Neonatal Stage Research Articles

Eicosanoid Biosynthesis in Male Reproductive Development: Effects of Perinatal Exposure to NSAIDs and Analgesic Drugs.

Increasing rates of infertility associated with declining sperm counts and quality, as well as increasing rates of testicular cancer are contemporary issues in the United States and abroad. These conditions are part of the Testicular Dysgenesis Syndrome, which includes a variety of male reproductive disorders hypothesized to share a common origin based on disrupted testicular development during fetal and neonatal stages of life. Male reproductive development is a highly regulated and complex process that relies on an intricate coordination between germ, Leydig, and Sertoli cells as well as other supporting cell types, to ensure proper spermatogenesis, testicular immune privilege, and endocrine function. The eicosanoid system has been reported to be involved in the regulation of fetal and neonatal germ cell development as well as overall testicular homeostasis. Moreover, non-steroidal anti-inflammatory drugs (NSAIDs) and analgesics with abilities to block eicosanoid synthesis by targeting either or both isoforms of cyclooxygenase enzymes, have been found to adversely affect male reproductive development. This review will explore the current body of knowledge on the involvement of the eicosanoid system in male reproductive development, as well as discuss adverse effects of NSAIDs and analgesic drugs administered perinatally, focusing on toxicities reported in the testis and on major testicular cell types. Rodent and epidemiological studies will be corroborated by findings in invertebrate models for a comprehensive report of the state of the field, and to add to our understanding of the potential long-term effects of NSAID and analgesic drug administration in infants.

Proteomic, mechanical, and biochemical characterization of cartilage development

The objective of this work is to examine the development of porcine cartilage by analyzing its mechanical properties, biochemical content, and proteomics at different developmental stages. Cartilage from the knees of fetal, neonatal, juvenile, and mature pigs was analyzed using histology, mechanical testing, biochemical assays, fluorophore-assisted carbohydrate electrophoresis, and bottom-up proteomics. Mature cartilage has 2.2-times the collagen per dry weight of fetal cartilage, and fetal cartilage has 2.1-times and 17.9-times the glycosaminoglycan and DNA per dry weight of mature cartilage, respectively. Tensile and compressive properties peak in the juvenile stage, with a tensile modulus 4.7-times that of neonatal. Proteomics analysis reveals increases in collagen types II and III, while collagen types IX, XI, and XIV, and aggrecan decrease with age. For example, collagen types IX and XI decrease 9.4-times and 5.1-times, respectively from fetal to mature. Mechanical and biochemical measurements have their greatest developmental changes between the neonatal and juvenile stages, where mechanotransduction plays a major role. Bottom-up proteomics serves as a powerful tool for tissue characterization, showing results beyond those of routine biochemical analysis. For example, proteomic analysis shows significant drops in collagen types IX, XI, and XIV throughout development, which shows insight into the permanence of cartilage's matrix. Changes in overall glycosaminoglycan content compared to aggrecan and link protein indicate non-enzymatic degradation of aggrecan structures or hyaluronan in mature cartilage. In addition to tissue characterization, bottom-up proteomics techniques are critical in tissue engineering efforts toward repair or regeneration of cartilage in animal models. Statement of significanceIn this study, the development of porcine articular cartilage is interrogated through biomechanical, biochemical, and proteomic techniques, to determine how mechanics and extracellular matrix composition change from fetal to mature cartilage. For the first time, a bottom-up proteomics approach is used to reveal a wide variety of protein changes through aging; for example, the collagen subtype composition of the cartilage increases in collagen types II and III, and decreases in collagen types IX, XI, and XIV. This analysis shows that bottom-up proteomics is a critical tool in tissue characterization, especially toward developing a deeper understanding of matrix composition and development in tissue engineering studies.

