Perinatal characteristics and early childhood follow up after ex-utero intrapartum treatment for head and neck teratomas by prenatal diagnosis.

BACKGROUND: Ex utero intrapartum treatment (EXIT) is utilized for safe delivery when a baby has a compromised airway. The purpose of this retrospective study was to examine the indications and outcomes of 11 children presenting with airway occluding oropharyngeal and cervical teratomas. METHODS: Study of all children with an airway occluding teratoma delivered via EXIT (2001-2018) in our unit. Primary outcomes included survival and tracheostomy at discharge. Data are reported using descriptive statistics as median (range) and rate (%). RESULTS: We performed 45 EXIT procedure performed between January 2001 and April 2018. Of these, eleven were for cervical and/or upper airway teratoma. Ten (91%) cases had associated polyhydramnios, two (18%) developed nonimmune hydrops, and eight (72%) delivered preterm. Six (45.5%) were performed as an emergency. Estimated blood loss was 1000 ml (500, 1000). The neonatal mortality rate was 18% (2/11) and 33% (3/9) of the survivors were discharged with a tracheostomy. CONCLUSION: EXIT is a reasonable option for delivery of babies with an occlusive upper airway mass. Neonatal survival depends on individualized factors but may be as high as 82% in those with teratoma.

Supplementation With the Sialic Acid Precursor N-Acetyl-D-Mannosamine Breaks the Link Between Obesity and Hypertension.

BACKGROUND: Obesity-related hypertension is a common disorder, and attempts to combat the underlying obesity are often unsuccessful. We previously revealed that mice globally deficient in the inhibitory immunoglobulin G (IgG) receptor FcγRIIB are protected from obesity-induced hypertension. However, how FcγRIIB participates is unknown. Studies were designed to determine if alterations in IgG contribute to the pathogenesis of obesity-induced hypertension. METHODS: Involvement of IgG was studied using IgG µ heavy chain-null mice deficient in mature B cells and by IgG transfer. Participation of FcγRIIB was interrogated in mice with global or endothelial cell-specific deletion of the receptor. Obesity was induced by high-fat diet (HFD), and blood pressure (BP) was measured by radiotelemetry or tail cuff. The relative sialylation of the Fc glycan on mouse IgG, which influences IgG activation of Fc receptors, was evaluated by Sambucus nigra lectin blotting. Effects of IgG on endothelial NO synthase were assessed in human aortic endothelial cells. IgG Fc glycan sialylation was interrogated in 3442 human participants by mass spectrometry, and the relationship between sialylation and BP was evaluated. Effects of normalizing IgG sialylation were determined in HFD-fed mice administered the sialic acid precursor N-acetyl-D-mannosamine (ManNAc). RESULTS: Mice deficient in B cells were protected from obesity-induced hypertension. Compared with IgG from control chow-fed mice, IgG from HFD-fed mice was hyposialylated, and it raised BP when transferred to recipients lacking IgG; the hypertensive response was absent if recipients were FcγRIIB-deficient. Neuraminidase-treated IgG lacking the Fc glycan terminal sialic acid also raised BP. In cultured endothelial cells, via FcγRIIB, IgG from HFD-fed mice and neuraminidase-treated IgG inhibited vascular endothelial growth factor activation of endothelial NO synthase by altering endothelial NO synthase phosphorylation. In humans, obesity was associated with lower IgG sialylation, and systolic BP was inversely related to IgG sialylation. Mice deficient in FcγRIIB in endothelium were protected from obesity-induced hypertension. Furthermore, in HFD-fed mice, ManNAc normalized IgG sialylation and prevented obesity-induced hypertension. CONCLUSIONS: Hyposialylated IgG and FcγRIIB in endothelium are critically involved in obesity-induced hypertension in mice, and supportive evidence was obtained in humans. Interventions targeting these mechanisms, such as ManNAc supplementation, may provide novel means to break the link between obesity and hypertension.

Aberrant DNA methylation as a diagnostic biomarker of diabetic embryopathy.

