium-stimulated growth (p < 0.001). Conclusions: Neutralization of recombinant TGFα and that present in human milk and HMM medium by TGFα antibody led to a consistent decrease in in vitro human fetal small intestine epithelial proliferation without affecting cell viability. These results support the hypothesis that TGFα, whether derived from human recombinant sources, human milk or HMM medium has a measurable, trophic effect on in vitro human gut epithelial cells.
Nonimmune Hydrops fetalis: Fetal and Neonatal Outcome during 1983–1992
Authors: Wafelman Leontien S. , Pollock Brad H. , Kreutzer Jacqueline , Richards Douglas S. , Hutchison Alastair A.
Published: April 2003

Prognostic factors for survival of 62 fetuses and neonates with nonimmune hydrops fetalis (NIHF) were studied retrospectively. Twenty-eight infants survived ≥28 days which is 45% for all fetuses and newborns diagnosed with NIHF and 61% for liveborns with unresolved NIHF. Univariate analysis identified that mortality was associated with the presence of ≥2 serous cavity effusions and a need for chest compressions at birth. Multivariate logistic regression analysis confirmed that the presence of ≥2 serous cavity effusions was significantly associated with mortality from NIHF <28 days after birth [OR = 48.2 (CI 3.6, 662.9) (p < 0.004)]. We conclude that, compared to published cases from the 1970s and early 1980s, survival of liveborns with NIHF seems improved. The decrease in stillbirths is more notable. The severity of hydrops at birth is the key determinant for survival.
CO2 Reactivity of the Cerebral Hemoglobin Concentration in Healthy Term Newborns Measured by Near Infrared Spectrophotometry
Authors: Dietz Vera , Wolf Martin , Keel Matthias , Siebenthal Kurt , Baenziger Oskar , Bucher Hans-Ulrich
Published: April 2003

CO2 reactivity of cerebral hemoglobin concentration was studied in 16 healthy term neonates on days 1 and 4 after birth using the near infrared spectrophotometry (NIRS) technique. The aim was to establish data on the physiological range of CO2 reactivity in healthy newborns and to investigate the influence of postnatal age on it. The CO2 reactivity measured by NIRS is expressed as the change of the total cerebral hemoglobin concentration (tHbR) per change of CO2 tension in µmol/l/kPa. We evaluated CO2 reactivity during increases and decreases of transcutaneous CO2 partial pressure and found in our methodological setting the data of the increases more reliable. In all infants but 1 we found a tHbR on day 1 with a mean value of 8.19 µmol/l/kPa (–1.39 to 18.87), in all infants on day 4 with a mean value of 9.54 µmol/l/kPa (2.76–25.88). There is a trend to higher values between day 1 and day 4 (difference = 2.25 µmol/l/kPa; p = 0.08). The noninvasive NIRS technique enabled us to test the cerebrovascular CO2 reactivity of the tHbR for the first time in healthy term newborns. Data on its physiologic range and variability are presented and compared to findings from ventilated infants and other age groups. As the CO2 reactivity might be an indicator for infants at risk of cerebral damage, it is necessary to have data on the physiological range of this parameter.
Diagnostic Value of Troponin T in Neonates of Mild Pre-Eclamptic Mothers
Authors: Narin Nazmi , Çetin Neşide , Kılıç Hüseyin , Başbuğ Mustafa , Narin Figen , Kafalı Mehpare , Ü züm Kazım , Genç Ercan , Üstünbaş H. Basri
Published: April 2003

