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Background:Intrauterine growth restriction (IUGR) exerts a negative impact on developing cardiomyocytes and emerging evidence suggests activation of oxidative stress pathways plays a key role in this altered development. Here, we provided pregnant guinea pig sows with PQQ, an aromatic tricyclic o-quinone that functions as a redox cofactor antioxidant, during the last half of gestation as a potential antioxidant intervention for IUGR-associated cardiomyopathy.Methods:Pregnant guinea pig sows were randomly assigned to receive PQQ or placebo at mid gestation and fetuses were identified as spontaneous IUGR (spIUGR) or normal growth (NG) near term yielding four cohorts: NG ± PQQ and spIUGR ± PQQ. Cross sections of fetal left and right ventricles were prepared and cardiomyocyte number, collagen deposition, proliferation (Ki67) and apoptosis (TUNEL) were analyzed.Results:Cardiomyocyte endowment was reduced in spIUGR fetal hearts when compared to NG; however, PQQ exerted a positive effect on cardiomyocyte number in spIUGR hearts. Cardiomyocytes undergoing proliferation and apoptosis were more common in spIUGR ventricles when compared with NG animals, which was significantly reduced with PQQ supplementation. Similarly, collagen deposition was increased in spIUGR ventricles and was partially rescued in PQQ-treated spIUGR animals.Conclusion:The negative influence of spIUGR on cardiomyocyte number, apoptosis, and collagen deposition during parturition can be suppressed by antenatal administration of PQQ to pregnant sows. These data identify a novel therapeutic intervention for irreversible spIUGR-associated cardiomyopathy.

Blood product transfusions are necessary for critically ill neonates on extracorporeal membrane oxygenation (ECMO). Transfusions are administered in response to unstudied arbitrary thresholds and may be associated with adverse outcomes. The objective of this study was to identify relationships between blood product components and mortality in neonates receiving ECMO support for respiratory indications.A retrospective review of neonates receiving ECMO for respiratory indications from 2002 to 2019 from a single quaternary-referral neonatal intensive care unit (NICU). Demographic and outcome data and transfusion volume (ml/kg/day) were harvested from the medical record, and baseline mortality risk was assessed using NEO-RESCUERS scores. The association between volume of red blood cells (RBC), platelet, plasma transfusion rates (ml/kg/day), and mortality on ECMO were assessed after adjustment for NEO-RESCUERS score. Cox proportional hazards (CPH) competing risk model was used to estimate hazard ratios (HR) and 95% confidence intervals (CI) for each variable and mortality outcome.Among 248 neonates undergoing ECMO for respiratory failure, overall survival was 93%. RBC, platelet, and plasma volume were highly associated with mortality during ECMO in an unadjusted model. After adjusting for NEO-RESCUERS score, RBC volume was associated with increased mortality risk (HR 1.013, 95% CI 1.004-1.022, p = .0043), but platelet and plasma volume were not associated with mortality.RBC, but not platelet or plasma volume, is associated with mortality in neonates on ECMO. Our findings refute previous studies demonstrating an association between platelet volume and mortality for neonates on ECMO.

Background Breast milk feedings are the optimal feeding choice for premature infants. Clinicians depend on accurate nutrient profiles of the breast milk in order to make informed decisions regarding the need for nutrient supplementation. Existing data for nutrient composition of preterm breast milk are dated and not representative of the current population of women delivering prematurely in the United States. Objectives The purpose of this prospective, longitudinal, single-center observational study was to measure the macronutrient and micronutrient composition of breast milk expressed by mothers, including women who self-identify as black, delivering preterm infants at ≤33 completed weeks of gestation. Methods We collected breast milk samples from mothers of preterm infants admitted to the neonatal intensive care unit at Augusta University Medical Center from January 2019 through November 2019. Mother's milk samples were collected on postpartum days 7, 14, 21, and 28 and analyzed for macronutrients (energy, fat, protein, and carbohydrates) and micronutrients (sodium, potassium, chloride, calcium, phosphorus, magnesium, vitamin D, and zinc). Results Thirty-eight mothers, mean age 27 ± 5.1 y and majority black (66%), provided milk for the study. The mean estimated gestational age and birth weight were 28.2 ± 2.8 weeks of gestation and 1098 ± 347 g, respectively, with 42% of mothers in the cohort delivering before week 28 of pregnancy. Differences in protein, sodium, potassium, calcium, phosphorus, and zinc concentrations based on race, day, and milk volume were identified. Dilution effects for protein, sodium, chloride, and vitamin D concentrations over time were identified. Conclusions Our study is among the first to characterize breast milk composition from women who delivered extremely preterm infants and adds to the evidence that race, gestational age, and volume influence the composition of preterm mother's milk. These factors should be considered when designing mother's milk-based feeds for premature infants.

Background Currently, reference ranges for renal oxygenation measured by near-infrared spectroscopy (NIRS) in preterm infants beyond the first days of life are lacking, especially those born prior to 29 weeks' gestation. Population estimates of renal oxygenation (rSO2) levels among preterm infants over time have yet to be established, leading to reluctance in clinical application. Purpose To characterize the distribution and estimate population parameters for renal oxygenation measured by NIRS during the first 14 days of life among preterm infants. Methods We prospectively observed rSO2 trends of 37 infants before 34 weeks' gestation and 1800-g or less birth weight for the first 14 days of life. Analyses included distribution fit tests, ordinary least squares (OLS) regression, and t tests. Results Average daily rSO2 variation steadily increased with 42% difference through the first 14 days of life. For all infants, renal rSO2 means peaked during the first 3 days of life and plateaued around 7 days. Daily rSO2 slopes were significantly lower among males and infants 29 weeks' or less gestation. Implications for practice Renal rSO2 during the first 14 days of life reflects normal extrauterine transition reaching stabilization around 7 days of life. Gestational age, birth weight, and gender may predict the early trajectory of rSO2 patterns. Population estimates provide parameters for renal rSO2 that may indicate early-onset tissue hypoxia when acute or significant drops from baseline occur. Implications for research We present a framework to guide future research using renal NIRS technology in preterm infants to determine deviations from expected trends that may precede renal injury.

Background Length of stay (LOS) is an important measure of quality; however, estimating LOS for rare populations such as gastroschisis is problematic. Our objective was to identify explanatory variables for LOS and build a model to estimate LOS in neonates with simple gastroschisis. Methods In 73 neonates with simple gastroschisis (47% female, 67% White), statistical correlations for 31 potential explanatory variables for LOS were evaluated using multivariate linear regression. Poisson regression was used to estimate LOS in predetermined subpopulations, and a life table model was developed to estimate LOS for simple gastroschisis. Results Female sex (−2.4 d), “time to silo placement” (0.9 d), total parenteral nutrition days (0.6 d), need for any nasogastric feedings (11.4 d) and at discharge (−7 d), “feeding tolerance” (0.4 d), days to first postoperative stool (−0.3 d), and human milk exposure (−3.4 d) associated with LOS in simple gastroschisis. Estimated LOS for preterm neonates was longer than term infants (5.4 versus 4.6 wk) but similar for estimates based on sex and race. Based on these associations, we estimate that >50% of neonates with simple gastroschisis will be discharged by hospital day 35. Conclusions We identified several associations that explained variations in LOS and developed a novel model to estimate LOS in simple gastroschisis, which may be applied to other rare populations.

