Neonatal Stage Research Articles

Inhibition of DNA methylation in newborns reprograms ischemia-sensitive biomarkers resulting in development of a heart ischemia-sensitive phenotype late in life

Adverse environmental stress exposure at critical perinatal stages can alter cardiovascular development, which could persist into adulthood and develop a cardiovascular dysfunctional phenotype late in life. However, the underlying molecular mechanisms remain largely unknown. The present study provided a direct evidence that DNA methylation is a key epigenetic mechanism contributing to the developmental origins of adult cardiovascular disease. We hypothesized that DNA hypomethylation at neonatal stage alters gene expression patterns in the heart, leading to development of a cardiac ischemia-sensitive phenotype late in life. To test this hypothesis, a DNA methylation inhibitor 5-Aza-2-deoxycytidine (5-Aza) was administered in newborn rats from postnatal day 1–3. Cardiac function and related key genes were measured in 2-week- and 2-month-old animals, respectively. 5-Aza treatment induced an age- and sex-dependent inhibition of global and gene-specific DNA methylation levels in left ventricles, resulting in a long-lasting growth restriction but an asymmetry increase in the heart-to-body weight ratio. In addition, treatment with 5-Aza enhanced ischemia and reperfusion-induced cardiac dysfunction and injury in adults as compared with the saline controls, which was associated with up-regulations of miRNA-181a and angiotensin II receptor type 1 & 2 gene expressions, but down-regulations of PKCε, Atg5, and GSK3β gene expressions in left ventricles. In conclusion, our results provide compelling evidence that neonatal DNA methylation deficiency is a key mechanism contributing to differentially reprogram cardiac gene expression patterns, leading to development of a heart ischemia-sensitive phenotype late in life.

Prevention and control of birth defects and rare diseases in the era of genomic medicine

Birth defects and rare diseases have become major public health problems, and early prevention and control are the most effective interventions. In recent years, with the rapid development of genomic techniques such as high-throughput sequencing, the level of screening and diagnosis of genetic birth defects and rare diseases has been greatly improved. This article reviews the application of genomic technologies in the pre-pregnancy, preimplantation, prenatal and neonatal stages, as well as the trend of clinical transformation, highlighting the broad prospects of constructing an early and precise prevention and control system in the era of genomic medicine.

Presentation and management of congenital heart disease in the first year of age

ResumenLas cardiopatías congénitas (CC) se definen como una anomalía estructural del corazón o de los grandes vasos intratorácicos. Constituyen la malformación congénita más frecuente al nacimiento. Al menos un tercio de los pacientes requieren algún tipo de intervención antes del año de edad. Las manifestaciones clínicas de las cardiopatías en la etapa neonatal se presentan con un amplio contexto clínico y se pueden confundir con problemas a nivel pulmonar o infeccioso, lo que dificulta su diagnóstico y con ello contribuyendo de forma importante a la mortalidad y morbilidad de estos pacientes, ya que se retrasa el diagnóstico y manejo oportuno. El monitoreo por oximetría de pulso en el periodo neonatal se utiliza actualmente como método diagnóstico para la detección de cardiopatías congénitas críticas; a pesar de que las detecta en forma temprana, en muchos países aún no se lleva a cabo. El objetivo de este artículo es ofrecer un panorama general de la presentación clínica, aspectos diagnósticos y manejo inicial de las CC en el primer año de edad que pueda ser de utilidad a los médicos de primer contacto para mejorar la atención en este grupo de pacientes.

Transmission of a Novel Imprinting Center Deletion Associated With Prader-Willi Syndrome Through Three Generations of a Chinese Family: Case Presentation, Differential Diagnosis, and a Lesson Worth Thinking About.