PURPOSE: Maternal diabetes is a known teratogen that can cause a wide spectrum of birth defects, collectively referred to as diabetic embryopathy (DE). However, the pathogenic mechanisms underlying DE remain uncertain and there are no definitive tests to establish the diagnosis. Here, we explore the potential of DNA methylation as a diagnostic biomarker for DE and to inform disease pathogenesis. METHODS: Bisulfite sequencing was used to identify gene regions with differential methylation between DE neonates and healthy infants born with or without prenatal exposure to maternal diabetes, and to investigate the role of allele-specific methylation at implicated sites. RESULTS: We identified a methylation signature consisting of 237 differentially methylated loci that distinguished infants with DE from control infants. These loci were found proximal to genes associated with Mendelian syndromes that overlap the DE phenotype (e.g., CACNA1C, TRIO, ANKRD11) or genes known to influence embryonic development (e.g., BRAX1, RASA3). Further, we identified allele-specific methylation (ASM) at 11 of these loci, within which 61.5% of ASM single-nucleotide variants are known expression quantitative trait loci (eQTLs). CONCLUSIONS: Our study suggests a role for aberrant DNA methylation and cis-sequence variation in the pathogenesis of DE and highlights the diagnostic potential of DNA methylation for teratogenic birth defects.

Cervical lymphatic malformations: Prenatal characteristics and ex utero intrapartum treatment.

BACKGROUND: The ex utero intrapartum treatment (EXIT) is utilized to transition fetuses with prenatally diagnosed airway obstruction to postnatal life. We describe the unique clinical course, diagnosis, treatment, and outcomes of patients with cervical lymphatic malformation (CLM) managed with EXIT. METHODS: Review of fetuses with diagnosed CLM was delivered by EXIT (2001-2018) in a tertiary referral fetal center. Outcomes included survival, tracheostomy at discharge, neonatal course after delivery, and pulmonary hypoplasia. Data are reported as median [range] and rate (%). RESULTS: Out of 45 patients delivered by EXIT, 10 were delivered for CLM: seven had polyhydramnios, one had nonimmune hydrops, five delivered preterm, and three were emergency EXITs. The EXIT time and estimated blood loss were 125 minutes (95, 158) and 900 mL (500, 1500), respectively. Airway was secured in all. There was one neonatal death (day 8) with prematurity, sepsis, and pulmonary hypoplasia. Three out of nine were discharged with a tracheostomy. CONCLUSION: In CLM, close monitoring for structural neck involvement and development of polyhydramnios are important and may be an indication for EXIT as the optimal delivery mode. An experienced multidisciplinary team is a key factor for an effective approach to the obstructed airway in CLM.

How Do Obstetric and Neonatology Teams Communicate Prior to High-Risk Deliveries?

BACKGROUND: Improving communication in healthcare improves the quality of care and patient outcomes, but communication between obstetric and neonatal teams before and during a high-risk delivery is poorly studied. STUDY DESIGN: We developed a survey to study communication between obstetric and neonatal teams around the time of a high-risk delivery. We surveyed neonatologists from North America and asked them to answer questions about their institutions' communication practices. RESULTS: The survey answers revealed variations in communication practices between responders. Most institutions relied on nursing to communicate obstetric information to the neonatal team. Although a minority of institutions used a standardized communication process to summon neonatology team or to communicate in the delivery room, these reported higher rates of information sharing and greater satisfaction with communication between services. CONCLUSION: Standardized communication procedures are an underutilized method of communication and have the potential to improve communication around high-risk deliveries.

How We Got Smart: Improving Interdisciplinary Communication When Summoning Neonatology to High-Risk Deliveries.

Communication around high-risk deliveries is critical to ensure patient safety. A hospital-wide system change in paging the neonatal resuscitation team (NRT) to deliveries was implemented but disliked. An interdisciplinary team seized the opportunity to explore opportunities for an enhanced system to improve communication. The team designed a new screen to our smart panel (responder 5 staff terminal, Rauland, Mount Prospect, Illinois) to page NRT with the location and primary indication for which they were needed at delivery. Surveys assessed user satisfaction among labor and delivery and NRT. Before and after implementation of the smart panel, we assessed number of NRT pages, frequency of NRT being paged prior to the delivery, the time between page and delivery, and use of the code button to summon help. Labor and delivery and NRT user satisfaction greatly improved with the smart panel. Frequency of NRT being paged before birth increased with fewer code pages being used to summon NRT to deliveries. A touch screen-based notification system can enhance timely notification to summon NRT to deliveries while concurrently enhancing satisfaction of providers in both the delivery room and on the NRT.

