Fetal Life Research Articles

Developmental programming: Preconceptional and gestational exposure of sheep to biosolids on offspring ovarian dynamics.

Developmental exposure to environmental chemicals (ECs) perturbs establishment and maintenance of the ovarian reserve across the reproductive lifetime, leading to premature follicle depletion and ovarian aging. Considering humans are exposed to a complex mixture of ECs, real-life models assessing their cumulative impact on the ovarian reserve are needed. Biosolids is a source of real-life mixture of ECs. While earlier studies demonstrated that grazing pregnant sheep on biosolids-treated pastures (BTP) did not influence establishment of the ovarian reserve in fetal life, its impact on subsequent depletion of ovarian reserve during reproductive life of offspring is unknown. We hypothesized that developmental exposure to biosolids accelerates depletion of ovarian reserve. Ovaries were collected from F1 juveniles (9.5weeks) and adults (2.5years) born to F0 ewes grazed on control inorganic fertilizer pastures or BTP from before conception and throughout gestation. The impact on follicular density, activation rate, and Anti-Müllerian hormone (AMH; mediator of activation) expression by immunohistochemistry was determined. Activation rate was increased in F1 BTP juveniles with a corresponding reduction in primordial follicle density. In contrast, activation rate and ovarian reserve were similar between control and F1 BTP adults. The density of AMH-positive antral follicles was lower in BTP juveniles, whereas AMH expression tended to be higher in antral follicles of BTP adults, consistent with the changes in the ovarian reserve. These findings of detrimental effects of developmental exposure to biosolids during juvenile life that normalizes in adults is supportive of a shift in activation rate likely related to peripubertal hormonal changes.

New Insights on the Formation of the Mitral Valve Chordae Tendineae in Fetal Life.

There is an increasing understanding that some mitral valve pathologies have developmental origins. The time course of valvulogenesis varies by animal model; in cattle, the branched chordae tendineae architecture becomes fully developed at full term. The mechanism by which chordae tendineae bifurcate during fetal development remains unknown. The current study presents a detailed description of bovine chordae tendineae formation and bifurcation during fetal development. Analysis of Movat Pentachrome-stained histological sections of the developing mitral valve apparatus was accompanied by micro-CT imaging. TEM imaging of chordae branches and common trunks allowed the measurement of collagen fibril diameter distributions. We observed a proteoglycan-rich "transition zone" at the junction between the fetal mitral valve anterior leaflet and chordae tendineae with "perforations" lined by MMP1/2 and Ki-67 expressing endothelial cells. This region also contained clusters of proliferating endothelial cells within the bulk of the tissue. We hypothesize this zone marks a region where chordae tendineae bifurcate during fetal development. In particular, perforations created by localized MMP activity serve as a site for the initiation of a "split" of a single chordae attachment into two. This is supported by TEM results that suggest a similar population of collagen fibrils runs from the branches into a common trunk. A clear understanding of normal mitral valvulogenesis and its signaling mechanisms will be crucial in developing therapeutics and/or tissue-engineered valve replacements.

Abstract 4120290: Sex-specific Impact of Early to Mid-gestational Testosterone Excess on Sheep Fetal and Adult Offspring Lungs

