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MRS of normal and impaired fetal brain development.

Cerebral maturation in the human fetal brain was investigated by in utero localized proton magnetic resonance spectroscopy (MRS). Spectra were acquired on a clinical MR system operating at 1.5 T. Body phased array coils (four coils) were used in combination with spinal coils (two coils). The size of the nominal volume of interest (VOI) was 4.5 cm(3) (20 mm x 15 mm x 15 mm). The MRS acquisitions were performed using a spin echo sequence at short and long echo times (TE = 30 ms and 135 ms) with a VOI located within the cerebral hemisphere at the level of the centrum semiovale. A significant reduction in myo-inositol and choline and an increase in N-acetylaspartate were observed with progressive age. The normal MR spectroscopy data reported here will help to determine whether brain metabolism is altered, especially when subtle anatomic changes are observed on conventional images. Some examples of impaired fetal brain development studied by MRS are illustrated.

Aging↗

Expression of gap junction genes, connexin40 and connexin43, during fetal mouse development.

The expression patterns of the gap junction genes connexin40 and connexin43 have been analyzed during late mouse fetal development, i.e., at embryonic days 14.5 and 16.5, by in situ hybridization and immunofluorescence. Connexin40 was found in endothelial cells of vessels, cardiomyocytes and in developing myoblasts and myotubes. Expression of connexin40 in developing muscle fibers was strong in the back muscles and weaker in the muscles of the limbs. The number of labeled cells in the back muscle decreased with ongoing differentiation of myoblasts, in accordance with the idea that connexin40 is only expressed in the early stages of muscle cell differentiation. Within a muscle bundle, connexin40 expression was predominantly found at the outermost side where myoblasts fuse to multinucleated myotubes. In contrast, connexin43 exhibits a wide and complex pattern of expression in fetal mouse development. It is found in organs originating from all three germ layers, such as epidermis, heart, lung, muscle, kidney and gut. Connexin43 transcript and protein were very abundant in tissues that had been undergoing inductive interactions, e.g., the inner enamel epithelium of the teeth, the glomeruli of the kidneys and the infundibulum forming the neural part of the pituitary gland. Very high connexin43 expression was found in the embryonic meninges (dura mater) and in the fetal adrenal cortex. During keratinocyte differentiation connexin43 mRNA expression decreased, being much stronger in the stratum basale than in stratum granulosum. No obvious discrepancy between the amount of mRNA and protein of either connexin was noticed, suggesting that there is no specific translational regulation at these developmental stages.

Animals↗

Significant fetal-maternal hemorrhage after termination of pregnancy: implications for development of fetal cell microchimerism.

OBJECTIVE: Recent reports that an association exists between fetal cell microchimerism and autoimmune disease has increased interest in the postpartum persistence of fetal cells. The purpose of this study was to determine, by means of quantitative polymerase chain reaction amplification, whether a significant fetalmaternal hemorrhage occurs after elective termination of pregnancy. STUDY DESIGN: Blood samples were obtained from 23 women who underwent termination of pregnancy immediately before venipuncture; these samples were subjected to analysis by quantitative polymerase chain reaction amplification with the use of Y-chromosome primers. There were 21 male and 2 female fetuses. Results were equilibrated to 16 mL and analyzed by a weighted linear regression analysis to evaluate the correlation between detected fetal nucleated cell equivalents and gestational weeks. RESULTS: Among the 21 known male fetuses, the median number of detected fetal nucleated cell equivalents was 1552 (range, 50-37,618). The female fetuses had no fetal nucleated cell equivalents detected. A positive dependence of male fetal nucleated cell equivalents on gestational age was shown (P <.001). CONCLUSION: Analysis by quantitative polymerase chain reaction amplification demonstrated a large fetal-maternal transfusion after elective abortion. Consideration of the biologic consequences of pregnancy and the potential for future development of fetal cell microchimerism must now extend to a larger population of women.

Abortion, Induced↗

Fetal brain development in diabetic guinea pigs.

