Weeks Of Human Gestation Research Articles

Littre´s hernia: a case presentation

We report a case of Littre’s hernia in a 64-year old woman, which is a very uncommon condition, consists on an hernia whose content corresponds to a remnant of the omphalomesenteric duct, called Meckel’s diverticulum, that results from incomplete obliteration of the vitelline duct between the fifth and sixth weeks of human gestation as the bowel settles into its permanent position within the abdominal cavity. The diagnosis was made from the clinical findings and supported by diagnostic auxiliaries such as ultrasound and computed axial tomography (CAT). The intervention performed was a pre-peritoneal laparoscopic inguinal transabdominal repair (TAPP). The fact that this condition was diagnosed until the sixth decade of age and that the patient was a woman enhances the rarity of this case.

Preterm birth affects both surfactant synthesis and lung liquid resorption actors in fetal sheep

IntroductionAfter birth, the lungs must resorb the fluid they contain. This process involves multiple actors such as surfactant, aquaporins and ENaC channels. Preterm newborns often exhibit respiratory distress syndrome due to surfactant deficiency, and transitory tachypnea caused by a delay in lung liquid resorption. Our hypothesis is that surfactant, ENaC and aquaporins are involved in respiratory transition to extrauterine life and altered by preterm birth. We compared these candidates in preterm and term fetal sheeps. Materials and methodsWe performed cesarean sections in 8 time-dated pregnant ewes (4 at 100 days and 4 at 140 days of gestation, corresponding to 24 and 36 weeks of gestation in humans), and obtained 13 fetal sheeps in each group. We studied surfactant synthesis (SP-A, SP-B, SP-C), lung liquid resorption (ENaC, aquaporins) and corticosteroid regulation (glucocorticoid receptor, mineralocorticoid receptor and 11-betaHSD2) at mRNA and protein levels. ResultsThe mRNA expression level of SFTPA, SFTPB and SFTPC was higher in the term group. These results were confirmed at the protein level for SP-B on Western Blot analysis and for SP-A, SP-B and SP-C on immunohistochemical analysis. Regarding aquaporins, ENaC and receptors, mRNA expression levels for AQP1, AQP3, AQP5, ENaCα, ENaCβ, ENaCγ and 11βHSD2 mRNA were also higher in the term group. DiscussionExpression of surfactant proteins, aquaporins and ENaC increases between 100 and 140 days of gestation in an ovine model. Further exploring these pathways and their hormonal regulation could highlight some new explanations in the pathophysiology of neonatal respiratory diseases.

On the Colorimetry of Neuropeptide Y Hypothalamus and Ligamentous Parts in Male and Female Deer: Immunohistochemical Analysis Report- May 2021

It is since 1992 that this research began after reading numerous articles which placed Neuropeptide Y (NPY) antibody in the regulation of calcium and stomach function. Research in posturology and osteopathy carried out since 1988 highlights the oral afferents in the postural balance of verticalization and hominization. In parallel, paleontological research, on the ventro-caudal concavity flexion of the sphenoid, by Pr Anne Dambricourt, CNRS and the study on the evolution of the neurocranium by Pr Yves Lignereux of the Toulouse natural history museum, have allowed this research to position itself on the anatomical and embryological level. Researchers such as Gulgun Sengul and Charles Watson took up the work of Dr.Yew Chan, et al., in 1999 showed the relevance of NPY, at the high dorsals level, up to the 12th week of gestation in humans. In their work on the spine, Lumbar Spine Discover, the authors Aspden and Porter showed that this ligament relevance would be verifiable on the whole of the supraspinous ligament up to the lumbar vertebrae, which was further studied in the 2016.

Prenatal alcohol exposure causes structural and functional cardiac defects, which can be prevented with folate supplementation