Using the translationally relevant sheep model of prenatal testosterone (T) excess, we previously reported intrauterine growth retardation (IUGR) in both sexes, adverse sex specific programming of fetal heart and cardiometabolic dysfunction in adult female offspring. Because of the intricate reciprocal relationship between the heart and lungs, we hypothesized that gestational T excess will have detrimental sex-specific effects on offspring lungs beginning as early as fetal life and extending into adulthood. Pregnant ewes were intramuscularly injected with 100 mg of testosterone propionate twice weekly from gestational days (GD) 30-90 (term 147 days) and offspring lungs were harvested at GD120, 30 days after cessation of T treatment; (n=4-7/group) and in adulthood (n=4-6/group) and processed for molecular and histological analyses. Data was analyzed by student T test within each sex and Cohen (d) effect size was calculated (Cohens d>0.8 represents large effect size. Lung collagen was significantly increased in T-male fetuses (TM) vs control males (CM) (p=0.01, d=1.99) that persisted into adulthood (TM vs CM: p=0.01, d=1.83). The effects of gestational T excess was evidenced as an increase in collagen only in the lungs of adult T-female fetuses (TF) relative to control females (CF) (p=0.003, d=2.38), but not during fetal life. Gestational T excess induced significant parallel increases in TUNEL positive nuclei/frame in TM fetuses relative to CM (n=3/group, p=0.01, d=3.35) persisting as a large magnitude increase of TUNEL positive nuclei/frame in adult TM (p=0.12, d=0.96). In TF females, apoptotic changes were not noted in fetal lungs but an increase of TUNEL positive nuclei/frame was evidenced in adult TF (p=0.08, d=1.14). At the molecular level prenatal T excess induced an increase in histone deacetylase 1 (HDAC1) expression in fetal TM vs CM (p=0.04, d=1.50), and decrease in HDAC1 in TF vs CF (p=0.10, d=1.09) suggestive of T-induced epigenetic alteration. Transcriptomic analysis of fetal lungs revealed upregulation of pathways associated with estrogen signaling and neuroactive ligand receptor interaction, and downregulation of pathways associated with protein processing in endoplasmic reticulum and antigen processing&presentation (unadjusted p< 0.05, log FC>1.5) in both sexes. Overall, early to mid-gestational exposure to testosterone adversely reprograms the lungs in sex specific fashion as early as fetal life extending into postnatal adult life.

A case report of patent ductus arteriosus in a Brazilian longhair female kitten

Among the congenital cardiac alterations observed in small pets, the persistence of the right aortic arch has been described as a rare anomaly in cats. The ductus arteriosus corresponds to a normal fetal vascular structure derived from the distal portion of the sixth left aortic arch that connects the pulmonary artery to the dorsal aorta. During fetal life, this structure has the function of transporting oxygenated blood from the maternal placenta to the aorta, bypassing the collapsed lungs of the fetus. At birth, the increase of O2 partial pressure dissolved in arterial blood (PaO2) and the decline in prostaglandin concentration cause the closure of the ductus arteriosus in the first hours of life, giving rise to the ligamentum arteriosus. If this process does not occur, the ductus arteriosus will remain patent. In this case report, a 4-month-old longhair female kitten was treated, and, during auscultation, a heart murmur was found. After performing a Doppler echocardiogram and color flow mapping, the presence of continuous turbulent flow in the pulmonary artery was demonstrated, characteristic of patent ductus arteriosus persistence. The animal was sent for surgery, and in the post-surgical Doppler echocardiogram, correction of patent ductus arteriosus was verified, demonstrating the absence of continuous turbulent flow in the pulmonary artery.

Lower limb interosseous membrane in foetuses.

The leg interosseous membrane (LIM) stabilises the tibia and the fibula. These two bones articulate at the proximal and distal tibiofibular joints. In addition, the LIM is the place of attachment of tibialis anterior muscle, extensor digitorum longus muscle, fibularis tertius muscle (anatomical variant), tibialis posterior muscle and flexor hallucis longus muscle. The specific structure of the collagen fibre network of the LIM provides durability comprising collagenous fibres that are predominately projected longitudinally, obliquely, and often transversely. 222 human foetuses (Male: 120, Female: 102) between 117 and 197 (median 177) days of foetal life were available for the study. The material derived from the foetal collection is stored in the Department of Human Morphology and Embryology, Division of Anatomy of the Medical University of Wroclaw. In this study, we assessed the variability of the foetal LIM using a novel dyeing technique to identify the LIM syndesmotic structure. Overall, the study of the three types of interosseous fibres (transverse, oblique, longitudinal) of the right/left leg revealed that the fibres run in all three directions with frequencies approximating 60-70%. However, there were differences in the frequency of fibre directions and in the size of LIM between sexes. After consideration of the directions and size of fibres of LIM, parts of it can be used for reconstruction of the upper limb interosseous membrane. Sexually dimorphic features of the LIM in the studied material confirm the different dynamics of lower limb growth in each sex.

