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Intrauterine growth restriction (IUGR) has been associated with increased perinatal morbidity and mortality and increased morbidity and metabolic abnormalities later in life. IUGR is characterized as the failure of a fetus to achieve his or her genetic growth potential in utero. Altered protein expression profiles associated with IUGR may be informative on the pathologic mechanisms of this condition and might reveal potential markers for postnatal complications. The aim of this study was to compare protein profiles of umbilical cord plasma from IUGR and appropriate for gestational age full-term neonates. Blood samples from doubly clamped umbilical cord at delivery from 10 IUGR and 10 appropriate for gestational age full-term neonates were analyzed by two-dimensional electrophoresis and MS. Prominent changes of the 2-HS glycoprotein/fetuin-A were observed in IUGR cases. Specifically we showed that these changes occur primarily at the level of post-translational modifications of the protein. Using a combination of mass spectrometry and classical biochemical assays, single and heavy chain forms of fetuin-A were found to lack the normally present O-linked sialic acids in IUGR neonates. Fetuin A is a glycoprotein that has been associated with promotion of in vitro cell replication, fetal growth and osteogenesis, and protection from Gram-negative bacterial endotoxins. Prominent defects in glycosylation/sialylation of fetuin-A revealed by our study might be responsible for impaired function of fetuin-A, leading to deficient fetal growth, especially osteogenesis, and/or to the development of complications frequently seen later in the lives of IUGR neonates.

Intrauterine growth restriction (IUGR) has been associated with increased perinatal morbidity and mortality and increased morbidity and metabolic abnormalities later in life. IUGR is characterized as the failure of a fetus to achieve his or her genetic growth potential in utero. Altered protein expression profiles associated with IUGR may be informative on the pathologic mechanisms of this condition and might reveal potential markers for postnatal complications. The aim of this study was to compare protein profiles of umbilical cord plasma from IUGR and appropriate for gestational age full-term neonates. Blood samples from doubly clamped umbilical cord at delivery from 10 IUGR and 10 appropriate for gestational age full-term neonates were analyzed by two-dimensional electrophoresis and MS. Prominent changes of the α2-HS glycoprotein/fetuin-A were observed in IUGR cases. Specifically we showed that these changes occur primarily at the level of post-translational modifications of the protein. Using a combination of mass spectrometry and classical biochemical assays, single and heavy chain forms of fetuin-A were found to lack the normally present O-linked sialic acids in IUGR neonates. Fetuin A is a glycoprotein that has been associated with promotion of in vitrocell replication, fetal growth and osteogenesis, and protection from Gram-negative bacterial endotoxins. Prominent defects in glycosylation/sialylation of fetuin-A revealed by our study might be responsible for impaired function of fetuin-A, leading to deficient fetal growth, especially osteogenesis, and/or to the development of complications frequently seen later in the lives of IUGR neonates.

Objective: The aim of the present cross-sectional study was to test the hypothesis that endothelin-3 (ET-3) is involved in PRL secretion via systemic hormonal interaction during labor. Materials and methods: Fifty healthy pregnant women with singleton pregnancies were included in the present study. At delivery, blood samples were drawn from umbilical vein and artery. At the same time, a blood sample was obtained from a peripheral vein of the mother. In all blood samples, plasma ET-3 and serum PRL concentrations were determined. The main outcome measures were the differences between maternal peripheral blood, umbilical artery and vein in terms of ET-3 and PRL levels, and the associations between ET-3 and PRL levels. Results: ET-3 values (mean±SEM) in umbilical artery did not differ significantly from those in umbilical vein (4.94±0.27 vs 5.05±0.32 pg/ml) but were in both vessels significantly higher than in maternal vein (1.14±0.56 pg/ml, p<0.001 ). Serum PRL values showed similar patterns. There was a significant positive correlation of the ET-3 levels between umbilical artery and vein (r=0.906, p<0.001), but not between maternal peripheral venous blood and the umbilical vessels. Similar correlations were found for PRL values. However, no significant correlations were found between ET-3 and PRL levels in all vessels studied. Conclusions: The present study demonstrates for the first time that ET-3 levels are higher in fetal than in maternal circulation at term. The lack of correlation between ET-3 and PRL levels suggests that ET-3 does not play an important endocrine role in the control of maternal and fetal PRL secretion during labor.

Objective: To determine during mid-trimester amniocentesis if elevated concentrations of ADAM-8 (A Disintegrin And Metalloprotease 8) and/or cortisol can recognize women at risk for spontaneous preterm delivery. Methods: The study involved 312 women who underwent mid-trimester amniocentesis. Thirteen patients, who progressed to preterm delivery, were matched with 21 controls for age, parity, gestational age at amniocentesis, and year of amniocentesis. ADAM-8 and cortisol levels were measured by enzyme-linked immunosorbent assay and radioimmunoassay, respectively. Results: ADAM-8 mean amniotic fluid concentrations were significantly higher in women with preterm delivery than in women delivering at term (mean 1213.9 [SE 96.7] pg/mL [range, 780 to 1854 pg/mLJ vs mean 937.2 [SE 50.3] pg/mL [range, 486 to 1508 pg/mL], P&lt;.02). Amniotic fluid ADAM-8 concentrations higher than 1149 pg/mL had the highest specificity and odds ratio (OR) in the identification of the women with increased risk for preterm delivery (sensitivity 61.5%; specificity 81.7%; OR, 9.6 [95% confidence interval (Cl), 1.8 to 50.3]). Women with preterm delivery had suggestively higher amnioticfiuid concentrations of cortisol (mean 1.3 [SE 0.2] µg/dL [range, 0.4 to 2.2 µg/dL]) than women delivering at term (mean 1.0 [SE 0.09] µLg/dL [range, 0.6 to 1.7 µg/dL], P&lt;.07). Furthermore, cortisol levels were positively correlated with ADAM-8 levels (Spearman’s r=.418, P&lt;.014). Conclusions: Elevated mid-trimester amnioticfiuid ADAM-8 concentrations possibly are a riskfactor for preterm delivery, particularly if ADAM-8 levels are greater than 1149 pg/mL. Potential intrauterine inflammation is also associated with suggestively increased amniotic fluid cortisol levels.

