Effects Of Growth Restriction Research Articles

Position statement on the management of pregnancy in sickle cell disease.

Sickle cell disease (SCD) is a hereditary haemoglobinopathy which causes multi-organ dysfunction. Pregnancies in SCD are high risk with significant maternal and fetal morbidity and mortality, including vaso-occlusive crises, thrombosis, anaemia, placental insufficiency, fetal growth restriction, preterm birth and medication effects. High level evidence on this topic is lacking. The Australian Sickle Cell Disease Working Group has reviewed international guidelines on this topic and provide an up-to-date and structured approach to the pre-conception, antenatal, birth and post-partum management of these women. Early and comprehensive multidisciplinary care involving experienced clinicians is recommended.

The effect of intrauterine growth restriction on the developing pancreatic immune system.

Immune cells in the pancreas are known to participate in organ development. However, the resident pancreatic immune system has yet to be fully defined. Immune cells also play a role in pathology and are implicated in diseases such as diabetes induced by intrauterine growth restriction (IUGR). We hypothesized that the resident immune system is established during neonatal development and disrupted by IUGR. Using single cell RNAseq and flow cytometry we identified many immune cell populations in the near-term fetus (at embryologic day 22) and neonatal (postnatal day 1, 7, &14) islets, non-endocrine pancreas, and the spleen in the rat. Using flow cytometry, we observed the resident immune system is established during neonatal development in the pancreas and spleen. We identified 9 distinct immune populations in the pancreatic islets and 8 distinct immune populations in the spleen by single cell RNAseq. There were no sex-specific differences in the relative proportion of immune cells in the pancreas or spleen. Finally, we tested if IUGR disrupted the neonatal immune system using bilateral uterine artery ligation. We found significant changes to the percentage of CD11B+ HIS48- and CD8+ T cells in the islets and non-endocrine pancreas and in the spleen. IUGR-induced alterations were influenced by the tissue environment and the sex of the offspring. Future research to define the role of these immune cells in pancreatic development may identify disrupted pathways that contribute to the development of diabetes following IUGR.

Dual Grain Refinement Effect for Pure Aluminum with the Addition of Micrometer-Sized TiB2 Particles.

The inefficiency of grain refinement processes has traditionally been attributed to the limited utilization of heterogeneous nucleation particles within master alloy systems, resulting in the formation of abundant inactive particles. This study aims to investigate the alternative influences of particles by incorporating external micrometer-sized TiB2 particles into the grain refinement process. Through a series of experiments, the refinement efficiency, grain refinement mechanism, and resultant microstructure of TiB2 particle-induced grain refinement specimens are comprehensively examined using various microscopy and analytical techniques, including polarization microscopy (OM), scanning electron microscopy (SEM), differential scanning calorimetry (DSC), and transmission electron microscopy (TEM). Our findings demonstrate a direct correlation between increased levels of TiB2 particles and enhanced grain refinement efficiency. Moreover, the microstructure analysis reveals the distribution of TiB2 particles along grain boundaries, forming a coating due to self-assembly phenomena, while regions with a lower particle content may exhibit irregular grain structures. DSC analysis further confirms reduced undercooling, indicating the occurrence of heterogeneous nucleation events. However, TEM observations suggest that heterogeneous nucleation is not significantly influenced by the growth restriction factor attributed to TiAl3 2DC compounds. The grain refinement mechanism involving TiB2 particles is elucidated to entail both heterogeneous nucleation and physical growth restriction effects. Specifically, a reduction in average grain size is attributed not only to heterogeneous nucleation but also to the physical growth restriction effect facilitated by the TiB2 particle coating. This study offers insights into leveraging particles that do not participate in heterogeneous nucleation within master alloy-based grain refinement systems.