Increased regurgitant blood flow has been linked to endocardial cushion defects and resultant congenital heart diseases (CHDs). Prenatal alcohol exposure (PAE) has been shown to alter early blood flow resulting in abnormal endocardial cushions and CHDs. Compounds, including folic acid (FA), mitigate PAE effects and prevent CHDs, but few studies have assessed their effects on blood flow. We modeled binge drinking in avian embryos at gastrulation. Embryos were exposed to ethanol alone, FA (3.2 μg/egg) alone, and the two simultaneously. We quantified in cardiac looping stages (equivalent to 4 weeks of human gestation) regurgitant blood flow with Doppler optical coherence tomography (OCT) and endocardial cushion volumes using OCT imaging. Incidences of abnormal body curvature and heart rates were also measured. Embryos exposed to ethanol showed significantly increased regurgitant blood flow compared to controls, while embryos given FA with ethanol had significantly reduced regurgitant blood flow but did not return to control levels. Ethanol exposure led to significantly smaller, abnormal endocardial cushions and the addition of FA improved their size, but they remained smaller than controls. Abnormal body curvatures after PAE were reduced in incidence but not fully prevented by FA. FA supplementation partially alleviated PAE induced abnormal cardiovascular function and morphology. Normal blood flow and endocardial cushions are both required to produce a healthy four-chambered heart. These findings support that FA supplementation should begin early in pregnancy to prevent heart as well as neural tube defects. Investigations into the efficacy of combinations of compounds to prevent PAE-induced defects is warranted.

Successful use of an artificial placenta–based life support system to treat extremely preterm ovine fetuses compromised by intrauterine inflammation

Exvivo uterine environment therapy is an experimental intensive care strategy for extremely preterm infants born between 21 and 24 weeks of gestation. Gas exchange is performed by membranous oxygenators connected by catheters to the umbilical vessels. The fetus is submerged in a bath of synthetic amniotic fluid. The lungs remain fluid filled, and pulmonary respiration does not occur. Intrauterine inflammation is strongly associated with extremely preterm birth and fetal injury. At present, there are no data that we are aware of to show that artificial placenta-based systems can be used to support extremely preterm fetuses compromised by exposure to intrauterine inflammation. To evaluate the ability of our exvivo uterine environment therapy platform to support extremely preterm ovine fetuses (95-day gestational age; approximately equivalent to 24 weeks of human gestation) exposed to intrauterine inflammation for a period of 120 hours, the following primary endpoints were chosen: (1) maintenance of key physiological variables within normal ranges, (2) absence of infection and inflammation, (3) absence of brain injury, and (4) gross fetal growth and cardiovascular function matching that of age-matched in utero controls. Ten ewes with singleton pregnancies were each given a single intraamniotic injection of 10-mg Escherichia coli lipopolysaccharides under ultrasound guidance 48 hours before undergoing surgical delivery for adaptation to exvivo uterine environment therapy at 95-day gestation (term=150 days). Fetuses were adapted to exvivo uterine environment therapy and maintained for 120 hours with constant monitoring of key vital parameters (exvivo uterine environment group) before being killed at 100-day equivalent gestational age. Umbilical artery blood samples were regularly collected to assess blood gas data, differential counts, biochemical parameters, inflammatory markers, and microbial load to exclude infection. Ultrasound was conducted at 48 hours after intraamniotic lipopolysaccharides (before surgery) to confirm fetal viability and at the conclusion of the experiments (before euthanasia) to evaluate cardiac function. Brain injury was evaluated by gross anatomic and histopathologic investigations. Eight singleton pregnant control animals were similarly exposed to intraamniotic lipopolysaccharides at 93-day gestation and were killed at 100-day gestation to allow comparative postmortem analyses (control group). Biobanked samples from age-matched saline-treated animals served as an additional comparison group. Successful instillation of lipopolysaccharides into the amniotic fluid exposure was confirmed by amniotic fluid analysis at the time of administration and by analyzing cytokine levels in fetal plasma and amniotic fluid. Data were tested for mean differences using analysis of variance. Six of 8 lipopolysaccharide control group (75%) and 8 of 10 exvivo uterine environment group fetuses (80%) successfully completed their protocols. Six of 8 exvivo uterine environment group fetuses required dexamethasone phosphate treatment to manage profound refractory hypotension. Weight and crown-rump length were reduced in exvivo uterine environment group fetuses at euthanasia than those in lipopolysaccharide control group fetuses (P<.05). There were no biologically significant differences in cardiac ultrasound measurement, differential leukocyte counts (P>.05), plasma tumor necrosis factor α, monocyte chemoattractant protein-1 concentrations (P>.05), or liver function tests between groups. Daily blood cultures were negative for aerobic and anaerobic growth in all exvivo uterine environment group animals. No cases of intraventricular hemorrhage were observed. White matter injury was identified in 3 of 6 lipopolysaccharide control group fetuses and 3 of 8 vivo uterine environment group fetuses. We report the use of an artificial placenta-based system to support extremely preterm lambs compromised by exposure to intrauterine inflammation. Our data highlight key challenges (refractory hypotension, growth restriction, and white matter injury) to be overcome in the development and use of artificial placenta technology for extremely preterm infants. As such challenges seem largely absent from studies based on healthy pregnancies, additional experiments of this nature using clinically relevant model systems are essential for further development of this technology and its eventual clinical application.