Objective:To determine during mid-trimester amniocentesis if elevated concentrations of ADAM-8 (A Disintegrin And Metalloprotease 8) and/or cortisol can recognize women at risk for spontaneous preterm delivery.Methods:The study involved 312 women who underwent mid-trimester amniocentesis. Thirteen patients, who progressed to preterm delivery, were matched with 21 controls for age, parity, gestational age at amniocentesis, and year of amniocentesis. ADAM-8 and cortisol levels were measured by enzyme-linked immunosorbent assay and radioimmunoassay, respectively.Results:ADAM-8 mean amniotic fluid concentrations were significantly higher in women with preterm delivery than in women delivering at term (mean 1213.9 [SE 96.7] pg/mL [range, 780 to 1854 pg/mL] vs mean 937.2 [SE 50.3] pg/mL [range, 486 to 1508 pg/mL], P < .02). Amniotic fluid ADAM-8 concentrations higher than 1149 pg/mL had the highest specificity and odds ratio (OR) in the identification of the women with increased risk for preterm delivery (sensitivity 61.5%; specificity 81.7%; OR, 9.6 [95% confidence interval (CI), 1.8 to 50.3]). Women with preterm delivery had suggestively higher amniotic fluid concentrations of cortisol (mean 1.3 [SE 0.2] μg/dL [range, 0.4 to 2.2 μg/dL]) than women delivering at term (mean 1.0 [SE 0.09] μg/dL [range, 0.6 to 1.7 μg/dL], P < .07). Furthermore, cortisol levels were positively correlated with ADAM-8 levels (Spearman's r = .418, P < .014).Conclusions:Elevated mid-trimester amniotic fluid ADAM-8 concentrations possibly are a risk factor for preterm delivery, particularly if ADAM-8 levels are greater than 1149 pg/mL. Potential intrauterine inflammation is also associated with suggestively increased amniotic fluid cortisol levels.

Objective: To determine and correlate midtrimester amniotic fluid concentrations of interferon ?-inducible T-cell a chemoattractant (ITAC, a chemokine directing the migration of activated T lymphocytes toward inflammation sites) and C-reactive protein (CRP) in women undergoing amniocentesis and subsequently delivering pre-or full-term infants. Methods: Among 312 women undergoing midtrimester transabdominal amniocentesis, 13 progressed to spontaneous delivery at less than 37 gestational weeks (GW). Subjects were matched for maternal age, parity, and GW at amniocentesis with 21 controls who delivered at greater than 37 GW. Amniotic fluid ITAC and CRP levels were determined by enzyme-linked immunosorbent assay (ELISA) and by nephelometry, respectively. Results: Both ITAC and CRP values were significantly higher (P =. 005 and P =.04, respectively) in the amniotic fluid of women delivering at less than 37 GW. A statistically significant correlation between amniotic fluid ITAC and CRP concentrations was also found (r =.366, P &lt;.05). The receiver operator curve (ROC) analysis of delivery at less than 37 GW gave the best cutoff point for ITAC at a concentration of 44 pg/mL and for CRP at a concentration of 0.16 mg/dL. Positive and negative predictive values for ITAC were 82% and 85%, respectively, and for CRP, 55% and 76%, respectively. Conclusions: Present data indicate that from the second trimester of pregnancy elevated amniotic fluid concentrations of ITAC are found in women delivering at less than 37 GW, as compared to women delivering at term. Therefore, ITAC in combination with other cytokines or CRP could possibly serve as predictor of preterm delivery.

Objective:To determine and correlate midtrimester amniotic fluid concentrations of interferon γ-inducible T-cell α chemoattractant (ITAC, a chemokine directing the migration of activated T lymphocytes toward inflammation sites) and C-reactive protein (CRP) in women undergoing amniocentesis and subsequently delivering pre-or full-term infants.Methods:Among 312 women undergoing midtrimester transabdominal amniocentesis, 13 progressed to spontaneous delivery at less than 37 gestational weeks (GW). Subjects were matched for maternal age, parity, and GW at amniocentesis with 21 controls who delivered at greater than 37 GW. Amniotic fluid ITAC and CRP levels were determined by enzyme-linked immunosorbent assay (ELISA) and by nephelometry, respectively.Results:Both ITAC and CRP values were significantly higher (P = .005 and P = .04, respectively) in the amniotic fluid of women delivering at less than 37 GW. A statistically significant correlation between amniotic fluid ITAC and CRP concentrations was also found (r = .366 P <.05). The receiver operator curve (ROC) analysis of delivery at less than 37 GW gave the best cutoff point for ITAC at a concentration of 44 PG/mL AND for CRP at a concentration of 0.16 mg/dL. Positive and negative predictive values for ITAC were 82% and 85%, respectively, and for CRP, 55% and 76%, respectively.Conclusions:Present data indicate that from the second trimester of pregnancy elevated amniotic fluid concentrations of ITAC are found in women delivering at less than 37 GW, as compared to women delivering at term. Therefore, ITAC in combination with other cytokines or CRP could possibly serve as predictor of preterm delivery.