Adalékok az abortusz büntetőjogi megítélésének történetéhez

Aim: To examine how the social and, at the same time, legal perception of induced abortion has changed since the Middle Ages. Examining the criminal law norms seems to be a good indicator of this because these norms are meant to play the role of a capstone for the protection of social values. Methodology: Processing and analysis of legal norms and literature data from a historical perspective. A value-oriented analysis of the mentioned sources accompanies this. Findings: The normative system of the middle ages was permeated by the Christian religion and the morality based on it. Thus, at this age, there was no doubt that taking away the life of the fetus was a sin and a crime as well. This rule prevailed in later times until 1945. The abortion ban that remained after the communist takeover was based on entirely different moral foundations. It was based on the fact that workers are needed for social development, and taking away fetal life deprives socialist society of this resource. State socialism later relaxed the rules. This change was followed by the criminal law with a significant lag until finally, in 1962, only illegal abortion was punishable. The changes after the regime change consolidated the legislative attitude according to which the fetus is not a human being. The criminal law norms are also in line with this. Value: Historical outline of the protection of fetal life, with particular regard to its protection under criminal law. Changes in European culture led to the development of different images of people. An imprint of these is the protection of fetal life.

Associations of fetal and infant growth patterns with behavior and cognitive outcomes in early adolescence

AbstractBackgroundFetal life and infancy might be critical periods for brain development leading to increased risks of neurocognitive disorders and psychopathology later in life. We examined the associations of fetal and infant weight growth patterns and birth characteristics with behavior and cognitive outcomes at the age of 13 years.MethodsPopulation‐based prospective cohort study from fetal life until adolescence. Pregnant women with a delivery date between April 2002 and January 2006 were eligible. Follow‐up measurements were available for 4716 children. Fetal weight was estimated in the second and third trimesters of pregnancy by ultrasonography. Infant weight was measured at birth and at 6, 12, and 24 months. Fetal and infant weight acceleration or deceleration were defined as a change in SD greater than 0.67 between time points. Total, internalizing and externalizing problems and attention‐deficit hyperactivity disorder (ADHD) symptoms were measured using Child Behavior Checklist (CBCL/6–18), autistic traits by the Social Responsiveness Scale (SRS) and intelligence quotient (IQ) by the Wechsler Intelligence Scale for Children‐Fifth Edition (WISC‐V).ResultsOne week longer gestational age at birth was associated with a −0.03 SDS (95% Confidence Interval (CI): −0.04, −0.01) lower total behavior problems score, a −0.02 SDS (95% CI: −0.04, −0.01) lower ADHD symptoms score. Also an increase in birth weight of 500 g was associated with a lower odds of having high externalizing problems (OR 0.92 (95% CI: 0.86, 0.98) and of having a low IQ score (OR 0.79 (95% CI: 0.71, 0.88). Compared to children with normal fetal and infant growth, those with accelerated fetal and infant growth had a 0.27 SDS higher IQ (95% Confidence Interval 0.11, 0.44).ConclusionsBoth fetal and infant weight development are associated with behavioral and cognitive outcomes in early adolescence. Follow‐up studies are needed to assess whether these associations link to later life mental health outcomes.

Epigenetic programming of obesity in early life through modulation of the kynurenine pathway.

Childhood obesity is a global health concern that has its origins before birth. Although genetics plays a crucial role, increasing evidence suggests that epigenetic modifications during fetal life could also influence its incidence. In this model, during the fetal period, interactions between genetic makeup, intrauterine factors, and environmental conditions, increase the risk of childhood obesity. This is in accordance with the Developmental Origins of Health and Disease (DOHaD) hypothesis, in which specific intrauterine environments can have long-lasting effects on the immune system's essential functions during crucial stages of fetal growth, resulting in permanent changes to the immune function of the offspring. Consequently, dysfunction can consequently make the offspring more prone to inflammatory and immune-related disorders later in life. In this review, we examine how maternal inflammation could influence the risk of childhood obesity. We propose that during pregnancy, modification of the expression of critical genes in metabolic and signaling pathways, such as the kynurenine (Kyn) pathway, occurs due to increased levels of maternal inflammation. We also propose that such expression differences are mediated by epigenetic changes. Furthermore, we also hypothesize that the Kyn pathway produces metabolites that have immunoregulatory effects and may play a crucial role in regulating inflammation during pregnancy. As a result, interventions aimed at improving maternal inflammation may be able to help alleviate the risk of childhood obesity.