Impact of High-Dose Caffeine on the Preterm Ovine Cerebrum and Cerebellum.

Caffeine is one of the few treatments available for infants with apnea of prematurity. As the recommended dosing regimen is not always sufficient to prevent apnea, higher doses may be prescribed. However, little is currently known about the impact of high-dose caffeine on the developing brain; thus, our aim was to investigate the consequences of a high-dose regimen on the immature ovine brain. High-dose caffeine (25 mg/kg caffeine base loading dose; 20 mg/kg daily maintenance dose; n = 9) or saline (n = 8) was administered to pregnant sheep from 105 to 118 days of gestation (DG; term = 147 days); this is broadly equivalent to 28–33 weeks of human gestation. At 119DG, the cerebral cortex, striatum, and cerebellum were assessed histologically and by immunohistochemistry. Compared with controls, caffeine-exposed fetuses showed (i) an increase in the density of Ctip2-positive layers V–VI projection neurons (p = 0.02), Tbr1-positive layers V–VI projection neurons (p < 0.0001), astrocytes (p = 0.03), and oligodendrocytes (p = 0.02) in the cerebral cortex, (ii) a decrease in the density of Cux1-positive layers II–IV projection neurons (p = 0.01) in the cerebral cortex, and (iii) a reduction in the area of Purkinje cell bodies in the cerebellum (p = 0.03). Comparing high-dose caffeine-exposed fetuses with controls, there was no difference (p > 0.05) in: (i) the volume of the cerebral cortex or striatum, (ii) the density of neurons (total and output projection neurons) in the striatum, (iii) dendritic spine density of layer V pyramidal cells, (iv) the density of cortical GABAergic interneurons, microglia, mature oligodendrocytes or proliferating cells, (v) total cerebellar area or dimensions of cerebellar layers, or (vi) the density of cerebellar white matter microglia, astrocytes, oligodendrocytes, or myelin. Daily exposure of the developing brain to high-dose caffeine affects some aspects of neuronal and glial development in the cerebral cortex and cerebellum in the short-term; the long-term structural and functional consequences of these alterations need to be investigated.

Successful use of an artificial placenta to support extremely preterm ovine fetuses at the border of viability

Exvivo uterine environment therapy is an experimental life support platform designed to reduce the risk of morbidity and mortality for extremely preterm infants born at the border of viability (21-24 weeks' gestation). To spare the functionally immature lung, this platform performs gas exchange via a membranous oxygenator connected to the umbilical vessels, and the fetus is submerged in a protective bath of artificial amniotic fluid. We and others have demonstrated the feasibility of extended survival with exvivo uterine environment therapy therapy in late preterm fetuses; however, there is presently no evidence to show that the use of such a platform can support extremely preterm fetuses, the eventual translational target for therapy of this nature. The objective of the study was to use our exvivo uterine environment therapy platform to support the healthy maintenance of 600-700 g/95 days gestational age (equivalent to 24 weeks of human gestation) sheep fetuses. Primary outcome measures were as follows: (1) maintenance of key physiological variables; (2) absence of infection; (3) absence of brain injury; and (4) growth and cardiovascular function patterns matching that of noninstrumented, age-matched in utero controls. Singleton fetuses from 8 ewes underwent surgical delivery at 95 days' gestation (term, 150 days). Fetuses were adapted to exvivo uterine environment therapy and maintained for 120 hours with real-time monitoring of key physiological variables. Umbilical artery blood samples were regularly collected to assess blood gas data, differential counts, inflammation, and microbial load to exclude infection. Brain injury was evaluated by gross anatomical and histopathological approaches after euthanasia. Nine pregnant control animals were euthanized at 100 days' gestation to allow comparative postmortem analyses. Data were tested for mean differences with an analysis of variance. Seven of 8 exvivo uterine environment group fetuses (87.5%) completed 120 hours of therapy with key parameters maintained in a normal physiological range. There were no significant intergroup differences (P > .05) in final weight, crown-rump length, and body weight-normalized lung and brain weights at euthanasia compared with controls. There were no biologically significant differences in hematological parameters (total or differential leucocyte counts and plasma concentration of tumor necrosis factor-α and monocyte chemoattractant protein 1) (P > .05). Daily blood cultures were negative for aerobic and anaerobic growth in all exvivo uterine environment animals. There was no difference in airspace consolidation between control and exvivo uterine environment animals, and there was no increase in the number of lung cells staining positive for the T-cell marker CD3. There were no increases in interleukin-1, interleukin-6, interleukin-8, tumor necrosis factor-α, and monocyte chemoattractant protein 1 mRNA expression in lung tissues compared with the control group. No cases of intraventricular hemorrhage were observed, and white matter injury was identified in only 1 exvivo uterine environment fetus. For several decades, there has been little improvement in outcomes of extremely preterm infants born at the border of viability. In the present study, we report the use of artificial placenta technology to support, for the first time, extremely preterm ovine fetuses (equivalent to 24 weeks of human gestation) in a stable, growth-normal state for 120 hours. With additional refinement, the data generated by this study may inform a treatment option to improve outcomes for extremely preterm infants.

