Growth and maturation of the fetal gastrointestinal tract near term prepares the offspring for the onset of enteral nutrition at birth. Structural and functional changes are regulated by the prepartum rise in cortisol in the fetal circulation, although the role of the coincident rise in plasma tri-iodothyronine (T3) is unknown. This study examined the effect of hypothyroidism on the structural development of the gastrointestinal tract and the activity of brush-border digestive enzymes in the ovine fetus near term. In intact fetuses studied between 100 and 144 days of gestation (dGA; term ∼145 days), plasma concentrations of T3, cortisol and gastrin; the mucosal thickness in the abomasum, duodenum, jejunum and ileum; and intestinal villus height and crypt depth increased with gestational age. Removal of the fetal thyroid gland at 105-110 dGA suppressed plasma thyroxine (T4) and T3 concentrations to the limit of assay detection in fetuses studied at 130 and 144 dGA, and decreased plasma cortisol and gastrin near term, compared to age-matched intact fetuses. Hypothyroidism was associated with reductions in the relative weights of the stomach compartments and small intestines, the outer perimeter of the intestines, the thickness of the gastric and intestinal mucosa, villus height and width, and crypt depth. The thickness of the mucosal epithelial cell layer and muscularis propria in the small intestines were not affected by gestational age or treatment. Activities of the brush border enzymes varied with gestational age in a manner that depended on the enzyme and region of the small intestines studied. In the ileum, maltase and dipeptidyl peptidase IV (DPPIV) activities were lower, and aminopeptidase N (ApN) were higher, in the hypothyroid compared to intact fetuses near term. These findings highlight the importance of thyroid hormones in the structural and functional development of the gastrointestinal tract near term, and indicate how hypothyroidism in utero may impair the transition to enteral nutrition and increase the risk of gastrointestinal disorders in the neonate.

As temperatures increase, there is growing evidence that species across much of the tree of life are getting smaller. These climate change-driven size reductions are often interpreted as a temporal analogue of the observation that individuals within a species tend to be smaller in the warmer parts of the species' range. For ectotherms, there has been a broad effort to understand the role of developmental plasticity in temperature-size relationships, but in endotherms, this mechanism has received relatively little attention in favour of selection-based explanations. We review the evidence for a role of developmental plasticity in warming-driven size reductions in birds and highlight insulin-like growth factors as a potential mechanism underlying plastic responses to temperature in endotherms. We find that, as with ectotherms, changes in temperature during development can result in shifts in body size in birds, with size reductions associated with warmer temperatures being the most frequent association. This suggests developmental plasticity may be an important, but largely overlooked, mechanism underlying warming-driven size reductions in endotherms. Plasticity and natural selection have very different constraining forces, thus understanding the mechanism linking temperature and body size in endotherms has broad implications for predicting future impacts of climate change on biodiversity.

Infants born moderate to late preterm constitute the majority of preterm births, yet guidelines for their nutritional care are unclear. Maternal milk is the most appropriate nutrition for these infants; however, its composition can be influenced by environmental factors. The present study therefore investigated perinatal predictors of human milk composition in a preterm cohort.

Milk was collected during the DIAMOND trial (DIfferent Approaches to Moderate and late preterm Nutrition: Determinants of feed tolerance, body composition and development) from 169 mothers of 191 infants at three time-points (5 and 10 days post partum and 4 months' corrected age). Leptin, adiponectin and insulin-like growth factor-1 (IGF-1) were analysed by enzyme-linked immunosorbent assay. Generalised mixed models were used to evaluate associations between milk composition and maternal/infant/perinatal factors.

Most findings were independent of collection time-point. Gestational diabetes was associated with lower adiponectin. Higher adiponectin and lower leptin were associated with higher socioeconomic status, higher maternal education and ability to fully breastfeed at discharge from hospital. Higher leptin was associated with high perceived stress during hospital admission. Milk IGF-1 displayed sex-specific patterns in association with maternal social deprivation.

Maternal, infant and environmental factors during the perinatal period were associated with milk compositional profiles throughout lactation. Further clinical trials should investigate the impact of such changes in terms of long-term infant outcomes.

Human milk is the best nutrition for the infant. However, its composition may be susceptible to alterations determined by pathological conditions mother and infant may face throughout pregnancy and in the perinatal period. This study found that perinatal factors are associated with human milk composition from early to late lactation. If human milk composition throughout lactation is "programmed" during pregnancy or early lactation, infants who were exposed in utero to environmental insults may still be exposed to them during lactation. The impact of human milk compositional alteration on infant growth following perinatal pathological events requires further investigation.