Influence of solute content and cooling rate on the preparation of semi-solid slurries for novel creep-resistant Mg-Gd-Ca-Zr alloys

The semi-solid Mg-Gd-Ca-Zr alloys slurries with fine and spherical α-Mg particles were successfully prepared. The influence of solute Gd and Zr contents, and cooling rate on the morphological evolution of α-Mg are systematically investigated. The results showed that addition of Zr will turn the coarse dendritic α-Mg particles into fine and globular particles. With the increase of Zr addition from 0 to 0.6 wt%, the particle size decreases, and the particle density and shape factor increase continuously. With the change of solute Gd content from 5 to 15 wt% in the Mg-yGd-2Ca-0.6Zr alloy, the particle size of α-Mg particles decreases continuously, and shape factor increases continuously. With cooling rate decreases from 3 to 1.5 °C/min, the α-Mg particles are slightly coarsened and the morphology are kept nearly globular, while with further decreasing into 0.5 °C/min, the α-Mg particles are severely coarsened and turned into irregular shape. The optimal Zr addition is ∼0.6 wt% and Gd addition is no less than 10 wt%, and the optimal cooling rate is 1.5–3 °C/min. The mechanisms for obtaining fine and spherical α-Mg particles through Zr and Gd additions are discussed to be different roles of heterogenous nucleation effects and growth restriction effects.

Neurodevelopmental outcomes of preterm and growth-restricted neonate with congenital heart defect: a systematic review and meta-analysis.

Based on a low level of evidence, prematurity and/or growth retardation appear to accentuate specific neurodevelopmental outcomes in certain CHD subgroups. Further evidence is needed to confirm these findings. PROSPERO [CRD42020201414]. • Children born with CHD, preterm birth, or growth restriction at birth are independently at higher risk for neurodevelopmental impairment. • The additional effect of preterm birth and/or growth restriction on neurodevelopmental outcomes in children with CHD remains unclear. • Prematurity and/or growth retardation appear to accentuate specific neurodevelopmental outcomes in certain CHD subgroups. • Children with CHD, particularly those born preterm or with growth restriction, should undergo lifelong systematic comprehensive neurodevelopmental assessment.

The Effect of an Early Life Motor Skill Intervention on Physical Activity in Growth-Restricted Mice.

Early life growth restriction significantly increases the risk of adulthood physical inactivity and thereby chronic disease incidence. Improvements in motor skill acquisition could result in greater physical activity engagement in the growth-restricted population, thus reducing chronic disease risk. The purpose of this study was to implement an early life motor training intervention to improve physical activity engagement in control and growth-restricted mice. Mice were growth restricted in early life utilizing a validated nutritive model or remained fully nourished in early life as a control. All mice were tested throughout early life for various components of motor skill acquisition. On postnatal day 10, mice were randomly assigned to engage in an early life motor skill intervention daily until postnatal day 21 or remained as a sedentary control. All mice were given access to an in-cage running wheel from postnatal days 45-70. Growth-restricted group (PGR) mice had impaired trunk and postural control, coordination/vestibular development, and hindlimb strength in early life compared with control mice. There were no differences in wheel running behavior between the trained and sedentary mice, although control mice ran at a faster average speed compared with PGR mice. Control female mice ran more than PGR female mice during the week 2 dark cycle. Early life growth restriction reduced motor skill attainment throughout early life, which may be associated with reduced ability to engage in physical activity in adulthood. The early life motor skill intervention did not elicit changes in body weight or physical activity engagement in control or PGR mice, indicating that a more intense/different intervention specifically targeting skeletal muscle may be necessary to counteract the detrimental effects of early life growth restriction.