Vitamin D Supply of Twins during Fetal Life, Its Relation to Anthropometric Parameters of Newborns and the Analysis of Other Factors Related to Birth Size

Background/Objectives: Vitamin D deficiencies are very common in pregnant women, raising concerns about adverse health outcomes in children. This issue has hardly been studied in multiple pregnancies, the prevalence of which has been steadily increasing. Therefore, our study investigated the relationship between newborns’ anthropometric parameters and the concentration of 25(OH)D in maternal blood of women with twin pregnancies and umbilical cord blood. Methods: The study included 50 women who gave birth after the 36th week of twin gestation. The concentration of 25(OH)D was determined in maternal blood collected during the antenatal period and in the umbilical cord blood of 100 newborns. Anthropometric parameters of the newborns (birth weight, length and head and chest circumference) were obtained from hospital records. Data on nutrition and lifestyle during pregnancy were collected from the patients during an interview conducted by a dietitian. Results: No relationship between maternal and neonatal cord blood vitamin D concentrations and any of the anthropometric parameters of the newborns was found. However, only 6% of the mothers and 13% of the newborns had vitamin D deficiency (≤20 ng/mL). The type of pregnancy and maternal height were the main factors associated with neonatal size. Newborns from dichorionic pregnancies were on average 202 g heavier (p < 0.001) and 1 cm longer (p = 0.006) than newborns from monochorionic pregnancies. Newborns of mothers ≤160 cm in height had on average 206 g lower birth weight (p = 0.006) and were 3.5 cm shorter (p = 0.003) compared to newborns of taller mothers. Conclusions: Therefore, in our study, the neonatal size of twins was not related to the vitamin D status but to other factors such as the type of pregnancy and maternal height.

Lung volumes are increased in fetuses with transposition of the great arteries on intrauterine MRI.

Fetal brain size is decreased in some children with complex CHDs, and the distribution of blood and accompanying oxygen and nutrients is regionally skewed from early fetal life dependent on the CHD. In transposition of the great arteries, deoxygenated blood preferentially runs to the brain, whereas the more oxygenated blood is directed towards the lungs and the abdomen. Knowledge of whether this impactsintrauterine organ development is limited. We investigated lung, liver, and total intracranial volume in fetuses with transposition of the great arteries using MRI.Eight fetuses with dextro-transposition and without concomitant disease or chromosomal abnormalities and 42 fetuses without CHD or other known diseases were scanned once or twice at gestational age 30 through 39 weeks. The MRI scans were conducted on a 1.5T system, using a 2D balanced steady-state free precession sequence. Slices acquired covered the entire fetus, slice thickness was 10 mm, pixel size 1.5 × 1.5 mm, and scan duration was 30 sec.The mean lung z score was significantly larger in fetuses with transposition compared with those without a CHD; mean difference is 1.24, 95% CI:(0.59;1.89), p < 0.001. The lung size, corrected for estimated fetal weight, was larger than in the fetuses without transposition; mean difference is 8.1 cm3/kg, 95% CI:(2.5;13.7 cm3/kg), p = 0.004.In summary, fetuses with dextro-transposition of the great arteries had both absolute and relatively larger lung volumes than those without CHD. No differences were seen in liver and total intracranial volume. Despite the small number of cases, the results are interesting and warrant further investigation.