Short bowel syndrome (SBS) remains the leading cause of neonatal intestinal failure. Milk fat globule epidermal growth factor-8 (MFG-E8), present in human milk, has homology with epidermal growth factor (EGF), known to enhance adaptation in SBS. In this pilot study, the role of oral MFG-E8 treatment in SBS was explored in neonatal piglets.

Neonatal piglets underwent 75% intestinal resection, either distal (jejunal-colonic [JC] anastomosis) or mid-intestinal (jejunal-ileal [JI] anastomosis). Piglets were randomized to intragastric treatment with MFG-E8  (5 mg/kg per day) or saline and were maintained on parenteral nutrition and enteral nutrition for 7 days. Adaptation was assessed by intestinal length and weight, histopathology, fecal fat analysis and RT-qPCR analysis of mucosal transcripts, including growth factors.

JI piglets demonstrated intestinal lengthening (P < 0.001), 2-fold greater in ileum than jejunum (P = 0.02), where lengthening was increased by MFG-E8 treatment (P = 0.02). JC piglets did not exhibit jejunal lengthening, regardless of treatment. Fat absorption was greater for JI piglets (P = 0.02), unaffected by treatment. In JI piglets, expression of Egf was increased in the ileum (P < 0.01) and MFG-E8 treatment increased Egfr (receptor) expression (P = 0.02).

MF-EG8 demonstrated site-specific trophic effects, only with JI anatomy. This may limit the utility of this treatment for SBS, except for rare patients with retained ileum. The mechanisms of these site-specific effects, however, and the role of MFG-E8 in neonatal gut growth and in diseases, such as necrotizing enterocolitis that commonly target ileum, warrant further exploration.

The insulin and insulin-like signaling (IIS) molecular network regulates cellular growth and division, and influences organismal metabolism, growth and development, reproduction, and lifespan. As a group, reptiles have incredible diversity in the complex life history traits that have been associated with the IIS network, yet the research on the IIS network in ectothermic reptiles is sparse. Here, we review the IIS network and synthesize what is known about the function and evolution of the IIS network in ectothermic reptiles. The primary hormones of this network-the insulin-like growth factors 1 and 2 (IGFs) likely function in reproduction in ectothermic reptiles, but the precise mechanisms are unclear, and likely range from influencing mating and ovulation to maternal investment in embryonic development. In general, plasma levels of IGF1 increase with food intake in ectothermic reptiles, but the magnitude of the response to food varies across species or populations and the ages of animals. Long-term temperature treatments as well as thermal stress can alter expression of genes within the IIS network. Although relatively little work has been done on IGF2 in ectothermic reptiles, IGF2 is consistently expressed at higher levels than IGF1 in juvenile ectothermic reptiles. Furthermore, in contrast to mammals that have genetic imprinting that silences the maternal IGF2 allele, in reptiles IGF2 is bi-allelically expressed (based on findings in chickens, a snake, and a lizard). Evolutionary analyses indicate some members of the IIS network are rapidly evolving across reptile species, including IGF1, insulin (INS), and their receptors. In particular, IGF1 displays extensive nucleotide variation across lizards and snakes, which suggests that its functional role may vary across this group. In addition, genetic variation across families and populations in the response of the IIS network to environmental conditions illustrates that components of this network may be evolving in natural populations. The diversity in reproductive physiology, metabolic plasticity, and lifespan among reptiles makes the study of the IIS network in this group a potentially rich avenue for insight into the evolution and function of this network. The field would benefit from future studies that discern the respective functions of IGF1 and IGF2 and how these functions vary across taxa, perfecting additional assays for measuring IIS components, and determining the role of IIS in different tissues.

The gastrointestinal tract (GIT) is a complex system, which changes in response to requirements of the body. GIT represents a barrier to the external environment. To achieve this, epithelial cells must renew rapidly. This renewal of epithelial cells starts in the fetal life under the influence of many GIT peptides by swallowing amniotic fluid (AF). Development and maturation of GIT is a very complex cascade that begins long before birth and continues during infancy and childhood by breast-feeding. Many factors like genetic preprogramming, local and systemic endocrine secretions and many trophic factors (TF) from swallowed AF contribute and modulate the development and growth of the GIT. GIT morphogenesis, differentiation and functional development depend on the activity of various TF in the AF. This manuscript will review the role of AF borne TF in the development of GIT.