Differential effects of growth restriction and immaturity on predicted psychomotor development at 4 years of age in preterm infants

Fetal growth restriction and immaturity are associated with poor neurocognitive development and child psychopathology affecting educational success at school and beyond. However, the differential effects of either obstetrical risk factor on predicted psychomotor development have not yet been deciphered. This study aimed to separately study the impact of growth restriction and that of immaturity on predicted psychomotor development at the preschool age of 4.3 (standard deviation, 0.8) years using birthweight percentiles in a prospective cohort of preterm infants born at ≤37+6/7 weeks of gestation. Differences between small for gestational age newborns with intrauterine growth restriction and those without were described. We examined predicted total psychomotor development score, predicted developmental disability index, calculated morphometric vitality index, and predicted intelligence quotient, Porteus Maze test score, and neurologic examination optimality score in 854 preterm infants from a large prospective screening cohort (cranial ultrasound screening, n=5,301). This was a prospective cranial ultrasound screening study with a single-center cohort observational design (data collection done from 1984-1988, analysis done in 2022). The study included 5,301 live-born infants, of whom 854 (16.1%) were preterm infants (≤37+6/7 weeks' gestation), and was conducted on the day of discharge of the mother at 5 to 8 days postpartum from a level 3 perinatal center. Predicted psychomotor development, as assessed by the predicted total psychomotor development score, predicted developmental disability index, calculated morphometric vitality index, predicted intelligence quotient, Porteus Maze test score, and neurologic examination optimality score were calculated. We related psychomotor development indices and measures to gestational age in 3 groups of birthweight percentiles (ie, 10%, 50%, and 90% for small, appropriate, and large for gestational age newborns, respectively) using linear regression analysis, analysis of variance, multivariate analysis of variance, and t test procedures. The key result of our study is the observation that in preterm infants born at ≤37+6/7 weeks of gestation, growth restriction as compared with immaturity is the prime risk factor for impairment of overall predicted psychomotor development, intelligence quotient, Porteus Maze test results, and neurologic examination optimality score at the preschool age of 4.3 (standard deviation, 0.8) years (P<.001). This is particularly true for intrauterine growth restriction. These detrimental effects of growth restriction become more prominent with decreasing gestational age (P<.001). As expected, growth restriction in preterm infants born at ≤37+6/7 weeks of gestation was associated with a number of obstetrical risk factors, including hypertension in pregnancy (P<.001), multiple pregnancy (P<.001), pathologic cardiotocography (P=.001), and low pH (P=.007), increased pCO2 (P=.009), and poor pO2 (P<.001) in umbilical arterial blood. Of note, there were no differences in cerebral hemorrhage or white matter damage among small, appropriate, and large for gestational age birthweight percentile groups, suggesting an independent mechanism of brain injury caused by preterm growth restriction resulting in poor psychomotor development. Compared with immaturity, growth restriction in preterm infants has more intense detrimental effects on psychomotor development, necessitating improved risk stratification. This finding has implications for clinical management, parental consultation, and early intervention strategies to improve school performance, educational success, and mental health in children. The mechanisms of brain injury specific to growth restriction in preterm infants require further elucidation.

On the Role of ZrN Particles in the Microstructural Development in a Beta Titanium Alloy Processed by Laser Powder Bed Fusion.

Additive manufacturing of titanium alloys usually ends up with large columnar grains due to the steep thermal gradients within melt pools during solidification. In this study, ZrN particles were added into a beta titanium alloy, Ti-10V-2Fe-3Al, with the aim of promoting columnar-to-equiaxed grain transition during laser bed powder fusion (L-PBF). It was found that the addition of ZrN leads to the development of alternate layers of equiaxed grains and refined columnar grains, which is in sharp contrast to the dominant large columnar grains formed in the pure L-PBF-processed titanium alloy. An investigation on single laser melted tracks revealed that the sample with added ZrN showed fine equiaxed grains in the upper regions of solidified melt pools and columnar grains in the lower regions, whereas the solidified melt pools of the pure titanium alloy were dominated by large columnar grains due to epitaxial growth from the previous layer. The formation of equiaxed grains in the former sample is attributed to multiple factors including an increased gradient of liquidus temperature due to the solution of N and a reduced actual melt temperature gradient due to the melting of high-melting-point ZrN particles, which would have expanded constitutional undercooling, a grain growth restriction effect induced by the segregation of N along grain boundaries and the accumulation of unmelted ZrN particles in the upper regions of melt pools. The addition of ZrN also resulted in significant α precipitation, which showed strong variant selection and was found to be driven by laser reheating and the N solution in the matrix.