PFAS-mediated disruptions on thyroid histology

Abstract Introduction/Objective Per-and polyfluroalkyl substances (PFAS), are environmental contaminants of emerging concern due to their abundance in the environment and potential adverse health impacts. PFAS are used in waterproof clothing, makeup, carpets, upholstery, cookware, and fast-food containers. These organic pollutants have been found in the blood of 98% of Americans and have been linked to disruption in thyroid hormones. During fetal life, thyroid hormones are crucial for brain development and alterations in these hormones can induce long-term impacts on intellectual and brain impairments. T3 and T4 are known to be altered by PFAS exposure, but the mechanism by which this is done remains unclear. Methods/Case Report Normal thyroid cells were treated for 72 hours with 1000 nM solution containing either GEnX, PFOA, PFOS, or 1% DMSO control. Immunofluorescence for actin, tubulin, and DAPI was performed using a Nikon spinning disk. In vivo studies where 8-week-old mice are gavaged with 7.5 mg/kg of PFOS, PFOA, and GenX or PBS control for 8 weeks. Results (if a Case Study enter NA) We hypothesized the PFAS treatment alters thyroid cells morphology and histology. Immunofluorescence staining of normal thyroid cells treated with PFAS show a decrease in actin stress fibers compared to control cells. PFAS treated mice show a decrease in follicle size compared to control (average 1017 um2 size, p=0.0483). Conclusion This is the first study to show changes in thyroid histology after 8 weeks of PFAS exposure. As structure and function are closely linked, it is likely that this reduction in follicle size and actin reorganization contribute to alterations in thyroid function. Future studies are needed to illuminate the mechanism by which PFAS alter thyroid function in vivo. Understanding the role of PFAS-mediated thyroid dysregulation will have far reaching implications on environmental regulations and considerations for limiting PFAS in our environment.

From Fetus to Eight: the CHILD Cohort Study.

The CHILD Cohort Study is an active multi-center longitudinal, prospective, population pregnancy cohort study following Canadian infants from fetal life until adulthood. We hypothesized that early life physical and psychosocial environments interact with biological factors (e.g. immunologic, genetic, physiologic, and metabolic) influencing burdensome non-communicable disease outcomes, including asthma and allergic disorders, growth and development, cardio-metabolic health, and neurodevelopmental outcomes that manifest during the life-course. Detailed clinical and physiologic phenotyping at strategic intervals was complemented by environmental sampling, actigraphy and global positioning system measures, biological sampling including gut, breastmilk and nasal microbiome, nutritional studies, genetics, and epigenetic profiling. Of 3,454 families recruited from 2008 to 2012, study retention was 96.0% at 1-year, 93.2% at 5-years and 90.7% at 8-years. Data collection during the SARS-2 COVID-19 pandemic was partially completed via virtual visits. A sub-cohort was implemented, capturing detailed information on the prevalence and predictors of SARS-CoV-2 infection and the health and psychosocial impact of the pandemic on Canadian families. The 13-year clinical assessment launched in 2022 will be completed in 2025. Ultimately, the CHILD Cohort Study provides a data science platform designed to enable a deep understanding of early life factors associated with the development of chronic non-communicable diseases and multimorbidity.

Origins of obesity in the womb: Fetal adiposity and its determinants.

Birth weight is an important predictor of perinatal complications and long-term health outcomes of offspring. Fetal programming influenced by maternal obesity, overnutrition, and hyperglycemia has been proposed as the fuel overload hypothesis. Recent investigations related with fetal body composition have revealed that neonatal adiposity can be predicted by fetal fat mass, and that maternal insulin resistance and serum leptin level are indicators of fetal adiposity. Based on the current evidence, the origins of obesity can partly be traced back into the fetal life. Further clarification of the determinants of fetal fat mass may lead to the clinical interventions and treatment strategies for fetal growth and development. This effort potentially leads to the elucidation of pathological conditions related with long-term health outcomes and the primary prevention of childhood obesity and early onset metabolic syndrome.

7395 Developmental Programming: Adverse Effects Of Prenatal Exposure To A Real-Life Environmental Chemical Mixture Via Biosolids On Ovarian Folliculogenesis In Adult Sheep