Prader–Willi syndrome (PWS) is a complex genetic syndrome caused by the loss of function of genes in 15q11-q13 that are subject to regulation by genomic imprinting and expressed from the paternal allele only. The main clinical features of PWS patients are hypotonia during the neonatal and infantile stages, accompanied by delayed neuropsychomotor development, hyperphagia, obesity, hypogonadism, short stature, small hands and feet, mental disabilities, and behavioral problems. However, PWS has a clinical overlap with other disorders, especially those with other gene variations or chromosomal imbalances but sharing part of the similar clinical manifestations with PWS, which are sometimes referred to as Prader–Willi syndrome-like (PWS-like) disorders. Furthermore, it is worth mentioning that significant obesity as a consequence of hyperphagia in PWS usually develops between the ages of 1 and 6 years, which makes early diagnosis difficult. Thus, PWS is often not clinically recognized in infants and, on the other hand, may be wrongly suspected in obese and intellectually disabled patients. Therefore, an accurate investigation is necessary to differentiate classical PWS from PWS-like phenotypes, which is imperative for further treatment. For PWS, it is usually sporadic, and very rare family history and affected siblings have been described. Here, we report the clinical and molecular findings in a three-generation family with a novel 550-kb microdeletion affecting the chromosome 15 imprinting center (IC). Overall, the present study finds that the symptoms of our patient are somewhat different from those of typical PWS cases diagnosed and given treatment in our hospital. The familial occurrence and clinical features were challenging to our diagnostic strategy. The microdeletion included a region within the complex small nuclear ribonucleoprotein polypeptide protein N (SNRPN) gene locus encompassing the PWS IC and was identified by using a variety of techniques. Haplotype studies suggest that the IC microdeletion was vertically transmitted from an unaffected paternal grandmother to an unaffected father and then caused PWS in two sibling grandchildren when the IC microdeletion was inherited paternally. Based on the results of our study, preimplantation genetic diagnosis (PGD) was applied successfully to exclude imprinting deficiency in preimplantation embryos before transfer into the mother’s uterus. Our study may be especially instructive regarding accurate diagnosis, differential diagnosis, genetic counseling, and PGD for familial PWS patients.

Vein of Galen Aneurysmal Malformations in Pediatric Patients Submitted to Endovascular Treatment: Report of 3 Cases

Abstract Objective To report three cases of vein of Galen aneurysmal malformation (VGAM) in pediatric patients treated at the hemodynamics lab of Hospital Santa Isabel (HSI) in Blumenau, state of Santa Catarina, Brazil, from 2006 to 2020. Clinical presentation, endovascular treatment, and postprocedure evolution to date are included. Case description Three children aged 5 to 12 months with cardiac, respiratory, or neurological damage in the neonatal stage, were referred to the neurosurgery service and diagnosed with VGAM. The three patients underwent endovascular embolization of the malformation, with different clinical evolution throughout outpatient follow-up. Conclusion Vein of Galen aneurysmal malformations are uncommon vascular abnormalities that, until the advent of endovascular embolization, were associated with high morbidity and mortality rates. Its prognosis is linked with initial clinic, early diagnosis, and timely surgical correction.

Optimized Tibial Nerve Stimulation Partially Reduces Visceral Hypersensitivity in Rats Mediated via Autonomic and Opioid Mechanisms

The aim of this study was to investigate the therapeutic effect and possible mechanisms of tibial nerve stimulation (TNS) on visceral hypersensitivity in rats. 1) The effects of TNS with five sets of parameters on visceral sensitivity in normal rats were evaluated by the assessment of abdominal electromyogram (EMG) and abdominal withdrawal reflex (AWR). 2) The effects and mechanisms of TNS with a special set of parameters (14Hz, 330 μsec, and 40% motor threshold) were evaluated in acute visceral hypersensitivity rats induced by restraint stress and colonic hypersensitized rats induced by acetic acid during the neonatal stage assessed by the EMG, AWR, and the spectral analysis of heart rate variability derived from the electrocardiogram. 1) In normal rats, TNS did not show any effect on the visceromotor reflex. 2) In rats with restraint stress-induced hypersensitivity, TNS with the special set of parameters reduced AWR scores and EMG responses to rectal distention at a pressure of 20-60 mmHg (p < 0.05, vs. baseline for both AWR and EMG). Concurrently, TNS increased vagal activity and decreased sympathetic activity (p < 0.03 for both). 3) Similar effects were noted on the EMG (p < 0.05, vs. baseline) and AWR (p < 0.05 vs. baseline) with acute and chronic TNS in rats with chronic colonic hypersensitivity and the effects were blocked by naloxone. TNS with parameters of 14Hz, 330 μsec, and 40% motor threshold is effective in improving visceral hypersensitivity in rodent models of colonic hypersensitivity via the modulation of autonomic and opioid mechanisms.