Wnt signaling in orofacial clefts: crosstalk, pathogenesis and models.

ABSTRACTDiverse signaling cues and attendant proteins work together during organogenesis, including craniofacial development. Lip and palate formation starts as early as the fourth week of gestation in humans or embryonic day 9.5 in mice. Disruptions in these early events may cause serious consequences, such as orofacial clefts, mainly cleft lip and/or cleft palate. Morphogenetic Wnt signaling, along with other signaling pathways and transcription regulation mechanisms, plays crucial roles during embryonic development, yet the signaling mechanisms and interactions in lip and palate formation and fusion remain poorly understood. Various Wnt signaling and related genes have been associated with orofacial clefts. This Review discusses the role of Wnt signaling and its crosstalk with cell adhesion molecules, transcription factors, epigenetic regulators and other morphogenetic signaling pathways, including the Bmp, Fgf, Tgfβ, Shh and retinoic acid pathways, in orofacial clefts in humans and animal models, which may provide a better understanding of these disorders and could be applied towards prevention and treatments.

Hamartin regulates cessation of mouse nephrogenesis independently of Mtor

Nephrogenesis concludes by the 36th week of gestation in humans and by the third day of postnatal life in mice. Extending the nephrogenic period may reduce the onset of adult renal and cardiovascular disease associated with low nephron numbers. We conditionally deleted either Mtor or Tsc1 (coding for hamartin, an inhibitor of Mtor) in renal progenitor cells. Loss of one Mtor allele caused a reduction in nephron numbers; complete deletion led to severe paucity of glomeruli in the kidney resulting in early death after birth. By contrast, loss of one Tsc1 allele from renal progenitors resulted in a 25% increase in nephron endowment with no adverse effects. Increased progenitor engraftment rates ex vivo relative to controls correlated with prolonged nephrogenesis through the fourth postnatal day. Complete loss of both Tsc1 alleles in renal progenitors led to a lethal tubular lesion. The hamartin phenotypes are not dependent on the inhibitory effect of TSC on the Mtor complex but are dependent on Raptor.

Early gestational ethanol exposure in mice: Effects on brain structure, energy metabolism and adiposity in adult offspring.

We examined whether an early-life event - ethanol exposure in the initial stages of pregnancy - affected offspring brain structure, energy metabolism, and body composition in later life. Consumption of 10% (v/v) ethanol by inbred C57BL/6J female mice from 0.5 to 8.5 days post coitum was used to model alcohol exposure during the first 3-4 weeks of gestation in humans, when pregnancy is not typically recognized. At adolescence (postnatal day [P] 28) and adulthood (P64), the brains of male offspring were scanned exvivo using ultra-high field (16.4T) magnetic resonance imaging and diffusion tensor imaging. Energy metabolism and body composition were measured in adulthood by indirect calorimetry and dual-energy X-ray absorptiometry (DXA), respectively. Ethanol exposure had no substantial impact on white matter organization in the anterior commissure, corpus callosum, hippocampal commissure, internal capsule, optic tract, or thalamus. Whole brain volume and the volumes of the neocortex, cerebellum, and caudate putamen were also unaffected. Subtle, but non-significant, effects were observed on the hippocampus and the hypothalamus in adult ethanol-exposed male offspring. Ethanol exposure was additionally associated with a trend toward decreased oxygen consumption, carbon dioxide production, and reduced daily energy expenditure, as well as significantly increased adiposity, albeit with normal body weight and food intake, in adult male offspring. In summary, ethanol exposure restricted to early gestation had subtle long-term effects on the structure of specific brain regions in male offspring. The sensitivity of the hippocampus to ethanol-induced damage is reminiscent of that reported by other studies - despite differences in the level, timing, and duration of exposure - and likely contributes to the cognitive impairment that characteristically results from prenatal ethanol exposure. The hypothalamus plays an important role in regulating metabolism and energy homeostasis. Our finding of altered daily energy expenditure and adiposity in adult ethanol-exposed males is consistent with the idea that central nervous system abnormalities also underpin some of the metabolic phenotypes associated with ethanol exposure in pregnancy.