Objective:Because soluble Fas (sFas) inhibits Fas-mediated apoptosis by preventing death signal transduction, we determined sFas concentrations in the follicular fluid (FF) and oocyte-cumulus complex culture medium (CM) from women undergoing in vitro fertilization (IV) in order to associate its concentrations with oocyte maturity, fertilization, and embryo quality.Methods:We studied 82 follicles from 11 healthy women (mean age, 35.4 ± 3.8 years) using a long protocol for IVF treatment. Individual FF and matched CM samples were immediately centrifuged at 4C and sFas concentrations were determined by sandwich enzyme-linked immunosorbent assays.Results:sFas concentrations were significantly higher in FF than in CM (P <.0001) and when oocytes were mature rather than immature (P <.002). Of 70 mature and 12 immature oocytes, 56 (80%) and two (16.6%), respectively, were fertilized. sFas concentrations in CM were significantly lower when mature oocytes were fertilized versus nonfertilized (P <.005). sFas concentrations in FF and CM were significantly related in an inverse manner to embryo quality (P = .004 and P = .0002, respectively).Conclusion:FF and CM from women undergoing IVF contain sFas. The latter has anti-apoptotic properties and levels are higher: in FF when oocytes are mature and in CM when oocytes are nonfertilized. Furthermore, FF and CM sFas concentrations are negatively correlated with embryo quality.

Objective: Because soluble Fas (sFas) inhibits Fas-mediated apoptosis by preventing death signal transduction, we determined sFas concentrations in the follicular fluid (FF) and oocyte-cumulus complex culture medium (CM) from women undergoing in vitro fertilization (IVF) in order to associate its concentrations with oocyte maturity, fertilization, and embryo quality. Methods: We studied 82 follicles from 11 healthy women (mean age, 35.4 ±3.8 years) using a long protocol for IVF treatment. Individual FF and matched CM samples were immediately centrifuged at 4C and sFas concentrations were determined by sandwich enzyme-linked immunosorbent assays. Results: sFas concentrations were significantly higher in FF than in CM (P&lt; .0001) and when oocytes were mature rather than immature (P&lt; .002). Of 70 mature and 12 immature oocytes, 56 (80%) and two (16.6%), respectively, were fertilized. sFas concentrations in CM were significantly lower when mature oocytes were fertilized versus nonfertilized (P&lt; .005). sFas concentrations in FF and CM were significantly related in an inverse manner to embryo quality (P= .004 and P= .0002, respectively). Conclusion: FF and CM from women undergoing IVF contain sFas. The latter has anti-apoptotic properties and levels are higher: in FF when oocytes are mature and in CM when oocytes are nonfertilized. Furthermore, FF and CM sFas concentrations are negatively correlated until embryo quality.

This study investigated in prepubertal obese children (POC), compared with prepubertal lean children (PLC), a possible relation among plasma total homocysteine (tHcy)—an independent risk factor for future atherosclerosis—and MCP-1 and RANTES, two circulating chemokines inducing leukocyte transendothelial migration (TEM), implicated in the initial stages of the inflammatory part of the atherosclerotic process. Seventy-two POC were evaluated for circulating tHcy, MCP-1, and RANTES, and compared with 42 healthy PLC. The mean adjusted (for age, sex as well as log10total insulin, vitB12, folate, total cholesterol, HDL cholesterol, log10triglycerides, and log10glucose levels) differences in tHcy, MCP-1, and RANTES levels between PLC and POC were all significant [1.16 nmol/mL (P= 0.03), 26.6 pg/mL (P= 0.02), and 52.9 pg/mL (P= 0.03), respectively]. In PLC, but not in POC, tHcy levels were negatively associated with both circulating MCP-1 (B = −1.68, P= 0.007) and RANTES (B = −1.16, P= 0.01) after adjusting for age, sex, BMI, as well as log10total insulin, vitB12, folate, total cholesterol, HDL cholesterol, log10triglycerides, and log10glucose levels. In conclusion, in POC there is a lack, in contrast to PLC, of a possibly autoregulatory, negative association of elevated tHcy levels to increased MCP-1 and RANTES levels. This could contribute to future, homocysteine-induced atherosclerosis.