Age-Related Neurometabolomic Signature of Mouse Brain.

Neurometabolites are the ultimate gene products in the brain and the most precise biomolecular indicators of brain endophenotypes. Metabolomics is the only "omics" that provides a moment-to-moment "snapshot" of brain circuits' biochemical activities in response to external stimuli within the context of specific genetic variations. Although the expression levels of neurometabolites are highly dynamic, the underlying metabolic processes are tightly regulated during brain development, maturation, and aging. Therefore, this study aimed to identify mouse brain metabolic profiles in neonatal and adult stages and reconstruct both the active metabolic network and the metabolic pathway functioning. Using high-throughput metabolomics and bioinformatics analyses, we show that the neonatal mouse brain has its distinct metabolomic signature, which differs from the adult brain. Furthermore, lipid metabolites showed the most profound changes between the neonatal and adult brain, with some lipid species reaching 1000-fold changes. There were trends of age-dependent increases and decreases among lipids and non-lipid metabolites, respectively. A few lipid metabolites such as HexCers and SHexCers were almost absent in neonatal brains, whereas other non-lipid metabolites such as homoarginine were absent in the adult brains. Several molecules that act as neurotransmitters/neuromodulators showed age-dependent levels, with adenosine and GABA exhibiting around 100- and 10-fold increases in the adult compared with the neonatal brain. Of particular interest is the observation that purine and pyrimidines nucleobases exhibited opposite age-dependent changes. Bioinformatics analysis revealed an enrichment of lipid biosynthesis pathways in metabolites, whose levels increased in adult brains. In contrast, pathways involved in the metabolism of amino acids, nucleobases, glucose (glycolysis), tricarboxylic acid cycle (TCA) were enriched in metabolites whose levels were higher in the neonatal brains. Many of these pathways are associated with pathological conditions, which can be predicted as early as the neonatal stage. Our study provides an initial age-related biochemical directory of the mouse brain and warrants further studies to identify temporal brain metabolome across the lifespan, particularly during adolescence and aging. Such neurometabolomic data may provide important insight about the onset and progression of neurological/psychiatric disorders and may ultimately lead to the development of precise diagnostic biomarkers and more effective preventive/therapeutic strategies.

Redefining the Role of Lymphotoxin Beta Receptor in the Maintenance of Lymphoid Organs and Immune Cell Homeostasis in Adulthood.

Lymphotoxin beta receptor (LTβR) is a promising therapeutic target in autoimmune and infectious diseases as well as cancer. Mice with genetic inactivation of LTβR display multiple defects in development and organization of lymphoid organs, mucosal immune responses, IgA production and an autoimmune phenotype. As these defects are imprinted in embryogenesis and neonate stages, the impact of LTβR signaling in adulthood remains unclear. Here, to overcome developmental defects, we generated mice with inducible ubiquitous genetic inactivation of LTβR in adult mice (iLTβRΔ/Δ mice) and redefined the role of LTβR signaling in organization of lymphoid organs, immune response to mucosal bacterial pathogen, IgA production and autoimmunity. In spleen, postnatal LTβR signaling is required for development of B cell follicles, follicular dendritic cells (FDCs), recruitment of neutrophils and maintenance of the marginal zone. Lymph nodes of iLTβRΔ/Δ mice were reduced in size, lacked FDCs, and had disorganized subcapsular sinus macrophages. Peyer`s patches were smaller in size and numbers, and displayed reduced FDCs. The number of isolated lymphoid follicles in small intestine and colon were also reduced. In contrast to LTβR-/- mice, iLTβRΔ/Δ mice displayed normal thymus structure and did not develop signs of systemic inflammation and autoimmunity. Further, our results suggest that LTβR signaling in adulthood is required for homeostasis of neutrophils, NK, and iNKT cells, but is dispensable for the maintenance of polyclonal IgA production. However, iLTβRΔ/Δ mice exhibited an increased sensitivity to C. rodentium infection and failed to develop pathogen-specific IgA responses. Collectively, our study uncovers new insights of LTβR signaling in adulthood for the maintenance of lymphoid organs, neutrophils, NK and iNKT cells, and IgA production in response to mucosal bacterial pathogen.