Abstract Disclosure: Y. Zhou: None. K.M. Halloran: None. M. Bellingham: None. N.P. Evans: None. R.G. Lea: None. K.D. Sinclair: None. V. Padmanabhan: None. The ovarian capacity to provide fertilizable oocytes, regulate folliculogenesis as well as activate and progress primordial follicles into preovulatory follicles are key contributing factors to female fertility and reproductive aging. In sheep, as in humans, while genetics play a role in establishing the ovarian reserve during fetal development, developmental insults such as inappropriate exposure to native steroids or environmental chemicals (ECs) can adversely impact the establishment of the ovarian reserve and, additionally can affect folliculogenesis. Considering humans are exposed to multiple ECs simultaneously which could have additive, synergistic, or antagonistic effects, real-life EC exposure models are needed to assess risks posed by EC exposure. Offspring from sheep grazed on biosolids-treated pasture offers one such real-life exposure model. Studies with day 140 fetuses found maternal exposure to a real-life EC mixture via biosolids increased the proportion of unhealthy transitory follicles (Lea et al., Sci Rep. 2016;6:22279). The present study tested if biosolids exposure during fetal life would impact folliculogenesis, follicle activation and follicle atresia during their adult life. Ovaries were derived from adult EasyCare ewes (age 31.4 ± 0.5 months) whose mothers were grazed on biosolids-treated (BTP, n=10) or inorganic fertilizer-treated (Control, n=10) pastures from preconception through to birth. Ovarian morphometry was undertaken to assess the distribution and health status of follicles. Follicular atresia was evaluated via the expression of Caspase-3, an apoptosis marker. Data analysis utilized Student's t-test for normally distributed variables and Mann-Whitney U tests for non-parametric comparisons. There were no differences in the absolute counts or the percentages of follicle classes at all stages of folliculogenesis, the density of primordial follicles in cortical tissue, or the follicular activation rate. An increase in the percentage of unhealthy activated follicles (post-primordial) was noted in the BTP group (p = 0.014), predominantly in the transitory stage (p = 0.021). Consistent with this, a higher density of Caspase-3 positive primary follicles was observed in the BTP group (p = 0.033). These findings indicate the adverse impacts of fetal exposure to an EC mixture via maternal biosolid exposure on the survival of early-stage activated follicles in adult sheep. The lack of difference in ovarian reserve between the control and BTP groups suggests compensatory mechanisms may be in place to prevent premature depletion of the ovarian reserve. Whether EC mixture exposure via biosolids also has an adverse effect on the quality of the surviving activated follicles remains to be determined. Funding source: NIH R01 ES030374. Presentation: 6/3/2024

Newborn adiposity is associated with cord blood DNA methylation at IGF1R and KLF7.

This study aimed to identify whether cord blood DNA methylation at specific loci is associated with neonatal adiposity, a key risk factor for childhood obesity. An epigenome-wide association study was conducted using the Hyperglycemia and Adverse Pregnancy Outcome (HAPO) Study as a discovery sample. Linear regression models adjusted for maternal and offspring covariates and cell counts were used to analyze associations between neonatal adiposity as measured by sum of three skinfold thicknesses and cord blood DNA methylation. Assays were performed with Illumina EPIC arrays (791,359 CpG sites after quality control). Replication was performed in an independent cohort, Genetics of Glucose regulation in Gestation and Growth (Gen3G). In 2740 HAPO samples, significant associations were identified at 89 CpG sites after accounting for multiple testing (Bonferroni-adjusted p < 0.05). Replication analyses conducted in 139 Gen3G participants confirmed associations for seven CpG sites. These included IGF1R, which encodes a transmembrane receptor involved in cell growth and survival that binds insulin-like growth factor I and insulin, and KLF7, which encodes a regulator of cell proliferation and inhibitor of adipogenesis; both are key regulators of growth during fetal life. These findings support epigenetic mechanisms in the developmental origins of neonatal adiposity and as potential biomarkers of metabolic disease risk.

Circular RNA hsa_circ_0081343 modulates trophoblast autophagy through Rbm8a nuclear translocation