Fetal brain development was investigated near term in guinea pigs rendered diabetic with streptozotocin. The liver and the placenta were used as reference organs. Compared to controls, those fetuses from diabetic animals had normal cerebrum and cerebellum weights, but higher liver and placenta weights in relation to fetal weights. Although liver and placenta cell number (DNA content) was unchanged, it was significantly increased in the fetal cerebrum and cerebellum of diabetics. Although the tissue protein concentration was decreased in the liver and the placenta, it was unchanged and even increased in the cerebrum and cerebellum, respectively. The concentration of myelin (cerebroside-sulfatide) was unchanged in the cerebrum, but it was increased in the cerebellum of diabetic animals. These data suggest that diabetes has a growth-promoting effect on the fetal brain cell number. Furthermore, differences in the protein content between fetal organs may reflect abnormalities in protein metabolism which do not affect the brain during diabetic pregnancies.

Animals↗

Development of fetal thymocytes in organ culture: effect of corticosteroids.

Corticosteroids affect the development of fetal foregut-derived organs in which epithelial-mesenchymal interactions are associated with the developmental process. The thymus is one such organ and is profoundly sensitive to corticosteroids when mature. In this study corticosterone (CS) effects on fetal thymocyte development were investigated using a fetal thymus organ culture system which allows the growth, differentiation, and function of developing thymocytes to be monitored in vitro. CS inhibited, but did not block growth of fetal thymocytes, although the appearance of mature thymocytes was inhibited, similar to previously reported effects of interleukin 2 (IL2). CS enhanced the proportion of Mac1+, Ia+ and FcR+ cells and maintained high levels of IL2 receptor (IL2R) positive immature cells. Functional cytotoxic cells were detected in CS-treated organ cultures which expressed a Thy 1-, CD8- phenotype, atypical for thymus derived killer cells. While this cytotoxicity may be stimulated by CS, it could simply be due to a relative depletion of the main pool of thymocytes. These cytotoxic cells may have a role in directing apoptotic mechanisms occurring during thymocyte development.

Adrenal Cortex Hormones↗

IGF-I, 17beta-estradiol and progesterone in SHR and in rats treated with L-NAME: fetal-placental development.

METHODS: The relationship between progesterone (P4), 17beta-estradiol, insulin-like growth factor (IGF-I) and embryonic and fetal development, were examined. Female Sprague Dawley rats were divided into two groups: control untreated (n=60) and treated (n=63) with L-NAME (N(omega)-nitro-L-arginine methyl ester), 15 mg/day in drinking water from the first day after mating to day 18 of gestation. A further group was formed (n=63) of spontaneously hypertensive rats (SHR). Mean systolic blood pressure was recorded daily. On days 6, 11 and 18 of pregnancy, the number of sites of implantation, litter and placenta weight was examined. In addition, serum levels of P4, 17beta-estradiol and IGF-I were determined. RESULTS: Systolic blood pressure (SBP) (mmHg) increased significantly in L-NAME and SHR rats over the course of the experiment. On day 6 of pregnancy, in the L-NAME group the number of implantation sites, levels of IGF-I and 17beta-estradiol were significantly lower than in the control group. In SHR, only the concentration of IGF-I was low (p<0.05). In contrast, on day 11 of pregnancy no variation was found in the parameters under study. On day 18 of gestation, a significant decrease in litter and placenta weight, concentration of P4 and IGF-I was observed in the experimental groups. CONCLUSION: The data further suggest that nitric oxide might regulate IGF-I production, indicating that growth factors may play an important role in fetal-placental development.

Animals↗

Fetal magnetic resonance imaging of the brain: technical considerations and normal brain development.

Fetal MRI examines non-invasively the unborn fetus. Ultrafast MRI sequences effectively suppress fetal motion. Multiple case reports and studies have shown that fetal MRI is particularly helpful in the evaluation of the central nervous system. The high contrast-to-noise ratio, the high spatial resolution, the multiplanar capabilities, the large field of view and the simultaneous visualisation of fetal and maternal structures have proven to be advantageous. Fetal MRI is particularly helpful in the evaluation of the normal and pathological development of the brain. Despite the fact that no side effects have been reported or are to be expected, the use of MRI during pregnancy is still limited to the second and third trimester of pregnancy. Magnetic resonance imaging contrast media are not to be used as it passes the placenta. Ultrasound remains the primary screening modality for fetal pathology; fetal MRI can serve as an adjunct or second-line imaging modality.

Brain↗

Development of fetal hearing.