Gnas Loss Causes Chondrocyte Fate Conversion in Cranial Suture Formation

Calvaria development is distinct from limb formation. Craniosynostosis is a skull deformity characterized by premature cranial suture fusion due to the loss of the GNAS gene and, consequently, its encoded protein Gαs. This birth defect requires surgery, with potential lethal consequences. So far, hardly any early-stage nonsurgical interventions for GNAS loss-related craniosynostosis are available. Here, we investigated the role of the Gnas gene in mice in guarding the distinctiveness of intramembranous ossification and how loss of Gnas triggered endochondral-like ossification within the cranial sutures. Single-cell RNA sequencing (scRNA-seq) of normal neonatal mice cranial suture chondrocytes showed a Hedgehog (Hh) inactivation pattern, which was associated with Gαs signaling activation. Loss of Gnas evoked chondrocyte-to-osteoblast fate conversion and resulted in cartilage heterotopic ossification (HO) within cranial sutures and fontanels of the mouse model, leading to a skull deformity resembling craniosynostosis in patients with loss of GNAS. Activation of ectopic Hh signaling within cranial chondrocytes stimulated the conversion of cell identity through a hypertrophy-like stage, which shared features of endochondral ossification in vivo. Reduction of Gli transcription activity by crossing with a loss-of-function Gli2 allele or injecting GLI1/2 antagonist hindered the progression of cartilage HO in neonatal stage mice. Our study uncovered the role of Gαs in maintaining cranial chondrocyte identity during neonatal calvaria development in mice and how reduction of Hh signaling could be a nonsurgical intervention to reduce skull deformity in craniosynostosis due to loss of GNAS.

DIX domain containing 1 (DIXDC1) modulates VEGFR2 level in vasculatures to regulate embryonic and postnatal retina angiogenesis

BackgroundIn sprouting angiogenesis, VEGFR2 level is regulated via a fine-tuned process involving various signaling pathways. Other than VEGF/VEGFR2 signaling pathway, Wnt/ β-catenin signaling is also important in vascular development. However, the crosstalk between these two signaling pathways is still unknown to date. In this study, we aimed to investigate the role of DIX domain containing 1 (DIXDC1) in vasculature, facilitating the crosstalk between VEGF/VEGFR2 and Wnt/ β-catenin signaling pathways.ResultsIn mice, DIXDC1 deficiency delayed angiogenesis at the embryonic stage and suppressed neovascularization at the neonatal stage. DIXDC1 knockdown inhibited VEGF-induced angiogenesis in endothelial cells in vitro by downregulating VEGFR2 expression. DIXDC1 bound Dishevelled Segment Polarity Protein 2 (Dvl2) and polymerized Dvl2 stabilizing VEGFR2 protein via its direct interaction. The complex formation and stability of VEGFR2 was potentiated by Wnt signaling. Moreover, hypoxia elevated DIXDC1 expression and likely modulated both canonical Wnt/β-catenin signaling and VEGFR2 stability in vasculatures. Pathological angiogenesis in DIXDC1 knockout mice was decreased significantly in oxygen-induced retinopathy (OIR) and in wound healing models. These results suggest that DIXDC1 is an important factor in developmental and pathological angiogenesis.ConclusionWe have identified DIXDC1 as an important factor in early vascular development. These results suggest that DIXDC1 represents a novel regulator of sprouting angiogenesis that links Wnt signaling and VEGFR2 stability and may have a potential role in pathological neovascularization.