Molecular-scale visualization of sarcomere contraction within native cardiomyocytes

Sarcomeres, the basic contractile units of striated muscle, produce the forces driving muscular contraction through cross-bridge interactions between actin-containing thin filaments and myosin II-based thick filaments. Until now, direct visualization of the molecular architecture underlying sarcomere contractility has remained elusive. Here, we use in situ cryo-electron tomography to unveil sarcomere contraction in frozen-hydrated neonatal rat cardiomyocytes. We show that the hexagonal lattice of the thick filaments is already established at the neonatal stage, with an excess of thin filaments outside the trigonal positions. Structural assessment of actin polarity by subtomogram averaging reveals that thin filaments in the fully activated state form overlapping arrays of opposite polarity in the center of the sarcomere. Our approach provides direct evidence for thin filament sliding during muscle contraction and may serve as a basis for structural understanding of thin filament activation and actomyosin interactions inside unperturbed cellular environments.

Energy metabolism in childhood neurodevelopmental disorders.

Whereas energy function in the aging brain and their related neurodegenerative diseases has been explored in some detail, there is limited knowledge about molecular mechanisms and brain networks of energy metabolism during infancy and childhood. In this review we describe current insights on physiological brain energetics at prenatal and neonatal stages, and in childhood. We then describe the main groups of inborn errors of energy metabolism affecting the brain. Of note, scarce basic neuroscience research in this field limits the opportunity for these disorders to provide paradigms of energy utilization during neurodevelopment. Finally, we report energy metabolism disturbances in well-known non-metabolic neurodevelopmental disorders. As energy metabolism is a fundamental biological function, brain energy utilization is likely altered in most neuropediatric diseases. Precise knowledge on mechanisms of brain energy disturbance will open the possibility of metabolic modulation therapies regardless of disease etiology.

Postnatal testicular development in Vietnamese pot-bellied pigs

The Vietnamese pot-bellied pig is a breed with high investigation potential. However, at the reproductive level, its testicular characteristics are still unknown, as well as the different stages of its development. Therefore, the objective of this work is to describe the postnatal testicular development of Vietnamese pot-bellied pigs. In this study, we used pigs grouped into the neonatal stage, animals at zero weeks; prepubertal stage, animals at three and eight weeks; pubertal stage, animals at twelve and sixteen weeks; and postpubertal stage animals at twenty, twenty-four, twenty-eight and thirty-two weeks of age. The neonatal stage is characterized by gonocytes at different migration phases. In the prepubertal stage, gonocytes were differentiated into spermatogonia at 3 weeks of age, and the first spermatocytes were observed at 7 weeks of age. Puberty was determined to start at 12 weeks because seminiferous tubules are found with complete spermatogenesis and the highest peaks in positive cell counting of androgen receptors (AR) and proliferating cell nuclear antigen (PCNA) factor that later decreased and further stabilized in the following weeks. In the postpubertal stage, an increase in seminiferous tubule areas was observed. The number of apoptotic cells ranged from low to null at all ages. Testosterone (T) and gonadotropin levels had two important peaks at 3 and 24 weeks. The seminiferous epithelium cycle was found to have 11 stages according to acrosome development. These characteristics of Vietnamese pot-bellied pig testes, which are different from rat testes and more similar to human testicles, make them a viable model to study human male reproductive biology. The postnatal testicular development of pot-bellied pigs is different from the postnatal testicular development of other breeds. Therefore, due to this difference in size and easy manipulation, the Vietnamese pig is an alternative for investigation compared to other pig breeds.