Neurofibromatosis type 1 (NF1) is a heritable cancer predisposition syndrome resulting from mutations in the NF1 tumor suppressor gene. Genotype-phenotype correlations for NF1 are rare due to the large number of NF1 mutations and role of modifier genes in manifestations of NF1; however, emerging reports suggest that persons with NF1 display a distinct anthropometric and metabolic phenotype featuring short stature, low body mass index (BMI), increased insulin sensitivity, and protection from diabetes. Nf1 heterozygous (Nf1+/−) mice accurately reflect the dominant inheritance of NF1 and are regularly employed as a model of NF1. Here, we sought to identify whether Nf1+/− mice recapitulate the anthropometric and metabolic features identified in persons with NF1. Littermate 16–20 week-old male wildtype (WT) and Nf1+/− C57B/6J mice underwent nuclear magnetic resonance (NMR), indirect calorimetry, and glucose/insulin/pyruvate tolerance testing. In some experiments, tissues were harvested for NMR and histologic characterization. Nf1+/− mice are leaner with significantly reduced visceral and subcutaneous fat mass, which corresponds with an increased density of small adipocytes and reduced leptin levels. Additionally, Nf1+/− mice are highly reliant on carbohydrates as an energy substrate and display increased glucose clearance and insulin sensitivity, but normal response to pyruvate suggesting enhanced glucose utilization and preserved gluconeogenesis. Finally, WT and Nf1+/− mice subjected to high glucose diet were protected from diet-induced obesity and hyperglycemia. Our data suggest that Nf1+/− mice closely recapitulate the anthropometric and metabolic phenotype identified in persons with NF1, which will impact the interpretation of previous and future translational studies of NF1.

The health benefits of breast milk feeding have been well-established, yet disparities exist, with African American mothers having the lowest breast milk feeding rates in the United States. This prospective, longitudinal study examined infant feeding (breast milk and/or infant formula) from birth to age 16 weeks, predictors of any breast milk feeding by age 1 week, and predictors of cessation of any breast milk feeding by ages 3, 8, and 16 weeks among primiparous African American mothers. This secondary analysis included 185 mother–infant dyads from the Sleep SAAF (Strong African American Families) study, a randomized clinical trial testing a responsive parenting vs. child safety control intervention. Mothers reported sociodemographic and psychosocial characteristics at age 1 week and infant feeding practices at ages 1, 3, 8, and 16 weeks. Rates of any breast milk feeding decreased from 66.5% at 1 week to 23.3% at 16 weeks. Bivariate logistic regression models showed that prepregnancy BMI (OR = 1.09), working prepregnancy (OR = 2.25), and food insecurity (OR = 2.49) significantly increased the odds of mothers feeding any breast milk by 1 week, whereas Special Supplemental Nutrition Program for Women, Infants, and Children (WIC) participation (OR = 0.21) significantly decreased the odds. Bivariate logistic regression models showed that Supplemental Nutrition Assistance Program (SNAP) participation (OR = 2.86) and racial discrimination (OR = 2.14) significantly increased the odds of cessation of any breast milk feeding by 3 weeks. SNAP (OR = 2.33) and WIC (OR = 2.38) participation significantly increased the odds of cessation of any breast milk feeding by 8 weeks, whereas higher prepregnancy BMI (OR = 0.95) decreased the odds. Higher mother’s age (OR = 0.92) significantly decreased the odds of cessation of any breast milk feeding by 16 weeks. The findings can be used to inform targeted interventions to promote mothers feeding any breast milk and help reduce breast milk feeding disparities among African American mothers.

Background The human milk-fed preterm infant is at risk for growth failure, micronutrient deficiencies, and neurocognitive delay. Although protective and better tolerated than formula, human milk alone cannot meet the high nutrient requirements of this population, and fortification is necessary. Clinicians use assumptions of preterm human-milk composition to determine the type and quantity of fortification. Objectives The objectives of this review were to identify evidence of macronutrient and micronutrient concentration in preterm human milk and to identify knowledge gaps regarding composition. Methods PubMed and the Cumulative Index to Nursing and Allied Health Literature were used to identify original articles published between January 1950 and December 2019. Results Twenty-seven articles were found containing original data on macronutrients and micronutrients. Most (67%) of the studies published after 2011 measured the macronutrients and included gestational ages from 28 to 36 weeks. Milk collection methods, experimental design, and analytical methods varied between studies. There are 15 countries represented in this review; all of the American studies (n = 7) were published from 1980 to 1984. Conclusions African American women, or women delivering before 28 weeks' gestation are not represented in the literature. Accurate and targeted human-milk fortification depends on comprehensive, complete, and representative human-milk nutrient data. We have aggregated all available preterm human-milk macronutrient and micronutrient data and reported trends associated with lactation stage and gestational age. This report can aid in the design of feeding plans that are appropriate for the gestational age of the preterm infant and the lactation stage of the breastmilk.

Central vascular thrombosis (CVT) in critically ill neonates carries significant clinical implications. Neonates with congenital heart disease (CHD) awaiting cardiac intervention might be associated with increased risk of thrombosis. Outcome analysis was undertaken. An analysis of 77 neonates with CHD who were admitted to the NICU prior to cardiac intervention between January 2015 and December 2016 was undertaken. Patients requiring extracorporeal life support prior to any cardiac intervention, or receiving prophylactic anticoagulation not related to central vascular catheter (CVC) were excluded. Diagnosis of CVT was provided based on clinical indication and verified with imaging that warranted anticoagulation therapy. Location of CVC and extent of CVT along with treatments, outcomes, and vascular access types and durations were assessed. Logistic regression multivariate analysis was used to assess predictors of outcome. Neonates with CHD were complicated with CVT in 10.4%. Longer duration of CVC was also associated with thrombosis in neonates with CHD (72.7 days vs. 29.3 days, p

Responsive parenting (RP) interventions reduce rapid infant weight gain but their effect for underserved populations is largely unknown. The Sleep SAAF (Strong African American Families) study is a two-arm randomized clinical trial for primiparous African American mother-infant dyads that compares an RP intervention to a child safety control over the first 16 weeks postpartum. Here we report on intervention effects on rapid infant weight gain and study implementation. Families were recruited from a mother/baby nursery shortly after delivery. Community Research Associates (CRAs) conducted intervention home visits at 3 and 8 weeks postpartum, and data collection home visits at 1, 8, and 16 weeks postpartum. To examine rapid infant weight gain, conditional weight gain (CWG) from 3 to 16 weeks, the primary outcome, and upward crossing of 2 major weight-for-age percentile lines were calculated. Among the 212 mother-infant dyads randomized, 194 completed the trial (92% retention). Randomized mothers averaged 22.7 years, 10% were married, and 49% participated in the Supplemental Nutrition Assistance Program (SNAP). Adjusting for covariates, mean CWG was lower among RP infants (0.04, 95% CI [-0.33, 0.40]) than among control infants (0.28, 95% CI [-0.08, 0.64]), reflecting non-significantly slower weight gain (p = 0.15, effect size d = 0.24). RP infants were nearly half as likely to experience upward crossing of 2 major weight-for-age percentile lines (14.1%) compared to control infants (24.2%), p = 0.09, odds ratio = 0.52 (95% CI [0.24, 1.12]). Implementation data revealed that participating families were engaged in the intervention visits and intervention facilitators demonstrated high fidelity to intervention materials. Findings show that RP interventions can be successfully implemented among African American families while suggesting the need for modifications to yield stronger effects on infant weight outcomes.