The TBX1/miR-193a-3p/TGF-β2 Axis Mediates CHD by Promoting Ferroptosis

Congenital heart disease (CHD) is the most common noninfectious cause of death during the neonatal stage. T-box transcription factor 1 (TBX1) is the main genetic determinant of 22q11.2 deletion syndrome (22q11.2DS), which is a common cause of CHD. Moreover, ferroptosis is a newly discovered kind of programmed cell death. In this study, the interaction among TBX1, miR-193a-3p, and TGF-β2 was tested using quantitative reverse transcription polymerase chain reaction (qRT-PCR), Western blotting, and dual-luciferase reporter assays. TBX1 silencing was found to promote TGF-β2 messenger ribonucleic acid (mRNA) and protein expression by downregulating the miR-193a-3p levels in H9c2 cells. In addition, the TBX1/miR-193a-3p/TGF-β2 axis was found to promote ferroptosis based on assessments of lipid reactive oxygen species (ROS) levels, Fe2+ concentrations, mitochondrial ROS levels, and malondialdehyde (MDA) contents; Cell Counting Kit-8 (CCK-8) assays and transmission electron microscopy; and Western blotting analysis of glutathione peroxidase 4 (GPX4), nuclear factor erythroid 2-related factor 2 (NRF2), heme oxygenase-1 (HO-1), NADPH oxidase 4 (NOX4), and acyl-CoA synthase long-chain family member 4 (ACSL4) protein expression. The protein expression of NRF2, GPX4, HO-1, NOX4, and ACSL4 and the level of MDA in human CHD specimens were also detected. In addition, TBX1 and miR-193a-3p expression was significantly downregulated and TGF-β2 levels were high in human embryonic CHD tissues, as indicated by the H9c2 cell experiments. In summary, the TBX1/miR-193a-3p/TGF-β2 axis mediates CHD by inducing ferroptosis in cardiomyocytes. TGF-β2 may be a target gene for CHD diagnosis and treatment in children.

Magnitude and associated factors of neonatal resuscitation among health care providers in selected public hospitals of Addis Ababa, Ethiopia, 2022. Multi center cross-sectional study

Background: The neonatal stage is one of the most vulnerable in a child's existence due to the high risks of mortality and illness during such a time. One-fourth of newborn mortality worldwide is caused by asphyxia, with Ethiopia bearing a disproportionately large share of this burden among low- and middle-income countries. Poor resuscitation brought on by inexperienced medical staff had a significant impact on this asphyxia-related mortality and morbidity. The aim of the study is to assess magnitude & associated factors toward neonatal resuscitation among nurses working in public hospitals in Addis Ababa, Ethiopia. Methods: An institution-based cross-sectional study was conducted in selected hospitals in Addis Ababa, Ethiopia. A total of 409 health professionals, including nurses, midwives, general practitioners, interns, residents, and obstetric gynecologists, worked in selected hospitals for this study. Data was collected using validated self-administered questionnaires. Bivariate analysis was used to see the association between each independent variable and the outcome variable, and multivariable logistic regression analysis was carried out to determine the effect of various factors on the outcome variable. All variables with a p-value ≤ 0.25 were taken into the multivariable model to control for all possible confounders. Results: A total of 409 healthcare professionals with a 100% response rate were included. The majority of 357 (87.3%) of the participants had adequate knowledge, and 365 (89.2%) had good practice in neonatal resuscitation. In this study, the odds of health care providers having work experience greater than 5 years were 3.14 (AOR=3.14, 95% CI: 1.20-8.19), receiving neonatal resuscitation training was 2.68 (AOR=2.68, 95% CI: 1.02-7.03), having adequate knowledge about neonatal resuscitation was 6.18 (AOR=6.18, 95% CI: 2.08–18.37), having appropriate suctioning for neonates was 6.14 (AOR=6.14, 95% CI: 2.39-15.74), and neonates during resuscitation placed under neutral positioning were 3.44 (AOR=3.44, 95% CI: 1.45-8.16) significantly associated with practice of neonatal resuscitation. Conclusion and Recommendation: The overall knowledge and practice score of health professionals was good. Hospital managers and decision makers also need to provide periodic supportive supervision and refreshment training to update knowledge and practice of HCPs.

True hermaphrodite of ovotestis in a 5-year-old child

Assigning possible and correct sex of individuals born with ambiguous genitalia, notably those with true hermaphroditism (TH) at their neonatal stage, is of paramount psychosocial advantage. A 5-year-old child with karyotype of 46, XX who was reared as male is herein presented. The right testicle was neither palpable in the scrotal sac nor in the inguinal canal. The left testicle was palpable in the scrotum and was of adequate size according to the child. A hormonal profile showed a testosterone level of 2.30 ng/dl (normal value: 30–50 ng/dl). Both testicular and ovarian tissues were found on one side (ovotestis), hence TH of ovotestis was confirmed. It is important to assign true sex for patients with an intersex disorder particularly those with TH so as to give positive psychosocial benefits for them as well as removing gonadal tissues which would lead to the development of gonadal malignancies.