Fetal and Neonatal Hematopoietic Progenitors Are Exquisitely Sensitive to MLL-ENL-Driven Leukemia Initiation

Translocations involving the MLL1/KMT2A gene are observed in both acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), but the frequency at which these mutations occurs is different at different stages of life. For example, MLL rearrangements are extremely common in infant leukemia (~70% of cases), but they are much less common in adolescent or adult AML (~5% of de novo adult AML). While the function of MLL fusion proteins has been extensively studied, it remains unclear why MLL-rearrangements are so common in infant leukemias as compared to adolescent or adult leukemias. One possibility is that fetal hematopoietic progenitors are more readily transformed by MLL fusion proteins than adult progenitors. Recent work in our lab has shown that a mutation commonly associated with adult AML, the FLT3-Internal Tandem Duplication, selectively activates leukemogenic transcriptional programs in adult as compared to fetal/neonatal progenitors (eLife 5:e18882). We have developed a system to test whether an analogous effect holds for MLL translocations - i.e. do they preferentially initiate leukemogenesis in fetal progenitors. We made use of a previously described tet-O doxycycline inducible mouse allele (Cell Reports 9:1246) to both spatially and temporally control expression of MLL-ENL, a common MLL fusion product (Fig. 1A). We found that MLL-ENL induction at fetal (E10.5) or neonatal (P0) stages caused AML to develop in most mice, but MLL-ENL induction at juvenile (P21) or adult (8 weeks) stages did not (Fig. 1B). Remarkably, AML developed with the greatest penetrance (100%) when MLL-ENL was induced at P0 as compared to both earlier and later developmental stages. In neonates, MLL-ENL profoundly depleted hematopoietic stem cells (HSCs) and, to a lesser extent, lineage-restricted hematopoietic progenitors (HPCs), and it caused expansion of myeloid progenitor populations. These effects began to dissipate by 10 weeks after birth. Changes in HSC and HPC frequency were not at all evident when MLL-ENL was induced at an adult stage, but by a year after MLL-ENL induction, the surviving mice had a significantly expanded HSC pool. MLL-ENL induced widespread changes in gene expression in neonatal HPCs. In contrast, very few changes in gene expression were observed in MLL-ENL expressing adult HPCs. Known targets of MLL-ENL, such as HoxA9, were more highly induced in neonatal HPCs than in adult HPCs, though expression was observed in older mice. Altogether, our data demonstrate a dynamic relationship between developmental stage and the transcriptional response to MLL-ENL, and they may help account for the high percentage of MLL rearrangements observed in infant leukemia. Furthermore, our findings have opened new lines of investigation into the relationship between the epigenetic landscapes of developing HSCs/HPCs and the programs that drive leukemogenesis. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

YAP/TEAD1 Complex Is a Default Repressor of Cardiac Toll-Like Receptor Genes.

Toll-like receptors (TLRs) are a family of pattern recognition receptors (PRRs) that modulate innate immune responses and play essential roles in the pathogenesis of heart diseases. Although important, the molecular mechanisms controlling cardiac TLR genes expression have not been clearly addressed. This study examined the expression pattern of Tlr1, Tlr2, Tlr3, Tlr4, Tlr5, Tlr6, Tlr7, Tlr8, and Tlr9 in normal and disease-stressed mouse hearts. Our results demonstrated that the expression levels of cardiac Tlr3, Tlr7, Tlr8, and Tlr9 increased with age between neonatal and adult developmental stages, whereas the expression of Tlr5 decreased with age. Furthermore, pathological stress increased the expression levels of Tlr2, Tlr4, Tlr5, Tlr7, Tlr8, and Tlr9. Hippo-YAP signaling is essential for heart development and homeostasis maintenance, and YAP/TEAD1 complex is the terminal effector of this pathway. Here we found that TEAD1 directly bound genomic regions adjacent to Tlr1, Tlr2, Tlr3, Tlr4, Tlr5, Tlr6, Tlr7, and Tlr9. In vitro, luciferase reporter data suggest that YAP/TEAD1 repression of Tlr4 depends on a conserved TEAD1 binding motif near Tlr4 transcription start site. In vivo, cardiomyocyte-specific YAP depletion increased the expression of most examined TLR genes, activated the synthesis of pro-inflammatory cytokines, and predisposed the heart to lipopolysaccharide stress. In conclusion, our data indicate that the expression of cardiac TLR genes is associated with age and activated by pathological stress and suggest that YAP/TEAD1 complex is a default repressor of cardiac TLR genes.

Allergen Exposure in Murine Neonates Promoted the Development of Asthmatic Lungs.