Chemokines, a superfamily of polypeptide mediators, are a key component of immune surveillance and are implicated in the initiation of the inflammatory cascade. This study investigated whether serum concentrations of the chemokines regulated upon activation, normal T-cell expressed and presumably secreted (RANTES) and interleukin-8 (IL-8) change in the perinatal period because of the transition from intra- to extrauterine life, and compared determined values in mothers (MS) (n = 30) with those in their fetuses (UC), neonates (day of life 1 [N1] and 4 [N4]), and controls (CS) (n = 20). RANTES serum concentrations were higher in MS than in UC ( p &lt; 0.006), N1 ( p &lt; 0.0001), N4 ( p &lt; 0.0001), and CS ( p &lt; 0.0001). IL-8 serum concentrations in MS and UC, respectively, were significantly lower than in N1 ( p &lt; 0.0002 and p &lt; 0.0007) and N4 ( p &lt; 0.0001 and p &lt; 0.0001). Thus, after birth, neonatal serum concentrations of RANTES decrease, possibly because of elimination of the placenta (probable production site), and neonatal serum concentrations of IL-8 increase, possibly triggered by environmental antigenic stimuli to which the neonate is exposed.

The studies reported investigated the concentrations of angiogenic, proliferative, and apoptotic factors in the follicular fluid (FF) of individual follicles, aspirated from women undergoing controlled ovarian hyperstimulation using a long protocol for IVF treatment. Furthermore, the association of the concentrations of the preceding factors with oocyte maturity was studied. Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiogenin, tissue polypeptide specific antigen (TPS), and soluble Fas (sFas) were all found in the FF of all follicles examined. Moreover, from the angiogenic factors only angiogenin concentrations, and from the apoptotic factors sFas concentrations (the soluble form expressing rather an antiapoptotic function), were positively associated with oocyte maturity, possibly indicating angiogenin's biological role beyond neovascularization and a lower apoptotic rate allowing oocytes to mature. Last, the abundant expression of TPS in FF may be indicative of intense cell proliferation, in cases of ovarian stimulation.

Objective: To determine postnatal changes in neonatal serum concentrations of interferon-γ (IFN-γ), interleukin-4 (IL-4) and its soluble receptor (sIL-4R). Methods: Forty-five healthyterm neonates, 25 of the neonates' mothers and 27 healthyadults (controls) participated in the study. Cytokine concentrations were measured in blood samples from the umbilical cord, from the neonates on the 1st and 5th dayafter birth, from mothers and from controls. Results: IFN-γ concentrations were significantlylower in the umbilical cord, compared to concentrations in the controls (p < 0.04), and increased significantlyfrom the umbilical cord to levels in neonates on day5 (p < 0.03). In mothers and the umbilical cord, IFN-γ concentrations were dependent on the mode of delivery, being higher after vaginal delivery than after elective Cesarean section (p < 0.005; p < 0.006, respectively). IL-4 concentrations in the umbilical cord for 1-day and 5-day neonates were significantlyelevated compared to those in mothers (p < 0.001; p < 0.0007; p < 0.0001, respectively) and controls (p < 0.05; p < 0.01; p < 0.006, respectively). sIL-4R concentrations in all neonatal samples were significantlyelevated compared to those in controls (p < 0.0001), the highest being found in 1-day-old neonates. A strong negative correlation was found between IL-4 and sIL-4R concentrations in 1- and 5-day-old neonates (r = -0.48, p < 0.002; r = -0.45, p < 0.0065, respectively). Moreover, IFN-γ/IL-4 ratio increased significantly from the umbilical cord to 5 days of life (p < 0.03). Conclusion: Our findings indicate an earlier development of IL-4 than IFN-γ, which could be viewed as a developmental characteristic in the ontogeny of the immune system.

The most important gene loci defining risk of type 1 diabetes mellitus (T1DM) are located within the HLA gene region. HLA-DQ molecules are of primary importance but HLA-DR gene products modify the risk conferred by HLA-DQ. The risk associated with an HLA genotype is defined by the particular combination of susceptible and protective alleles. The highest risk is associated with a combination of two different risk haplotypes (7% risk to develop T1DM in Finland) whereas protective genotypes covering 69% of population have a risk of less than 0.2%). The complicated analysis of HLA genotypes is simplified by strong linkage disequilibrium between HLA-DRB1, -DQA1 and -DQB1 loci. In many cases one can deduce the alleles of other loci based on determination of the alleles in one locus. Differences between various populations in the frequency of marker alleles and in the linkages between them has to be taken into account. We have developed PCR based typing methods that utilize blood spot samples, microtiter plate format and lanthanide labeled oligonucleotide probes to define HLA-DQ and -DR alleles relevant for T1DM risk. Typing is run stepwise so that after initial HLA-DQB1 typing only those samples will be further analyzed in which -DQA1 or -DRB1 typing is informative and expected to contribute to the risk estimation. This method has been used to screen more than 50,000 newborn infants in Finland over a time period of 6 years, and it has been able to identify most children who have developed T1D during the follow-up period. The efficiency of the procedure has also been tested in Finnish and Greek populations. © 2002 Wiley-Liss, Inc.