Targeting the epigenome to treat neurodegenerative diseases or delay their onset: a perspective

Targeting the epigenome to treat neurodegenerative diseases or delay their onset: a perspective

EEG-Based Neonatal Sleep Stage Classification Using Ensemble Learning

Sleep stage classification can provide important information regarding neonatal brain development and maturation. Visual annotation, using polysomnography (PSG), is considered as a gold standard for neonatal sleep stage classification. However, visual annotation is time consuming and needs professional neurologists. For this reason, an internet of things and ensemble-based automatic sleep stage classification has been proposed in this study. 12 EEG features, from 9 bipolar channels, were used to train and test the base classifiers including convolutional neural network, support vector machine, and multilayer perceptron. Bagging and stacking ensembles are then used to combine the outputs for final classification. The proposed algorithm can reach a mean kappa of 0.73 and 0.66 for 2-stage and 3-stage (wake, active sleep, and quiet sleep) classification, respectively. The proposed network works as a semi-real time application because a smoothing filter is used to hold the sleep stage for 3 min. The high-performance parameters and its ability to work in semi real-time makes it a promising candidate for use in hospitalized newborn infants.

Functional brain maturation and sleep organisation in neonates with congenital heart disease.

Neonates with Congenital Heart Disease (CHD) have structural delays in brain development. To evaluate whether functional brain maturation and sleep-wake physiology is also disturbed, the Functional Brain Age (FBA) and sleep organisation on EEG during the neonatal period is investigated. We compared 15 neonates with CHD who underwent multichannel EEG with healthy term newborns of the same postmenstrual age, including subgroup analysis for d-Transposition of the Great Arteries (d-TGA) (n=8). To estimate FBA, a prediction tool using quantitative EEG features as input, was applied. Second, the EEG was automatically classified into the 4 neonatal sleep stages. Neonates with CHD underwent neurodevelopmental testing using the Bayley Scale of Infant Development-III at 24 months. Preoperatively, the FBA was delayed in CHD infants and more so in d-TGA infants. The FBA was positively correlated with motor scores. Sleep organisation was significantly altered in neonates with CHD. The duration of the sleep cycle and the proportion of Active Sleep Stage 1 was decreased, again more marked in the d-TGA infants. Neonates with d-TGA spent less time in High Voltage Slow Wave Sleep and more in Tracé Alternant compared to healthy terms. Both FBA and sleep organisation normalised postoperatively. The duration of High Voltage Slow Wave Sleep remained positively correlated with motor scores in d-TGA infants. Altered early brain function and sleep is present in neonates with CHD. These results are intruiging, as inefficient neonatal sleep has been linked with adverse long-term outcome. Identifying how these rapid alterations in brain function are mitigated through improvements in cerebral oxygenation, surgery, drugs and nutrition may have relevance for clinical practice and outcome.

Analysis of an outpatient child hearing health program: from screening to referral for rehabilitation.

To analyze the stages of a hearing health program, from screening to referral for rehabilitation, based on the quality indicators for neonatal screening programs. This is a cohort, observational, retrospective study encompassing all newborns included in the Municipal Information System of Mogi Mirim, São Paulo, from 2010 to 2016. Besides the data present in the Information System on Live Newborns, the newborn's age at the first test, test and diagnosis results, and referrals for rehabilitation were analyzed, based on the quality indicator criteria recommended by the Neonatal Hearing Screening Care Guidelines, with a statistical program. A total of 7,800 newborns participated. The following results were obtained in the analysis of the program quality indicators: 1) Neonatal hearing screening stage: 97% coverage in the first test; 91% of newborns by 30 days old; 2) Diagnosis stage: 0.24% referred after failing the second test; 94.73% adherence; 13.66% confirmed diagnosis by 3 months old; 3) Rehabilitation stage: 100% began speech-language-hearing therapy immediately after the diagnosis; 20% received the hearing aid within 1 month from diagnosis. The program, conducted in an outpatient setting, met the recommendations of the guidelines presented by the Ministry of Health concerning the coverage and age at first examination, age at screening up to 1 month old, referral for diagnosis, and beginning the intervention. These results were obtained thanks to institutional support from the municipality.