The gut of the human neonate is colonized rapidly after birth from an early sparse and highly distinct microbiota to a more adult-like and convergent state, within 1 to 3 years. The progression of colonizing bacterial species is non-random. During the first months of life several shifts commonly occur in the species prevalent in our guts. Although the sequential progression of these species is remarkably consistent across individuals and geographies, there is inter-individual variation in the rate of progression. Our study and others suggest that the rate is influenced by environmental factors, and influences our future health. In this article, we review our recent contribution to cataloging the developing infant gut microbiota alongside other important recent studies. We suggest testable hypotheses that arise from this synthesis.

Comparative morphological study of the placentas in women with preeclampsia and small-for-date fetuses was carried out. Expression of insulin-like growth factor-1 (IGF-1), insulin-like growth factor-2 (IGF-2), and insulin-like growth factor binding protein-3 (IGFBP-3) was detected by immunohistochemical methods. Low expression of IGF-1 and high expression of IGF-2 and IGFBP-3 in the placental tissue depending on preeclampsia severity were detected. The most pronounced changes were found in preeclampsia associated with small-for-date fetuses.

The present study was designed to evaluate the effects of human amniotic fluid (HAF) on the growth of human corneal endothelial cells (HCECs) and to establish an in vitro method for expanding HCECs. HCECs were cultured in DMEM-F12 supplemented with 20% fetal bovine serum (FBS). Confluent monolayer cultures were trypsinized and passaged using either FBS- or HAF-containing media. Cell proliferation and cell death ELISA assays were performed to determine the effect of HAF on cell growth and viability. The identity of the cells cultured in 20% HAF was determined using immunocytochemistry (ICC) and real-time reverse transcription polymerase chain reaction (RT-PCR) techniques to evaluate the expression of factors that are characteristic of HCECs, including Ki-67, Vimentin, Na+/K+-ATPase and ZO-1. HCEC primary cultures were successfully established using 20% HAF-containing medium, and these cultures demonstrated rapid cell proliferation according to the cell proliferation and death ELISA assay results. The ICC and real time RT-PCR results indicated that there was a higher expression of Na+/K+-ATPase and ZO-1 in the 20% HAF cell cultures compared with the control (20% FBS) (P < 0.05). The 20% HAF-containing medium exhibited a greater stimulatory effect on HCEC growth and could represent a potential enriched supplement for HCEC regeneration studies.

The objectives of health management of ewes during pregnancy are as follows: (i) successful completion of pregnancy at term, (ii) birth of healthy and viable lambs, with optimal birth and potential weaning bodyweight, (iii) optimum milk production during the subsequent lactation and (iv) improved management in relation to drug residues in animal products. Knowledge of the physiological background of pregnancy in ewes: changes, mechanisms and interactions, during pregnancy is important for the overall health management of ewes during pregnancy. Health management of pregnant ewes includes diagnosis of pregnancy and evaluation of the number of foetuses borne, which will support strategies for subsequent management of the flock. Nutritional management of ewes depends upon the stage of lactation and specifically aims to (i) prevention of pregnancy toxaemia and other metabolic diseases during the peri-partum period, (ii) formation of colostrum in appropriate quantity and quality, (iii) production of lambs with normal future birth bodyweight and (iv) support of increased milk yield during the subsequent lactation. At the end of lactation, udder management of pregnant ewes includes its clinical examination, culling of ewes considered unsuitable for lactation and, possibly, the intramammary administration of antibiotics; objectives of that procedure are (i) to cure infections which have occurred during the previous lactation and (ii) to prevent development of new mammary infection during the dry period. Management of abortions includes the correct and timely diagnosis of the causative agent of the disorder, as well as the strategic administrations of chemotherapeutic agents, aiming to prevent abortions in flocks with confirmed infection with an abortifacient agent, especially if no appropriate vaccinations had been carried out before the mating season. During the final stage of pregnancy, health management of ewes includes administration of appropriate anthelmintic drugs, aiming to eliminate gastrointestinal helminthes (thus, increasing production output of ewes) and preventing the built-up of parasitic burdens in the environment (thus, reducing infection of lambs during their neonatal period). Vaccinations of pregnant ewes aim to protect these animals, as well as their offspring, especially against diseases which are a frequent cause of neonatal mortality (e.g., clostridial infections). Health management also aims to prevent the main metabolic disorders of pregnant ewes (i.e., pregnancy toxaemia and hypocalcaemia), as well as to monitor flocks for development of these disorders. Health management of pregnant ewes is completed with application of husbandry practices before the start of the lambing season. Finally, in some cases, health management may include induction and synchronisation of lambings, which is a management or therapeutic procedure.