Objective To compare the expression of intercellular adhesion molecule‐1 (ICAM‐1), vascular cell adhesion molecule‐1 (VCAM‐1), platelet endothelial cell adhesion molecule‐1 (PECAM‐1) and E‐selectin in placental bed biopsies (endothelium of spiral arteries as well as trophoblastic cells) from normal and pre‐eclamptic pregnancies

Objectives:To study serum levels of vascular endothelial growth factor (VEGF), a potent angiogenic factor, during distinct periods of the female life span and compare them with corresponding levels of age-matched males. It is hypothesized that VEGF might be increased at periods of enhanced angiogenesis.Methods:Venous blood was drawn from healthy females (n = 59) and males (n = 53) divided into six groups: fetuses (cord blood), neonates, children, adults (same females in the proliferative and secretory phases of their menstrual cycle), pregnant, and elderly (postmenopausal). Serum VEGF levels were measured by an enzyme immunoassay.Results:Females showed 49% higher serum VEGF levels than males (t = 2.74, P = .01). Cord and neonatal blood levels were significantly increased compared with those of adults (t = 2.41, P = .02, and t = 5.81, P = .0001, respectively). All female age groups presented higher serum VEGF levles than the group of women in the proliferative phase of the cycle; nevertheless, VEGF levels in the secretory phase did not differ (t = 1.85, P = .07).Conclusions:Serum VEGF levels are higher in females than in males and during life periods characterized by enhanced growth and development, implying increased rates of angiogenesis.

Objectives: To study serum levels of vascular endothelial growth factor (VEGF), a potent angiogenic factor, during distinct periods of the female life span and compare them with corresponding levels of age-matched males. It is hypothesized that VEGF might be increased at periods of enhanced angiogenesis. Methods: Venous blood was drawn from healthy females (n= 59) and males (n= 53) divided into six groups: fetuses (cord blood), neonates, children, adults (same females in the proliferative and secretory phases of their menstrual cycle), pregnant, and elderly (postmenopausal). Serum VEGF levels were measured by an enzyme immunoassay. Results: Females showed 49% higher serum VEGF levels than males (t= 2.74, P= .01). Cord and neonatal blood levels were significantly increased compared with those of adults (t= 2.41, P= .02, and t= 5.81, P= .0001, respectively). All female age groups presented higher serum VEGF levles than the group of women in the proliferative phase of the cycle; nevertheless, VEGF levels in the secretory phase did not differ (t= 1.85, P= .07). Conclusions: Serum VEGF levels are higher in females than in males and during life periods characterized by enhanced growth and development, implying increased rates of angiogenesis.

These studies investigated whether serum levels of the angiogenic factors angiogenin, basic fibroblast growth factor (bFGF), and vascular endothelial growth factor (VEGF) change soon after birth due to the elimination of the placenta and to diminished angiogenic but increased adaptational demands in extrauterine life. Also investigated was whether serum levels correlate with sex, birth weight, or mode of delivery. Serum from healthy mothers and their healthy full-term infants at birth (umbilical cord, UC), day 1 (N1) and day 4 (N4) postpartum was analyzed by enzyme immunoassays. Angiogenin levels were higher in maternal serum and rose significantly from UC to N1 and N4, possibly because of the elimination of the placenta, which produces an angiogenin inhibitor. bFGF and VEGF maternal levels were lower than fetal and neonatal ones. Although neonatal bFGF levels did not differ from fetal levels, possibly reflecting diminished angiogenesis ex utero, VEGF levels increased in neonatal serum, possibly signifying adaptational demands. Neither factor depended on sex, mode of delivery, or birth weight. Thus, significant differences from normal reference values of the studied factors might reflect ill-defined situations of the placenta and fetusnewborn serving as early diagnostic markers.

This study investigated serum levels of basic fibroblast growth factor (b FGF), a potent angiogenic factor, during distinct periods of the female life and compared them with corresponding levels in age-matched males. Healthy females (n = 59) and males (n = 53) were included in the study, divided into six groups: fetuses (cord blood), neonates, children, adults (females in proliferative and secretory phase), pregnant and “elderly” men and women. Serum b FGF levels were measured by an enzyme immunoassay. No statistically significant difference was found between both genders. Blood levels in fetuses and neonates were significantly increased as compared to adults (p = 0.01, p = 0.02, respectively). Restricting the analysis to females, all age groups, but fetuses (p = 0.05), demonstrated no difference when compared to proliferative phase adults. In conclusion, b FGF serum levels do not differ between males and females and are elevated in fetal and neonatal life, when growth and development are enhanced.

This study investigated whether serum levels of the potent angiogenic factors basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), which are abundantly produced in uteroby the placenta and fetal tissues, change after birth at term, consequent to diminished angiogenic but increased adaptational demands in extrauterine life. Moreover, whether serum levels of the above factors correlate with sex, birth weight, or mode of delivery was also evaluated. One milliliter of blood was drawn from 30 healthy, appropriate for gestational age, full-term infants on d 1 (N1) and 4 (N4) postnatally. In 10 of the above cases maternal and umbilical cord blood samples were also drawn. Serum was analyzed by enzyme immunoassays, using commercial kits. Levels of bFGF and VEGF were significantly lower in maternal serum than in umbilical cord (p= 0.02 and 0.036, respectively) or N1 (p= 0.009 and 0.006, respectively) and N4 serum (p= 0.009 and 0.006, respectively). Levels of bFGF in umbilical cord serum did not differ significantly from those in N1 and N4. In contrast, levels of VEGF rose in N1, differing significantly from levels in umbilical cord serum (p= 0.008). Both factors did not change from N1 to N4. Neither bFGF nor VEGF serum levels depended on sex, mode of delivery, or birth weight. In conclusion, bFGF levels in neonates do not differ from levels in fetuses, possibly reflecting diminished angiogenesis in extrauterine life, which already has started in utero. On the contrary, neonatal levels of VEGF rise significantly after birth, possibly signifying adaptation demands, in addition to angiogenesis, as VEGF is also considered a regulator of normal function.