Coupling of Fcγ receptor I to Fcγ receptor IIb by SRC kinase mediates C-reactive protein impairment of endothelial function.

RATIONALE: Elevations in C-reactive protein (CRP) are associated with increased cardiovascular disease risk and endothelial dysfunction. CRP antagonizes endothelial nitric oxide synthase (eNOS) through processes mediated by the IgG receptor Fcγ receptor IIB (FcγRIIB), its immunoreceptor tyrosine-based inhibitory motif, and SH2 domain-containing inositol 5'-phosphatase 1. In mice, CRP actions on eNOS blunt carotid artery re-endothelialization. OBJECTIVE: How CRP activates FcγRIIB in endothelium is not known. We determined the role of Fcγ receptor I (FcγRI) and the basis for coupling of FcγRI to FcγRIIB in endothelium. METHODS AND RESULTS: In cultured endothelial cells, FcγRI-blocking antibodies prevented CRP antagonism of eNOS, and CRP activated Src via FcγRI. CRP-induced increases in FcγRIIB immunoreceptor tyrosine-based inhibitory motif phosphorylation and SH2 domain-containing inositol 5'-phosphatase 1 activation were Src-dependent, and Src inhibition prevented eNOS antagonism by CRP. Similar processes mediated eNOS antagonism by aggregated IgG used to mimic immune complex. Carotid artery re-endothelialization was evaluated in offspring from crosses of CRP transgenic mice (TG-CRP) with either mice lacking the γ subunit of FcγRI (FcRγ(-/-)) or FcγRIIB(-/-) mice. Whereas re-endothelialization was impaired in TG-CRP vs wild-type, it was normal in both FcRγ(-/-); TG-CRP and FcγRIIB(-/-); TG-CRP mice. CONCLUSIONS: CRP antagonism of eNOS is mediated by the coupling of FcγRI to FcγRIIB by Src kinase and resulting activation of SH2 domain-containing inositol 5'-phosphatase 1, and consistent with this mechanism, both FcγRI and FcγRIIB are required for CRP to blunt endothelial repair in vivo. Similar mechanisms underlie eNOS antagonism by immune complex. FcγRI and FcγRIIB may be novel therapeutic targets for preventing endothelial dysfunction in inflammatory or immune complex-mediated conditions.

A recorder/time coach decreases time errors during neonatal resuscitation: A randomized, simulation-based clinical trial.

Aim: To evaluate the effects of a hands-off recorder/time coach versus an additional hands-on healthcare provider on Neonatal Resuscitation Program (NRP) algorithm compliance and team member workload in neonatal resuscitations. Methods: Two interventions were studied using a 2 × 2 factorial design: an additional hands-on team member and the presence of a designated, hands-off recorder/time coach. The recorder/time coach documented interventions and delivered pre-specified prompts at defined points during the resuscitation. The primary outcome was cumulative time error. Secondary outcomes were time to first dose of IV epinephrine, overall team performance as assessed by the Neonatal Resuscitation Performance Evaluation (NRPE) score, and workload assessed by the NASA Task Load Index (NASA TLX). Results: 64 teams were studied. Teams with a recorder had a significantly lower cumulative time error compared to teams without a recorder (p < 0.001). An additional hands-on team member did not change cumulative time error. There was no difference in time to first dose of IV epinephrine or NRPE score in these comparisons. Ad-hoc analysis did reveal a significant increase in time to IV epinephrine in teams with the minimum of four total members (p = 0.025). A recorder/time coach increased team leader NASA TLX overall workload score (p = 0.047), but an additional hands-on team member did not. Conclusion: A designated, hands-off recorder/time coach improved compliance by decreasing cumulative time error in teams performing complex simulated neonatal resuscitations.

Simulation training for urgent postnatal fetal tracheal balloon removal: Two learning methods.