Necrotizing enterocolitis (NEC ) can be a devastating disease in the NIC U population. The current standard of practice of not providing enteral nutrition to the critically ill and the premature infant is thought to result in pathophysiologic changes of the gastrointestinal (GI) tract that may result in the development of NEC. Various methods of preventing or reducing the incidence of NEC in the NIC U have been explored. One such method is the enteral administration of simulated amniotic fluid (SAF). This article compares, contrasts, and reviews the available evidence regarding the use of SAF feedings as a means of reducing GI tract changes associated with nothing-by-mouth (NPO) status.

Alteration of placental structure may influence fetal overgrowth and complications of maternal diabetes. We examined the placenta in a cohort of offspring of mothers with type 1 diabetes (OT1DM) to assess structural changes and determine whether these were related to maternal A1C, fetal hematocrit, fetal hormonal, or metabolic axes.

Placental samples were analyzed using stereological techniques to quantify volumes and surface areas of key placental components in 88 OT1DM and 39 control subjects, and results related to maternal A1C and umbilical cord analytes (insulin, leptin, adiponectin, IGF-I, hematocrit, lipids, C-reactive protein, and interleukin-6).

Intervillous space volume was increased in OT1DM (OT1DM 250 + or - 81 cm(3) vs. control 217 + or - 65 cm(3); P = 0.02) with anisomorphic growth of villi (P = 0.025). The placentas showed a trend to increased weight (OT1DM 690 + or - 19 g; control 641 + or - 22 g; P = 0.08), but villous, nonparenchymal, trophoblast, and capillary volumes did not differ. Villous surface area, capillary surface area, membrane thickness, and calculated morphometric diffusing capacity were also similar in type 1 diabetic and control subjects. A1C at 26-34 weeks associated with birth weight (r = 0.27, P = 0.03), placental weight (r = 0.41, P = 0.0009), and intervillous space volume (r = 0.38, P = 0.0024). In multivariate analysis of cord parameters in OT1DM, fetal IGF-I emerged as a significant correlate of most components (intervillous space, villous, trophoblast, and capillary volumes, all P < 0.01). By contrast, fetal insulin was only independently associated with capillary surface area (positive, r(2) = 6.7%; P = 0.02).

There are minimal placental structural differences between OT1DM and control subjects. Fetal IGF-I but not fetal insulin emerges as a key correlate of placental substructural volumes, thereby facilitating feedback to the placenta regarding fetal metabolic demand.

Intrafetal insulin-like growth factor (IGF)-I promotes cardiac hypertrophy in the late-gestation fetal sheep; whether these effects are sustained is unknown. IGF-I was infused for 4 days at 80 microg/h from 121 to 125 days of gestation, and its effects at 128 days, 3 days after the infusion stopped, were determined by comparison with untreated fetal sheep. After IGF-I treatment, fetal weights were similar to those in control fetuses but kidney weights were bigger (P < 0.05), as were spleen weights of male fetuses (P < 0.05). Cardiac myocytes were larger in female than male fetal sheep (P < 0.001). IGF-I increased male (P < 0.001) but not female myocyte volumes. IGF-I did not alter the proportions of uni- or binucleated right or left ventricular myocytes. Female fetal sheep had a greater proportion of binucleated cardiac myocytes than males (P < 0.05). IGF-I-treated fetuses had a slightly greater proportion of right ventricular nuclei in cell cycle phase G(2)/M and a reduced proportion of G(0)/G(1) phase nuclei (P < 0.1). Therefore, evidence for IGF-I-stimulated cardiac cell hyperplasia in fetal sheep in late gestation was limited. In conclusion, the greater sizes and larger proportion of binucleated cardiac myocytes in female fetal sheep suggest that myocyte maturation may occur earlier in females than in males. This may explain in part the male sex-specific responsiveness of cardiac hypertrophy to IGF-I in late gestation. If IGF-I-stimulated cardiomyocyte growth is accompanied by maturation of contractile function, IGF-I may be a potential therapeutic agent for maintaining cardiac output in preterm males.

Nutrition plays a major role in the modulation of the evolving human gut influencing all the main components of the intestinal ecosystem. The regulatory role of nutrition is particularly crucial in the early postnatal period but it continues also in subsequent ages when the development of the gastrointestinal tract is completed. Recent data support the hypothesis that nutrition can affect some inherited disorders of gastrointestinal tract. These "epigenetic" mechanisms are involved in the development of intestinal enzymes, hormones, transporters, and immunity. This is an expanding research area related to the possible nutritional intervention in selected clinical condition. This paper is focused on the main components and mechanisms of action of the nutritional modulation on intestinal development.