This study investigated serum angiogenin levels of the potent angiogenic factor angiogenin, during fetal and neonatal life, childhood, adulthood, pregnancy and postmenopause and compared them with respective levels in age-matched males. Serum angiogenin levels were measured by an enzyme immunoassay in 139 healthy male and female subjects, allocated in the above six groups. Multiple linear regression applied (a) for both genders and (b) only for females showed serum angiogenin levels in adults to differ statistically highly significantly from levels in cord blood (P = 0.0001), neonates (P = 0.0001), children (P = 0.0001), and pregnant women (P, = 0.01), but not from “elderly” subjects (P = 0.80). A significant difference existed between levels in the proliferative and secretory phase of the menstrual cycle (P = 0.006). Furthermore, a significant trend for serum angiogenin levels with advancing age groups was noted (P = 0.0001). In conclusion, serum angiogenin levels increase significantly from fetal life to adulthood, possibly implying additional biological functions to that of angiogenesis.

This study investigated whether serum levels of the potent angiogenic factors basic fibroblast growth factor (bFGF) and vascular endothelial growth factor (VEGF), which are abundantly produced in utero by the placenta and fetal tissues, change after birth at term, consequent to diminished angiogenic but increased adaptational demands in extrauterine life. Moreover, whether serum levels of the above factors correlate with sex, birth weight, or mode of delivery was also evaluated. One milliliter of blood was drawn from 30 healthy, appropriate for gestational age, full-term infants on d 1 (N1) and 4 (N4) postnatally. In 10 of the above cases maternal and umbilical cord blood samples were also drawn. Serum was analyzed by enzyme immunoassays, using commercial kits. Levels of bFGF and VEGF were significantly lower in maternal serum than in umbilical cord (p = 0.02 and 0.036, respectively) or N1 (p = 0.009 and 0.006, respectively) and N4 serum (p = 0.009 and 0.006, respectively). Levels of bFGF in umbilical cord serum did not differ significantly from those in N1 and N4. In contrast, levels of VEGF rose in N1, differing significantly from levels in umbilical cord serum (p = 0.008). Both factors did not change from N1 to N4. Neither bFGF nor VEGF serum levels depended on sex, mode of delivery, or birth weight. In conclusion, bFGF levels in neonates do not differ from levels in fetuses, possibly reflecting diminished angiogenesis in extrauterine life, which already has started in utero. On the contrary, neonatal levels of VEGF rise significantly after birth, possibly signifying adaptation demands, in addition to angiogenesis, as VEGF is also considered a regulator of normal function.

Objective: We evaluated the effect of estrogen administration on endothelin (ET) secretion in primary amenorrheic (PA) adolescent girls. Methods: Fifteen PA adolescents (ten hypergonadotropic, group A; five hypogonadotropic, group B) were treated with estrogen and progestogen tablets. A control group often healthy adolescents (group C) was included in the study. The ET 1–21, FSH, and LH plasma levels were tested bejore treatment (PrT) and immediately after the last estrogen tablet but bejore the progestogen administration (PoT). Results: A statistically significant difference (P&lt;.01) in ET 1–21 plasma values was found between PrT (9.66 ± 0.80 pmol/L) and PoT (7.56 ± 0.89 pmol/L) levels in group A cases. A similar reduction (P&lt;.05) was recorded between PrT (8.06 ± 0.46 pmol/L) and PoT (5.59 ± 0.53 pmol/L) ET 1–21 plasma levels in group B cases. Endothelin 1–21 plasma PrT values were higher in both group A and B cases in comparison with controls (6.66 ± 0.44 pmol/L; P&lt; .01, P&lt; .1, respectively). Conclusion: Estrogens administered to PA adolescents reduce ET 1–21 plasma levels in both hyper- and hypogonadotropism.

Objective:We evaluated the effect of estrogen administration on endothelin (ET) secretion in primary amenorrheic (PA) adolescent girls.Methods:Fifteen PA adolescents (ten hypergonadotropic, group A; five hypogonadotropic, group B) were treated with estrogen and progestogen tablets. A control group of ten healthy adolescents (group C) was included in the study. The ET 1-21, FSH, and LH plasma levels were tested before treatment (PrT) and immediately after the last estrogen tablet but before the progestogen administration (PoT).Results:A statistically significant difference (P < .01) in ET 1-21 plasma values was found between PrT (9.66 ± 0.80 pmol/L) and PoT (7.56 ± 0.89 pmol/L) levels in group A cases. A similar reduction (P < .05) was recorded between PrT (8.06 ± 0.46 pmol/L) and PoT (5.59 ± 0.53 pmol/L) ET 1-21 plasma levels in group B cases. Endothelin 1-21 plasma PrT values were higher in both group A and B cases in comparison with controls (6.66 ± 0.44 pmol/L; P < .01, P < .1, respectively).Conclusions:Estrogens administered to PA adolescents reduce ET 1-21 plasma levels in both hyper- and hypogonadotropism.