The enduring impact of neurulation stage alcohol exposure: A combined behavioral and structural neuroimaging study in adult male and female C57BL/6J mice

Prenatal alcohol exposure (PAE) can cause behavioral and brain alterations over the lifespan. In animal models, these effects can occur following PAE confined to critical developmental periods, equivalent to the third and fourth weeks of human gestation, before pregnancy is usually recognized. The current study focuses on PAE during early neurulation and examines the behavioral and brain structural consequences that appear in adulthood. On gestational day 8 C57BL/6J dams received two alcohol (2.8g/kg, i.p), or vehicle, administrations, four hours apart. Male and female offspring were reared to adulthood and examined for performance on the elevated plus maze, rotarod, open field, Morris water maze, acoustic startle, social preference (i.e. three-chambered social approach test), and the hot plate. A subset of these mice was later evaluated using magnetic resonance imaging to detect changes in regional brain volumes and shapes. In males, PAE increased exploratory behaviors on the elevated plus maze and in the open field; these changes were associated with increased fractional anisotropy in the anterior commissure. In females, PAE reduced social preference and the startle response, and decreased cerebral cortex and brain stem volumes. Vehicle-treated females had larger pituitaries than did vehicle-treated males, but PAE attenuated this sex difference. In males, pituitary size correlated with open field activity, while in females, pituitary size correlated with social activity. These findings indicate that early neurulation PAE causes sex specific behavioral and brain changes in adulthood. Changes in the pituitary suggest that this structure is especially vulnerable to neurulation stage PAE.

Measuring Absolute RNA Copy Numbers at High Temporal Resolution Reveals Transcriptome Kinetics in Development.

Transcript regulation is essential for cell function, and misregulation can lead to disease. Despite technologies to survey the transcriptome, we lack a comprehensive understanding of transcript kinetics, which limits quantitative biology. This is an acute challenge in embryonic development, where rapid changes in gene expression dictate cell fate decisions. By ultra-high-frequency sampling of Xenopus embryos and absolute normalization of sequence reads, we present smooth gene expression trajectories in absolute transcript numbers. During a developmental period approximating the first 8 weeks of human gestation, transcript kinetics vary by eight orders of magnitude. Ordering genes by expression dynamics, we find that "temporal synexpression" predicts common gene function. Remarkably, a single parameter, the characteristic timescale, can classify transcript kinetics globally and distinguish genes regulating development from those involved in cellular metabolism. Overall, our analysis provides unprecedented insight into the reorganization of maternal and embryonic transcripts and redefines our ability to perform quantitative biology.

Understanding the ontogeny of the immune system to promote immune-mediated health for life.

Understanding the ontogeny of the human immune system is a prerequisite to developing efficient and safe interventions aimed at providing long-term protection against infectious pathogens or inflammatory disorders originating early in life. The immune system of the fetus and the newborn infant had long been considered as “immature.” This insight is based on the observation that infectious diseases are often more severe or more prolonged in early life. However, studies performed in the 80s have shown that cells involved in innate immune responses develop as early as the fourth week of gestation in humans and that mature fetal T and B lymphocytes can be detected by the end of the first trimester of gestation already. More recent evidence indicates that fetal precursors are at the origin of adult tissueresident macrophages. In addition, studies of immune responses to alloantigens and pathogens in utero demonstrated that effector and regulatory responses are operational during human fetal life, further indicating that the immune system is not fundamentally immature in early life, but simply differs from immune responses observed in later life. Studies are now needed to determine the signals involved in the regulation of the functional programing of immune cells in early life and to define how these signals could be targeted to protect against infectious diseases as well as chronic inflammatory disorders. The objective of the Research Topic is to provide an overview of the current state of knowledge of the ontogeny of the immune system and of the pathogenesis of important infectious and inflammatory diseases in early life. Four themes emerged from the excellent contributions that have been assembled here.