To evaluate the postpartum time course of changes in insulin-like growth factors (IGFs) and their binding proteins (IGFBPs).

Breast milk IGF-I and IGF-II and IGFBP-1, IGFBP-2, and IGFBP-3 levels were determined in 23 women with babies born at term, from day 4 until up to 9 months after birth.

The IGFBP-3 levels were highest from day 4 to day 6 and then decreased by days 10-12. In contrast, IGF-I and IGF-II and IGFBP-1 and IGFBP-2 showed little change over the first 2 weeks after birth. Subsequently, all the IGF components showed a moderate decline over approximately the first 1-3 months and then stable levels up to 9 months after birth.

Although the possibility cannot be excluded that these changes in levels of IGFs and their binding proteins in human milk represent passive loss from the mammary gland, we speculate that higher early levels of the human milk IGF system contribute to maturation of the infant gut.

To date, there is no known prenatal treatment for intrauterine growth restriction (IUGR). IGF-I is an important regulator of fetal growth and circulating IGF-I concentrations are reduced in IUGR fetuses. We investigated whether any of three different methods of fetal IGF-I administration would reverse IUGR in sheep. Animals were randomized into five groups: control (n = 17), IUGR + saline (SAL, n = 17), IUGR + iv IGF-I (IGF-IV, n = 14), IUGR + intraamniotic IGF-I (IGF-AF, n = 14), or IUGR + intraamniotic IGF-I with nutrients (IGF-NUT, n = 16). Weekly IGF-I dose was 360 microg in each treatment group. IUGR was induced by placental embolization between 93 and 99 d and treatment was from 100-128 d gestation (term = 147 d). Embolization caused asymmetrical IUGR with reduced fetal growth rates and body and organ weights, but increased brain to liver weight ratio, at post mortem. Embolized fetuses were also hypoxemic and hypoglycemic and had reduced circulating IGF-I and insulin concentrations. IGF-AF and IGF-IV significantly increased fetal growth rates, but only IGF-AF significantly increased fetal liver weight, compared with saline-treated fetuses. Fetal weights and brain to liver weight ratios in all IGF-I-treated fetuses were intermediate between the control and SAL groups. Addition of nutrients reduced the effects of amniotic IGF-I treatment and increased fetal hemoglobin and lactate concentrations. Treatments did not change fetal plasma IGF-I and insulin concentrations. This is the first report of an intrauterine treatment significantly increasing fetal growth rate in established IUGR. Amniotic IGF-I administration may provide the basis for a clinically applicable prenatal treatment for the IUGR fetus.

Recent research data suggest a significant role of prolonged low serum insulin-like growth factor (IGF)-I concentration in the genesis of retinopathy of prematurity (ROP). Evidence also reveals significant early postnatal nutritional deficits and growth deceleration among premature newborns.

Since serum IGF-I concentration is positively related to nutritional status, particularly protein nutrition, it would suggest that protein under-nutrition may be a major determinant of low serum IGF-I concentration and in the high risk of ROP.

The uninterrupted passage of amniotic fluid through the gastrointestinal tract is hypothesized to influence both intestinal and overall fetal somatic development. The effect of in utero esophageal ligation (EL) and therefore the exclusion of AF on somatic growth, small intestinal (SI) morphology and proliferation, and the expression of the glucose transporter sodium-glucose cotransporter 1 (SGLT-1) in both normal and intrauterine growth-retarded (IUGR) fetal rabbits were evaluated.

Thirteen pregnant New Zealand white rabbits underwent surgery on day 24 of their normal 31-day gestation. Ipsilateral normal and IUGR fetuses underwent EL; the contralateral normal and IUGR fetuses underwent cervical exploration only forming 4 study groups (control-normal, control-IUGR, EL-normal and EL-IUGR). Rabbits were killed on day 31. Small intestinal villus height was measured, and epithelial cell proliferation was deter mined by proliferating cell nuclear antigen staining. Sodium-glucose cotransporter 1 messenger RNA (mRNA) and protein expressions were analyzed. Statistical analysis was performed using 2-way analysis of variance.

Esophageal ligation reduced fetal weight in IUGR by 15% and in normal by 10%. Villus height was significantly reduced in IUGR versus normal in both control and EL (control, P = 0.01; EL, P = 0.05). Intrauterine growth-retarded fetuses had reduced SI proliferation versus normal in both control and EL. Sodium-glucose cotransporter 1 mRNA production in EL fetuses was equal to control fetuses. Esophageal ligation-normal and EL-IUGR fetuses exhibited reduced protein levels and decreased staining for SGLT-1 in villus enterocytes.