OBJECTIVE: To study the association between the circulating concentrations of endothelin-3 and prolactin in the early puerperium. DESIGN: Prospective clinical study, including twenty-five healthy puerperal women breast-feeding their healthy full-term infants. METHODS: Venous blood was drawn on day 1 and 4 post partum, and plasma endothelin-3 and serum prolactin were determined. RESULTS: Circulating endothelin-3 and prolactin levels on day 4 did not differ significantly from the corresponding levels on day 1. However, a significant negative correlation was found on day 4 between endothelin-3 and prolactin values (r = -0.688, P < 0.001) and an even stronger negative association existed between the net change in endothelin-3 from days 1 to 4 and the corresponding change in prolactin values (r = -0.732, P < 0.001). CONCLUSIONS: On the fourth day post partum, lactating healthy women show negative correlation between circulating endothelin-3 and prolactin levels. Whether this indicates a role for endothelin-3 in the control of prolactin secretion in the post partum period remains to be clarified.

Endothelins (ETs) are highly vasoconstrictive 21-amino acid peptides possessing also cell-proliferative properties. They have been implicated in a variety of perinatal pathologic conditions, and their plasma concentrations have been found elevated in humans at birth. The purpose of this study was to determine ET 1-21 plasma concentrations in healthy and ill preterm infants and to investigate possible concentration changes with time from birth in cases of normal and abnormal adaptation to extrauterine life. The study comprised 36 preterm infants. Twenty-eight, comprising group A, were healthy (22/28) or minimally affected (6/28) and 8, comprising group B, were moderately (2/8) or severely ill (6/8) requiring continuous positive airway pressure or intermittent positive pressure ventilation as well as surfactant administration. All infants in group B had intraventricular hemorrhage grade ≥ II. Venous blood from all neonates was drawn on days 1 and 4 and ET 1-21 plasma concentrations were determined by radioimmunoassay (Amersham kit RPA 5559). ET 1-21 plasma concentrations were on day 1: 16.25 ± 8.14 and 21.81 ± 5.87 and on day 4: 12.89 ± 4.56 and 16.16 ± 5.43 pmol/l, for groups A and B, respectively. The statistical analysis showed a significant reduction in plasma ET concentrations on day 4 in both groups (p = 0.009 and p = 0.025, respectively). Nevertheless, ET 1-21 plasma concentrations were on day 4 significantly higher in ill preterm infants presenting symptoms from tissues involved in the elimination of ETs from the circulation as well as in their production.

The serum vitamin E levels of 11 full-term and 10 premature infants, jaundiced and subjected to phototherapy, were measured and compared with 9 premature and 10 full-term jaundiced control infants. No differences were observed before or after phototherapy or 1 week after stopping it. The same negative results were noted in the two groups of infants regarding the values of microhematocrit, Hb and reticulocytes.

Total glycosylated hemoglobin has been evaluated postpartum using a colorimetric (thiobarbituric acid: TBA) method in 50 mothers of large-for-gestational-age (LGA) infants ( > 90th percentile by weight). 30 women without potential risk factors for chemical diabetes who gave birth to appropriate-for-gestational-age (AGA) infants formed the control group. When compared to the control mothers, mean total glycosylated hemoglobin (TBA color) levels were significantly higher in the mothers of LGA infants (p < 0.01). 4 of the latter had an abnormal oral glucose tolerance test (GTT) done within 5 days postpartum and significantly elevated glycosylated hemoglobin compared to mothers of LGA infants with normal GTT (p < 0.001). Furthermore, a significant linear correlation was found for mothers of LGA infants between TBA color levels and each of the following: fasting serum glucose (p < 0.001), 1-hour serum glucose (p < 0.001), 2-hour serum glucose (p < 0.001), and infant birth weight (p < 0.05). Analysis of TBA color levels early postpartum might be an alternative method for detecting unsuspected chemical diabetes in pregnancy.

Objective: To study the impact of intrauterine growth restriction (IUGR) on anti-angiogenesis, by determining and comparing circulating levels of the potent anti-angiogenic factor endostatin, in full-term IUGR (under the 10th customized centile) and appropriate for gestational age (AGA) fetuses, neonates, as well as their mothers, granted that IUGR implies hypoxia and endostatin is down-regulated by the latter. Methods: In 20 IUGR cases (mainly due to hypertension or preeclampsia) and 20 AGA controls we determined circulating endostatin levels, by enzyme immunoassay in the serum of mothers (MS), umbilical cords (UC-mixed arteriovenous blood)-representing the fetal state, and asymptomatic neonates on day 1 (N1) and 4 (N4) of life-signifying transition and stabilization to extrauterine life, respectively. Results: Endostatin levels were significantly higher in AGA than IUGR UC, N1, and N4 (P&lt;.0000, P=.0006, P=.024, respectively). Furthermore, UC endostatin levels positively correlated with the customized centiles of the infants (Spearman correlation coefficient 0.69, P=.00001). Conclusion: IUGR is characterized by lower circulating endostatin concentrations in the fetus and neonate, possibly because under lower oxygen concentrations an unbalanced state of angiogenesis stimulators versus inhibitors takes place.