Trans-2-Enoyl-CoA Reductase Tecr-Driven Lipid Metabolism in Endothelial Cells Protects against Transcytosis to Maintain Blood-Brain Barrier Homeostasis.

The transport and metabolism of lipids in cerebrovascular endothelial cells (ECs) have been hypothesized to regulate blood-brain barrier (BBB) maturation and homeostasis. Long-chain polyunsaturated fatty acids (LCPUFAs) as the important lipids components of cell membranes are essential for the development and function of BBB, but the direct links of lipid metabolism and ECs barrier function remain to be established. Here, we comprehensively characterize the transcriptomic phenotype of developmental cerebrovascular ECs in single-cell resolution and firstly find that trans-2-enoyl-CoA reductase (Tecr), a very-long-chain fatty acid synthesis, is highly expressed during barriergenesis and decreased after BBB maturation. EC-specific knockout of Tecr compromises angiogenesis due to delayed vascular sprouting. Importantly, EC-specific deletion of Tecr loss restrictive quality of vascular permeability from neonatal stages to adulthood, with high levels of transcytosis, but maintains the vascular tight junctions. Moreover, lipidomic analysis shows that the expression of Tecr in ECs is associated with the containing of omega-3 fatty acids, which directly suppresses caveolae vesicles formation. These results reveal a protective role for Tecr in BBB integrity and suggest that Tecr as a novel therapeutic target in the central nervous system (CNS) diseases associated with BBB dysfunction.

Toxicity of internalized polyalanine to cells depends on aggregation

In polyalanine (PA) diseases, the disease-causing transcription factors contain an expansion of alanine repeats. While aggregated proteins that are responsible for the pathogenesis of neurodegenerative disorders show cell-to-cell propagation and thereby exert toxic effects on the recipient cells, whether this is also the case with expanded PA has not been studied. It is also not known whether the internalized PA is toxic to recipient cells based on the degree of aggregation. In this study, we therefore prepared different degrees of aggregation of a peptide having 13 alanine repeats without flanking sequences of PA disease-causative proteins (13A). The aggregated 13A was spontaneously taken up by neuron-like cultured cells. Functionally, strong aggregates but not weak aggregates displayed a deficit in neuron-like differentiation in vitro. Moreover, the injection of strong but not weak 13A aggregates into the ventricle of mice during the neonatal stage led to enhanced spontaneous motor activity later in life. Thus, PA in the extracellular space has the potential to enter adjacent cells, and may exert toxicity depending on the degree of aggregation.

Fatty acid compositions of immature and mature testis are differently responsive to dietary docosahexasenoic acid during development in rats exposed to prenatal ethanol

BackgroundEthanol (EtOH) exposure impairs, but docosahexaenoic acid (DHA) supports testis functions. This study investigated whether dietary DHA and prenatal EtOH exposure affected fatty acid profiles equally in immature and mature testis during developmental stages. MethodsFemale rats were exposed to ± EtOH (3g/kg BW, twice a day via gavage) throughout pregnancy, while consuming a diet supplemented ± DHA (1.4%, w/w). Pups were continued on their mother's diet after weaning with testes collected for fatty acid analysis at different stages of reproductive development, at gestational day 20 (GD20) and postnatal day (PD) 4, 21, 49, and 90, to present fetal, neonatal, weaning, prepubertal and adult stages, respectively. ResultsRegardless of EtOH exposure, dietary DHA significantly increased in testis DHA at all ages, with testis at weaning and prepuberty being more responsive to the diet (p<0.0002). Immature testis at GD20 and PD4 contained more DHA than n-6 docosapentaenoic acid (n-6 DPA) compared to mature testis while being well responsive to the maternal DHA diet through gestation and lactation. The level of n-6 very long chain fatty acids and (VLCFA) and n-6 DPA, distinctively increased from weaning and prepuberty, respectively, and were not reduced by the DHA diet at prepuberty and adulthood. Prenatal EtOH minimally affected testis fatty acids during development. ConclusionImmature and mature testis responds differently to dietary DHA. The age around sexual maturity might be a critical time for dietary intervention as testis was more responsive to diet at this time point. The increase in DPA and n-6 VLCFA in matured testis while not affected by dietary DHA, indicates their critical roles in male reproductive function in rodents.