When should we prescribe high-dose folic acid to prevent congenital heart defects?

Provide a rationale for attempting prevention of congenital heart defects (CHDs). Prevention of neural-tube defects can be achieved with preconceptional use of folic acid. Extrapolating results from animal studies to human pregnancy shows that folate deficiency as well as one-time exposure to environmental factors in the first 2 to 3 weeks of human gestation can result in severe CHD. Considering that approximately 50% of pregnancies are unplanned, this period of pregnancy can be considered high risk for cardiac, as well as neural, birth defects, as the woman usually is not aware of her pregnancy and may not yet be taking precautionary actions to protect the developing embryo. In mammals, folate supplementation prevents CHD induced by alcohol, by lithium, or by elevation of the metabolite homocysteine. Optimal protection of cardiogenesis was observed to occur with folate supplementation provided on the morning after conception and at higher doses than currently available in prenatal vitamin supplementation. Clinical studies show a similar pattern with high doses of folic acid required to prevent CHD. Today, all patients with a family history of CHD should discuss the prenatal use of folate supplementation with their obstetricians prior to becoming pregnant.

Sterol metabolism disorders and neurodevelopment—an update

Cholesterol has numerous quintessential functions in normal cell physiology, as well as in embryonic and postnatal development. It is a major component of cell membranes and myelin, and is a precursor of steroid hormones and bile acids. The development of the blood brain barrier likely around 12-18 weeks of human gestation makes the developing embryonic/fetal brain dependent on endogenous cholesterol synthesis. Known enzyme defects along the cholesterol biosynthetic pathway result in a host of neurodevelopmental and behavioral findings along with CNS structural anomalies. In this article, we review sterol synthesis disorders in the pre- and post-squalene pathway highlighting neurodevelopmental aspects that underlie the clinical presentations and course of Smith-Lemli-Opitz Syndrome (SLOS), mevalonic aciduria (MVA) or the milder version hyper-immunoglobulinemia D and periodic fever syndrome (HIDS), Antley-Bixler syndrome with genital anomalies and disordered steroidogenesis (ABS1), congenital hemidysplasia with icthyosiform nevus and limb defects (CHILD) syndrome, CK syndrome, sterol C4 methyl oxidase (SC4MOL) deficiency, X-linked dominant chondrodysplasia punctata 2(CDPX2)/ Conradi Hunermann syndrome, lathosterolosis and desmosterolosis, We also discuss current controversies and share thoughts on future directions in the field.

The Heart-Placenta Axis in the First Month of Pregnancy: Induction and Prevention of Cardiovascular Birth Defects

Extrapolating from animal studies to human pregnancy, our studies showed that folate (FA) deficiency as well as one-time exposure to environmental factors in the first two to three weeks of human gestation can result in severe congenital heart defects (CHDs). Considering that approximately 49% of pregnancies are unplanned, this period of pregnancy can be considered high-risk for cardiac, as well as for neural, birth defects, as the woman usually is not aware of her pregnancy and may not yet be taking precautionary actions to protect the developing embryo. Using avian and mouse vertebrate models, we demonstrated that FA supplementation prevents CHD induced by alcohol, lithium, or elevation of the metabolite homocysteine, a marker for FA deficiency. All three factors affected the important Wnt signaling pathway by suppressing Wnt-mediated gene expression in the heart fields, resulting in a delay of cardiomyocyte migration, cardiomyogenesis, and CHD. Optimal protection of cardiogenesis was observed to occur with FA supplementation provided upon morning after conception and at higher doses than the presently available in prenatal vitamin supplementation. Our studies demonstrate pathways and cell processes that are involved with protection of one-carbon metabolism during heart development.