We previously demonstrated that fetal allergen exposure caused T-helper 2 (Th2) cell sensitization. Although neonates are immunologically more mature than fetuses, asthmatic lungs were reportedly mitigated by neonatal allergen administration, mechanically referring to regulatory T-cells and TGF-β signaling but lacking the immunological profiles after neonatal exposure. To reappraise the immunological outcome of neonatal allergen exposure, we injected adjuvant-free ovalbumin intraperitoneally into 2-day-old BALB/c neonates, followed by aerosolized ovalbumin inhalation in adulthood. Mice were examined for the immunological profiles specifically after neonatal exposures, lung function and histology (hematoxylin-eosin or periodic acid Schiff staining), and gene expressions of intrapulmonary cytokines (IL-4, IL-5, IL-13 and IFN-γ) and chemokines (CCL17, CCL22, CCL11 and CCL24). Neonatal ovalbumin exposure triggered Th2-skewed sensitization and ovalbumin-specific IgE production. Subsequent ovalbumin inhalation in adulthood boosted Th2 immunity and caused asthmatic lungs with structural and functional alterations of airways. Gender difference mainly involved airway hyperresponsiveness and resistance with greater female susceptibility to methacholine bronchospastic stimulation. In lungs, heightened chemoattractant gene expressions were only granted to neonatally ovalbumin-sensitized mice with aerosolized ovalbumin stress in adulthood, and paralleled by upregulated Th2 cytokine genes. Thus, aeroallergen stress in atopic individuals might upregulate the expression of intrapulmonary chemoattractants to recruit Th2 cells and eosinophils into the lungs, pathogenically linked to asthma development. Conclusively, murine neonates were sensitive to allergen exposures. Exposure events during neonatal stages were crucial to asthma predisposition in later life. These findings from a murine model point to allergen avoidance in neonatal life, possibly even very early in utero, as the best prospect of primary asthma prevention.

In trans neuregulin3-Caspr3 interaction controls DA axonal bassoon cluster development

Dopamine (DA) transmission is critical to motivation, movement, and emotion. Unlike glutamatergic and GABAergic synapses, the development of DA synapses is less understood. We show that bassoon (BSN) clusters along DA axons in the core of nucleus accumbens (NAcc) were increased in neonatal stages and reduced afterward, suggesting DA synapse elimination. Remarkably, DA neuron-specific ablating neuregulin 3 (NRG3), a protein whose levels correlate with BSN clusters, increased the clusters and impaired DA release and behaviors related to DA transmission. An unbiased screen of transmembrane proteins with the extracellular domain (ECD) of NRG3 identified Caspr3 (contactin associate-like protein 3) as a binding partner. Caspr3 was enriched in striatal medium spiny neurons (MSNs). NRG3 and Caspr3 interact in trans, which was blocked by Caspr3-ECD. Caspr3 null mice displayed phenotypes similar to those in DAT-Nrg3f/f mice in DA axonal BSN clusters and DA transmission. Finally, invivo disruption of the NRG3-Caspr3 interaction increased BSN clusters. Together, these results demonstrate that DA synapse development is controlled by trans interaction between NRG3 in DA neurons and Caspr3 in MSNs, identifying a novel pair of cell adhesion molecules for brain circuit wiring.

Incidence and risk factors of congenital heart disease in Qingdao: a prospective cohort study

BackgroundMany studies have been conducted to assess the incidence of congenital heart disease (CHD). However, results were greatly inconsistent among these studies with a broad range of findings.MethodsA prospective census-based cohort study was conducted in Qingdao, China, from August 1, 2018 to April 30, 2019. All of the local registered pregnant women were continuously investigated and followed from 15 to 20 weeks of gestation to delivery, tracking the CHD cases in both the fetal and neonatal stages. A logistic regression model was applied to assess the association between CHD and possible risk factors.ResultsThe positive rate of prenatal CHD screening was 14.36 per 1000 fetuses and the incidence of CHD was 9.38 per 1000 live births. Results from logistic regression indicated that, living in the countryside (odds ratio, (OR): 0.771; 95% confidence interval, (CI): 0.628–0.946) and having a childbearing history (OR: 0.802; 95%CI: 0.676–0.951) were negatively associated with CHD. However, twin pregnancy (OR: 1.957, 95% CI: 1.245–3.076), illness in the first trimester (OR: 1.306; 95% CI: 1.048–1.628), a family history of CHD (OR: 7.156; 95% CI: 3.293–15.552), and having a child with a birth defect (OR: 2.086; 95% CI: 1.167–3.731) were positively associated with CHD.ConclusionCHD is a serious health problem in Qingdao. The CHD incidence found in this study was similar to existing research. The positive rate of prenatal CHD screening was higher than the incidence of neonatal CHD. Moreover, CHD risk factors were identified in our study, and our findings may have great implications for formation CHD intervention strategies.