The measurement of myocardial damage by newer, highly specific markers of myocardial damage is now possible, including cardiac structural proteins such as troponin T (TnT). In neonates of pre-eclamptic mothers, it identifies minor myocardial damage missed by other biochemical markers. The present study was designed to determine the diagnostic value of TnT concentrations in neonates of pre-eclamptic mothers. Fifteen neonates of pre-eclamptic mothers were studied (9 boys and 6 girls), and 17 healthy full-term neonates (9 boys and 8 girls) were selected as a control group. The serum TnT concentration in neonates of pre-eclamptic mothers (0.70 ng/ml) was significantly higher than that in the control group (0.10 ng/ml). In an echocardiographic study, the mean mitral peak velocity at an atrial contraction (A) value of 39 cm/s in neonates of pre-eclamptic mothers was significantly lower than that in the control group (53 cm/s), and the mean mitral peak velocity of early diastole to peak velocity of the atrial contraction (E/A) value (1.75) in neonates of pre-eclamptic mothers was significantly higher than that in the control subjects (1.23). In conclusion, our study demonstrated high levels of cardiac TnT, lower mitral A values and high mitral E/A values in neonates of pre-eclamptic mothers, presumably associated with mild myocardial damage in the neonates of pre-eclamptic mothers.
Insulin Modulates Cellular Proliferation in Developing Human Jejunum and Colon
Authors: Ménard Daniel , Corriveau Lina , Beaulieu Jean-François
Published: April 2003

Several lines of evidence suggest an important role for insulin in the regulatory mechanism of rodent small intestinal development. To investigate its potential implication in human gut, the immunofluorescent localization of insulin receptors (IR) and the influence of insulin (30 µU or 3 mU/ml) on [3H]-thymidine incorporation and on lactase and alkaline phosphatase activities were studied in fetal jejunum and colon (14–19 weeks). We demonstrate the early presence of IR, mainly detected in the basolateral portion of enterocytes and colonocytes along the crypt-villus axis. Insulin increased [3H]-thymidine incorporation as well as epithelial labeling indices in cultured explants from jejunum and colon without affecting enzymic activities. This study establishes, for the first time, that insulin stimulates proliferation of epithelial cells expressing IR in both segments without affecting brush border hydrolases in the developing human gut.
Some Risk Factors for Cerebral Palsy in Very Premature Infants: Importance of Premature Rupture of Membranes and Monochorionic Twin Placentation
Authors: Burguet A. , Monnet E. , Pauchard J.Y. , Roth Ph. , Fromentin C. , Dalphin M.L. , Allemand H. , Maillet R. , Menget A.
Published: April 2003

Objective: To delineate the perinatal risk factors of neurodevelopmental disabilities in very preterm birth applying logistic regression analysis. Design: This prospective, geographically defined collaborative study was carried out in the Franche-Comté region of France. Subjects: From October 1, 1990 to September 30, 1992, perinatal and follow-up data were collected on 203 consecutive live-born singleton or twin non-malformed infants with strictly ascertained gestational ages of less than 33 weeks. Main Outcome Measure: The rate of cerebral palsy and/or severe mental retardation as diagnosed by a family physician or pediatrician with a screening-skill test performed at 2 years of age. Results: 167/171 (98%) survivors were evaluated. Twenty-two of the 167 examined infants (13%) showed signs of cerebral palsy, and 10 of these had severe cerebral palsy or mental retardation. Risk factors for disabilities were selected by a multivariate approach: premature rupture of membranes ≥48 h (OR 4.3, 95% CI 1.6–11.8); monochorionic twin placentation (OR 6.0, 95% CI 1.7–21.3), and respiratory distress syndrome (OR 2.8, 95% CI 1.1–7.1). Conclusion: This geographically defined prospective study gives epidemiological data and highly suggests that there is a link between prenatal events (premature rupture of membranes, monochorionic twin placentation), postnatal events (respiratory distress syndrome), and neurological disabilities in former preterm infants.
Role of Nitric Oxide in Cardiovascular Responses to Endotoxemia in Neonatal Lambs
Authors: Milstein Jay M. , Milano Emil , Goetzman Boyd W. , Bennett Stephen H.
Published: April 2003