OBJECTIVE: In fetuses with severe congenital diaphragmatic hernia, fetal endoluminal tracheal occlusion (FETO) with balloon increases survival and reduces morbidity. Balloon removal is often scheduled electively. In urgent cases, in-utero removal is impossible and removal immediately after delivery has to occur, posing risk of death from airway obstruction. Medical staff need training in urgent removal. Ideal training method is unclear; thus, we compared the performance of two groups trained by different methods. METHODS: 24 medical students were randomly assigned to two different learning methods for removal: Group 1 (in-person lecture) and Group 2 (online video). Both methods presented the same information: endoscopic instrument set-up, anatomical landmarks for intubation, and balloon removal. All participants were evaluated using the same instruments and high-fidelity simulator, comparing time for instrument set-up and simulate balloon removal (including removal attempts). RESULTS: Group 1 took significantly less time for instrument set-up compared to Group 2 [62 (30-92) secs vs 81 (57-108) secs; p < 0.01)]; no difference in time to intubate and locate the balloon [75 (50-173) secs vs 92 (32-232) secs; p 0.42], or number of attempts. CONCLUSION: There was no difference between video training and in-person training with regards to the time taken to locate the FETO balloon in the trachea and to simulate its removal.

Format Changes Improve Learner Satisfaction in Local Neonatal Resuscitation Program Skills Education.

BACKGROUND: The Neonatal Resuscitation Program (NRP) is a national education program that prepares learners to resuscitate newborn babies. Our local Texas Children's Hospital (TCH) NRP educational class incorporates skills training and high-fidelity simulations of neonatal resuscitation scenarios. The skills training had four elements we believed were not ideal. 1. Learners went to skills stations in groups, but different teams were formed for performing the scenario simulations in the latter half of the class. 2. The skills stations were visited in random order and not necessarily the actual order in the skills would be performed in a clinical situation. 3. Educational content presented at the skills station was highly variable depending on the instructor. 4. Emphasis was on instructors teaching content over learners practicing and demonstrating skills. In March 2019 we restructured the skills education portion completely to address all four of these problems. OBJECTIVES: To determine how changes to the design of our skills education affected learner satisfaction with the NRP course. METHODS: Using the principles of situated cognition, the skills education was restructured by leadership planning and consensus. We made four changes. 1. Teams were assigned from the beginning of class, and these teams practiced all skills and performed the simulations together. 2. Every team went through the skills stations in the order they would perform them in an actual resuscitation. 3. Videos were made to teach the "gold standard" information needed for the skills stations. 4. Instructors were asked to think of themselves as coaches and not teachers, letting the videos do the education, and they focused on improving skill performance. A survey was designed and disseminated by e-mail to all learners of the first 13 classes taught using the new educational format (n=196). The survey asked learners to compare their experience of the new format compared to their memory of the previous format. RESULTS: A total of 163 learners responded and completely finished the survey (83% response rate). Of the 163 respondents, 109 learners (67%) had taken the course in the past at TCH and filled out the survey questions comparing the new format to the past format. Out of the total, 93% of learners (n=101) judged the new format to be "better" or "much better." The percentage of learners that attributed the improvement to the changes we made were: 70% for team assignments from the beginning (n=76), 74% for skills performed in order (n=81), 68% for video-based education (n=74), and 76% for instructors as coaches (n=83). Learners rated the videos used for education very highly. CONCLUSIONS: The reformat of our skills education has improved our learners' experience during NRP training. The highest-rated change was asking our instructors to operate as coaches rather than teachers.

Effects of Team Size and a Decision Support Tool on Healthcare Providers' Workloads in Simulated Neonatal Resuscitation: A Randomized Trial.