IntroductionFetal growth restriction (FGR) is a kind of obstetric complication that seriously endangers fetal life. Recent studies reported significant reduction of hsa_circ_0081343 in human placenta developed in FGR and is involved in cell migration, invasion, and apoptosis of trophoblast by acting as microRNA sponges. Autophagy is required for invasion of trophoblast cells and for vascular remodeling during placentation. In this study, we aimed to explore the mechanistic link between hsa_circ_0081343 and autophagy. MethodsWe investigated the interactions between hsa_circ_0081343 and RNA-binding proteins were studied by RNA pull-down assay, mass spectrometry and RNA immunoprecipitation assay. The mechanism of nuclear translocation of Rbm8a were assessed by reverse transcription-quantitative PCR, Western blot, immunofluorescence and Co-Immunoprecipitation. Western blot, immunofluorescence and transmission electron microscopy were performed to elucidate the mechanism underlying hsa_circ_0081343 and/or Rbm8a mediated regulation of autophagy. Resultshsa_circ_0081343 served as an RNA-binding protein (RBP) sponge. RNA binding motif protein 8A (Rbm8a) was directly bound to hsa_circ_0081343 in the cytoplasm, while knockdown of hsa_circ_0081343 facilitated Rbm8a localization in the nucleus. We also identified Rbm8a as a potential import cargo for Importin13 (Ipo13), which transported Rbm8a across the nuclear membrane into the nucleus.Ipo13 recognized Rbm8a via a functional nuclear localization signal (NLS). Furthermore, the mechanistic study revealed that hsa_circ_0081343-mediated nuclear translocation of Rbm8a activated trophoblast autophagy. DiscussionOur results suggest that hsa_circ_0081343 could bind to RBP and the interaction between hsa_circ_0081343 and Rbm8a participate in regulating autophagy. These findings offer novel molecular targets and insights for a potential therapeutic strategy against FGR.

Prevalence of Abnormalities and Normal Variants in the Adolescent Knee on MRI in a Population-Based Cohort of 3800 Knees

Background: Many adolescents experience knee pain, and only some undergo detailed imaging. In this population, the prevalence of abnormalities and normal variants on magnetic resonance imaging (MRI) scans is unknown. Purpose: To investigate the prevalence of abnormalities and normal variants of the knee on MRI scans and their relationship with participant characteristics in the general young adolescent population. Study Design: Cross-sectional study; Level of evidence, 3. Methods: This study was part of an open population-based cohort study that focuses on health, growth, and development from fetal life until adulthood. Between 2017 and 2020, adolescents aged 12 to 15 years underwent MRI of both knees. These MRI scans were assessed in a standardized way for abnormalities and normal variants to determine their prevalence. Logistic regression was used to analyze the presence of abnormalities and normal variants in relation to sex, height, weight, body mass index–standard deviation (BMI-SD), and ethnicity. Results: A total of 1910 participants (median age, 13.5 years; interquartile range, 13.4-13.7 years; 52% girls) were included in this study. Of them, 370 (19.4%) participants had at least 1 abnormality or normal variant. Bone marrow edema around the knee was the most prevalent finding, affecting 140 (7.3%) participants. In 107 (5.6%) participants, nonossifying fibromas were found. A total of 43 (2.3%) participants had characteristics of Osgood-Schlatter disease, 16 (0.8%) showed characteristics of Sinding-Larsen-Johansson syndrome, and osteochondritis dissecans was found in 13 (0.7%) participants. Variants such as discoid menisci were found in 40 (2.1%) participants and a bipartite patella in 21 (1.1%) participants. There were multiple associations between abnormalities or variants and participant characteristics, including bone marrow edema being more often present in boys (odds ratio [OR], 2.44; 95% CI, 1.69-3.52) and those with a lower BMI-SD (OR, 0.85; 95% CI, 0.73-0.98). Osgood-Schlatter and osteochondritis dissecans were more often present in boys (OR, 4.21 [95% CI, 2.01-8.85] and OR, 13.18 [95% CI, 1.71-101.58], respectively). Discoid menisci were associated with a non-Western ethnicity (OR, 2.06; 95% CI, 1.07-3.96) and higher BMI-SD (OR, 2.34; 95% CI, 1.76-3.11). Conclusion: Abnormalities and normal variants on MRI scans of the knees are common in adolescents. Physicians who are involved in the treatment of adolescents with knee pain need to be aware of this prevalence so that these children will not be overtreated or misdiagnosed.