Amniotic fluid exclusion by in utero EL reduced fetal weight. Small intestinal proliferation was not affected by EL. Although SGLT-1 mRNA and protein were produced in all 4 groups, exposure of the fetal gastrointestinal tract to amniotic fluid appears necessary for proper brush border expression of nutrient transporter proteins.

Amniotic fluid (AF) is a complex substance essential to fetal well-being. This article reviews recent discoveries and the current understanding of the origin and circulation of AF and its nutritive, protective, and diagnostic functions. Future directions for AF research are also discussed.

Insulin-like growth factor I (IGF-I) is necessary for normal development of retinal blood vessels in mice and humans. Because retinopathy of prematurity (ROP) is initiated by abnormal postnatal retinal development, we hypothesized that prolonged low IGF-I in premature infants might be a risk factor for ROP.

We conducted a prospective, longitudinal study measuring serum IGF-I concentrations weekly in 84 premature infants from birth (postmenstrual ages: 24-32 weeks) until discharge from the hospital. Infants were evaluated for ROP and other morbidity of prematurity: bronchopulmonary dysplasia (BPD), intraventricular hemorrhage (IVH), and necrotizing enterocolitis (NEC).

Low serum IGF-I values correlated with later development of ROP. The mean IGF-I +/- SEM level during postmenstrual ages 30-33 weeks was lowest with severe ROP (25 +/- 2.41 micro g/L), 29 +/- 1.76 micro g/L with moderate ROP, and 33 +/- 1.72 micro g/L with no ROP. The duration of low IGF-I also correlated strongly with the severity of ROP. The interval from birth until serum IGF-I levels reached >33 micro g/L was 23 +/- 2.6 days for no ROP, 44 +/- 4.8 days for moderate ROP, and 52 +/- 7.5 days for severe ROP. Each adjusted stepwise increase of 5 micro g/L in mean IGF-I during postmenstrual ages 30 to 33 weeks decreased the risk of proliferative ROP by 45%. Other complications (NEC, BPD, IVH) were correlated with ROP and with low IGF-I levels. The relative risk for any morbidity (ROP, BPD, IVH, or NEC) was increased 2.2-fold (95% confidence interval: 1.41-3.43) if IGF-I was <or=33 micro g/L at 33 weeks' postmenstrual age.

These results indicate that persistent low serum concentrations of IGF-I after premature birth are associated with later development of ROP and other complications of prematurity. IGF-I is at least as strong a determinant of risk for ROP as postmenstrual age at birth and birth weight.

In previous studies it has been shown that handling produced stress in pregnant blue fox vixens increasing plasma level and adrenal in vitro production of cortisol. Moreover, this treatment increased plasma cortisol levels in the fetuses. The present study was designed to examine effects of a 1-min daily handling stress applied to pregnant blue fox vixens on fetal gonadal steroidogenesis. Plasma concentrations of oestradiol and testosterone, gonadal content and gonadal in vitro production of these steroids, and response to exogenous hCG as well as gonadal weights, and anogenital distances were measured in control (C, n=69) and stressed (S, n=54) fetuses on 47-48 days of pregnancy. Maternal stress induced a suppression of gonadal steroidogenesis in the fetuses. The decreased testosterone content in the testes and oestradiol content in the ovaries were demonstrated in stressed fetuses compared with control (testosterone: 4.91+/-0.46 vs. 7.35+/-0.87 ng/both testes, P<0.05; oestradiol: 29.1+/-3.4 vs. 46.5+/-4.9 ng/both ovaries, P<0.05). The ovarian oestradiol in vitro production in female fetuses from stressed mothers was decreased in comparison with control (3.69+/-0.39 vs. 7.52+/-1.51 pg/ovary/h, P<0.05). The same difference was observed between stressed and control male fetuses in the testosterone testicular response to hCG (5.34+/-0.64 vs. 8.73+/-0.40 ng/testis/h, P<0.05). The ovarian weight from stressed fetuses was lower in comparison with control (12.9+/-0.7 vs. 16.8+/-0.6 mg, P<0.05). The anogenital distance in female fetuses from stressed vixens was also reduced (0.6+/-0.03 vs. 0.8+/-0.02 cm, P<0.01). These results indicate that prenatal stress resulted in a significant reduction of hormonal and morphometric measures of the reproductive system in blue fox fetuses with more drastic effects in female fetuses.