Volume Overload Initiates an Immune Response in the Right Ventricle at the Neonatal Stage.

Background: Pulmonary regurgitation caused by the correction or palliation of pediatric tetralogy of Fallot (TOF) leads to chronic right ventricular (RV) volume overload (VO), which induces adolescent RV dysfunction. A better understanding of the molecular mechanism by which VO initiates neonatal RV remodeling may bring new insights into the post-surgical management of pediatric TOF.Methods and Results: We created a fistula between the abdominal aorta and inferior vena cava on postnatal day 1 (P1) using a rat model to induce neonatal VO. Echocardiography revealed that the velocity and velocity- time-integral of the pulmonary artery (PA) were significantly elevated, and hematoxylin and eosin (H&E) staining showed that the diameter of the RV significantly increased. RNA-seq analysis of the RV on P7 indicated that the top 10 enriched Gene Ontology (GO) terms and the top 20 enriched terms in the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis were associated with immune responses. Flow-cytometric analysis demonstrated that the number of CD4+and CD8+ immune cells were significantly augmented in the VO group compared with the sham group.Conclusions: A neonatal cardiac VO rat model on P1 was successfully created, providing a platform for studying the molecular biology of neonatal RV under the influence of VO. VO - induces an immune response at the neonatal stage (from P1 to P7), suggesting that immune responses may be an initiating factor for neonatal RV remodeling under the influence of VO and that immunosuppressants may be used to prevent pediatric RV remodeling caused by VO.

FLT3 ITD and NUP98 translocations Cooperate to Induce Type I Interferon Signaling That Impedes Hematopoietic Progenitor Differentiation