Proteomics reveals dynamic metabolic changes in human hematopoietic stem progenitor cells from fetal to adulthood

BackgroundHematopoietic stem progenitor cells (HSPCs) undergo phenotypical and functional changes during their emergence and development. Although the molecular programs governing the development of human hematopoietic stem cells (HSCs) have been investigated broadly, the relationships between dynamic metabolic alterations and their functions remain poorly characterized.MethodsIn this study, we comprehensively described the proteomics of HSPCs in the human fetal liver (FL), umbilical cord blood (UCB), and adult bone marrow (aBM). The metabolic state of human HSPCs was assessed via a Seahorse assay, RT‒PCR, and flow cytometry-based metabolic-related analysis. To investigate whether perturbing glutathione metabolism affects reactive oxygen species (ROS) production, the metabolic state, and the expansion of human HSPCs, HSPCs were treated with buthionine sulfoximine (BSO), an inhibitor of glutathione synthetase, and N-acetyl-L-cysteine (NAC).ResultsWe investigated the metabolomic landscape of human HSPCs from the fetal, perinatal, and adult developmental stages by in-depth quantitative proteomics and predicted a metabolic switch from the oxidative state to the glycolytic state during human HSPC development. Seahorse assays, mitochondrial activity, ROS level, glucose uptake, and protein synthesis rate analysis supported our findings. In addition, immune-related pathways and antigen presentation were upregulated in UCB or aBM HSPCs, indicating their functional maturation upon development. Glutathione-related metabolic perturbations resulted in distinct responses in human HSPCs and progenitors. Furthermore, the molecular and immunophenotypic differences between human HSPCs at different developmental stages were revealed at the protein level for the first time.ConclusionThe metabolic landscape of human HSPCs at three developmental stages (FL, UCB, and aBM), combined with proteomics and functional validations, substantially extends our understanding of HSC metabolic regulation. These findings provide valuable resources for understanding human HSC function and development during fetal and adult life.

Diagnosis of Congenital Heart Disease in Adulthood: How Often, How Relevant?

Congenital heart disease (CHD) is typically detected during fetal life, infancy, or early childhood. However, there is no published data regarding the proportion of congenital heart defects that are diagnosed in adulthood or the impact of these defects. Retrospective analyses of all consecutive patients (n = 1,010) referred to an adult CHD unit between 2018 and 2023. We analyzed the proportion of cases diagnosed in adulthood, defining the type of defect, reasons for diagnosis, complications, and need for intervention. In total, 26.5% of patients were diagnosed in adulthood (mean age 47 ± 16 years). Overall, 75% were in New York Heart Association class I/IV. Most were mild complexity lesions (57.5%). The most common diagnoses were pre-tricuspid shunts, including ostium secundum atrial septal defect (ASD, 23.9%), partial anomalous pulmonary vein drainage (18.3%), and other types of ASD (5.9%). Bicuspid aortic valve (16.8%) and aortic coarctation (8.2%) were common. Other diagnoses included Ebstein's anomaly (5.6%), ventricular septal defect (4.5%), patent ductus arteriosus (2.6%), or congenitally corrected transposition of the great arteries (2.6%). The main reason for diagnostic work-up was cardiac symptoms (28.4%) such as dyspnea (19%) and palpitations (7.1%), followed by incidental findings on imaging (25.4%). A total of 47.4% had some complications, the most common being pulmonary hypertension (24.3%). Surgical repair was required in 27.2% and 25.4% underwent percutaneous intervention. About one-fourth of patients with CHD were diagnosed in adulthood, and up to 42.5% had moderate or severe complexity lesions. A significant proportion had developed complications at the time of diagnosis and half of them required intervention.

Role of stress and early-life stress in the pathogeny of inflammatory bowel disease.

Numerous preclinical and clinical studies have shown that stress is one of the main environmental factor playing a significant role in the pathogeny and life-course of bowel diseases. However, stressful events that occur early in life, even during the fetal life, leave different traces within the central nervous system, in area involved in stress response and autonomic network but also in emotion, cognition and memory regulation. Early-life stress can disrupt the prefrontal-amygdala circuit thus favoring an imbalance of the autonomic nervous system and the hypothalamic-pituitary adrenal axis, resulting in anxiety-like behaviors. The down regulation of vagus nerve and cholinergic anti-inflammatory pathway favors pro-inflammatory conditions. Recent data suggest that emotional abuse at early life are aggravating risk factors in inflammatory bowel disease. This review aims to unravel the mechanisms that explain the consequences of early life events and stress in the pathophysiology of inflammatory bowel disease and their mental co-morbidities. A review of therapeutic potential will also be covered.