Inflammation-related proteins in the blood of extremely low gestational age newborns. The contribution of inflammation to the appearance of developmental regulation

BackgroundWe wanted to assess to what extent concentrations of circulating proteins appear to be developmentally regulated, and to what extent such regulation is influenced by intra-uterine inflammation.MethodsWe measured 22 proteins in blood obtained on postnatal days 1, 7, and 14 from 818 children born before the 28th week of gestation for whom we also had information about placenta morphology.ResultsWithin the narrow gestational age range of this sample, some protein concentrations increase in blood with increasing gestational age. More commonly, the concentrations of inflammation-related proteins decrease with increasing gestational age. We observed this inverse pattern both in children whose placenta was and was not inflamed.Conclusions/InferencesRegardless of whether or not the placenta is inflamed, the concentrations of inflammation-related proteins in early blood specimens appear to be developmentally regulated with the most common pattern being a decrease with increasing gestational age.     

新生儿出生体重、胎龄与血清铁水平相关性分析

目的探讨新生儿出生体重、胎龄与血清铁水平的相关性,为促进新生儿生长发育提供科学依据。方法采用全自动生化分析法分别对49例足月儿及49例早产儿的血清铁(SI)、血清铁蛋白(SF)和总铁结合力(TIBC)进行检测。结果足月儿的血清铁、血清铁蛋白和总铁结合力水平均明显高于早产儿(P0.05),而且血清铁蛋白、血清铁水平与出生体重、胎龄密切相关(P0.05)。结论足月儿与早产儿的铁含量存在明显差异,适量补充铁剂,可促进小儿体格与智能的健康成长。     

Real-time ultrasonic fetal head measurement and gestational age in dairy goats

Dairy breed goat fetuses (n = 219) of known gestational age (Day 39 to Day 100) were examined transabdominally using a real-time ultrasound scanner with a 5 MHz linear-array transducer. Maximum head width was measured in symmetrical images using electronic linear distance calipers. This biparietal diameter (BPD) can be accurately measured as early as Day 40, but measurement becomes difficult after Day 105 of gestation due to the variability of fetal location and posture. The uniform, linear increase in BPD in the second trimester should allow for the accurate assignment of gestational age for doe confinement or induction of kidding.     

Plasma F2-isoprostanes are elevated in newborns and inversely correlated to gestational age

F(2)-isoprostanes, prostaglandin F(2)-like compounds formed by free radical-catalyzed lipid peroxidation, are considered the most reliable markers of oxidative stress. It has been repeatedly suggested that newborns are exposed to conditions of oxidative stress resulting from the change from a low oxygen pressure in utero to a high oxygen pressure at birth. We measured the levels of F(2)-isoprostanes in plasma of newborns by gas chromatography/mass spectrometry and we found that F(2)-isoprostanes are significantly higher in term newborns compared to healthy adults. The greatest values were found in preterm newborns in whom F(2)-isoprostanes are even higher than in term babies. Moreover a significant inverse correlation was found between the plasma levels of isoprostanes and the gestational age. A quite normal level of isoprostanes was found in the mothers both at delivery and during pregnancy. Placental total F(2)-isoprostanes (sum of free plus esterified) were significantly higher in preterm compared to term deliveries and such a difference might account for the difference in plasma isoprostanes. Plasma non-protein-bound iron is higher in preterm than in term newborns, even if no correlation was found with plasma F(2)-isoprostanes. Erythrocyte desferrioxamine-chelatable iron content (0 time) and release (24 h of aerobic incubation) are higher in newborns than in adults and in preterm than in term newborns, but again no correlation was found with plasma F(2)-isoprostanes. The marked increase in plasma isoprostanes suggests that oxidative stress is a feature of the physiopathological changes seen in the perinatal period.     

New definition of small for gestational age based on fetal growth potential

Accurate definition of small for gestational age (SGA) is essential for antenatal as well as postnatal care. SGA is associated with significant antenatal and postnatal pathology. The term, however, includes constitutional smallness, and it is essential to adjust for physiological variation in order to identify those babies who are pathologically small. Maternal height, weight, parity, ethnic origin and the baby's gender have all been found to be significantly associated with normal variation in birth weight. These variables need to be adjusted for to calculate the true growth potential, which can be represented as individually customized fetal growth curves and birth weight percentiles (www.gestation.net). This method for calculating growth potential has been validated in a number of international studies. 'Customized SGA' defines neonates with intrauterine growth restriction, while 'small-normal' does not represent increased risk. Currently, coefficients are being developed for more ethnic groups, to broaden the international applicability of individualized standards. Work is also underway to incorporate the customized birth weight percentile as the starting point of infant growth curves.     