FLT3-Internal Tandem Duplication (FLT3 ITD) mutations occur at similar frequencies in both childhood and adult acute myeloid leukemia (AML) patients, but they cooperate with different initiating mutations at different ages. In childhood AML, FLT3 ITD often cooperates with translocations that generate fusion proteins, such as NUP98 translocations (NUP98-t). In adult AML, FLT3 ITD often cooperates with mutations that inactivate RUNX1, DNMT3A, TET2 and other genes that regulate self-renewal and myeloid differentiation. This raises the question of whether FLT3 ITD induces similar, or distinct, changes in gene expression and cell fate when it arises in the setting of pediatric and adult driver mutations. To answer this question, we evaluated pre-leukemic changes in hematopoiesis and gene expression in neonatal and juvenile mice that carried pediatric-like FLT3 ITD/NUP98-HOXD13 and adult-like FLT3 ITD/Runx1 DEL/+ mutation profiles. Both NUP98-HOXD13 (NHD13) and Runx1 DEL/+ severely depleted phenotypic hematopoietic stem cells (HSCs) when coupled with FLT3 ITD. However, FLT3 ITD/NHD13 cooperated to enhancer ectopic self-renewal capacity in lineage committed hematopoietic progenitor cells (HPCs) whereas FLT3 ITD/Runx1 DEL/+ did not. FLT3 ITD/NHD13 and FLT3 ITD/Runx1 DEL/+ both induced changes in gene expression and enhancer activation that were not seen with either mutation alone. These cooperative changes were almost entirely non-overlapping. The most notable cooperative change in FLT3 ITD/NHD13 HPCs was activation of a type I Interferon target gene signature. By contrast, this signature was actively repressed in FLT3 ITD/Runx1 DEL/+ HPCs due to mir155 activation. Thus, FLT3 ITD/NHD13 and FLT3 ITD/Runx1 DEL/+ mutations have largely non-overlapping, cooperative effects on hematopoietic cell fate and gene expression.Interferon signaling sustained the FLT3 ITD/NHD13 HPC population by impeding differentiation into more committed myeloid progenitors. When we deleted the type I interferon receptor (Ifnar) on a FLT3 ITD/NHD13 background, the HPC population was virtually eliminated, yet the pre-granulocyte monocyte (pGM) and granulocyte-monocyte progenitor (GMP) populations expanded. HPC proliferation and death did not change in the absence of Ifnar. These findings suggest that type I interferon impedes HPC differentiation into pGMs during the neonatal and juvenile stages of life. Of note, ectopic interferon was insufficient to enhancer HPC numbers in setting of a sole NHD13 mutation. Thus, interferon is necessary to sustain FLT3 ITD/NHD13 HPCs, but not sufficient, and other signaling pathways downstream of FLT3 ITD must cooperate with NHD13 in parallel to drive HPC expansion. To our surprise, Ifnar deletion did not reduce repopulating activity in FLT3 ITD/NHD13 bone marrow - as measured by limiting dilution transplants - it simply shifted repopulating activity to more committed pGMs. Our raise two important conceptual points. First, we show that different initiating mutations can elicit completely different transcriptional responses downstream of FLT3 ITD. Precision medicine strategies must account for these differences as effective therapies for adult FLT3 ITD AML may not yield similar success in the pediatric population. Second, type I interferon shapes pre-leukemic hematopoiesis in the setting of FLT3 ITD/NUP98-t mutations. In doing so, the mutant cells may hijack a program that we recently identified as promoting normal perinatal HPC expansion. DisclosuresNo relevant conflicts of interest to declare.

Mode Switch of Ca2 + Oscillation-Mediated Uterine Peristalsis and Associated Embryo Implantation Impairments in Mouse Adenomyosis.

Adenomyosis is a debilitating gynecological disease of the uterus with no medicinal cure. The tissue injury and repair hypothesis for adenomyosis suggests that uterine hyperperistalsis or dysperistalsis plays a pivotal role in establishing adenomyotic lesions. However, specific impairments in uterine peristalsis and the underlying cellular signals for these changes in adenomyosis remain elusive. Here, we report a precision-cut uterine slice preparation that preserves in vivo uterine architecture and generates peristalsis similar to that seen in the whole uterus. We found that uterine peristalsis in neonatal mice at day 14 and adult mice at day 55 presents as bursts with multiple peaks induced by intracellular Ca2+ oscillations. Using a mouse model of adenomyosis induced by tamoxifen, a selective estrogen receptor modulator, we discovered that uterine peristalsis and Ca2+ oscillations from adenomyotic uteri on days 14 and 55 become spikes (single peaks) with smaller amplitudes. The peak frequency of Ca2+ oscillations or peristalsis does not show a difference between control and adenomyotic mice. However, both the estimated force generated by uterine peristalsis and the total Ca2+ raised by Ca2+ oscillations are smaller in uteri from adenomyotic mice. Uteri from adenomyotic mice on day 14, but not on day 55, exhibit hyperresponsiveness to oxytocin. Embryo implantations are decreased in adenomyotic adult mice. Our results reveal a mode switch from bursts to spikes (rather than an increased peak frequency) of uterine Ca2+ oscillations and peristalsis and concurrent hyperresponsiveness to oxytocin in the neonatal stage are two characteristics of adenomyosis. These characteristics may contribute to embryo implantation impairments and decreased fertility in adenomyosis.

The Development of the Mesoprefrontal Dopaminergic System in Health and Disease.