Reduced in utero substrate supply decreases mitochondrial abundance and alters the expression of metabolic signalling molecules in the fetal sheep heart.

Babies born with fetal growth restriction (FGR) are at higher risk of developing cardiometabolic diseases across the life course. The reduction in substrate supply to the developing fetus that causes FGR not only alters cardiac growth and structure but may have deleterious effects on metabolism and function. Using a sheep model of placental restriction to induce FGR, we investigated key cardiac metabolic and functional markers that may be altered in FGR. We also employed phase-contrast magnetic resonance imaging MRI to assess left ventricular cardiac output (LVCO) as a measure of cardiac function. We hypothesized that signalling molecules involved in cardiac fatty acid utilisation and contractility would be impaired by FGR and that this would have a negative impact on LVCO in the late gestation fetus. Key glucose (GLUT4 protein) and fatty acid (FATP, CD36 gene expression) substrate transporters were significantly reduced in the hearts of FGR fetuses. We also found reduced mitochondrial numbers as well as abundance of electron transport chain complexes (complexes II and IV). These data suggest that FGR diminishes metabolic and mitochondrial capacity in the fetal heart; however, alterations were not correlated with fetal LVCO. Overall, these data show that FGR alters fetal cardiac metabolism in late gestation. If sustained ex utero, this altered metabolic profile may contribute to poor cardiac outcomes in FGR-born individuals after birth. KEY POINTS: Around the time of birth, substrate utilisation in the fetal heart switches from carbohydrates to fatty acids. However, the effect of fetal growth restriction (FGR) on this switch, and thus the ability of the fetal heart to effectively metabolise fatty acids, is not fully understood. Using a sheep model of early onset FGR, we observed significant downregulation in mRNA expression of fatty acid receptors CD36 and FABP in the fetal heart. FGR fetuses also had significantly lower cardiac mitochondrial abundance than controls. There was a reduction in abundance of complexes II and IV within the electron transport chain of the FGR fetal heart, suggesting altered ATP production. This indicates reduced fatty acid metabolism and mitochondrial function in the heart of the FGR fetus, which may have detrimental long-term implications and contribute to increased risk of cardiovascular disease later in life.

EP14.01: The effect of fetal growth restriction on maternal pre‐eclampsia in discordant dichorionic twin

EP14.01: The effect of fetal growth restriction on maternal pre‐eclampsia in discordant dichorionic twin

Effects of Intrauterine Growth Restriction (IUGR) on Growth and Body Composition Compared to Constitutionally Small Infants.

(1) Intrauterine growth restriction (IUGR) is associated with multiple morbidities including growth restriction and impaired neurodevelopment. Small for gestational age (SGA) is defined as a birth weight <10th percentile, regardless of the etiology. The term is commonly used as a proxy for IUGR, but it may represent a healthy constitutionally small infant. Differentiating between IUGR and constitutionally small infants is essential for the nutritional management. (2) Infants born at <37 weeks of gestation between 2017 and 2022, who underwent body composition measurement (FFM: fat-free mass; FM: fat mass) at term-equivalent age, were included in this study. Infants with IUGR and constitutionally small infants (SGA) were compared to infants appropriate for gestational age (AGA). (3) A total of 300 infants (AGA: n = 249; IUGR: n = 40; SGA: n = 11) were analyzed. FFM (p < 0.001) and weight growth velocity (p = 0.022) were significantly lower in IUGR compared to AGA infants, but equal in SGA and AGA infants. FM was not significantly different between all groups. (4) The FFM Z-score was significantly lower in IUGR compared to AGA infants (p = 0.017). Being born constitutionally small compared to AGA had no impact on growth and body composition. These data showed that early aggressive nutritional management is essential in IUGR infants to avoid impaired growth and loss of FFM.