Previous research has revealed that the human fetus responds to sound, but to date there has been little systematic investigation of the development of fetal hearing. The development of fetal behavioural responsiveness to pure tone auditory stimuli (100 Hz, 250 Hz, 500 Hz, 1000 Hz, and 3000 Hz) was examined from 19 to 35 weeks of gestational age. Stimuli were presented by a loudspeaker placed on the maternal abdomen and the fetus's response, a movement, recorded by ultrasound. The fetus responded first to the 500 Hz tone, where the first response was observed at 19 weeks of gestational age. The range of frequencies responded to expanded first downwards to lower frequencies, 100 Hz and 250 Hz, and then upwards to higher frequencies, 1000 Hz and 3000 Hz. At 27 weeks of gestational age, 96% of fetuses responded to the 250 Hz and 500 Hz tones but none responded to the 1000 Hz and 3000 Hz tones. Responsiveness to 1000 Hz and 3000 Hz tones was observed in all fetuses at 33 and 35 weeks of gestational age, respectively. For all frequencies there was a large decrease (20-30 dB) in the intensity level required to elicit a response as the fetus matured. The observed pattern of behavioural responsiveness reflects underlying maturation of the auditory system. The sensitivity of the fetus to sounds in the low frequency range may promote language acquisition and result in increased susceptibility to auditory system damage arising from exposure to intense low frequency sounds.

Audiometry, Pure-Tone↗

The effect of maternal exercise on somatic growth and lung development of fetal rats: morphologic and morphometric studies.

Our study was aimed at elucidating the effect of strenuous maternal exercise (running at a speed of 20 m/min) on fetal somatic growth and lung development. Dams were separated into three groups: (1) exercising during the entire course of pregnancy; (2) exercising from the 16th to the 20th gestational day; and (3) controls treated in the same manner as the exercising animals, but not exercised. There were no differences in the mother's body weight (mother's body weight--total body weight of the fetuses) among the three groups. Overall growth and lung development in fetuses from mothers that exercised during the entire course of pregnancy showed markedly decreased size and weight of body and lung, smaller air spaces and thicker future alveolar walls, and fewer osmiophilic lamellated bodies in alveolar type II cells. The morphometric data of fetuses from mothers that had exercised only during late gestation were similar to those of control animals. The ratio of fetal lung volume to body weight was the same in all three groups. These findings indicate that long-term strenuous maternal exercise induces retardation of fetal lung development, possibly accompanied by a disturbance of overall growth. Maternal exercise represents another means of manipulating lung development.

Animals↗

Temporal and spatial selection against parthenogenetic cells during development of fetal chimeras.

The fate of parthenogenetic cells was investigated during development of fetal and early postnatal chimeras. On day 13 of embryonic development, considerable contribution of parthenogenetic cells was observed in all tissues of chimeric embryos, although selection against parthenogenetic cells seemed to start before day 13. Between days 13 and 15 of development, parthenogenetic cells came under severe selective pressure, which was most striking in tongue. The disappearance of parthenogenetic cells from tongue coincided with the beginning of myoblast fusion in this tissue. Severe selection against parthenogenetic cells was also observed in pancreas and liver, although in the latter, parthenogenetic cells were eliminated later than in skeletal muscle or pancreas. In other tissues, parthenogenetic cells may persist and participate to a considerable extent throughout the gestation period and beyond, although a significant decrease was observed in all tissues. Parthenogenetic in equilibrium fertilized chimeras were significantly smaller than their non-chimeric littermates at all developmental stages. These results suggest that the absence of paternal chromosomes is largely incompatible with the maintenance of specific differentiated cell types. Furthermore, paternally derived genes seem to be involved in the regulation of proliferation of all cell types, as indicated by the drastic growth decceleration of parthenogenetic in equilibrium fertilized chimeras and the overall decrease of parthenogenetic cells during fetal development. Chromosomal imprinting may have a role in maintaining a balance between cell growth and differentiation during embryonic development. The major exception to the selective elimination of parthenogenetic cells appear to be the germ cells; viable offspring derived from parthenogenetic oocytes were detected, sometimes at a high frequency in litters of female parthenogenetic in equilibrium fertilized chimeras.

Animals↗

Skeletal development in fetal pig specimens: MR imaging of femur with histologic comparison.

