Effect of Maternal Preeclampsia on Cardiac Structure and Function in Very Low Birth Weight Infants.

OBJECTIVE: We aimed to determine whether exposure to severe maternal preeclampsia (PE) in very low birth weight (VLBW) infants is associated with hypertrophic cardiac changes and altered hemodynamics. STUDY DESIGN: Case-control study of VLBW infants born at Los Angeles General Medical Center from May 2015 to August 2023, who had an echocardiogram within the first 7 days of life. Cases were infants exposed to maternal PE and controls were infants not exposed to maternal PE matched by birth weight (BW) 1:1. Laboratory, placental pathology results, hemodynamic data and clinical outcomes were collected and compared between cases and control infants. RESULTS: A total of 43 cases matched by BW with control infants were studied. There were no significant anatomical cardiac changes by echocardiography between cases and control infants. Cases had significantly higher blood pressure within the first 72 hours of life and lower ejection fraction (EF), fractional shortening, and peak systolic flow velocity through their patent ductus arteriosus (PDA) within the first week of life. Cases were more likely to be smaller despite being born at a later gestational age (GA), as well as small for GA with placental weight less than 10th percentile compared to control infants. CONCLUSION: Our findings indicate that infants born to mothers with PE have higher systemic vascular resistance as evidenced by elevated blood pressure, and lower EF and shortening fraction and higher pulmonary vascular resistance as evidenced by lower peak flow velocity through the PDA. We did not observe hypertrophic cardiac changes in exposed infants. These findings should be considered in clinical decision-making during management of these infants. KEY POINTS: · VLBW infants exposed to severe PE have higher rate of Small for gestational age and smaller placentas.. · VLBW infants exposed to severe PE have higher systemic vascular resistance during transitional period and lower EF and fractional shortening.. · VLBW infants exposed to severe PE have higher pulmonary vascular resistance..

Wnt5a Promotes AT1 and Represses AT2 Lineage-Specific Gene Expression in a Cell-Context-Dependent Manner.

Lung maturation is not limited to proper structural development but also includes differentiation and functionality of various highly specialized alveolar cell types. Alveolar type 1 (AT1s) cells occupy nearly 95% of the alveolar surface and are critical for establishing efficient gas exchange in the mature lung. AT1 cells arise from progenitors specified during the embryonic stage as well as alveolar epithelial progenitors expressing surfactant protein C (Sftpcpos cells) during postnatal and adult stages. Previously, we found that Wnt5a, a non-canonical Wnt ligand, is required for differentiation of AT1 cells during the saccular phase of lung development. To further investigate the role of Wnt5a in AT1 cell differentiation, we generated and characterized a conditional Wnt5a gain-of-function mouse model. Neonatal Wnt5a gain-of-function disrupted alveologenesis through inhibition of cell proliferation. In this setting Wnt5a downregulated ß-catenin-dependent canonical Wnt signaling, repressed AT2 (anti-AT2) and promoted AT1 (pro-AT1) lineage-specific gene expression. In addition, we identified 2 subpopulations of Sftpchigh and Sftpclow alveolar epithelial cells. In Sftpclow cells, Wnt5a exhibits pro-AT1 and anti-AT2 effects, concurrent with inhibition of canonical Wnt signaling. Interestingly, in the Sftpchigh subpopulation, although increasing AT1 lineage-specific gene expression, Wnt5a gain-of-function did not change AT2 gene expression, nor inhibit canonical Wnt signaling. Using primary epithelial cells isolated from human fetal lungs, we demonstrate that this property of Wnt5a is evolutionarily conserved. Wnt5a therefore serves as a selective regulator that ensures proper AT1/AT2 balance in the developing lung.

Assessment and management of neonates with unrepaired congenital heart disease.

PURPOSE OF REVIEW: To review preoperative assessment and management of neonates with congenital heart disease (CHD). RECENT FINDINGS: The spectrum for neonates with CHD can be wide and complex. An in-depth understanding of their physiology is the first step in assessing their hemodynamics and developing an effective therapeutic strategy. SUMMARY: There is significant heterogeneity in the anatomy and physiology in newborns with CHD. Their complex pathophysiology can be simplified into seven basic subtypes, which include systolic dysfunction, diastolic dysfunction, excessive pulmonary blood flow, obstructed pulmonary blood flow, obstructed systemic blood flow, transposition physiology, and single ventricle physiology. It is important to note these physiologies are not mutually exclusive, and this review summarizes the hemodynamic and therapeutic strategies available for the preoperative neonate with CHD.

Hedgehog-responsive PDGFRa(+) fibroblasts maintain a unique pool of alveolar epithelial progenitor cells during alveologenesis.