Influence of maternal age, gestational age and fetal gender on expression of immune mediators in amniotic fluid

ABSTRACT: BACKGROUND: Variations in cytokine and immune mediator expression patterns in amniotic fluid due to gestational age, maternal age and fetal gender were investigated. METHODS: Amniotic fluid samples were obtained from 192 women, 82 with a mid-trimester amniocentesis (median gestational age 17 weeks) and 110 with a caesarean section not in labor (median gestational age 39 weeks). Amniotic fluid was screened by commercial ELISAs for the TH1/TH2/TH17 cytokines and immune mediators IL-1 beta, IL-2, IL-4, IL-6, IL-8, IL-10, IL-12, IL-15, IL-17, TNF alpha, GROalpha, MIP1alpha, MIP1beta, histone, and IP10. Analysis was by Bonferroni correction for multiple comparisons. RESULTS: None of the 15 examined cytokines revealed any differences in expression patterns regarding fetal gender and age of the mothers. Significant differences were found in IL-4, IL-10, IL-12 TNF- alpha and MIP1-beta with respect to gestational age. CONCLUSIONS: Cytokines utilized as biomarkers in the diagnosis of intrauterine infections are not influenced in their expression pattern by fetal gender or maternal age, but may vary with respect to gestational age.     

Standards of morphological development in fetuses and newborns as a method of defining fetal age

Whenever the calendar age of the studied fetal material is not known we are bound to reconstruct it by replacing it with the developmental age. In this paper some common developmental standards used in the determination of fetal age are reviewed. The standards, as found in the relevant literature, are tested against a control group for their accuracy in predicting fetal age. The results indicate considerable discrepancy among the various standards. Further, the developmental ages defined by these standards often differ considerably from the known menstrual age. My own attempt to present a more reliable set of developmental standards is based on the analysis of three morphological features commonly used in biological assessment. Body weight, crown-heel length, and crown-rump length are measured in weekly termed groups representing the 20th-42nd weeks of intrauterine life. The accuracy of body weight and crown-heel length in predicting fetal age is tested both within and against a control group. Statistical analysis show no significant differences between the predicted and known fetal ages. These results indicate that body weight and crown-heel length are reliable developmental standards from which fetal age can be defined.     

Animal models for small for gestational age and fetal programming of adult disease

Fetal growth retardation is a fetal adaptation in response to inadequate supply of oxygen and/or nutrients. Animal models of intrauterine growth retardation are an invaluable tool to question the genetic, molecular and cellular events that determine fetal growth and development. Rodent and non-litter bearing animals are mammalian system with similar embryology,anatomy and physiology to humans. Utilization of these systems has led to a greater understanding of the pathophysiology and consequences of intrauterine growth retardation. These observations are comparable to that observed in humans born small for gestational age, and are of interest because of the known association between poor fetal growth and development of adult disease. All the experimental manipulations described here have altered a number of metabolic and physiological variables, but the pattern of alterations seems to vary with the procedure and species employed. This review describes animal models for intrauterine growth retardation and assesses their potentials and limitations at aiming to improve strategies for the prevention of adult disease.     

Organ and gestational age effects of maternal nutrient restriction on global methylation in fetal baboons

Background  A sub-optimal intrauterine environment alters the trajectory of fetal development with profound effects on life-time health. Altered methylation, a proposed epigenetic mechanism responsible for these changes, has been studied in non-primate species but not nonhuman primates. We tested the hypotheses that global methylation in fetal baboon demonstrates organ specificity, gestational age specificity, and changes with maternal nutritional status.
Methods  We measured global DNA methylation in fetuses of control fed (CTR) and nutrient restricted mothers fed 70% of controls (MNR) for brain, kidney, liver and heart at 0.5 and 0.9 gestation (G).
Results  We observed organ and gestation specific changes that were modified by maternal diet. Methylation in CTR fetuses was highest in frontal cortex and lowest in liver. MNR decreased methylation in 0.5G kidney and increased methylation in 0.9G kidney and frontal cortex.
Conclusion  These results demonstrate a potential epigenetic mechanism whereby reduced maternal nutrition has long-term programming effects on fetal organ development.     