To determine whether systemic cardiovascular responses to gram-negative endotoxemia are mediated by nitric oxide, we evaluated time-dependent changes in contractility and hemodynamics in a neonatal sheep model subjected to nitric oxide synthesis inhibition with L-Name (Nω-nitro-L-arginine methyl ester). Four groups were studied: control (C), endotoxin (E), endotoxin L-Name where the nitric oxide synthase inhibitor was given prior to endotoxin (ELN), and a control L-Name group pretreated with L-Name (CLN). The contractility, measured as end-systolic elastance (Ees), increased transiently in the E group and then returned to baseline. In contrast, Ees declined over time in the ELN group. In terms of peripheral hemodynamics, both the E and ELN groups demonstrated significant progressive decreases in blood pressure and vascular resistance. The results of this study suggest that nitric oxide contributes to the newborn contractile response of the heart to endotoxin, but does not appear to mediate the systemic vascular relaxation response.
Effect of Initial Nitric Oxide Concentration on Outcome in Infants with Persistent Pulmonary Hypertension of the Newborn
Authors: Wood Karen S. , McCaffrey Martin J. , Donovan Jocelyn C. , Stiles Alan D. , Bose Carl L.
Published: April 2003

A randomized nonblinded comparison of two treatment groups was performed to determine whether treatment of infants with persistent pulmonary hypertension of the newborn using a continuous 6-ppm dose of inhaled nitric oxide (iNO) changes the likelihood of death or utilization of extracorporeal membrane oxygenation (ECMO) when compared to infants treated with 20 ppm iNO for 4 h followed by 6 ppm. Twenty-nine infants with a gestational age ≥34 weeks and a diagnosis of persistent pulmonary hypertension of the newborn were enrolled during the 3- year study period. The relative risk (20/6 vs. 6 ppm) for treatment with ECMO was 3.11 (p = 0.02), for death it was 2.80 (p = 0.32), and for either death or ECMO it was 3.42 (p = 0.006). There was no apparent advantage of treatment with a higher dosage of iNO at the initiation of therapy in the reduction of death or utilization of ECMO. These data suggest that a continuous lower dose of iNO results in a comparable improvement in oxygenation as a short exposure of higher dose iNO at the initiation of therapy.
Role of Serum Leptin in the Regulation of Weight Gain in Early Infancy
Authors: Harigaya Akira , Onigata Kazumichi , Nako Yasushi , Nagashima Kanji , Morikawa Akihiro
Published: April 2003

We investigated the changes in the serum leptin concentration from birth to 30 days of age in order to determine the effects of leptin in early infancy. Twenty-seven Japanese term infants (12 boys and 15 girls) were examined. The serum leptin concentration at 3–6 days of age was significantly lower than that in cord blood (p < 0.0001) and was significantly higher at 30 days than at 3–6 days (p < 0.0001). The serum leptin concentration did not differ with gender or nutrition. The body weight gain and the magnitude of leptin rise that occurred between 3–6 and 30 days of age showed a significant positive correlation (r = 0.79; p < 0.0001). These changes in leptin levels suggest that leptin plays an important role in the regulation of weight gain in early infancy.
Treadmill Training EnhancesGlucose Tole rance More in Pregnant than in Virgin Rats
Authors: Muñoz C. , López-Luna P. , Herrera E.
Published: April 2003

To determine whether aerobic training throughout gestation modifies glucose tolerance, female Wistar rats were mated or kept nonpregnant and run or not on a 10° slope treadmill for 5 days/week at 20 m/min, starting with a 20-min run, and with a progressive daily increase of 5 min, reaching a 75-min run on the 20th day of protocol or gestation. The exercise protocol did not modify food intake, maternal and fetal weights, litter size or blood lactic acid levels. The rise in blood glucose after an oral glucose load (2 g/kg body weight) did not differ between trained and untrained nonpregnant rats but was lower in trained than in untrained pregnant rats. In the untrained rats the rise in plasma insulin levels after the glucose load was much greater in pregnant than in nonpregnant rats; in trained rats this difference between groups was attenuated by the greater effect of exercise decreasing the plasma insulin response to the glucose load in pregnant than in nonpregnant rats. Thus, an aerobic exercise protocol that does not modify the outcome of pregnancy does significantly reduce the altered oral glucose tolerance in pregnant rats and only has a minor effect in nonpregnant rats.
Gestational Magnesium Deficiency Is Deleterious to Fetal Outcome
Authors: Almonte Rosalita A. , Heath Deanne L. , Whitehall John , Russell Miranda J. , Patole Sanjay , Vink Robert
Published: April 2003