Accumulation of lipid-laden foam cells in the arterial wall plays a central role in atherosclerotic lesion development, plaque progression, and late-stage complications of atherosclerosis. However, there are still fundamental gaps in our knowledge of the underlying mechanisms leading to foam cell formation in atherosclerotic arteries. Here, we investigated the role of receptor-independent macropinocytosis in arterial lipid accumulation and pathogenesis of atherosclerosis. Genetic inhibition of fluid-phase macropinocytosis in myeloid cells ( LysMCre + Nhe1 fl/fl ) and repurposing of a Food and Drug Administration (FDA)–approved drug that inhibits macrophage macropinocytosis substantially decreased atherosclerotic lesion development in low-density lipoprotein (LDL) receptor–deficient and Apoe −/− mice. Stimulation of macropinocytosis using genetic ( H-RAS G12V ) and physiologically relevant approaches promoted internalization of unmodified native (nLDL) and modified [e.g., acetylated (ac) and oxidized (ox) LDL] lipoproteins in both wild-type and scavenger receptor (SR) knockout ( Cd36 −/− / Sra −/− ) macrophages. Pharmacological inhibition of macropinocytosis in hypercholesterolemic wild-type and Cd36 −/− / Sra −/− mice identified an important role of macropinocytosis in LDL uptake by lesional macrophages and development of atherosclerosis. Furthermore, serial section high-resolution imaging, LDL immunolabeling, and three-dimensional (3D) reconstruction of subendothelial foam cells provide visual evidence of lipid macropinocytosis in both human and murine atherosclerotic arteries. Our findings complement the SR paradigm of atherosclerosis and identify a therapeutic strategy to counter the development of atherosclerosis and cardiovascular disease.

ImportanceBlack individuals in the US experience sleep disparities beginning in infancy and continuing throughout the lifespan, suggesting early interventions are needed to improve sleep.ObjectiveTo investigate whether a responsive parenting (RP) intervention for Black mothers improves infant sleep and increases responsive sleep parenting practices.Design, Setting, and ParticipantsThis is a post hoc secondary analysis of the Sleep SAAF (Strong African American Families) study, a randomized clinical trial comparing an RP intervention with a safety control condition over the first 16 weeks post partum. Data were collected between spring 2018 and summer 2021. Families were recruited from the mother-infant nursery at Augusta University Medical Center, Augusta, Georgia, and completed home visits at 1, 3, 8, and 16 weeks post partum. Primiparous Black mother-infant dyads were screened for eligibility using medical records. Results were analyzed on an intention-to-treat model. Data were analyzed from March 2022 to January 2023.InterventionsThe RP intervention curriculum focused on infant sleep, soothing and crying, and feeding. The control group received a safety intervention. Community research associates delivered the interventions during home visits at 3 and 8 weeks post partum.Main Outcomes and MeasuresThe primary end point was infant sleep duration at 16 weeks. Mothers reported on bedtime routine and sleep behaviors, infant sleep duration, and nighttime waking and feeding at 8 and 16 weeks post partum using questionnaires.ResultsA total of 212 Black mothers (mean [SD] age, 22.7 [4.5] years) were randomized, including 208 mothers (98.6%) who identified as non-Hispanic and 3 mothers (1.4%) who identified as Hispanic; 108 mothers were randomized to the RP group and 104 mothers were randomized to the control group. At 16 weeks post partum, infants in the RP group had longer reported nighttime sleep duration (mean difference, 40 [95% CI, 3 to 77] minutes), longer total sleep duration (mean difference, 73 [95% CI, 14 to 131] minutes), fewer nighttime wakings (mean difference, −0.4 [95% CI, −0.6 to −0.1] wakings), and greater likelihood of meeting guidelines of at least 12 hours of total sleep per day (risk ratio [RR], 1.4 [95% CI, 95% CI, 1.1 to 1.8]) than controls. Relative to controls, mothers in the RP group more frequently reported engaging in some RP practices, including giving the baby a few minutes to fall back asleep on their own (RR, 1.6 [95% CI, 1.0 to 2.6]) and being less likely to feed their baby as the last activity before bed (RR, 0.5 [95% CI, 0.3 to 0.8]).Conclusions and RelevanceThis secondary analysis of a randomized clinical trial found that an RP intervention for Black families improved infant sleep and increased some responsive sleep parenting practices.Trial RegistrationClinicalTrials.gov Identifier: NCT03505203

Background The objective of this study was to determine whether human milk supplemented with a novel human milk-based human milk fortifier (Novel HMF), compared with a bovine milk-based HMF (Bovine HMF), supports preterm infant growth through 36 weeks' postmenstrual age (PMA). Methods This single-center, prospective trial compared growth and nutrition outcomes of preterm infants provided a human milk-based diet (mother's own milk or donor milk) supplemented with a Novel HMF with historic controls provided Bovine HMF. Preterm infants with an estimated gestational age (EGA) between 23 and 33 weeks' PMA and birth weight between 750 and 1800 g were eligible for study inclusion. Weight, length, and head circumference (HC) were monitored weekly. The occurrence of late-onset sepsis, nil per os (NPO) days, necrotizing enterocolitis, metabolic acidosis, and serious adverse events were monitored. Results Birth weight, length, HC, and EGA were similar between the Novel HMF (n = 37) and Bovine HMF (n = 49) groups. The days to regain birth weight was shorter in the Novel HMF group (9.4 ± 4.0 vs 11.4 ± 4.8, P = .0343), with similar weight gain (g/day) from birth to 36 weeks' PMA. Adjusted weight growth velocity (g/kg/day) was significantly higher in the Novel HMF group at 14 and 21 days but similar at 36 weeks' PMA. The Novel HMF group experienced fewer NPO days with a similar total number of feeding days. Conclusions A novel, multinutrient, human milk-based HMF is well tolerated and meets the nutrition needs of preterm infants.