PURPOSE: To evaluate the magnetic resonance (MR) imaging features of the developing femur in fetal pig specimens. MATERIALS AND METHODS: MR images of 15 fetal pig femurs, which were categorized into three groups of specimens representing each third of the gestational period, were used to compare increasing femoral length (as an indication of gestational age) with epiphyseal growth in multiple dimensions by using Pearson product moment correlation. Physeal-epiphyseal demarcation, visibility of the secondary ossification center and its physis, prominence of the perichondrial structures (ie, groove of Ranvier and bone bark), metaphyseal undulation, and corticomedullary differences were evaluated qualitatively. These features were also evaluated on histologic sections. RESULTS: With femoral length measurements used as indications of gestational age, there were three, five, and seven fetal pig specimens in each gestation group. During fetal development, the cartilaginous epiphysis of the distal femur transformed from an oval to a bicondylar structure, with most of the growth occurring sagittally (P < .001). Physeal-epiphyseal demarcation, visibility of the secondary ossification center and its physis, and metaphyseal undulation increased later in gestation. Detection of perichondrial structures, however, was greatest during the middle third of gestation and decreased thereafter. During the fetal period, the perichondrial groove of Ranvier and the bone bark were easily identifiable at MR imaging. Marrow cavitation increased with gestation. CONCLUSION: MR imaging depicts fetal pig skeletal features that can be confirmed histologically and that may prove to be useful at human prenatal skeletal imaging.

Animals↗

Some aspects of fetal laryngeal development.

Some aspects of morphological and physiological development of the fetal larynx are presented. Histochemical confirmation and determinations of fetal glandular activity are needed. Anomalous development of the larynx is still conjecture, but congenital cystic formation with glandular development appears possible after the fifth month of human fetal life.

Female↗

The fetal origins of memory: the role of dietary choline in optimal brain development.

Fetal nutrition sets the stage for organ function in later life. In this review we discuss the fetal and neonatal origins of brain function. Numerous research observations point to the importance of choline for the developing fetus and neonate. This essential nutrient is involved in 1-carbon metabolism and is the precursor for many important compounds, including phospholipids, acetylcholine, and the methyl donor betaine. Dietary intake of choline by the pregnant mother and later by the infant directly affects brain development and results in permanent changes in brain function. In rodents, perinatal supplementation of choline enhances memory and learning functions, changes that endure across the lifespan. Conversely, choline deficiency during these sensitive periods results in memory and cognitive deficits that also persist. Furthermore, recent studies suggest that perinatal choline supplementation can reduce the behavioral effects of prenatal stress and the cognitive effects of prenatal alcohol exposure in offspring. The likely mechanism for these effects of choline involves DNA methylation, altered gene expression, and associated changes in stem cell proliferation and differentiation. The currently available animal data on choline and hippocampal development are compelling, but studies are needed to determine whether the same is true in humans.

Brain↗

[Expression patterns of sonic hedgehog signaling molecules in human fetal prostate development].

OBJECTIVE: To investigate whether the sonic hedgehog signaling pathway is involved in the development of human fetal prostate, and to evaluate the changing staining patterns of its molecules, sonic hedgehog (SHH), patchedl (PTC1), smoothened (SMO), and GLI1, in the human fetal prostate at various gestation stages. METHODS: Fifteen human fetal prostate specimens at various developmental stages (10 - 39 weeks) were included in this study. SHH, PTC1, SMO and GLI1 were detected in all the specimens by immunohistochemical technique. All the slides were observed and assessed under the light microscope. RESULTS: SHH, PTC1, SMO and GLI1 could be detected in human fetal prostate tissues, and their expression formed two surges, the former at week 16, and the latter at week 28. The staining of SHH and SMO was distributed only in the ductal epithelium but not in the stroma. The expression of PTC1 and GLI1 could be found mainly in the epithelium, with minimal staining in the stroma. CONCLUSION: The sonic hedgehog signaling pathway is involved in the development of the human fetal prostate. The high expression of its molecules at early gestation stages might be associated with the induction of prostatic buds, while their abundant expression at later gestation stages might be related to the prostate ductal branching, growth, differentiation and morphogenesis.

Gene Expression Regulation, Developmental↗

Factors involved in the testicular development from fetal mouse ovaries following transplantation.