A number of recent epidemiological findings have implicated magnesium as being essential to fetal well-being. Few studies, however, have examined the relationship between maternal requirements for dietary magnesium and subsequent mortality and morbidity in offspring. The present study uses a rodent model of dietary-induced hypomagnesemia to investigate the effects of magnesium deficiency prior to and during gestation on neonatal morbidity and mortality. Magnesium deficiency during gestation significantly increased neonatal mortality and morbidity. Such increases were associated with a reduced free magnesium concentration in both maternal and offspring blood and an increased incidence of periventricular hemorrhage and edema in newborn pups as observed by magnetic resonance imaging and histology. Animals fed a magnesium-deficient diet before mating but given magnesium supplementation during gestation did not demonstrate a significant change in neonatal mortality and morbidity when compared to control animals. The significant improvement in fetal outcome with dietary magnesium supports the concept of magnesium supplementation during pregnancy.
Postnatal Exposure to Androgens Alters Renal Ornithine Decarboxylase Ontogeny and Abolishes Renal Sexual Dimorphism in Mice
Authors: Sánchez-Capelo Amelia , Tejada Francisco , Ruzafa Carolina , Cremades Asunción , Peñafiel Rafael
Published: April 2003

The mouse kidney presents marked sexual dimorphism, manifested not only in renal size but also in the subcellular structure and enzyme activity. Ornithine decarboxylase (ODC), a key enzyme in the biosynthetic pathway of polyamines, is induced in the kidney by androgens, and its activity is higher in the kidney of male mice. The renal differences between male and female mice are not manifested during the first weeks of life and start to be expressed after weaning, simultaneously with the increase in plasma testosterone concentration. Treatment of newborn mice before postnatal day 21 with a single dose of testosterone propionate (TP, 200 μg/animal) did not increase renal ODC activity or renal size. From day 21 the same treatment elicited significant increases in renal ODC, especially in females where the basal activity of control animals was much lower than in males. The repeated injection of TP during the first 10 days of life (200 μg/animal, days 1, 4, 7 and 10) promoted an early increase in renal ODC activity but abolished the physiological rise observed in male mice at puberty and adulthood. This treatment dramatically reduced the secretion of the sexual hormones, testosterone, estradiol and progesterone, by the gonads, and diminished renal size as well as ODC and β-glucuronidase activities in male mice. Stanozolol produced effects similar to those of TP, while the nonsteroidal antiandrogen, flutamide, did not apparently affect the normal development of the male or female kidney. The results indicate that: (a) kidney sexual dimorphism is not congenital; (b) neonatal androgens are not required to induce the sexual dimorphism of the mouse kidney; (c) the neonatal kidney is unresponsive to testosterone; (d) the premature and repeated exposure to supraphysiological levels of testosterone may accelerate the ontogeny of renal ODC but can abolish later testosterone secretion and hence alter the sexual characteristics of the male kidney, and (e) the postnatal treatment with androgens does not affect the response of the adult kidney to exogenous androgens. One can conclude that the postnatal manipulation of androgens may accelerate the development of the mechanisms of androgen responsiveness in some tissues but it may alter neural structures, probably the GnRH pulse generator, that control testosterone secretion.
Effects of Hypoxia and Reoxygenation with 21% and 100%-Oxygen on Cerebral Nitric Oxide Concentration and Microcirculation in Newborn Piglets
Authors: Kutzsche Stefan , Kirkeby Ole J. , Rise Ingunn R. , Saugstad Ola D.
Published: April 2003