Aims Chronic adventitial and medial infiltration of immune cells play an important role in the pathogenesis of abdominal aortic aneurysms (AAAs). Nicotinic acid (niacin) was shown to inhibit atherosclerosis by activating the anti-inflammatory G protein-coupled receptor GPR109A [also known as hydroxycarboxylic acid receptor 2 (HCA2)] expressed on immune cells, blunting immune activation and adventitial inflammatory cell infiltration. Here, we investigated the role of niacin and GPR109A in regulating AAA formation. Methods and results Mice were supplemented with niacin or nicotinamide, and AAA was induced by angiotensin II (AngII) infusion or calcium chloride (CaCl2) application. Niacin markedly reduced AAA formation in both AngII and CaCl2 models, diminishing adventitial immune cell infiltration, concomitant inflammatory responses, and matrix degradation. Unexpectedly, GPR109A gene deletion did not abrogate the protective effects of niacin against AAA formation, suggesting GPR109A-independent mechanisms. Interestingly, nicotinamide, which does not activate GPR109A, also inhibited AAA formation and phenocopied the effects of niacin. Mechanistically, both niacin and nicotinamide supplementation increased nicotinamide adenine dinucleotide (NAD+) levels and NAD+-dependent Sirt1 activity, which were reduced in AAA tissues. Furthermore, pharmacological inhibition of Sirt1 abrogated the protective effect of nicotinamide against AAA formation. Conclusion Niacin protects against AAA formation independent of GPR109A, most likely by serving as an NAD+ precursor. Supplementation of NAD+ using nicotinamide-related biomolecules may represent an effective and well-tolerated approach to preventing or treating AAA.

Alterations in perinatal conditions (such as preterm birth) is linked to adult health and disease, in particular, the cardiovascular system. Neddylation, a novel posttranslational modification through which the ubiquitin-like protein NEDD8 is conjugated to protein substrates, has emerged as an important mechanism regulating embryonic cardiac chamber maturation. However, the importance of neddylation in postpartum cardiac development has not been investigated. Here, we aimed to determine whether transient, postnatal inhibition of neddylation has immediate and prolonged impact on the structure and function of the neonatal and adult hearts. Sprague-Dawley pups were given three intraperitoneal injections of MLN4924 (MLN), a specific neddylation inhibitor, at postnatal days (P)1, 3, and 5. Cardiac structure and function were temporally assessed during aging and after 2 wk of isoproterenol (ISO) infusion in adulthood. MLN treatment resulted in modest reduction of neddylated proteins in neonatal hearts. The MLN-treated rats developed cardiac hypertrophy and dysfunction by P7, which was accompanied by significantly reduced cardiomyocyte proliferation. At 3 mo of age, cardiac contractile function was restored in MLN-treated rats, but MLN-treated hearts displayed hypertrophic phenotype. Whereas ISO infusion triggered compensatory cardiac hypertrophy without impairing cardiac contractility in the control rats, the MLN-treated rats displayed a similar degree of hypertrophy, which quickly progressed to decompensation with ventricular wall thinning, chamber dilatation, and reduced ejection fraction as well as exacerbated pathological cardiac remodeling. Our findings suggest that neddylation is required for postnatal cardiac development and that perturbation of neddylation during development predisposes adult hearts to cardiac failure under stress conditions. NEW & NOTEWORTHY Our study demonstrates that perinatal perturbation of neddylation induces cardiomyopathy, impairs postnatal cardiac development, and increases susceptibility to catecholamine-induced cardiac dysfunction. The results reveal a previously unappreciated role of neddylation in postnatal cardiac maturation and call for close monitoring for the potential cardiotoxicity of MLN4924 (pevonedistat) and other agents that modify neddylation, especially in pregnant women and preadolescents.

Background Perinatal growth has important implications for cardiac development. Low birth weight is associated with cardiovascular (CV) events and mortality, and animal studies have shown that fetal growth restriction is associated with cardiac remodeling in the perinatal period leading to a permanent loss of cardiomyocyte endowment and compensatory hypertrophy. Aims To determine associations of birthweight (BW) and multiple proportionality indexes (body mass index (BMI); weight/length2 and Ponderal index (PI); weight/length3) at birth on one hand, with left ventricular (LV) structure and function during adolescence. Subjects 379 healthy adolescents aged 14–18 years in Augusta, Georgia. Outcome measures LV structure and function parameters, including intraventricular septal thickness in diastole (IVSd), LV internal dimension in diastole (LVIDd), LV internal diameter in systole (LVIDs), LV posterior wall thickness in diastole (LVPWd), relative wall thickness (RWT), midwall fractional shortening (MFS), and ejection fraction, were assessed by echocardiography. Results When associations of birthweight, birth BMI, and birth PI with LV structure and function parameters were separately evaluated with linear regression adjusting for age, sex, race, Tanner stage, socioeconomic status, and physical activity, significant positive associations of BW with LVIDd (P = 0.004), birth BMI with LV mass index (P = 0.01), and birth PI with IVSd (P = 0.02), LVPWd (P = 0.03), and LV mass index (P = 0.002) were identified. When LV structure and function parameters were compared across PI tertiles, a significant U-shaped trend for LV mass index (Pquadratic = 0.04) was identified. Conclusions Our adolescent data suggest that proportionality at birth may identify associations between perinatal growth and cardiac remodeling independent of birthweight alone.

Introduction: The objectives of this retrospective cohort study were to examine the effect of vitamin K administration on hemorrhagic and thrombotic complications, blood product utilization, and outcomes in neonatal extracorporeal membrane oxygenation (ECMO). Methods: In the pilot study, complications, blood product use, and outcome data for neonates who received ( n = 21) or did not receive ( n = 18) a single dose of vitamin K (5 mg) immediately after initiation of ECMO for respiratory failure between 2006 and 2010 were compared. In the validation cohort, complications and outcomes were compared for 74 consecutive neonates supported with ECMO for respiratory failure who received ( n = 45) or did not receive ( n = 29) additional vitamin K once daily for prothrombin time (PT) ⩾14 seconds during ECMO from 2014 to 2019. Results: In the pilot study, vitamin K at ECMO initiation was associated with fewer thrombotic complications and similar hemorrhagic complications. The volume of fresh frozen plasma was higher in neonates who received vitamin K, but total blood product and other component volume did not differ between groups. ECMO run time, survival off ECMO, survival to discharge, and length of stay did not differ between cohorts. In the validation cohort, neonates who received additional vitamin K during ECMO had longer ECMO run time and length of stay, but no difference in mortality was observed. Further, thrombotic and hemorrhagic complications as well as blood product exposure were similar between cohorts. Conclusions: These data suggest that routine vitamin K administration may have limited or no benefit during neonatal ECMO.