Renal insufficiency in children born preterm: examining the role of neonatal acute kidney injury.

To identify the prevalence of renal insufficiency (RI) in children with a history of prematurity and acute kidney injury (AKI). This prospective cohort study evaluated renal function in children born preterm at 5-9 years of age. Univariable analyses compared perinatal and follow-up data from subjects with and without AKI history, and with and without current RI. Regression analyses were attempted to model RI as a function of AKI and other clinical risk factors. Fifteen of 43 (35%) participants had previously undiagnosed RI. Only children with no AKI history or neonatal stage 1 AKI presented for follow-up. Children born preterm with a history of stage 1 AKI had higher serum creatinine (sCr) at follow-up, but were not more likely to have RI compared to children without stage 1 AKI history (RI prevalence 30% and 36% in AKI and non-AKI group, respectively). The high prevalence of RI in this preterm cohort at middle childhood follow-up highlights the need for routine kidney health assessments in this population. Large multicenter studies are needed to further characterize the impact of premature birth and mild AKI on renal function throughout childhood.

Selective ablation of inner hair cells and subsequent in-situ hair cell regeneration in the neonatal mouse cochlea

Loss of hair cells (HCs) accounts for most sensorineural hearing loss, and regeneration of cochlear HCs is considered as the ultimate strategy for restoring hearing. Several lines of evidence have shown that Lgr5+ progenitor cells can spontaneously regenerate new HCs after HC loss at the neonatal stage, and most of which are immature. IHCs are resistant to ototoxic drugs and noise and cannot be ablated efficiently in order to precisely investigate IHC regeneration in existing hearing injury models, and thus we generated a new transgenic mouse model by inserting diphtheria toxin receptor (DTR) under the control of the Vglut3 promoter. In this model, IHCs were selectively ablated in a dose-dependent manner after the injection of diphtheria toxin (DT) at the neonatal stage, while OHCs remained intact with normal hair bundle structures until adulthood. With this IHC-specific injury model, we observed HC regeneration from Lgr5+ progenitors after IHC ablation at the neonatal stage. Some of the newly generated HCs replaced the lost IHCs in-situ and re-build the structure of the organ of Corti through the asymmetrical mitosis of progenitor cells. While, the majority of the regenerated HCs did not survive until adulthood, and the loss of spiral ganglion neurons was observed after the IHC ablation, which led to profound hearing loss after DT injection in Vglut3DTR+ mice at the neonatal stage. The model presented here shows promise for investigating the mechanisms behind IHC loss and subsequent regeneration.

VEGF receptor 2 (KDR) protects airways from mucus metaplasia through a Sox9-dependent pathway.

Mucus-secreting goblet cells are the dominant cell type in pulmonary diseases, e.g., asthma and cystic fibrosis (CF), leading to pathologic mucus metaplasia and airway obstruction. Cytokines including IL-13 are the major players in the transdifferentiation of club cells into goblet cells. Unexpectedly, we have uncovered a previously undescribed pathway promoting mucous metaplasia that involves VEGFa and its receptor KDR. Single-cell RNA sequencing analysis coupled with genetic mouse modeling demonstrates that loss of epithelial VEGFa, KDR, or MEK/ERK kinase promotes excessive club-to-goblet transdifferentiation during development and regeneration. Sox9 is required for goblet cell differentiation following Kdr inhibition in both mouse and human club cells. Significantly, airway mucous metaplasia in asthmatic and CF patients is also associated with reduced KDR signaling and increased SOX9 expression. Together, these findings reveal an unexpected role for VEGFa/KDR signaling in the defense against mucous metaplasia, offering a potential therapeutic target for this common airway pathology.

Evaluación de la función tiroidea en el recién nacido pretérmino o de muy bajo peso

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 (1500-1000g VLBW or <1000g) 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.