Bioelectric sensors for continuous registration of nitric oxide (NO) concentrations in tissues provide a new tool for invasive measurement of this gaseous molecule. This study sought to validate cerebral NO measurements using an amperiometric sensor. A series of experiments in 1- to 3-day-old piglets was carried out to study the response of NO and microcirculation during hypoxia (FiO2 0.06) and reoxygenation with 100% and 21% oxygen. Two-channel laser Doppler flowmetry was performed in the forebrain cortex. Significant decreases of NO levels were observed immediately after induction of hypoxemia (p < 0.05). During reoxygenation with 21 or 100% O2 for 30 min, NO increased significantly compared to the values at the end of hypoxia (p < 0.05). The increase of NO levels in the 100% oxygen group was greater than the increase in the 21% oxygen group (p < 0.05). There were no significant differences between the two groups during the following 3.5 h of observation. A significant increase in CBF was found in the first 2 min of hypoxia (p < 0.05), it then continued to fall to values significantly lower than baseline values at the end of hypoxemia (p < 0.05). During reoxygenation CBF normalised and there were consistent but no significant differences between the two reoxygenation groups. We conclude that NO concentration decreased during the course of hypoxia. Hypoxia-induced cerebral hyperaemia occurred in spite of significantly lower NO concentrations. Reoxygenation with 21 or 100% O2 restored CBF in both groups similarly, although values were higher after reoxygenation with 100% O2 compared to air. In fact, reoxygenation with 100% O2 led to supranormal levels of NO by contrast to 21% O2.
Effect of C1-Inhibitor in a Rat Model of Necrotizing Enterocolitis
Authors: Sonntag Josef , Wagner Mathias H. , Liu Guosheng , Vogel Martin , Walka Matthias M. , Maier Rolf F.
Published: April 2003

Our aim was to investigate the effect of C1-inhibitor (C1-INH) in a rat model of necrotizing enterocolitis (NEC). Twenty-four anesthetized and artificially ventilated rats received 0.1 mg/kg endotoxin. Fifteen minutes later, the animals in the study group (n = 12) were treated with 200 IU/kg C1-INH whereas the control animals (n = 12) received normal saline. In all animals, FiO2 was reduced after 90 min from 0.21 to 0.05 and ventilation continued until 180 min or death. All animals developed shock symptoms. Drop in mean arterial blood pressure was more pronounced and survival time was shorter in the control group. Whereas the C1-INH activity increased in the study group, it decreased in the control group. The extent of macroscopic intestinal lesions did not differ between the groups. In conclusion, C1-INH did not prevent shock, but mitigated and delayed its course.
Vascular Endothelial Growth Factor in Pulmonary Lavage Fluid from Premature Infants: Effects of Age and Postnatal Dexamethasone
Authors: D’Angio Carl T. , Maniscalco William M. , Ryan Rita M. , Avissar Nelly E. , Basavegowda Kumar , Sinkin Robert A.
Published: April 2003

Corticosteroids are used to ameliorate bronchopulmonary dysplasia (BPD). They also affect normal development, including the expression of growth factors such as vascular endothelial growth factor (VEGF). Deep pulmonary lavage specimens were collected on days 1, 3, 7 and 28 of life in 40 infants of <34 weeks of gestation at birth during a randomized controlled trial of two doses of dexamethasone (DEX) at 12 and 24 h of age for BPD prophylaxis. VEGF was measured by enzyme-linked immunosorbent assay. The 18 DEX and 21 control subjects had similar gestations, birth weights and oxygen requirements at study entry. Lavage VEGF tripled between day 1 and 3 in both groups. The day 7 levels were higher in DEX subjects than in controls. DEX and control values were similar on day 28. Higher lavage VEGF levels on days 1 and 3 were also correlated with lower gestational age at birth. Lavage VEGF levels were not associated with the development of BPD. We speculate that these DEX- and age-associated changes in VEGF may affect pulmonary angiogenesis.
Role of Nitric Oxide in Regulating Neonatal Porcine Pulmonary Artery Smooth Muscle Cell Proliferation
Authors: Ambalavanan Namasivayam , Mariani Gonzalo , Bulger Arlene , Philips, III Joseph B.
Published: April 2003