Background Conflicting statements by stakeholders in obstetric care have suggested different criteria for defining peripartum fever and suspected intraamniotic infection, which have not been evaluated. Methods A case-control study of pregnancies between 35 and 41 weeks at a single tertiary care center between January 2016 and December 2017. Cases with pathology-confirmed chorioamnionitis were identified, and demographic data, risk factors, and neonatal outcomes were extracted from the medical record. The American College of Gynecology (ACOG) and National Institutes of Health (NIH) Workshop guidelines for identifying isolated maternal fever and suspected intraamniotic infection were applied, retrospectively. Odds ratios, sensitivity/specificity, and predictive value of each guideline for pathology-confirmed chorioamnionitis and for secondary outcomes of interest were determined. Results 943 mother-infant dyads were evaluated including 41 (4.3%) with pathology-confirmed chorioamnionitis. Among cases, 18 (43.9%) experienced any maternal temperature ≥38°C (100.4°F) with 12 (29.2%) and 8 (19.5%) cases meeting criteria for isolated maternal fever according to the ACOG and Workshop guidelines, respectively. Furthermore, the ACOG and Workshop guidelines correctly identified 6 (14.6%) and 3 (7.3%) of cases of pathology-confirmed chorioamnionitis with high agreement between definitions (κ = 0.63). Laboratory evaluation, antimicrobial exposure, and prolonged length of stay in offspring are substantially higher in cases as compared to controls. Conclusions Guidelines that rely on maternal fever definitions for the diagnosis of suspected intraamniotic infection exhibit high agreement with low sensitivity, but high specificity and negative predictive value for pathology-confirmed chorioamnionitis. Maternal temperature ≥38°C continues to drive clinical decision-making for both mother and offspring.

Vascular endothelial growth factor receptor type 2 (VEGFR2, also known as KDR and FLK1) signalling in endothelial cells (ECs) is essential for developmental and reparative angiogenesis. Reactive oxygen species and copper (Cu) are also involved in these processes. However, their inter-relationship is poorly understood. Evidence of the role of the endothelial Cu importer CTR1 (also known as SLC31A1) in VEGFR2 signalling and angiogenesis in vivo is lacking. Here, we show that CTR1 functions as a redox sensor to promote angiogenesis in ECs. CTR1-depleted ECs showed reduced VEGF-induced VEGFR2 signalling and angiogenic responses. Mechanistically, CTR1 was rapidly sulfenylated at Cys189 at its cytosolic C terminus after stimulation with VEGF, which induced CTR1-VEGFR2 disulfide bond formation and their co-internalization to early endosomes, driving sustained VEGFR2 signalling. In vivo, EC-specific Ctr1-deficient mice or CRISPR-Cas9-generated redox-dead Ctr1(C187A)-knockin mutant mice had impaired developmental and reparative angiogenesis. Thus, oxidation of CTR1 at Cys189 promotes VEGFR2 internalization and signalling to enhance angiogenesis. Our study uncovers an important mechanism for sensing reactive oxygen species through CTR1 to drive neovascularization.

Central vascular thrombosis (CVT) in critically ill neonates carries significant clinical implications. Neonates with congenital heart disease (CHD) awaiting cardiac intervention might be associated with increased risk of thrombosis. Outcome analysis was undertaken. An analysis of 77 neonates with CHD who were admitted to the NICU prior to cardiac intervention between January 2015 and December 2016 was undertaken. Patients requiring extracorporeal life support prior to any cardiac intervention, or receiving prophylactic anticoagulation not related to central vascular catheter (CVC) were excluded. Diagnosis of CVT was provided based on clinical indication and verified with imaging that warranted anticoagulation therapy. Location of CVC and extent of CVT along with treatments, outcomes, and vascular access types and durations were assessed. Logistic regression multivariate analysis was used to assess predictors of outcome. Neonates with CHD were complicated with CVT in 10.4%. Longer duration of CVC was also associated with thrombosis in neonates with CHD (72.7 days vs. 29.3 days, p 0.001). Independent predictors of outcome included lower gestational age and CHD with single-ventricle (SV) anatomy (p 0.05). In neonates with CHD awaiting cardiac intervention risk of CVT is substantial. Duration CVC, lower gestational age and SV anatomy are risk determinants of outcome. Standardized development of customized surveillance protocols tailored to this unique subsets of neonates and adherence to quality guidelines can influence outcome.

Aims Impaired lymphatic drainage of the arterial wall results in intimal lipid accumulation and atherosclerosis. However, the mechanisms regulating lymphangiogenesis in atherosclerotic arteries are not well understood. Our studies identified elevated levels of matrix protein R-spondin 2 (RSPO2) in atherosclerotic arteries. In this study, we investigated the role of RSPO2 in lymphangiogenesis, arterial cholesterol efflux into lesion-draining lymph nodes (LNs) and development of atherosclerosis. Methods and results The effect of RSPO2 on lymphangiogenesis was investigated using human lymphatic endothelial cells (LEC) in vitro and implanted Matrigel plugs in vivo. Cellular and molecular approaches, pharmacological agents, and siRNA silencing of RSPO2 receptor LGR4 were used to investigate RSPO2-mediated signalling in LEC. In vivo low-density lipoprotein (LDL) tracking and perivascular blockade of RSPO2–LGR4 signalling using LGR4-extracellular domain (ECD) pluronic gel in hypercholesterolemic mice were utilized to investigate the role of RSPO2 in arterial reverse cholesterol transport and atherosclerosis. Immunoblotting and imaging experiments demonstrated increased RSPO2 expression in human and mouse atherosclerotic arteries compared to non-atherosclerotic controls. RSPO2 treatment inhibited lymphangiogenesis both in vitro and in vivo. LGR4 silencing and inhibition of RSPO2–LGR4 signalling abrogated RSPO2-induced inhibition of lymphangiogenesis. Mechanistically, we found that RSPO2 suppresses PI3K-AKT-endothelial nitric oxide synthase (eNOS) signalling via LGR4 and inhibits activation of the canonical Wnt-β-catenin pathway. ApoE−/− mice treated with LGR4-ECD developed significantly less atherosclerosis compared with control treatment. Finally, increased arterial lymphatic vessel density and improved lymphatic drainage of fluorescently labelled LDL to deep cervical LNs were observed in LGR4-ECD-treated mice. Conclusion These findings demonstrate that RSPO2 inhibits lymphangiogenesis via LGR4 and downstream impairment of AKT-eNOS-nitric oxide signalling. These results may also inform new therapeutic strategies to promote lymphangiogenesis and improve cholesterol efflux from atherosclerotic arteries.

Objective Inflammation in adipose tissues in obesity promotes insulin resistance and metabolic disease. The Duffy antigen receptor for chemokines (DARC) is a promiscuous non-signaling receptor expressed on erythrocytes and other cell types that modulates tissue inflammation by binding chemokines such as monocyte chemoattractant protein-1 (MCP-1) and by acting as a chemokine reservoir. DARC allelic variants are common in humans, but the role of DARC in modulating obesity-related metabolic disease is unknown. Methods We examined body weight gain, tissue adiposity, metabolic parameters and inflammatory marker expression in wild-type and DARC knockout mice fed a chow diet (CD) and high fat diet (HFD). Results Compared to wild-type mice, HFD-fed DARC knockout mice developed glucose intolerance and insulin resistance independent of increases in body weight or adiposity. Interestingly, insulin sensitivity was also diminished in lean male DARC knockout mice fed a chow diet. Insulin production was not reduced by DARC gene deletion, and plasma leptin levels were similar in HFD fed wild-type and DARC knockout mice. MCP-1 levels in plasma rose significantly in the HFD fed wild-type mice, but not in the DARC knockout mice. Conversely, adipose tissue MCP-1 levels were higher, and more macrophage crown-like structures were detected, in the HFD fed DARC knockout mice as compared with the wild-type mice, consistent with augmented adipose tissue inflammation that is not accurately reflected by plasma levels of DARC-bound MCP-1 in these mice. Conclusions These findings suggest that DARC regulates metabolic function and adipose tissue inflammation, which may impact obesity-related disease in ethnic populations with high frequencies of DARC allelic variants.