The lung alveolus is lined with alveolar type 1 (AT1) and type 2 (AT2) epithelial cells. During alveologenesis, increasing demand associated with expanding alveolar numbers is met by proliferating progenitor AT2s (pAT2). Little information exists regarding the identity of this population and their niche microenvironment. We show that during alveologenesis, Hedgehog-responsive PDGFRa(+) progenitors (also known as SCMFs) are a source of secreted trophic molecules that maintain a unique pAT2 population. SCMFs are in turn maintained by TGFß signaling. Compound inactivation of Alk5 TßR2 in SCMFs reduced their numbers and depleted the pAT2 pool without impacting differentiation of daughter cells. In lungs of preterm infants who died with bronchopulmonary dysplasia, PDGFRa is reduced and the number of proliferative AT2s is diminished, indicating that an evolutionarily conserved mechanism governs pAT2 behavior during alveologenesis. SCMFs are a transient cell population, active only during alveologenesis, making them a unique stage-specific niche mesodermal cell type in mammalian organs.

Decoding the IGF1 signaling gene regulatory network behind alveologenesis from a mouse model of bronchopulmonary dysplasia.

Lung development is precisely controlled by underlying gene regulatory networks (GRN). Disruption of genes in the network can interrupt normal development and cause diseases such as bronchopulmonary dysplasia (BPD) - a chronic lung disease in preterm infants with morbid and sometimes lethal consequences characterized by lung immaturity and reduced alveolarization. Here, we generated a transgenic mouse exhibiting a moderate severity BPD phenotype by blocking IGF1 signaling in secondary crest myofibroblasts (SCMF) at the onset of alveologenesis. Using approaches mirroring the construction of the model GRN in sea urchin's development, we constructed the IGF1 signaling network underlying alveologenesis using this mouse model that phenocopies BPD. The constructed GRN, consisting of 43 genes, provides a bird's eye view of how the genes downstream of IGF1 are regulatorily connected. The GRN also reveals a mechanistic interpretation of how the effects of IGF1 signaling are transduced within SCMF from its specification genes to its effector genes and then from SCMF to its neighboring alveolar epithelial cells with WNT5A and FGF10 signaling as the bridge. Consistently, blocking WNT5A signaling in mice phenocopies BPD as inferred by the network. A comparative study on human samples suggests that a GRN of similar components and wiring underlies human BPD. Our network view of alveologenesis is transforming our perspective to understand and treat BPD. This new perspective calls for the construction of the full signaling GRN underlying alveologenesis, upon which targeted therapies for this neonatal chronic lung disease can be viably developed.

Persistence of fecal indicator bacteria in Santa Monica Bay beach sediments.

Monitoring the water quality of recreational beaches is only one step toward understanding microbial contamination -- the primary cause of beach closings. The surf zone sediment reservoir is typically overlooked and may also be important. This study involved monitoring the fecal indicator bacteria (FIB) levels in water and sediment at three ocean beaches (two exposed and one enclosed) during a storm event, conducting laboratory microcosm experiments with sediment from these beaches, and surveying sediment FIB levels at 13 beaches (some exposed and some enclosed). Peaks in Escherichia coli and enterococci concentrations in water and sediment coincided with storm activity at the two exposed beaches, while levels of both FIB were consistently high and irregular at the enclosed beach. Results from microcosm experiments showing similar, dramatic growth of FIB in both overlying water and sediment from all beaches, as well as results from the beach survey, support the hypothesis that the quiescent environment rather than sediment characteristics can explain the elevated sediment FIB levels observed at enclosed beaches. This work has implications for the predictive value of FIB measurements, and points to the importance of the sediment reservoir.

Effect of chemical speciation on toxicity of mercury to Escherichia coli biofilms and planktonic cells.

While it is known that microbial uptake of mercury (Hg) by planktonic cultures is influenced by the extracellular speciation of mercury in aquatic systems, Hg uptake in biofilm cultures is understudied. We compared the importance of Hg(II) speciation in toxicity to both planktonic and biofilm cultures of the Gram-negative bacterium Escherichia coli 055. Variable chloride chemistry experiments were carried out to modify mercury speciation. Biofilms were observed to be more resistant to Hg than planktonic cells. In both planktonic and biofilm cultures, the toxicity of Hg increased and then decreased along the chloride gradient. The percent reduction in cell viability was linearly related to the concentration of HgCl2(0) when Hg-chloro complexes dominated the speciation, consistent with a passive diffusion model. However, toxicity to both planktonic cells and biofilms at low salinities could not be explained by passive diffusion alone, which suggests that microbial uptake of Hg in both planktonic cells and biofilms may occur by both passive diffusion of neutral species and facilitated uptake. The relationship between toxicity and chloride concentration was similar in the presence and absence of a biofilm, indicating that the presence of the biofilm does not drastically change the relative availability of the dominant mercury species.