A model of preeclampsia in rats: the reduced uterine perfusion pressure (RUPP) model

Preeclampsia is defined as new-onset hypertension with proteinuria after 20 wk gestation and is hypothesized to be due to shallow trophoblast invasion in the spiral arteries thus resulting in progressive placental ischemia as the fetus grows. Many animal models have been developed that mimic changes in maternal circulation or immune function associated with preeclampsia. The model of reduced uterine perfusion pressure in pregnant rats closely mimics the hypertension, immune system abnormalities, systemic and renal vasoconstriction, and oxidative stress in the mother, and intrauterine growth restriction found in the offspring. The model has been successfully used in many species; however, rat and primate are the most consistent in comparison of characteristics with human preeclampsia. The model suffers, however, from lack of the ability to study the mechanisms responsible for abnormal placentation that ultimately leads to placental ischemia. Despite this limitation, the model is excellent for studying the consequences of reduced uterine blood flow as it mimics many of the salient features of preeclampsia during the last weeks of gestation in humans. This review discusses these features.

A Conserved Pbx-Wnt-p63-Irf6 Regulatory Module Controls Face Morphogenesis by Promoting Epithelial Apoptosis

Morphogenesis of mammalian facial processes requires coordination of cellular proliferation, migration, and apoptosis to develop intricate features. Cleft lip and/or palate (CL/P), the most frequent human craniofacial birth defect, can be caused by perturbation of any of these programs. Mutations ofWNT, P63, and IRF6 yield CL/P in humans and mice; however, how these genes are regulated remains elusive. We generated mouse lines lacking Pbx genes in cephalic ectoderm and demonstrated that they exhibit fully penetrant CL/P and perturbed Wnt signaling. We also characterized a midfacial regulatory element that Pbx proteins bind to control the expression of Wnt9b-Wnt3, which in turn regulates p63. Altogether, we establish a Pbx-dependent Wnt-p63-Irf6 regulatory module in midfacial ectoderm that is conserved within mammals. Dysregulation of this network leads to localized suppression of midfacial apoptosis and CL/P. Ectopic Wnt ectodermal expression in Pbx mutants rescues the clefting, opening avenues for tissue repair.

Pre- and Postnatal Influences of Neurohormonal Triggering and Behaviour on the Immune System of Offspring

It has been realized for some time that exposure of the developing neonate from conception through birth to (toxic) environmental agents can affect the subsequent health and well-being of the offspring. While organogenesis (the first eight weeks of human gestation) is recognized to be a highly susceptible period for the induction of malformations, the fetal/neonatal developmental phases are now acknowledged to be just as sensitive for many well-documented developmental deficits, amongst which are immune-related disorders. In addition, developing predominantly from studies of maternal stress during pregnancy, a growing body of literature now exists to show that changes in the neurohormonal milieu of both mother/infant during pregnancy and weaning can change immune potential of the offspring. Perhaps even more provocative, there is data to suggest that immune changes in the pregnant mother can in turn modify behavior in offspring. The review below provides a framework for consideration of many of the factors contributing to such processes, and their possible mechanism(s) of action.

Doppler flow velocity waveforms in the embryonic chicken heart at developmental stages corresponding to 5–8 weeks of human gestation

To obtain Doppler velocity waveforms from the early embryonic chicken heart by means of ultrasound biomicroscopy and to compare these waveforms at different stages of embryonic development. We collected cardiac waveforms using high-frequency Doppler ultrasound with a 55-MHz transducer at Hamburger-Hamilton (HH) stages 18, 21 and 23, which are comparable to humans at 5 to 8 weeks of gestation. Waveforms were obtained at the inflow tract, the primitive left ventricle, the primitive right ventricle and at the outflow tract in 10 different embryos per stage. M-mode recordings were collected to study opening and closure of the cushions. By exploring the temporal relationship between the waveforms, using a secondary Doppler device, cardiac cycle events were outlined. Our results demonstrate that stage- and location-dependent intracardiac blood flow velocity waveforms can be obtained in the chicken embryo. The blood flow profiles assessed at the four locations in the embryonic heart demonstrated an increase in peak velocity with advancing developmental stage. In the primitive ventricle the 'passive' (P) filling peak decreased whereas the 'active' (A) filling peak increased, resulting in a decrease in P to A ratio with advancing developmental stage. M-mode recordings demonstrated that the fractional closure time of the atrioventricular cushions increased from 20% at stage HH 18 to 60% at stage HH 23. High-frequency ultrasound biomicroscopy can be used to define flow velocity waveforms in the embryonic chicken heart. This may contribute to an understanding of Doppler signals derived from valveless embryonic human hearts at 5 to 8 weeks of gestation, prior to septation.