Background: Maternal nutrient restriction (MNR) is a widespread cause of fetal growth restriction (FGR), an independent predictor of heart disease and cardiovascular mortality. Our objective was to examine the developmental and long-term impact of MNR-induced FGR on cardiac structure in a model that closely mimics human development. Methods: A reduction in total caloric intake spanning pregestation through to lactation in guinea pig sows was used to induce FGR. Proliferation, differentiation, and apoptosis of cardiomyocytes were assessed in late-gestation fetal, neonatal, and adult guinea pig hearts. Proteomic analysis and pathway enrichment were performed on fetal hearts. Results: Cardiomyocyte proliferation and the number of mononucleated cells were enhanced in the MNR–FGR fetal and neonatal heart, suggesting a delay in cardiomyocyte differentiation. In fetal hearts of MNR–FGR animals, apoptosis was markedly elevated and the total number of cardiomyocytes reduced, the latter remaining so throughout neonatal and into adult life. A reduction in total cardiomyocyte number in adult MNR–FGR hearts was accompanied by exaggerated hypertrophy and a disorganized architecture. Pathway analysis identified genes related to cell proliferation, differentiation, and survival. Conclusions: FGR influences cardiomyocyte development during critical windows of development, leading to a permanent deficiency in cardiomyocyte number and compensatory hypertrophy in a rodent model that recapitulates human development.

Purpose Neurofibromatosis type 1 (NF1) is the result of inherited mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin. Eye manifestations are common in NF1 with recent reports describing a vascular dysplasia in the retina and choroid. Common features of NF1 retinopathy include tortuous and dilated feeder vessels that terminate in capillary tufts, increased endothelial permeability, and neovascularization. Given the retinal vascular phenotype observed in persons with NF1, we hypothesize that preserving neurofibromin may be a novel strategy to control pathologic retinal neovascularization. Methods Nf1 expression in human endothelial cells (EC) was reduced using small hairpin (sh) RNA and EC proliferation, migration, and capacity to form vessel-like networks were assessed in response to VEGF and hypoxia. Wild-type (WT), Nf1 heterozygous (Nf1+/-), and Nf1flox/+;Tie2cre pups were subjected to hyperoxia/hypoxia using the oxygen-induced retinopathy model. Retinas were analyzed quantitatively for extent of retinal vessel dropout, neovascularization, and capillary branching. Results Neurofibromin expression was suppressed in response to VEGF, which corresponded with activation of Mek-Erk and PI3-K-Akt signaling. Neurofibromin-deficient EC exhibited enhanced proliferation and network formation in response to VEGF and hypoxia via an Akt-dependent mechanism. In response to hyperoxia/hypoxia, Nf1+/- retinas exhibited increased vessel dropout and neovascularization when compared with WT retinas. Neovascularization was similar between Nf1+/- and Nf1flox/+;Tie2cre retinas, but capillary drop out in Nf1flox/+;Tie2cre retinas was significantly reduced when compared with Nf1+/- retinas. Conclusions These data suggest that neurofibromin expression is essential for controlling endothelial cell proliferation and retinal neovascularization and therapies targeting neurofibromin-deficient EC may be beneficial.

BACKGROUND The objective of this study was to assess complications and patient outcomes associated with a lower reflexive red blood cell (RBC) transfusion threshold for neonates undergoing extracorporeal membrane oxygenation (ECMO) for hypoxic respiratory failure. STUDY DESIGN AND METHODS A retrospective cohort study was conducted at a single tertiary neonatal intensive care unit of neonates undergoing ECMO support for refractory hypoxic respiratory failure for more than 24 hours between December 2009 and December 2014. Seventy-two neonates received ECMO support for hypoxic respiratory failure for longer than 24 hours during the study period. Patient cohorts were determined based on transfusion threshold of hematocrit (Hct) level of less than 40% (December 2009-October 2012) and Hct level of less than 35% (November 2012-December 2014). RESULTS Patients who had a lower threshold for transfusion (Hct

Background We sought to examine the effect of routine antithrombin III (AT3) infusion on hemorrhagic and thrombotic complications, blood product utilization, and circuit lifespan in neonatal extracorporeal membrane oxygenation (ECMO). Methods We performed a retrospective cohort study of 162 infants placed on ECMO for hypoxic respiratory failure. Infants requiring ECMO for primary cardiac support were excluded. Demographic data, time on ECMO, blood product usage, coagulation profile, and complications were compared between 90 control patients and 72 patients treated with AT3. Results Infants receiving AT3 during ECMO had less thrombotic and similar bleeding complications as compared to infants receiving standard anticoagulation therapy. Total blood product infusion during ECMO was decreased (54.7±20.1 vs. 67.4±34.9mL/kg per day, p =0.001) in infants receiving AT3 during ECMO. Tighter control of activated clotting time and higher serum heparin anti-Xa levels were observed in the AT3 cohort during the first days of ECMO support. 1st ECMO circuit lifespan did not differ between groups. Conclusions Routine administration of AT3 in neonates receiving ECMO therapy was associated with tighter control of anticoagulation and a reduction in thrombotic events without increasing unwanted bleeding. However, circuit lifespan was unaffected. Level of evidence Level III.

Aneurysms are characterized by structural deterioration of the vascular wall leading to progressive dilatation and, potentially, rupture of the aorta. While aortic aneurysms often remain clinically silent, the morbidity and mortality associated with aneurysm expansion and rupture are considerable. Over 13,000 deaths annually in the United States are attributable to aortic aneurysm rupture with less than 1 in 3 persons with aortic aneurysm rupture surviving to surgical intervention. Environmental and epidemiologic risk factors including smoking, male gender, hypertension, older age, dyslipidemia, atherosclerosis, and family history are highly associated with abdominal aortic aneurysms, while heritable genetic mutations are commonly associated with aneurysms of the thoracic aorta. Similar to other forms of cardiovascular disease, family history, genetic variation, and heritable mutations modify the risk of aortic aneurysm formation and provide mechanistic insight into the pathogenesis of human aortic aneurysms. This review will examine the relationship between heritable genetic and epigenetic influences on thoracic and abdominal aortic aneurysm formation and rupture.