A literature review was performed to survey the available information on the potential of bone growth factors in skeletal reconstruction in the maxillofacial area. The aim of this review was to characterize the biological and developmental nature of the growth factors considered, their molecular level of activity and their osteogenic potential in craniofacial bone repair and reconstruction. A total of 231 references were selected for evaluation by the content of the abstracts. All growth factors considered have a fundamental role in growth and development. In postnatal skeletal regeneration, PDGF plays an important role in inducing proliferation of undifferentiated mesenchymal cells. It is an important mediator for bone healing and remodelling during trauma and infection. It can enhance bone regeneration in conjunction with other growth factors but is unlikely to provide entirely osteogenic properties itself. IGFs have an important role in general growth and maintenance of the body skeleton. The effect of local application of IGFs alone in craniofacial skeletal defects has not yet shown a clear potential for enhancement of bone regeneration in the reported dosages. The combination of IGF-I with PDGF has been effective in promoting bone regeneration in dentoalveolar defects around implants or after periodontal bone loss. TGFbeta alone in skeletal reconstruction appears to be associated with uncertain results. The presence of committed cells is required for enhancement of bone formation by TGFbeta. It has a biphasic effect, which suppresses proliferation and osteoblastic differentiation at high concentrations. BMPs, BMP2, BMP4 and BMP7 in particular, appear to be the most effective growth factors in terms of osteogenesis and osseous defect repair. Efficacy of BMPs for defect repair is strongly dependent on the type of carrier and has been subject to unknown factors in clinical feasibility trials resulting in ambiguous results. The current lack of clinical data may prolong the period until this factor is introduced into routine clinical application. PRP is supposed to increase proliferation of undifferentiated mesenchymal cells and to enhance angiogenesis. There is little scientific evidence about the benefit of PRP in skeletal reconstructive and preprosthetic surgery yet and it is unlikely that peri-implant bone healing or regeneration of local bone into alloplastic material by the application of PRP alone will be significantly enhanced.

To investigate, in the late-gestation ovine fetus: 1) amino acid concentrations in blood and amniotic fluid, 2) the effects of intrauterine growth restriction (IUGR) induced by placental embolization on these concentrations, 3) fetal gut uptake of glutamine in healthy and IUGR fetuses, and 4) the effects of intraamniotic insulin-like growth factor-I (IGF-1) treatment on these parameters.

Fetuses were randomly assigned to control (n = 9), IUGR + saline (n = 9), or IUGR + IGF-1 (n = 11) groups. IUGR was induced by uteroplacental embolization from 114 to 119 days (term = 145 days). IUGR fetuses received daily intraamniotic injections of saline or IGF-1 (20 microg/d) from 120 to 130 days.

Baseline amino acid concentration was higher in fetal blood than amniotic fluid for all essential amino acids except lysine and histidine, but was lower for serine, alanine, and methylhistidine. Embolization reduced total amino acid concentration in blood and amniotic fluid by approximately 15%. Concentrations were reduced for serine, glutamine, and methylhistidine in blood and for serine in amniotic fluid, but were increased for glycine, alanine, and asparagine in blood and for alanine in amniotic fluid. Glutamine was taken up by the fetal gut (glutamine:oxygen quotient of 0.65) and citrulline was released by the gut. IGF-1 treatment did not alter amino acid concentration in blood or amniotic fluid, but reduced gut uptake of glutamine from blood and the gut glutamine:oxygen quotient by 15%. Citrulline release was unchanged.

These data suggest that amniotic fluid amino acids are not simply filtered from fetal blood and may provide an important pool of nutrients for the fetus. They demonstrate for the first time that glutamine is taken up by the fetal gut. IGF-1 treatment may promote gut utilization of amino acids from the amniotic fluid pool.

Maturation of the fetal gastrointestinal tract (GIT) is influenced by both luminal stimuli (e.g. swallowed fluid) and hormonal factors (e.g. endogenous cortisol release). The aims of the present study were 1) to investigate GIT growth and maturation during the last 20% of gestation in pigs (term = 114 +/- 2 d), and 2) to investigate the effect of esophageal ligation, to prevent fetal swallowing, at 80% to 91% gestation. In normal fetuses, marked increases occurred during late gestation in body weight (+95%), relative intestinal weight (+79%, g kg(-1) body weight), activity of some digestive enzymes (1.5- to 10-fold), and absorption of glucose and intact proteins (3- to 6-fold). Fetuses with ligated esophagi had lowered body weight (-20%), reduced intestinal weight (-43%), aminopeptidase A activity (-24%), and glucose absorption (-27%), while lactase, sucrase, and dipeptidylpeptidase IV activities were increased (+40-50%), compared with sham-operated fetuses (all p < 0.05). Other parameters of GIT function remained unchanged by esophageal obstruction (absorption of amino acids and immunoglobulin, activity of chymosin, amylase, trypsin, chymotrypsin, maltase, aminopeptidase N -- all expressed per gram GIT tissue). Ligated fetuses had elevated cortisol levels, which is known to stimulate fetal GIT maturation. We conclude that the rapid development of GIT function in late gestation is diminished by esophageal obstruction, mainly due to slower GIT growth and not inhibition of normal functional development of enterocytes.