Buprenorphine and methadone differentially alter early brain development in human cortical organoids

Buprenorphine (BUP) and methadone (MTD) are used for medication-assisted treatment (MAT) in opioid use disorder. Although both medications show improved maternal and neonatal outcomes compared with illicit opioid use during pregnancy, BUP has exhibited more favorable outcomes to newborns than MTD. The underlying cellular and molecular mechanisms for the difference between BUP and MTD are largely unknown. Here, we examined the growth and neuronal activity in human cortical organoids (hCOs) exposed to BUP or MTD. We found that the growth of hCOs was significantly restricted in the MTD-treated but not in the BUP-treated hCOs and BUP attenuated the growth-restriction effect of MTD in hCOs. Furthermore, a κ-receptor agonist restricted while an antagonist alleviated the growth-restriction effect of MTD in hCOs. Since BUP is not only a μ-agonist but a κ-antagonist, the prevention of this growth-restriction by BUP is likely due to its κ-receptor-antagonism. In addition, using multielectrode array (MEA) technique, we discovered that both BUP and MTD inhibited neuronal activity in hCOs but BUP showed suppressive effects only at higher concentrations. Furthermore, κ-receptor antagonist nBNI did not prevent the MTD-induced suppression of neuronal activity in hCOs but the NMDA-antagonism of MTD (that BUP lacks) plays a role in the inhibition of neuronal activity. We conclude that, although both MTD and BUP are μ-opioid agonists, a) the additional κ-receptor antagonism of BUP mitigates the MTD-induced growth restriction during neurodevelopment and b) the lack of NMDA antagonism of BUP (in contrast to MTD) induces much less suppressive effect on neural network communications.

Fetal insular measurements in pregnancy with estimated fetal weight

A growing body of evidence suggests that fetal growth restriction is associated with changes in brain structures as a result of chronic hypoxia. However, less is known about the effects of growth restriction on the fetal insula, particularly in less severely affected late-onset growth-restricted fetuses. This study aimed to (1) compare sonographic insular measurements between fetal-growth restricted, small-for-gestational-age, and appropriate-for-gestational-age control fetuses; and (2) evaluate the association of sonographic insular measurements with perinatal and neurodevelopmental outcomes in fetuses categorized as fetal-growth restricted or small-for-gestational-age. This was a cohort study of singleton nonanomalous pregnancies with an estimated fetal weight <10th centile. Using data from the last examination before delivery, fetal insular depth, Sylvian fissure depth, hypoechoic insular zone thickness, circumference, and area were measured. All measurements were adjusted for by head circumference. Neurodevelopmental outcomes were evaluated at 2 to 3 years of age using the Bayley-III scales. Kruskal-Wallis H tests were performed to compare insular measurements between groups. Paired t tests were used to compare insular measurements between appropriate-for-gestational-age fetuses and gestational age-matched growth-restricted fetuses. Insular measurements for patients with and without an adverse perinatal outcome were compared using independent-samples t-tests. Spearman correlations were performed to evaluate the relationship of insular measurements to the percentile scores for each of the 5 Bayley-III subscales and to a summative percentile of these subscales. A total of 89 pregnancies were included in the study; 68 of these pregnancies had an estimated fetal weight <10th percentile (fetal-growth restricted: n=39; small-for-gestational-age: n=29). The appropriate-for-gestational-age cohort consisted of 21 pregnancies. The gestational age at measurement was similar between fetal-growth restricted and small-for-gestational-age groups, but lower in the appropriate-for-gestational-age group. Differences between groups were noted in normalized insular depth, Sylvian fissure depth, and hypoechoic insular zone (P<.01). Normalized insular depth and hypoechoic insular zone circumference were larger in the growth-restricted cohort (P<.01). Normalized Sylvian fissure depth was smaller in the growth-restricted cohort (P<.01). There were no significant differences in insular measurements between pregnancies with and without an adverse perinatal outcome. Bayley-III results were available in 32 of the growth-restricted cases. Of all insular measurements, hypoechoic insular zone circumference was inversely correlated with the adaptive behavior Bayley-III score. In our cohort, fetuses with estimated fetal weight <10th percentile had smaller Sylvian fissure depths and larger insular depths and hypoechoic insular zone circumferences than normally grown controls. A larger hypoechoic insular zone circumference was substantially correlated with worse neurodevelopmental outcomes in early childhood. We speculate that enlargement of this region may be an indication of accelerated neuronal maturation in growth-restricted fetuses with mild hypoxia.