Background Responsive parenting interventions that shape parenting behaviors in the areas of sleep and soothing, appropriate and responsive feeding, and routines represent a promising approach to early obesity prevention and have demonstrated effectiveness in our previous trials. However, this approach has yet to be applied to the populations most at-risk for the development of early obesity, including African Americans. The Sleep SAAF (Strong African American Families) study is a two-arm randomized controlled clinical trial evaluating whether a responsive parenting intervention focused on promoting infant sleeping and self-soothing can prevent rapid weight gain during the first 16 weeks postpartum among first-born African American infants. The responsive parenting intervention is compared to a child safety control intervention. Methods Three hundred first-time African American mothers and their full-term infants will be enrolled from one mother/baby nursery. Following initial screening and consent in the hospital, mothers and infants are visited at home by Community Research Associates for data collection visits at 1 week, 8 weeks, and 16 weeks postpartum and for intervention visits at 3 weeks and 8 weeks postpartum. The primary study outcome is a between-group comparison of infant conditional weight gain (CWG) scores from 3 weeks to 16 weeks; additional weight-related outcomes include differences in change in infants’ weight for age over time and differences in infants’ weight outcomes at age 16 weeks. Several other outcomes reflecting infant and maternal responses to intervention (e.g., sleeping, soothing, feeding, maternal self-efficacy, maternal depressive symptoms) are also assessed. Discussion The Sleep SAAF trial can inform efforts to prevent rapid weight gain and reduce risk for obesity early in the lifespan among African Americans. Trial registration NCT03505203. Registered April 3, 2018 in clinicaltrials.gov. Electronic supplementary material The online version of this article (10.1186/s12887-019-1583-7) contains supplementary material, which is available to authorized users.

Background Neurologic complications including hemorrhage, ischemia, and infarction are often identified in neonates undergoing extracorporeal membrane oxygenation (ECMO) and may contribute to the high morbidity observed in ECMO survivors. Screening for intracranial complications is reliant on bedside transcranial ultrasound (CUS) prior to and during ECMO therapy, and advanced imaging [i.e. computed tomography (CT)/magnetic resonance imaging (MRI)] is recommended after completion of ECMO support. The goal of this study is to describe the correlation of intracranial complications identified on CUS during ECMO and MRI after completion of ECMO. Methods Fifty-five neonates underwent ECMO support at the Children’s Hospital of Georgia at Augusta University from January 1, 2012 to December 31, 2017. Forty-four (80%) had a brain MRI performed prior to transfer or discharge. Ultrasound studies were reviewed by a single blinded pediatric radiologist and MRIs were reviewed by a single blinded neuro-radiologist. Results Of the 44 neonates with post-ECMO MRI, CUS during ECMO identified intracranial lesions in nine neonates, which were all confirmed on post-ECMO MRI. Sixteen subjects (46%) with unremarkable CUS during ECMO had identifiable lesions on post-ECMO MRI, yielding a sensitivity of 36% and a specificity of 100% for CUS in the detection of intracranial lesions. Despite the lack of correlation between CUS and MR, 84.6% of survivors exhibited normal development at 24 months of age. Conclusion While necessary for the identification of intracranial lesions during neonatal ECMO, CUS demonstrated low correlation with post-ECMO MRI in the identification of intracranial lesions, which supports Extracorporeal Life Support Organization (ELSO) recommendations.

Treatment of gastroschisis often requires multiple surgical procedures to re-establish abdominal domain, reduce abdominal contents, and eventually close the abdominal wall. In patients who have concomitant respiratory failure requiring extracorporeal membrane oxygenation (ECMO), this process becomes further complicated. This situation is rare and only five such cases have been reported in the ECMO registry database. Management of three of the five patients along with results and implications for future care of similar patients is discussed here. Two patients had respiratory failure due to meconium aspiration syndrome and one patient had persistent acidosis as well as worsening pulmonary hypertension leading to the decision of ECMO. The abdominal contents were placed in a spring-loaded silastic silo while on ECMO and primary closure was performed three to six days after the decannulation. All three patients survived and are developmentally appropriate. We recommend avoiding aggressively reducing the abdominal contents and using a silo to conservatively reducing the gastroschisis while the patient is on ECMO therapy. Keeping the intra-abdominal pressure below 20 mm Hg can possibly reduce ECMO days and ventilator time and has been shown to decrease morbidity and mortality. Patients with gastroschisis and respiratory failure requiring ECMO can have good outcomes despite the complexity of required care.

Neurofibromatosis type 1 (NF1) predisposes individuals to early and debilitating cardiovascular disease. Loss of function mutations in the NF1 tumor suppressor gene, which encodes the protein neurofibromin, leads to accelerated p21(Ras) activity and phosphorylation of multiple downstream kinases, including Erk and Akt. Nf1 heterozygous (Nf1(+/-)) mice develop a robust neointima that mimics human disease. Monocytes/macrophages play a central role in NF1 arterial stenosis as Nf1 mutations in myeloid cells alone are sufficient to reproduce the enhanced neointima observed in Nf1(+/-) mice. Though the molecular mechanisms underlying NF1 arterial stenosis remain elusive, macrophages are important producers of reactive oxygen species (ROS) and Ras activity directly regulates ROS production. Here, we use compound mutant and lineage-restricted mice to demonstrate that Nf1(+/-) macrophages produce excessive ROS, which enhance Nf1(+/-) smooth muscle cell proliferation in vitro and in vivo. Further, use of a specific NADPH oxidase-2 inhibitor to limit ROS production prevents neointima formation in Nf1(+/-) mice. Finally, mononuclear cells from asymptomatic NF1 patients have increased oxidative DNA damage, an indicator of chronic exposure to oxidative stress. These data provide genetic and pharmacologic evidence that excessive exposure to oxidant species underlie NF1 arterial stenosis and provide a platform for designing novels therapies and interventions.

Understanding mechanisms of childhood disease and development of rational therapeutics are fundamental to progress in pediatric intensive care specialties. However, Division Chiefs and Department Chairs face unique challenges when building effective laboratory-based research programs in Neonatal and Pediatric Intensive Care, owing to high clinical demands necessary to maintain competence as well as financial pressures arising from fund flow models and the current extramural funding climate. Given these factors, the role of institutional support that could facilitate successful transition of promising junior faculty to independent research careers is ever more important. Would standardized guidelines of such support provide greater consistency among institutions? We addressed preliminary questions during a national focus group, a workshop and a survey of junior and senior academicians to solicit recommendations for optimal levels of protected time and resources when starting an independent laboratory. The consensus was that junior faculty should be assigned no more than 8 wk clinical service and should obtain start-up funds of $500K-1M exclusive of a 5-y committed salary support. Senior respondents placed a higher premium on protected time than junior faculty.