Gastroschisis, low maternal age, and fetal morbidity outcomes

OBJECTIVE: To determine if the risk for fetal growth inhibition among gastroschisis-afflicted fetuses is heightened among younger gravidas (teen mothers). METHOD: This was a retrospective cohort study on live-born infants with isolated gastroschisis delivered in New York State from 1983 through 1999. We compared infants of mature (>20 years) mothers with those of younger (<20 years) mothers with respect to the following indices of fetal morbidity outcomes: low birth weight and very low birth weight, preterm and very pre-term, and small for gestational age. We used adjusted odds ratios to approximate relative risks. RESULTS: A total of 368 infants with isolated gastroschisis were analyzed. The two groups differed in terms of mean gestational age at delivery [Mean + standard deviation(SD) for infants with gastroschisis born to mature mothers = 37.2 weeks +/- 2.8 versus 36.3 weeks + 3.6 for those of teenage mothers(p = 0.01)], as well as mean birth weight [mean birth weight +/- SD for infants with gastroschisis born to mature mothers = 2562.4 grams +548.8 versus 2367.9 grams +/- 645.2 for those of younger mothers (p = 0.004)]. Infants of teen mothers were about twice as likely to be of low birth weight (OR = 1.70; 95% CI = 1.05-2.77) and about three times as likely to be born very preterm when compared to those of mature mothers (OR = 2.80; 95% Cl = 1.02-8.00). No significant differences were observed with respect to very low birth weight, pre-term and small for gestational age. CONCLUSION: Low maternal age appears to be a risk factor for low birth weight and very preterm birth among gastroschisis-affected fetuses. This information is potentially useful for planning by care providers and in counseling affected parents.     

Chemical composition of fetal hemoglobin in Sardinian newborns

G gamma:A gamma composition of 54 newborns from Sardinia was determined by electrophoresis on polyacrylamide gels containing urea and Triton X-100. G gamma was present at a concentration of 67% with bimodal distribution (with mean values at 65 and 70% respectively). Concentration higher than 76% was not observed. When Hb F in peripheral blood was below 70%, G gamma:A gamma ratio correlates with Hb F%.     

Effects of gestational age on myocardial blood flow and coronary flow reserve in pressure-loaded ovine fetal hearts

To test the hypothesis that coronary flow and coronary flow reserve are developmentally regulated, we used fluorescent microspheres to investigate the effects of acute (6 h) pulmonary artery banding (PAB) on baseline and adenosine-enhanced right (RV) and left ventricular (LV) blood flow in two groups of twin ovine fetuses (100 and 128 days of gestation, term 145 days, n = 6 fetuses/group). Within each group, one fetus underwent PAB to constrict the main pulmonary artery diameter by 50%, and the other twin served as a nonbanded control. Physiological measurements were made 6 h after the surgery was completed; tissues were then harvested for analysis of selected genes that may be involved in the early phase of coronary vascular remodeling. Within each age group, arterial blood gas values, heart rate, and mean arterial blood pressure were similar between control and PAB fetuses. Baseline endocardial blood flow in both ventricles was greater in 100 than 128-day fetuses (RV: 341 +/- 20 vs. 230 +/- 17 ml*min(-1)*100 g(-1); LV: 258 +/- 18 vs. 172 +/- 23 ml*min(-1)*100 g(-1), both P < 0.05). In both age groups, RV and LV endocardial blood flows increased significantly in control animals during adenosine infusion and were greater in PAB compared with control fetuses. After PAB, adenosine further increased RV blood flow in 128-day fetuses (from 416 +/- 30 to 598 +/- 33 ml*min(-1)*g(-1), P < 0.05) but did not enhance blood flow in 100-day animals (490 +/- 59 to 545 +/- 42 ml*min(-1)*100 g(-1), P > 0.2). RV vascular endothelial growth factor and Flk-1 mRNA levels were increased relative to controls (P < 0.05) in 128 but not 100-day PAB fetuses. We conclude that in the ovine fetus, developmentally related differences exist in 1) baseline myocardial blood flows, 2) the adaptive response of myocardial blood flow to acute systolic pressure load, and 3) the responses of selected genes involved in vasculogenesis to increased load in the fetal myocardium.     

The ratio of plasma bioactive to immunoreactive ACTH-like activity increases with gestational age in the fetal lamb.

The fetal ovine pituitary-adrenal axis plays an important role in the timing of parturition, in fetal lung maturation, and in fetal and neonatal responses to stress. While the ovine pituitary during the last third of gestation (term = 145 days) is capable of secreting immunoreactive ACTH (iACTH) in response to various stimuli, plasma cortisol levels frequently do not reflect the rise in plasma ACTH. Therefore, we examined the relationship between plasma iACTH and steroidogenic ACTH-like activity (bACTH) in a group of immature fetal lambs (Group I: gestational age = 97 +/- 2 days, mean +/- SEM, n = 16) and a group of near-term fetuses (Group II: gestational age = 136 +/- 1 days, n = 13) following acute exteriorization. Plasma iACTH was determined by RIA. Plasma bACTH was determined by the ability of glass-extracted material to stimulate corticosterone (B) production in an acutely dispersed rat adrenal bioassay. Plasma iACTH and bACTH levels varied among animals within age groups, with iACTH tending to be higher in immature fetal lambs (Group I) than near-term lambs (Group II) and bACTH being higher (P < 0.05) near term than earlier (Group I: iACTH = 807 +/- 273 pg/ml, bACTH = 173 +/- 44 pg/ml; Group II: iACTH = 405 +/- 85 pg/ml, bACTH = 371 +/- 96 pg/ml). The proportion of iACTH that had biologic activity (e.g. B/I ratio) was significantly greater in the older than in the younger fetuses (Group II: B/I = 0.862 +/- 0.109; Group I: B/I = 0.462 +/- 0.105 P < 0.01).(ABSTRACT TRUNCATED AT 250 WORDS)     