INTRODUCTION: Optimal resuscitation team size for workload distribution among team members is not known. In addition, decision support tools (DSTs) are available to improve team performance, but the effect on workload is not known. Because increased workload can impair performance, we aimed to determine whether team size or use of a DST alters workload in healthcare providers (HCPs) while performing neonatal resuscitation. METHODS: We report a substudy of a randomized, 2 × 2 factorial design study using 109 Neonatal Resuscitation Program-trained HCPs. Healthcare providers were randomized to 1 of 4 permutations, including team size of 2 versus 3 and using DST versus memory alone while performing 2 simulated neonatal resuscitations. The HCPs' workload was assessed by the National Aeronautics and Space Administration Task Load Index obtained after each scenario. Mixed effects linear models compared the effect of team size and DST use on National Aeronautics and Space Administration Task Load Index scores. RESULTS: When all team members were combined, there was an increased workload in teams of 2 HCPs compared with teams of 3 and was primarily due to an increase in workload on the team leaders. Decision support tool use increased workload for the other team members in the first of the 2 scenarios but did not increase workload in the second scenario. CONCLUSIONS: Teams of 2 HCPs reported a higher workload compared with teams of 3 HCPs. Decision support tool use can increase workload for other team members when first introduced as a new task. This study highlights the need to consider factors that negatively affect mental workload when determining the composition of a resuscitation team.

Relationship Between Umbilical Cord Gas Values and Neonatal Outcomes: Implications for Electronic Fetal Heart Rate Monitoring.

OBJECTIVE: To evaluate the relationship between umbilical artery cord gas values and fetal tolerance of labor, as reflected by Apgar score. We hypothesized the existence of wide biological variability in fetal tolerance of metabolic acidemia, which, if present, would weaken one fundamental assumption underlying the use of electronic fetal heart rate (FHR) monitoring. METHODS: We conducted a retrospective cohort study of term, singleton, nonanomalous fetuses delivered in our institution between March 2012 and July 2020. Universally obtained umbilical cord gas values and Apgar scores were extracted. We calculated Spearman correlation coefficients and receiver operating characteristic curves for various levels of umbilical artery pH, base excess, and Apgar scores. RESULTS: We analyzed data from 29,787 deliveries. The statistical correlation between umbilical artery pH and base excess and both 1- and 5-minute Apgar scores was weak or nonexistent in all pH range subgroups (range 0.064-0.213). Receiver operating characteristic curve analysis suggested umbilical artery pH value of 7.22 yields the best discrimination for prediction of a severely depressed newborn (5-minute Apgar score less than 4), but sensitivity and specificity for this predictive value remains poor to moderate. CONCLUSION: The use of electronic FHR monitoring is predicated on a documented relationship between FHR patterns and umbilical artery pH, and an assumed correlation between pH and fetal outcomes, reflecting fetal tolerance of labor and delivery. Our data demonstrate a weak-to-absent correlation between metabolic acidemia and even short-term fetal condition, thus significantly weakening this latter assumption. No amount of future modification of FHR pattern interpretation to better predict newborn pH is likely to lead to improved newborn outcomes, given this weakness in a fundamental assumption on which FHR monitoring is based.

Tablet-Based Decision Support Tool Improves Performance of Neonatal Resuscitation: A Randomized Trial in Simulation.

INTRODUCTION: Decision support tools (DST) may aid compliance of teams with the Neonatal Resuscitation Program (NRP) algorithm but have not been adequately tested in this population. Furthermore, the optimal team size for neonatal resuscitation is not known. Our aim was to determine whether use of a tablet-based DST or team size altered adherence to the NRP algorithm in teams of healthcare providers (HCPs) performing simulated neonatal resuscitation. METHOD: One hundred nine HCPs were randomized into a team of 2 or 3 and into using a DST or memory alone while performing 2 simulation scenarios. The primary outcome was NRP compliance, assessed by the modified Neonatal Resuscitation Performance Evaluation (NRPE). Secondary outcomes were the subcomponents of the NRPE score, cumulative time error (the cumulative time in seconds to perform resuscitation tasks in error, early or late, from NRP guidelines), and the interaction between DST and team size. RESULTS: Decision support tool use improved total NRPE score when compared with memory alone (p = 0.015). There was no difference in NRPE score within teams of 2 compared with 3 HCPs. Cumulative time error was decreased with DST use compared with memory alone but was not significant (p = 0.057). Team size did not affect time error. CONCLUSIONS: Teams with the DST had improved NRP adherence compared with teams relying on memory alone in 1 of 2 scenarios. Two and 3 HCP teams performed similarly. Given the positive results observed in the simulated environment, further testing the DST in the clinical environment is warranted.