Insulin-like growth factor I (IGF-I) is an important regulator of fetal growth, and circulating concentrations are reduced in intrauterine growth-restricted (IUGR) fetuses. We investigated whether IGF-I administered into amniotic fluid could ameliorate IUGR in fetal sheep. Fetuses were assigned to control (n = 9), IUGR+saline (n = 12), or IUGR+IGF-I groups (daily intra-amniotic IGF-I injections of 20 microg, n = 13). IUGR was induced by placental embolization from 114 to 120 days. Treatment was from 120 to 130 days of gestation. Embolization produced asymmetrically IUGR fetuses with decreased body weight and lighter, thinner-walled guts. Fetal plasma and amniotic IGF-I levels were reduced. During treatment, fetal plasma, but not amniotic, IGF-I levels recovered in the saline group but remained depressed in the IGF-I-treated group. IGF-I treatment restored gut weight and wall thickness to control levels and increased the number of crypt mitoses. Fetal weight was similar to that of controls, but spleen, liver, and thymic weights were reduced by 30-37%, and placentome growth was altered. Amniotic fluid IGF-I supplementation may provide the basis of future therapeutic approaches to IUGR, but the systemic effects require further investigation.

Erythropoietin (Epo) receptors are present on enterocytes of fetal and neonatal small bowel but the role of Epo in the bowel is not known.

We tested the following hypotheses: (1) enterally dosed Epo is absorbed from the intestines of neonatal rats, (2) Epo acts as a trophic factor in developing small bowel, and (3) the trophic effects of Epo are dependent on the route of administration.

The dose dependent effects of enterally dosed recombinant human erythropoietin (rEpo 0--1000 U/kg/day) were studied in artificially raised rat pups and compared with dam raised controls and dam raised pups given rEpo in rat milk. After one week, reticulocyte counts, haematocrits, and plasma Epo concentrations were measured, and calibrated morphometric measurements of villi were performed. The effects of route of rEpo administration (enteral v parenteral) on erythropoiesis, bowel growth, and disaccharidase activity were studied in nursing pups treated for one and two weeks.

Serum Epo concentrations ranged from undetectable (<0.6 mU/ml) to 8.4 mU/ml in control and enterally dosed pups (median 1.8 mU/ml), and from 4.9 to 82.3 mU/ml (median 20.4 mU/ml) in parenterally dosed animals. No increase in haematocrit or reticulocyte count was noted in enterally treated pups compared with controls after up to two weeks of treatment. Small bowel length was greater in rEpo treated pups, and a dose dependent increase in villus surface area which was independent of the route of dosing and associated with increased BrdU uptake was found.

rEpo is not enterally absorbed in an intact and functional form from the intestines of neonatal rat pups. Thus enterally dosed rEpo has no erythropoietic effects. However, rEpo acts as a trophic factor in developing rat small bowel whether given enterally or parenterally.

Retinopathy of prematurity is a blinding disease, initiated by lack of retinal vascular growth after premature birth. We show that lack of insulin-like growth factor I (IGF-I) in knockout mice prevents normal retinal vascular growth, despite the presence of vascular endothelial growth factor, important to vessel development. In vitro, low levels of IGF-I prevent vascular endothelial growth factor-induced activation of protein kinase B (Akt), a kinase critical for endothelial cell survival. Our results from studies in premature infants suggest that if the IGF-I level is sufficient after birth, normal vessel development occurs and retinopathy of prematurity does not develop. When IGF-I is persistently low, vessels cease to grow, maturing avascular retina becomes hypoxic and vascular endothelial growth factor accumulates in the vitreous. As IGF-I increases to a critical level, retinal neovascularization is triggered. These data indicate that serum IGF-I levels in premature infants can predict which infants will develop retinopathy of prematurity and further suggests that early restoration of IGF-I in premature infants to normal levels could prevent this disease.