We have previously shown that fetal mouse ovaries develop testicular structures after transplantation into adult male mice. The mechanisms of gonadal sex reversal is poorly understood. In the present study, we examined how a host environment is involved in the induction of testicular development in ovarian grafts. Fetal ovaries on the twelfth day of gestation were microencapsulated with semipermeable membranes, transplanted beneath the kidney capsules of adult male mice, and fixed for histological examinations between the sixteenth and twenty-second day after transplantation. Fifteen of forty-seven ovarian grafts were found to be completely enclosed in microcapsules, whereas the microcapsule membranes of other grafts were partly broken or had been lost. These differences of microencapsulation conditions made it possible to study the role of host factors in gonadal sex reversal. All ovarian grafts surrounded by microcapsule membranes developed ovarian structures. In contrast, most ovarian grafts which had lost the microcapsules developed testicular structures in addition to ovarian structures. When ovarian grafts were partially enclosed in microcapsule membranes, testicular structures developed only in the area in contract with the host kidney. These results suggest that direct interaction between the ovarian graft and cells or large macromolecules from the host is involved in the development of testicular structures in ovarian grafts.

Animals↗

Prenatal stressors of human life affect fetal brain development.

In a population-based study, 3021 women in a central Copenhagen district received a questionnaire on environmental and psychological factors during mid-gestation. Of these, 70 women were selected consecutively on the basis of moderate to severe stressful life-events (DSM-III-R categories 3 to 5), in combination with an inadequate social network. They were compared with 50 non-stressed women with an intact social network. Stress and smoking significantly affected birthweight and head circumference. When birthweight was corrected, stress remained a significant determinant of small head circumference, indicating a specific effect on brain development. Stress also led to a suboptimal Prechtl neonatal neurological score. These findings suggest the existence of a fetal stress syndrome with adverse effects on fetal development, including deficient brain development.

Brain↗

Measures of folding applied to the development of the human fetal brain.

Previous work has suggested the existence of differences between the cerebral cortex of normal individuals, and those of patients with diseases such as epilepsy and schizophrenia. These shape abnormalities may be of developmental origin. Improved shape measures could provide useful tools for neuroscience research and patient diagnosis. We consider the theoretically desirable properties of measures of brain shape. We have implemented seven measures, three from the neuroscience literature, and four new to this field. Three of the measures are zero-order and four are second-order with respect to the surface. We validate the measures using simple geometrical shapes, and a collection of magnetic resonance scans of ten histologically normal ex vivo fetal brains with gestational ages from 19-42 weeks. We then apply the measures to MR scans from two histologically abnormal ex vivo brains. We demonstrate that our implementation of the measures is sensitive to anatomical variability rather than to the discreteness of the image data. All the measures were sensitive to changes in shape during fetal development. Several of the measures could distinguish between the normal and abnormal fetal brains. We propose a multivariate approach to studying the shape of the cerebral cortex, in which both zero-order and second-order measures are used to quantify folding.

Aging↗

[Development of fetal organs and adaptation to extrauterine life].

Under unsatisfactory environmental conditions, such as the mother's illness, placental insufficiency, PROM, etc., the fetus must make the transition to extrauterine life from an unfortunate intrauterine existence. The adaptation process of the fetus to extrauterine environment in these cases is extreme importance. In our present investigation, we studied the developmental pattern of the functions of each fetal organ and the specific aspects of fetal metabolism. Using the brush border technique, we clarified that the fetal absorptional function of intestine developed from the 24th week of gestation and reached adult level in 32nd gestational weeks. The fetal renal reabsorption function developed from the 30th week of gestation and reached adult level in 36 gestational weeks. The liver function (enzymatic activity, etc.) remained low during the entire fetal life and developed gradually after birth. Taurine plays an important metabolical role and has a specific transport system during fetal life. The coagulation of vitamin K-dependent factors and activity remained low level at 27-31st gestational week, reaching full term level after 30 days. The switching of HbF to HbA was delayed more significantly in premature infants than in full term infants, but this delay of switching is effectively corrected by the increase of 2.3 DPG in premature infants. Immune response remained immature even in the full term fetus, but the non-specific immune response (NK activity, LAK activity, etc.) developed in the early fetal period and showed characteristic activity. The steroids which originated from the fetal-placental unit related intimately to the continuity of pregnancy and fetal development.

Adaptation, Physiological↗