Objective: To study the impact of intrauterine growth restriction (IUGR) on anti-angiogenesis, by determining and comparing circulating levels of the potent anti-angiogenic factor endostatin, in full-term IUGR (under the 10th customized centile) and appropriate for gestational age (AGA)fetuses, neonates, as well as their mothers, granted that IUGR implies hypoxia and endostatin is down-regulated by the latter.Methods: In 20 IUGR cases (mainly due to hypertension or preeclampsia) and 20 AGA controls we detenmined circulating endostatin levels, by enzyme immunoassay in the serum of mothers (MS), umbilical cords (UC-mixed arteriovenous blood)-representing the fetal state, and asymptomatic neonates on day 1 (N1) and 4 (N4) of lfe-signifying transition and stabilization to extrauterine life, respectively.Results: Endostatin levels were significantly higher in AGA than IUGR UC, N1, and N4 (P <. 0000, P = .0006, P = .024, respectively). Furthermore, UC endostatin levels positively correlated with the customized centiles of the infants (Spearman correlation coefficient 0. 69, P = .00001).Conclusions: IUGR is characterized by lower circulating endostatin concentrations in the fetus and neonate, possibly because under lower oxygen concentrations an unbalanced state of angiogenesis stimulators versus inhibitors takes place.

Objective:To determine, during normal pregnancy, maternal serum (MS) and anniotic fluid (AF) concentrations of soluble Fas (sFas), an apoptosis-suppressing molecule that might play a role in the apoptotic process. Soluble Fas levels might explain existing immunotolerance, fetal well being, and rupture of membranes at term.Methods:Sixty-six healthy, nonsmoking, pregnant women (mean age 32.6 ± 4.8 years) with uncomplicated singleton pregnancies (15 in the first trimester, 30 in the second trimeste, and 21 at term vaginal delivery) and 20 healthy nonpregnant women (mean age 32.5 ± 3.8 years) were included in the study. MS and AF sFas concentrations were measured by a sandwich enzyme-linked immunosorbent assay, and parametric tests were used in the statistical analysis.Results:MS and AF sFas concentrations significantly depended on gestational age (P < .0008 and P < .0002, respectively). MS concentratiosn were significantly lower in the first trimester than those in the second trimester (P < .003), those at term (P < .03), and those in nonpregnant controls (P < .005). AF concentrations decreased significantly at term compared with those in the second trimester (P < .0003). AF sFas concentrations in the second trimester and at term were significantly lower than respective MS concentrations (P < .00001).Conclusions:MS sFas concentrations decreased significantly in the first trimester of pregnancy, possibly affecting semiallograft tolerance. In the second trimester, concentrations return to control levels and remain unchanged until delivery. AF sFas concentrations decrease at term compared with the second trimester, possibly indicating increased apoptosis in preparation for rupture of membranes.

Objective: To determine, during normal pregnancy, maternal serum (MS) and anniotic fluid (AF) concentrations of soluble Fas (sFas), an apoptosis-suppressing molecule that might play a role in the apoptotic process. Soluble Fas levels might explain existing immunotolerance, fetal well being, and rupture of membranes at term. Methods: Sixty-six healthy, nonsmoking, pregnant women (mean age 32.6 ± 4.8 years) with uncomplicated singleton pregnancies (15 in the first trimester, 30 in the second trimeste, and 21 at term vaginal delivery) and 20 healthy nonpregnant women (mean age 32.5 ± 3.8 years) were included in the study. MS and AF sFas concentrations were measured by a sandwich enzyme-linked immunosorbent assay, and parametric tests were used in the statistical analysis. Results: MS and AF sFas concentrations significantly depended on gestational age (P&lt; .0008 and P&lt; .0002, respectively). MS concentratiosn were significantly lower in the first trimester than those in the second trimester (P&lt; .003), those at term (P&lt; .03), and those in nonpregnant controls (P&lt;.005). AF concentrations decreased significantly at term compared with those in the second trimester (P&lt; .0003). AF sFas concentrations in the second trimester and at term were significantly lower than respective MS concentrations (P&lt; .00001). Conclusions: MS sFas concentrations decreased significantly in the first trimester of pregnancy, possibly affecting semiallograft tolerance. In the second trimester, concentrations return to control levels and remain unchanged until delivery. AF sFas concentrations decrease at term compared with the second trimester, possibly indicating increased apoptosis in preparation for rupture of membranes.

Microangiopathy, one of the most important complications of diabetes mellitus in humans, is associated with increased angiogenic response and proliferative lesions in various organs. Angiogenin, a polypeptide with a molecular size of 14 kD, is a potent inducer of vascular growth. This study aimed at investigating whether serum angiogenin levels are elevated in children and adolescents (youngsters) with insulin-dependent diabetes mellitus and whether angiogenin levels are affected by duration and metabolic control of the disease. It is assumed that angiogenin levels reflect the increased angiogenesis associated with microangiopathy, whether clinically evident or not. Forty diabetic youngsters were compared with 30 healthy control subjects(mean age ± SD, 14.3 ± 3.6 y and 13.8 ± 3.6 y, respectively). The patients' disease duration and glycosylated Hb were (mean± SD) 6.2 ± 3.8 y and 9.6 ± 1.8%, respectively. Angiogenin (ng/mL) was measured in serum samples by an enzyme immunoassay and was found to be significantly higher (mean ± SE) in patients (353.3± 20.0) than in control subjects (244.7 ± 9.6) (p = 0.0002). Levels did not vary with age, but were significantly higher in females compared with male subjects (p = 0.01). In the diabetic youngsters no significant differences were noticed with respect to duration or metabolic control of the disease. In conclusion, serum angiogenin levels were found to be increased among diabetic youngsters, irrespective of the duration and metabolic control of the disease, as well as in female subjects, with or without diabetes.