Outcomes of Planned Compared With Urgent Deliveries Using a Multidisciplinary Team Approach for Morbidly Adherent Placenta.

OBJECTIVE: To compare outcomes between planned and urgent cesarean hysterectomy for morbidly adherent placenta managed by a multidisciplinary team. METHODS: This is a retrospective case-control study of women with singleton pregnancies with antenatally suspected and pathologically confirmed morbidly adherent placenta who underwent cesarean hysterectomy between January 1, 2011, and February 30, 2017. Timing of delivery was classified as either planned (delivery at 34-35 weeks of gestation) or urgent (need for urgent delivery as a result of uterine contractions, bleeding, or both). The primary outcome variable was composite maternal morbidity. Logistic regression analysis was used to evaluate risk factors for urgent delivery. RESULTS: One hundred thirty patients underwent hysterectomy. Sixty (46.2%) required urgent delivery. Composite maternal morbidity was identified in 34 (56.7%) of the urgent and 26 (37.1%) of the planned deliveries (P=.03). Fewer units of red blood cells and fresh frozen plasma were transfused in the planned delivery group (red blood cells, median interquartile range 3 [0-8] versus 1 [0-4], P=.02; fresh frozen plasma, median interquartile range 1 [0-2] versus 0 [0-0], P=.001). Rates of low Apgar score and respiratory distress syndrome were higher in the urgent compared with the planned delivery group (5-minute Apgar score less than 7, 34 [59.6%] versus 14 [23.3%], P<.01; respiratory distress syndrome, 34 [61.8%] versus 16 [27.1%], P<.01). A history of two or more prior cesarean deliveries was an independent predictor of urgent delivery (adjusted odds ratio 11.4, 95% CI 1.8-71.1). CONCLUSION: Women with morbidly adherent placenta requiring urgent delivery have a worse outcome than women with planned delivery. Women with morbidly adherent placenta and two or more prior cesarean deliveries are at increased risk for urgent delivery. In such women, scheduling delivery before the standard 34- to 35-week timeframe may be reasonable.

Improving communication between obstetric and neonatology teams for high-risk deliveries: a quality improvement project.

Summoning is a key component of communication between obstetrics and neonatal resuscitation team (NRT) in advance of deliveries. A paging system is a commonly used summoning tool. The timeliness and information contained in the page help NRT to optimally prepare for postdelivery infant care. Our aim was to increase the frequency that summoning pages contained gestational age and reason for NRT attendance to >90%. At baseline, 8% of pages contained gestational age and 33% of pages contained a reason for NRT attendance. Sequential Plan-Do-Study-Act cycles were used as our model for quality improvement. During the 8-month improvement period, the per cent of pages increased to 97% for gestational age and 97% for reason for NRT attendance. Measures of page timeliness, our balancing measure, did not change. Summoning communication between obstetric and NRT is crucial for optimal perinatal outcomes. The active involvement of all stakeholders throughout the project resulted in the development of a standardised paging tool and a more informative paging process, which is a key communication tool used in many centres.

Developmental regulation of neurotransmitter phenotype through tetrahydrobiopterin.

During development, sympathetic neurons innervating rodent sweat glands undergo a target-induced change in neurotransmitter phenotype from noradrenergic to cholinergic. Although the sweat gland innervation in the adult mouse is cholinergic and catecholamines are absent, these neurons continue to express tyrosine hydroxylase (TH), the rate-limiting enzyme in catecholamine synthesis. The developmental suppression of noradrenergic function in these mouse sympathetic neurons is not well understood. We investigated whether the downregulation of the enzyme aromatic l-amino acid decarboxylase (AADC) or the TH cofactor tetrahydrobiopterin (BH4) could account for the loss of catecholamines in these neurons. AADC levels did not decrease during development, and adult cholinergic sympathetic neurons were strongly immunoreactive for AADC. In contrast, BH4 levels dropped significantly in murine sweat gland-containing footpads during the time period when the gland innervation was switching from making norepinephrine to acetylcholine. Immunoreactivity for the rate-limiting BH4 synthetic enzyme GTP cyclohydrolase (GCH) became undetectable in the sweat gland neurons during this phenotypic conversion, suggesting that sweat glands reduce BH4 levels by suppressing GCH expression during development. Furthermore, extracts from sweat gland-containing footpads suppressed BH4 in cultured mouse sympathetic neurons, and addition of the BH4 precursor sepiapterin rescued catecholamine production in neurons treated with footpad extracts. Together, these results suggest that the mouse sweat gland-derived cholinergic differentiation factor functionally suppresses the noradrenergic phenotype during development by inhibiting production of the TH cofactor, BH4. These data also indicate that GCH expression, which is often coordinately regulated with TH expression, can be controlled independently of TH during development.