Midbrain dopaminergic neurons located in the substantia nigra and the ventral tegmental area are the main source of dopamine in the brain. They send out projections to a variety of forebrain structures, including dorsal striatum, nucleus accumbens, and prefrontal cortex (PFC), establishing the nigrostriatal, mesolimbic, and mesoprefrontal pathways, respectively. The dopaminergic input to the PFC is essential for the performance of higher cognitive functions such as working memory, attention, planning, and decision making. The gradual maturation of these cognitive skills during postnatal development correlates with the maturation of PFC local circuits, which undergo a lengthy functional remodeling process during the neonatal and adolescence stage. During this period, the mesoprefrontal dopaminergic innervation also matures: the fibers are rather sparse at prenatal stages and slowly increase in density during postnatal development to finally reach a stable pattern in early adulthood. Despite the prominent role of dopamine in the regulation of PFC function, relatively little is known about how the dopaminergic innervation is established in the PFC, whether and how it influences the maturation of local circuits and how exactly it facilitates cognitive functions in the PFC. In this review, we provide an overview of the development of the mesoprefrontal dopaminergic system in rodents and primates and discuss the role of altered dopaminergic signaling in neuropsychiatric and neurodevelopmental disorders.

131 Can Maternal Nutrition in Dairy Cattle Impact Gut Health in Dairy Calves?

Abstract The nutritional management, health and welfare of the dairy calf has historically received less attention due to limited research, and recommendations largely focused on passive transfer of immunity and early weaning strategies. Gastrointestinal diseases and disorders remain the leading cause of mortality and morbidity in dairy calves worldwide. Despite the recent thrust in dairy calf nutrition research, major knowledge gaps still exist regarding how maternal nutrition during pregnancy and postpartum impact gastrointestinal health and function, especially during the fetal and neonatal stages when the developmental plasticity is highest. Recent research has focused on how prepartum nutrition and management can influence colostrum quality and has characterized numerous bioactive proteins, lipids, and carbohydrates that may play a critical role in gastrointestinal function and development. It has also been shown that colostrum plays a fundamental role in promoting colonization with commensal bacteria; however, delaying colostrum feeding or abruptly transitioning calves from colostrum to milk decreased the colonization of beneficial bacteria and impaired gastrointestinal development. With respect to the maternal nutrient supply via milk, it is important to note that calves have been traditionally fed less than half of voluntary intake or fed milk replacer formulations that can largely differ in composition from that of maternal milk. Recent research indicated that common milk replacer formulations may impair gastrointestinal function, highlighting the need to question existing nutritional regimens. In addition, feeding prophylactic antibiotics in milk, as well as waste milk containing antibiotic residues, are common practices in the dairy industry, despite recent studies reporting that these practices can increase calf susceptibility to infections by disrupting gut microbiome and gut function. Although our knowledge how maternal factors impact the gastrointestinal tract of calves is limited, it is clear there are great opportunities to further develop prenatal and postnatal nutritional programs to improve dairy calf gastrointestinal health.

Assessment of thyroid function in the preterm and/or very low birth weight newborn

The screening program or early detection of congenital hypothyroidism is one of the greatest advances achieved in Pediatrics. Thyroid hormones are essential for brain development and maturation, which continue into the neonatal stage. Alterations in thyroid function in premature and underweight children in the first months of life causes irreversible damage to the central nervous system and is one of the most frequent and avoidable causes of mental retardation. Diagnosis in the neonatal period is difficult, so it requires an analytical study to be able to carry out the appropriate treatment.The relevance of this problem justifies its communication to all areas of pediatrics. The main objective is to avoid brain damage in these patients. Other aspects to optimize the adequate development of these children with all the necessary periodic controls and to achieve the inclusion of the diagnosis of thyroid alterations during the stay in neonatal units and in the first months of life, need to implement the resources of the health centers and continue advancing according to current knowledge.In this document, we will focus on the screening of preterm newborns VLBW (<32 weeks of gestation) and/or very low weight for gestational age (1500–1000 g VLBW or <1000 g) and the function evaluation protocol thyroid in premature babies.We update the diagnostic procedures, the essential and complementary tests required, the etiology and the differential diagnoses in this pathology.