Nitric oxide (NO), which is known to inhibit systemic vascular smooth muscle cell proliferation, is used in the management of neonatal pulmonary hypertension. Our objectives were to determine: (1) if endogenous NO production by neonatal porcine pulmonary artery smooth muscle cells (PASMCs) varied with oxygen tension in vitro, and (2) the effect of exogenous NO and inducible NO synthase (iNOS) stimulators and inhibitors on PASMC proliferation and apoptosis. PASMCs were exposed to different conditions (varying PO2, NO donors and scavengers, iNOS stimulators and inhibitors) and proliferation, apoptosis, and cyclic guanosine 5′-monophosphate (cGMP) assessed. PASMCs proliferated best between 5 and 10% O2 but cGMP levels were similar at all oxygen levels. NO donors (S-nitroso-N-acetyl-penicillamine, NOC-12, NOC-18) inhibited PASMC proliferation in a dose-dependent manner with associated cGMP increases, while NO scavengers (carboxy-PTIO), iNOS stimulators (interleukin-1β, lipopolysaccharide), and iNOS inhibitors (aminoethylisothiourea) did not affect proliferation or cGMP. No changes in apoptosis were found at the concentrations of NO donors or iNOS stimulators used. These results suggest that while exogenous NO inhibits PASMC proliferation, endogenous NO may not regulate proliferation during changes in oxygen tension or cytokine levels. Endothelial derived and inhaled NO may attenuate smooth muscle hyperplasia and vascular remodeling. Inducible NOS in porcine PASMCs appears resistant to stimulation with interleukin-1β or lipopolysaccharide. The mechanisms underlying hypoxia-mediated changes in PASMC proliferation require investigation.
What Is the Place of Genetics in the Pathogenesis of Pre-Eclampsia?
Authors: Broughton Pipkin F.
Published: April 2003

It is most unlikely that there is a single ‘pre-eclampsia (PE) gene’. We are probably looking for a cluster of polymorphisms which, possibly in conjunction with environmental factors, predispose to the development of the condition. Accurate phenotyping is vital for any genetic studies of PE, and since the disease is only clinically-detectable in the second half of pregnancy, is particularly difficult. It is increasingly likely that there is a fetal genetic contribution which can only be examined after birth. Candidate genes examined on the basis of displayed or hypothetical pathophysiological effects, but for which no evidence of association or linkage has been found have included HLA-DRβ, HLA-G, and tumour necrosis factor alpha (chromosome 6), angiotensin-converting enzyme (chromosome 17) and CuZn superoxide dismutase (chromosome 21). Chromosomal exclusion mapping and a pedigree study suggest a role for genes on chromosomes 1, 3, 4, 9 or 18. Two genes concerned with clotting, those for factor 5 and methylenetetrahydrofolate reductase, lie on chromosome 1. Both have polymorphisms present in significantly higher frequency in women with PE, as well as showing functional abnormality. They probably predispose to the development of the condition, without being necessary for it. The angiotensinogen (Aogen) gene also lies on chromosome 1. The renin-angiotensin system may be activated during the early stages of PE and subsequently suppressed. In some populations, a relatively common polymorphism is present in raised frequency in women with PE, but it is also raised in non-pregnant hypertensive subjects. However, it is in partial linkage disequilibrium with another polymorphism which shows significantly distorted transmission from mother to fetus in PE pregnancies. Furthermore, its expression is significantly raised in the decidual spiral arteries; abnormal placentation is a feature of PE. We have also shown that a relatively common polymorphism in the angiotensin AT1 receptor gene (chromosome 3) is associated with raised density of the receptor. Thus far, studies of candidate genes have been on a small scale and have very much reflected the pathophysiological research interests of the investigators. The multifaceted nature of PE and the difficulties of accurate phenotyping require the accumulation of a large, very carefully phenotyped, database. It is hoped that funding will become available this year in the UK to allow the collection of such a database. The introduction of chip technology should allow genome scanning of the resource.