Publications by authors named "Nathan C Sundgren"

14 Publications

  • Page 1 of 1

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

Prenat Diagn 2021 Mar 9;41(4):497-504. Epub 2021 Feb 9.

Division of Fetal Therapy and Surgery, Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pd.5894DOI Listing
March 2021

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

Simul Healthc 2020 Aug;15(4):243-250

From the Section of Neonatology, Department of Pediatrics (C.M.R., K.E.P., J.L.H., N.C.S.), Baylor College of Medicine & Texas Children's Hospital, Houston, TX; and Center for Medical Simulation and Innovative Education (J.L.A.), Johns Hopkins All Children's Hospital, St. Petersburg, FL.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/SIH.0000000000000422DOI Listing
August 2020

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

Circulation 2019 12 10;140(24):2005-2018. Epub 2019 Oct 10.

University of Texas Southwestern Medical Center, Dallas (J.P., W.V., S.B., I.S.Y., K.T., A.S., H.C., N.C.S., A.R., K.L.C., C.M., P.W.S.).

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 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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCULATIONAHA.119.043490DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7027951PMC
December 2019

Aberrant DNA methylation as a diagnostic biomarker of diabetic embryopathy.

Genet Med 2019 11 17;21(11):2453-2461. Epub 2019 Apr 17.

Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1038/s41436-019-0516-zDOI Listing
November 2019

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

Prenat Diagn 2019 03;39(4):287-292

Division of Maternal Fetal Medicine, Department of Obstetrics and Gynecology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1002/pd.5428DOI Listing
March 2019

Conjoined twins: Pre-birth management, changes to NRP, and transport.

Semin Perinatol 2018 10 30;42(6):321-328. Epub 2018 Jul 30.

Department of Pediatrics, Section of Neonatology, Baylor College of Medicine, Texas Children's Hospital, Houston, TX 77030, USA. Electronic address:

The management of conjoined twins is complex and requires careful preparation. Pre-birth management includes prenatal counseling, which is important due to the overall poor prognosis. In instances of trial of life, the delivery must be tailored to address the anticipated anatomy based on prenatal imaging and anticipated physiology. A multidisciplinary team is essential to anticipate and address the ergonomic challenges and medical issues related to organ fusion, cross-circulation and associated anomalies. There are several suggested modifications to the current Neonatal Resuscitation Program algorithm including modifications to initial assessment, airway management, administration of chest compressions, obtaining emergency access, and medication dosing. Simulation is essential to address challenges, practice Neonatal Resuscitation Program modifications, delineate clear roles during delivery and practice communication. This paper offers a discussion of unique issues associated with delivery of conjoined twins and recommendations on how to approach these challenges based on our experience and available literature.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1053/j.semperi.2018.07.008DOI Listing
October 2018

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

J Perinat Neonatal Nurs 2018 Jul/Sep;32(3):250-256

Departments of Pediatrics, Section of Neonatology (Drs Sundgren, Gokulakrishnan, Hagan, and Suresh and Ms Kainer) and Critical Care Medicine (Ms D'Ambrosio and Dr Graf), Baylor College of Medicine, Houston, Texas; Departments of Quality and Safety (Dr Kelly) and Information Services (Ms Witt), Texas Children's Hospital, Houston.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/JPN.0000000000000333DOI Listing
November 2018

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

BMJ Open Qual 2017 14;6(2):e000095. Epub 2017 Dec 14.

Department of Neonatology, Texas Children's Hospital, Houston, Texas, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1136/bmjoq-2017-000095DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5736089PMC
December 2017

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

Obstet Gynecol 2018 02;131(2):234-241

Divisions of Maternal-Fetal Medicine and Gynecologic Oncology and Inpatient Women's Service, Department of Obstetrics and Gynecology, the Department of Pediatrics and Neonatology, the Department of Urology, and the Division of Transfusion Medicine, Department of Pathology & Immunology, Baylor College of Medicine and Texas Children's Hospital, Houston, Texas.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1097/AOG.0000000000002442DOI Listing
February 2018

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

Am J Perinatol 2018 Jan 20;35(1):10-15. Epub 2017 Jul 20.

Section of Neonatology, Department of Pediatrics, Texas Children's Hospital, Baylor College of Medicine, Houston, Texas.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1055/s-0037-1604391DOI Listing
January 2018

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

Hypertension 2015 Feb 3;65(2):456-62. Epub 2014 Nov 3.

From the Department of Pediatrics, Section of Neonatology, Baylor College of Medicine, Houston, TX (N.C.S., B.-M.D.B.); and Department of Internal Medicine, Division of Cardiology, Hypertension Section (W.V.) and Department of Pediatrics, Center for Pulmonary and Vascular Biology (K.T., I.S.Y., K.L.C., C.M., P.W.S.), University of Texas Southwestern Medical Center, Dallas.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/HYPERTENSIONAHA.114.04670DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4419357PMC
February 2015

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

Circ Res 2011 Oct 22;109(10):1132-40. Epub 2011 Sep 22.

Division of Pulmonary and Vascular Biology, Department of Pediatrics, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1161/CIRCRESAHA.111.254573DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3215097PMC
October 2011

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

Am J Physiol Regul Integr Comp Physiol 2003 Dec 28;285(6):R1481-9. Epub 2003 Aug 28.

Department of Physiology and Pharmacology, Oregon Health and Science University, Portland, Oregon 97239, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://dx.doi.org/10.1152/ajpregu.00232.2003DOI Listing
December 2003

Developmental regulation of neurotransmitter phenotype through tetrahydrobiopterin.

J Neurosci 2002 Nov;22(21):9445-52

Department of Physiology and Pharmacology, Oregon Health and Sciences University School of Medicine, Portland, Oregon 97239, USA.

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.
View Article and Find Full Text PDF

Download full-text PDF

Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6758055PMC
November 2002