Serum-free culture and characterization of renal epithelial cells isolated from human fetal kidneys of varying gestational age

Summary Cell cultures were initiated from seven human fetal kidneys that varied in gestational age from 90 days to newborn. The growth medium utilized was a 1:1 mixture of Dulbecco’s modified Eagle’s and Ham’s F12 supplemented with selenium (5 ng/ml), insulin (5μg/ml), transferrin (5μg/ml), hydrocortisone (36 ng/ml), triiodothyronine (4 pg/ml), and epidermal growth factor (10 ng/ml). For all the kidney isolates, initial cell attachment occurred within 12 h through multicell spheroids, and by 24 h a rapidly growing population of cells was obtained. Confluency was reached within 3 to 6 days. A combination of light microscopy, immunohistochemistry, and ultrastructural evaluation was utilized to characterize the resulting cultures as epithelial and homogeneous within each isolate and among the isolates. That is, regardless of gestational age of the fetal kidney used as starting material, an identical or highly similar population of cells was obtained. By light microscopy, the cultures were noted to form very few domes, the number being an indication of transport activity. However, ultrastructural examination revealed that the cells were noted to form domes composed of only a few cells or “micro-domes” that would not be visible by light microscopy. Within the micro-domes as well as other areas of the monolayer an apparent absence of tight junctions was noted by routine transmission electron microscopy. However, by freeze fracture analysis cells were shown to possess sealing strands, the structural component of tight junctions. It is postulated that the tight junctions of fetal epithelial cells are structurally altered as compared to tight junctions in adult renal epithelial cell cultures.     

Estimation of gestational age and assessment of canine fetal maturation using radiology and ultrasonography: a review

Since the duration of pregnancy in the bitch is relatively short, it is critical that fetuses are fully mature prior to delivery for them to survive. For breeders to be able to prepare for normal whelpings and align medical care in case of emergency, an estimated due date is necessary. In cases where ovulation timing is lacking and there is a singleton fetus or oversize fetuses, it is necessary to ascertain gestational age prior to setting the date of Cesarean section. In high-risk pregnancies, where there is poor or no ovulation timing, determination of fetal maturation and gestational age will assist in determining if pregnancy has progressed long enough to allow delivery of viable puppies. In cases where bitches are receiving supplemental progesterone for pregnancy maintenance medications must be discontinued at an appropriate time to permit delivery of viable puppies. It also allows for estimation of the likelihood of fetal survival if the pregnancy is terminated due to failing bitch health, with subsequent surgical delivery of the fetuses. Use of breeding dates alone does not provide due dates with adequate accuracy. In cases where there has been inadequate or no breeding management or ovulation timing, estimation of due date can be performed at the time of pregnancy diagnosis, or closer to term. Radiography can be used to confirm pregnancy and facilitate determination of gestational age, beginning 45d after the LH surge. Ultrasonography can be used from 19 to 21d after the LH surge to term to confirm pregnancy and predict gestational age, and from 25 or 26d to term to assess fetal viability and fetal stress.     

Loss of quantum yield in extremely low light

It has generally been assumed that the photosynthetic quantum yield of all C₃ plants is essentially the same for all unstressed leaves at the same temperature and CO₂ and O₂ concentrations. However, some recent work by H.C. Timm et al. (2002, Trees 16:47–62) has shown that quantum yield can be reduced for some time after leaves have been exposed to darkness. To investigate under what light conditions quantum yield can be reduced, we carried out a number of experiments on leaves of a partial-shade (unlit greenhouse)-grown Coleus blumei Benth. hybrid. We found that after leaves had been exposed to complete darkness, quantum yield was reduced by about 60%. Only very low light levels were needed for quantum yield to be fully restored, with 5 mol quanta m^–2 s^–1 being sufficient for 85% of the quantum yield of fully induced leaves to be achieved. Leaves regained higher quantum yields upon exposure to higher light levels with an estimated time constant of 130 s. It was concluded that the loss of quantum yield would be quantitatively important only for leaves growing in very dense understoreys where maximum light levels might not exceed 5 mol quanta m^–2 s^–1 even in the middle of the day. Most leaves, even in understorey conditions, do, however, experience light levels in excess of 5 mol quanta m^–2 s^–1 over periods where they obtain most of their carbon so that the loss of quantum yield would affect total carbon gain of those leaves only marginally.Abbreviations FBPase Fructose-1,6-bisphosphatase - RuBP Ribulose-1,5-bisphosphate - Rubisco RuBP carboxylase/oxygenase