Effects of Fetal Growth Restriction on Postnatal Gut Microbiota in a Rat Model.

Fetal growth restriction (FGR) indicates increased risks of lifestyle-related diseases in adulthood. Previous studies showed the association between human gut dysbiosis and various diseases. However, reports examining the relationship between FGR and gut microbiota are scarce. Herein, we hypothesized that FGR may cause gut dysbiosis and analyzed the gut microbiota in a FGR rat model by restricting maternal protein intake during pregnancy. The FGR group was developed by feeding pregnant Sprague Dawley rats a diet containing 7% protein until birth. Control rats were fed 21% protein. Fecal samples of 2-11-week-old pups were collected weekly. DNA was extracted from each sample and subjected to polymerase chain reaction (PCR) amplification and sequencing. Additionally, short-chain fatty acids in the cecum were analyzed at 2 weeks of age, when there were differences in the occupancy of the gut microbiota. Comparative analysis of the gut microbiota showed differences only at 2 weeks of age. Verrucomicrobia was significantly more abundant in the control group ( q < 0.1), whereas pathogenic bacteria, including Enterococcus and Enterobacteriaceae , tended to increase in the FGR group. The abundance of acetic and butyric acid-producing bacteria also differed between groups. Acetic acid in the cecum was considerably decreased in the FGR group, while butyric acid was increased compared to that in the control group. Normalizing the alteration of FGR on postnatal gut microbiota may have beneficial effects for the host, since the FGR group caused gut dysbiosis.

Impact of perinatal factors on biomarkers of cardiovascular disease risk in preadolescent children.

This review aims to summarize associations of the perinatal environment with arterial biophysical properties in childhood, to elucidate possible perinatal origins of adult cardiovascular disease (CVD). A systematic search of PubMed database was performed (December 2020). Studies exploring associations of perinatal factors with arterial biophysical properties in children 12 years old or less were included. Properties studied included: pulse wave velocity; arterial stiffness or distensibility; augmentation index; intima-media thickness of aorta (aIMT) or carotids; endothelial function (laser flow Doppler, flow-mediated dilatation). Two reviewers independently performed study selection and data extraction. Fifty-two of 1084 identified records were included. Eleven studies explored associations with prematurity, 14 explored maternal factors during pregnancy, and 27 explored effects of low birth weight, small-for-gestational age and foetal growth restriction (LBW/SGA/FGR). aIMT was consistently higher in offspring affected by LBW/SGA/FGR in all six studies examining this variable. The cause of inconclusive or conflicting associations found with other arterial biophysical properties and perinatal factors may be multifactorial: in particular, measurements and analyses of related properties differed in technique, equipment, anatomical location, and covariates used. aIMT was consistently higher in LBW/SGA/FGR offspring, which may relate to increased long-term CVD risk. Larger and longer term cohort studies may help to elucidate clinical significance, particularly in relation to established CVD risk factors. Experimental studies may help to understand whether lifestyle or medical interventions can reverse perinatal changes aIMT. The field could be advanced by validation and standardization of techniques assessing arterial structure and function in children.

Lactoferrin/sialic acid prevents adverse effects of intrauterine growth restriction on neurite length: investigations in an in vitro rabbit neurosphere model.