Retinopathy of prematurity (ROP) is the leading cause of blindness in infants. We have investigated the efficacy of the secondary bile acid ursodeoxycholic acid (UDCA) and its taurine and glycine conjugated derivatives tauroursodeoxycholic acid (TUDCA) and glycoursodeoxycholic acid (GUDCA) in preventing retinal neovascularization (RNV) in an experimental model of ROP. Seven-day-old mice pups (P7) were subjected to oxygen-induced retinopathy (OIR) and were treated with bile acids for various durations. Analysis of retinal vascular growth and distribution revealed that UDCA treatment (50 mg/kg, P7&ndash, P17) of OIR mice decreased the extension of neovascular and avascular areas, whereas treatments with TUDCA and GUDCA showed no changes. UDCA also prevented reactive gliosis, preserved ganglion cell survival, and ameliorated OIR-induced blood retinal barrier dysfunction. These effects were associated with decreased levels of oxidative stress markers, inflammatory cytokines, and normalization of the VEGF&ndash, STAT3 signaling axis. Furthermore, in vitro tube formation and permeability assays confirmed UDCA inhibitory activity toward VEGF-induced pro-angiogenic and pro-permeability effects on human retinal microvascular endothelial cells. Collectively, our results suggest that UDCA could represent a new effective therapy for ROP.

Perivascular adipose tissue (PVAT) surrounds the arterial adventitia and plays an important role in vascular homeostasis. PVAT expands in obesity, and inflamed PVAT can locally promote endothelial dysfunction and atherosclerosis. Here, using adipose tissue transplantation, we tested the hypothesis that expansion of PVAT can also remotely exacerbate vascular disease. Fifty milligrams of abdominal aortic PVAT was isolated from high-fat diet (HFD)-fed wild-type mice and transplanted onto the abdominal aorta of lean LDL receptor knockout mice. Subcutaneous and visceral adipose tissues were used as controls. After HFD feeding for 10 weeks, body weight, glucose/insulin sensitivity, and lipid levels were measured. Adipocytokine gene expression was assessed in the transplanted adipose tissues, and the thoracic aorta was harvested to quantify atherosclerotic lesions by Oil-Red O staining and to assess vasorelaxation by wire myography. PVAT transplantation did not influence body weight, fat composition, lipid levels, or glucose/insulin sensitivity. However, as compared with controls, transplantation of PVAT onto the abdominal aorta increased thoracic aortic atherosclerosis. Furthermore, PVAT transplantation onto the abdominal aorta inhibited endothelium-dependent relaxation in the thoracic aorta. MCP-1 and TNF-α expression was elevated, while adiponectin expression was reduced, in the transplanted PVAT tissue, suggesting augmented inflammation as a potential mechanism for the remote vascular effects of transplanted PVAT. These data suggest that PVAT expansion and inflammation in obesity can remotely induce endothelial dysfunction and augment atherosclerosis. Identifying the underlying mechanisms may lead to novel approaches for risk assessment and treatment of obesity-related vascular disease.

The lack of effective therapies to limit neurovascular injury in ischemic retinopathy is a major clinical problem. This study aimed to examine the role of ureohydrolase enzyme, arginase 1 (A1), in retinal ischemia-reperfusion (IR) injury. A1 competes with nitric oxide synthase (NOS) for their common substrate l-arginine. A1-mediated l-arginine depletion reduces nitric oxide (NO) formation by NOS leading to vascular dysfunction when endothelial NOS is involved but prevents inflammatory injury when inducible NOS is involved. Studies were performed using wild-type (WT) mice, global A1+/− knockout (KO), endothelial-specific A1 KO, and myeloid-specific A1 KO mice subjected to retinal IR injury. Global as well as myeloid-specific A1 KO mice showed worsened IR-induced neuronal loss and retinal thinning. Deletion of A1 in endothelial cells had no effect, while treatment with PEGylated (PEG) A1 improved neuronal survival in WT mice. In addition, A1+/− KO mice showed worsened vascular injury manifested by increased acellular capillaries. Western blotting analysis of retinal tissue showed increased inflammatory and necroptotic markers with A1 deletion. In vitro experiments showed that macrophages lacking A1 exhibit increased inflammatory response upon LPS stimulation. PEG-A1 treatment dampened this inflammatory response and decreased the LPS-induced metabolic reprogramming. Moreover, intravitreal injection of A1 KO macrophages or systemic macrophage depletion with clodronate liposomes increased neuronal loss after IR injury. These results demonstrate that A1 reduces IR injury-induced retinal neurovascular degeneration via dampening macrophage inflammatory responses. Increasing A1 offers a novel strategy for limiting neurovascular injury and promoting macrophage-mediated repair.

The use of point-of-care sonography in clinical settings such as emergency medicine and intensive care units has increased, but adoption in neonatology has been slow. Unlike the focused assessment with sonography for trauma scan used in adults, a quick bedside scan to rapidly evaluate an acutely deteriorating neonate does not exist. The objective of our article is to introduce a focused bedside ultrasound scan that is easy to learn, rapidly performed, and relatively inexpensive.© 2018 by the American Institute of Ultrasound in Medicine.

Perinatal asphyxia is a common cause of morbidity and mortality in the newborn and is associated with myocardial injury in a significant proportion of cases. Biomarkers, echocardiography, and rhythm disturbances are sensitive indicators of myocardial ischemia and may predict mortality. We present a case of severe myocardial dysfunction immediately after delivery managed with extracorporeal membrane oxygenation (ECMO) and discuss the role of cardiac biomarkers, echocardiography, electrocardiography, and ECMO in the asphyxiated newborn.

Oxidative stress plays a fundamental role in abdominal aortic aneurysm (AAA) formation. Activated polymorphonuclear leukocytes (or neutrophils) are associated with AAA and express myeloperoxidase (MPO), which promotes inflammation, matrix degradation, and other pathological features of AAA, including enhanced oxidative stress through generation of reactive oxygen species. Both plasma and aortic MPO levels are elevated in patients with AAA, but the role of MPO in AAA pathogenesis has, heretofore, never been investigated. Here, we show that MPO gene deletion attenuates AAA formation in two animal models: ANG II infusion in apolipoprotein E-deficient mice and elastase perfusion in C57BL/6 mice. Oral administration of taurine [1% or 4% (wt/vol) in drinking water], an amino acid known to react rapidly with MPO-generated oxidants like hypochlorous acid, also prevented AAA formation in the ANG II and elastase models as well as the CaCl2 application model of AAA formation while reducing aortic peroxidase activity and aortic protein-bound dityrosine levels, an oxidative cross link formed by MPO. Both MPO gene deletion and taurine supplementation blunted aortic macrophage accumulation, elastin fragmentation, and matrix metalloproteinase activation, key features of AAA pathogenesis. Moreover, MPO gene deletion and taurine administration significantly attenuated the induction of serum amyloid A, which promotes ANG II-induced AAAs. These data implicate MPO in AAA pathogenesis and suggest that studies exploring whether taurine can serve as a potential therapeutic for the prevention or treatment of AAA in patients merit consideration. NEW & NOTEWORTHY Neutrophils are abundant in abdominal aortic aneurysm (AAA), and myeloperoxidase (MPO), prominently expressed in neutrophils, is associated with AAA in humans. This study demonstrates that MPO gene deletion or supplementation with the natural product taurine, which can scavenge MPO-generated oxidants, can prevent AAA formation, suggesting an attractive potential therapeutic strategy for AAA.