IgG receptor FcγRIIB plays a key role in obesity-induced hypertension.

There is a well-recognized association between obesity, inflammation, and hypertension. Why obesity causes hypertension is poorly understood. We previously demonstrated using a C-reactive protein (CRP) transgenic mouse that CRP induces hypertension that is related to NO deficiency. Our prior work in cultured endothelial cells identified the Fcγ receptor IIB (FcγRIIB) as the receptor for CRP whereby it antagonizes endothelial NO synthase. Recognizing known associations between CRP and obesity and hypertension in humans, in the present study we tested the hypothesis that FcγRIIB plays a role in obesity-induced hypertension in mice. Using radiotelemetry, we first demonstrated that the hypertension observed in transgenic mouse-CRP is mediated by the receptor, indicating that FcγRIIB is capable of modifying blood pressure. We then discovered in a model of diet-induced obesity yielding equal adiposity in all study groups that whereas FcγRIIB(+/+) mice developed obesity-induced hypertension, FcγRIIB(-/-) mice were fully protected. Levels of CRP, the related pentraxin serum amyloid P component which is the CRP-equivalent in mice, and total IgG were unaltered by diet-induced obesity; FcγRIIB expression in endothelium was also unchanged. However, whereas IgG isolated from chow-fed mice had no effect, IgG from high-fat diet-fed mice inhibited endothelial NO synthase in cultured endothelial cells, and this was an FcγRIIB-dependent process. Thus, we have identified a novel role for FcγRIIB in the pathogenesis of obesity-induced hypertension, independent of processes regulating adiposity, and it may entail an IgG-induced attenuation of endothelial NO synthase function. Approaches targeting FcγRIIB may potentially offer new means to treat hypertension in obese individuals.

Extracellular signal-regulated kinase and phosphoinositol-3 kinase mediate IGF-1 induced proliferation of fetal sheep cardiomyocytes.

Growth of the fetal heart involves cardiomyocyte enlargement, division, and maturation. Insulin-like growth factor-1 (IGF-1) is implicated in many aspects of growth and is likely to be important in developmental heart growth. IGF-1 stimulates the IGF-1 receptor (IGF1R) and downstream signaling pathways, including extracellular signal-regulated kinase (ERK) and phosphoinositol-3 kinase (PI3K). We hypothesized that IGF-1 stimulates cardiomyocyte proliferation and enlargement through stimulation of the ERK cascade and stimulates cardiomyocyte differentiation through the PI3K cascade. In vivo administration of Long R3 IGF-1 (LR3 IGF-1) did not stimulate cardiomyocyte hypertrophy but led to a decreased percentage of cells that were binucleated in vivo. In culture, LR3 IGF-1 increased myocyte bromodeoxyuridine (BrdU) uptake by three- to five-fold. The blockade of either ERK or PI3K signaling (by UO-126 or LY-294002, respectively) completely abolished BrdU uptake stimulated by LR3 IGF-1. LR3 IGF-1 did not increase footprint area, but as expected, phenylephrine stimulated an increase in binucleated cardiomyocyte size. We conclude that 1) IGF-1 through IGF1R stimulates cardiomyocyte division in vivo; hyperplastic growth is the most likely explanation of IGF-1 stimulated heart growth in vivo; 2) IGF-1 through IGF1R does not stimulate binucleation in vitro or in vivo; 3) IGF-1 through IGF1R does not stimulate hypertrophy either in vivo or in vitro; and 4) IGF-1 through IGF1R requires both ERK and PI3K signaling for proliferation of near-term fetal sheep cardiomyocytes in vitro.