Intrauterine growth restriction (IUGR) is a well-known cause of impaired neurodevelopment during life. In this study, we aimed to characterize alterations in neuronal development underlying IUGR and discover strategies to ameliorate adverse neurodevelopment effects by using a recently established rabbit in vitro neurosphere culture. IUGR was surgically induced in pregnant rabbits by ligation of placental vessels in one uterine horn, while the contralateral horn remained unaffected for normal growth (control). At this time point, rabbits were randomly assigned to receive either no treatment, docosahexaenoic acid (DHA), melatonin (MEL), or lactoferrin (LF) until c-section. Neurospheres consisting of neural progenitor cells were obtained from control and IUGR pup's whole brain and comparatively analyzed for the ability to differentiate into neurons, extend neurite length, and form dendritic branching or pre-synapses. We established for the very first time a protocol to cultivate control and IUGR rabbit neurospheres not only for 5 days but under long-term conditions up to 14 days under differentiation conditions. Additionally, an in vitro evaluation of these therapies was evaluated by exposing neurospheres from non-treated rabbits to DHA, MEL, and SA (sialic acid, which is the major lactoferrin compound) and by assessing the ability to differentiate neurons, extend neurite length, and form dendritic branching or pre-synapses. We revealed that IUGR significantly increased the neurite length after 5 days of cultivation in vitro, a result in good agreement with previous in vivo findings in IUGR rabbits presenting more complex dendritic arborization of neurons in the frontal cortex. MEL, DHA, and SA decreased the IUGR-induced length of primary dendrites in vitro, however, only SA was able to reduce the total neurite length to control level in IUGR neurospheres. After prenatal in vivo administration of SAs parent compound LF with subsequent evaluation in vitro, LF was able to prevent abnormal neurite extension. We established for the first time the maintenance of the rabbit neurosphere culture for 14 days under differentiation conditions with increasing complexity of neuronal length and branching up to pre-synaptic formation. From the therapies tested, LF or its major compound, SA, prevents abnormal neurite extension and was therefore identified as the most promising therapy against IUGR-induced changes in neuronal development.

Effects of intrauterine growth restriction on embryonic hippocampal dentate gyrus neurogenesis and postnatal critical period of synaptic plasticity that govern learning and memory function.

Intrauterine growth restriction (IUGR) complicates up to 10% of human pregnancies and is the second leading cause of perinatal morbidity and mortality after prematurity. The most common etiology of IUGR in developed countries is uteroplacental insufficiency (UPI). For survivors of IUGR pregnancies, long-term studies consistently show a fivefold increased risk for impaired cognition including learning and memory deficits. Among these, only a few human studies have highlighted sex differences with males and females having differing susceptibilities to different impairments. Moreover, it is well established from brain magnetic resonance imaging that IUGR affects both white and gray matter. The hippocampus, composed of the dentate gyrus (DG) and cornu ammonis (CA) subregions, is an important gray matter structure critical to learning and memory, and is particularly vulnerable to the chronic hypoxic-ischemic effects of UPI. Decreased hippocampal volume is a strong predictor for learning and memory deficits. Decreased neuron number and attenuated dendritic and axonal morphologies in both the DG and CA are additionally seen in animal models. What is largely unexplored is the prenatal changes that predispose an IUGR offspring to postnatal learning and memory deficits. This lack of knowledge will continue to hinder the design of future therapy to improve learning and memory. In this review, we will first present the clinical susceptibilities and human epidemiology data regarding the neurological sequelae after IUGR. We will follow with data generated using our laboratory's mouse model of IUGR, that mimics the human IUGR phenotype, to dissect at the cellular and molecular alterations in embryonic hippocampal DG neurogenesis. We will lastly present a newer topic of postnatal neuron development, namely the critical period of synaptic plasticity that is crucial in achieving an excitatory/inhibitory balance in the developing brain. To our knowledge, these findings are the first to describe the prenatal changes that lead to an alteration in postnatal hippocampal excitatory/inhibitory imbalance, a mechanism that is now recognized to be a cause of neurocognitive/neuropsychiatric disorders in at-risk individuals. Studies are ongoing in our laboratory to elucidate additional mechanisms that underlie IUGR-induced learning and memory impairment and to design therapy aimed at ameliorating such impairment.

Influence of trace silicon addition on microstructure and properties of Ti6Al4V fabricated by wire arc additive manufacturing

To provide a pathway to improve the tensile properties of wire arc additive manufactured Ti6Al4V, the microstructures and properties of Ti6Al4V-0.1Si produced by the wire arc additive manufacturing were investigated in this study. It was demonstrated that the tensile strength of Ti6Al4V-0.1Si improved more than 100 MPa compared with traditional WAAM Ti6Al4V. The microstructures of WAAM Ti6Al4V and Ti6Al4V-0.1Si mainly consists of basket-weave structures but the width of the α-phase lamellae of Ti6Al4V-0.1Si is significantly lower.The added Si is solid-soluble on the α phase matrix of Ti6Al4V, which reduces the β phase transition temperature. Si as well produces the high growth restriction effect, then the α phase size is refined. The fine grain and solid solution strengthening are the main reasons for the increase in the strength of titanium alloy after adding trace Si.

Cardiac morphology in neonates with fetal growth restriction.

Assess effects of fetal growth restriction (FGR) on cardiac modelling in premature and term neonates. Prospective echocardiographic study of a cohort of FGR neonates (n = 21) and controls (n = 41) with normal prenatal growth and circulation. Unadjusted for gestational age, birth weight, sex, and twin/singleton, Late-FGR neonates had smaller hearts than controls, with globular left ventricles and symmetrical right ventricles. Adjusted estimates showed smaller left ventricles and similarly sized right ventricles, with symmetrical left and right ventricles. Early-FGR (compared with Late-FGR) had smaller hearts and globular left ventricles in unadjusted estimates, but after adjustment, sizes and shapes were similar. FGR had significant impact on cardiac modelling, seen in both statistical models unadjusted and adjusted for gestational age, birth weight, sex, and twin/singleton. The adjustments, however, refined the results and revealed more specific effects of FGR, thus underscoring the importance of statistical adjustments in such studies.

Transamniotic stem cell therapy (TRASCET) for intrauterine growth restriction (IUGR): A comparison between placental and amniotic fluid donor mesenchymal stem cells

PurposeTransamniotic stem cell therapy (TRASCET) with donor mesenchymal stem cells (MSCs) has been shown experimentally to reverse central effects of intrauterine growth restriction (IUGR). We sought to compare amniotic-fluid and placenta-derived MSCs (afMSCs and pMSCs, respectively) as TRASCET donor cells in a murine IUGR model. MethodsPregnant Sprague-Dawley dams (n=8) were exposed to alternating 12-hour hypoxia (10.5% O2) cycles, starting on gestational day 15 (E15; term=E21-22). On E17, fetuses (n=100) were divided into four groups. An untreated group had no further manipulations (n=24). Three groups received volume-matched intra-amniotic injections of either saline (sham; n=27), or suspensions of afMSCs (n=24), or pMSCs (n=25). Normal fetuses served as controls (n=21). All infused MSCs consisted of syngeneic Lewis rat cells phenotyped by flow cytometry and GFP-labeled. At term, fetal and placental morphometrics were calculated, and placental TNF-α levels were determined by ELISA. Statistical comparisons were by Fischer's T-test or Wilcoxon rank sum test (p≤0.05). ResultsOverall survival of the hypoxic groups was 83% (83/100). Compared to normal, maternal-adjusted fetal weights were significantly decreased in all hypoxia groups (pairwise p<0.001), however only the afMSC group showed higher adjusted-fetal weights than sham (p<0.001). Placental efficiency was decreased in untreated, sham, and pMSC groups (p<0.001-0.056) but normalized in the afMSC group (p=0.205). Maternal-adjusted placental weights were lower than normal in all hypoxia groups (p<0.001-0.045), except for the pMSC group (p=0.387). ConclusionsAmniotic fluid-derived mesenchymal stem cells are superior to their placenta-derived counterparts in transamniotic stem cell therapy for intrauterine growth restriction in a rat model. Level of EvidenceBasic/Translational science.