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Browse Health

Credentials

Education ?

Medical School Score Rankings
Emory University (1966)
  •  
Top 25%

Awards & Distinctions ?

Awards  
Associate Editor, Reproductive Sciences (JSGI) (1993)
SSPR Founders Award (2005)
Perinatal Research Society (1981)
Associate Editor, Early Human Development (1986)
George L. Mac Gregor Professorship of Pediatrics - 1993-Present (1993)
Appointments
University of Texas Southwestern Medical School at Dallas
Professor
Associations
American Board of Pediatrics

Affiliations ?

Dr. Rosenfeld is affiliated with 6 hospitals.

Hospital Affiliations

Score

Rankings

  • UT Southwestern University Hospital - Zale Lipshy
    5151 Harry Hines Blvd, Dallas, TX 75235
    •  
    Top 25%
  • UT Southwestern University Hospital - St. Paul
    5909 Harry Hines Blvd, Dallas, TX 75235
    •  
    Top 25%
  • Children's Medical Center of Dallas
    1935 Motor St, Dallas, TX 75235
    •  
    Top 25%
  • Parkland Health & Hospital System
    5201 Harry Hines Blvd, Dallas, TX 75235
    •  
  • University Hospital - St Paul
  • UT Southwestern St Paul Hospital
  • Publications & Research

    Dr. Rosenfeld has contributed to 178 publications.
    Title Echocardiographic Predictors of Symptomatic Patent Ductus Arteriosus in Extremely-low-birth-weight Preterm Neonates.
    Date November 2010
    Journal Journal of Perinatology : Official Journal of the California Perinatal Association
    Excerpt

    Identify echocardiographic parameters at <or=4 day postnatal that predict the subsequent need for closure of a clinically significant patent ductus arteriosus (sPDA) in extremely-low-birth-weight neonates (ELBW).

    Title Regulation of the Cgmp-cpkg Pathway and Large-conductance Ca2+-activated K+ Channels in Uterine Arteries During the Ovine Ovarian Cycle.
    Date August 2010
    Journal American Journal of Physiology. Endocrinology and Metabolism
    Excerpt

    The follicular phase of the ovine ovarian cycle demonstrates parallel increases in ovarian estrogens and uterine blood flow (UBF). Although estrogen and nitric oxide contribute to the rise in UBF, the signaling pathway remains unclear. We examined the relationship between the rise in UBF during the ovarian cycle of nonpregnant sheep and changes in the uterine vascular cGMP-dependent pathway and large-conductance Ca(2+)-activated K(+) channels (BK(Ca)). Nonpregnant ewes (n = 19) were synchronized to either follicular or luteal phase using a vaginal progesterone-releasing device (CIDR), followed by intramuscular PGF(2alpha), CIDR removal, and treatment with pregnant mare serum gonadotropin. UBF was measured with flow probes before tissue collection, and second-generation uterine artery segments were collected from nine follicular and seven luteal phase ewes. The pore-forming alpha- and regulatory beta-subunits that constitute the BK(Ca), soluble guanylyl cyclase (sGC), and cGMP-dependent protein kinase G (cPKG) isoforms (cPKG(1alpha) and cPKG(1beta)) were measured by Western analysis and cGMP levels by RIA. BK(Ca) subunits were localized by immunohistochemistry. UBF rose >3-fold (P < 0.04) in follicular phase ewes, paralleling a 2.3-fold rise in smooth muscle cGMP and 32% increase in cPKG(1alpha) (P < 0.05). sGC, cPKG(1beta), and the BK(Ca) alpha-subunit were unchanged. Notably, expression of beta(1)- and beta(2)-regulatory subunits rose 51 and 79% (P <or= 0.05), respectively. Increases in endogenous ovarian estrogens in follicular-phase ewes result in increases in UBF associated with upregulation of the cGMP- and cPKG-dependent pathway and increased vascular BK(Ca) beta/alpha-subunit stoichiometry, suggesting enhanced BK(Ca) activation contributes to the follicular phase rise in UBF.

    Title Prenatal Closure of the Ductus Arteriosus and Maternal Ingestion of Anthocyanins.
    Date July 2010
    Journal Journal of Perinatology : Official Journal of the California Perinatal Association
    Excerpt

    Prenatal closure of the ductus arteriosus (DA) is associated with maternal ingestion of cyclooxygenase inhibitors during pregnancy. We report a case of prenatal DA closure after maternal ingestion of MonaVie, a juice blend containing the cyclooxygenase and nitric oxide synthase inhibitors anthocyanins and proanthocyanidins. A G(2)P(0)Ab(1) woman had an uncomplicated first and second trimester and normal 20-week fetal ultrasound. At 37 weeks, she developed polyhydramnios; a fetal echocardiogram showed right atrial and ventricular (RV) enlargement with RV dysfunction. Immediately after birth, there was pulmonary hypertension by echocardiogram with DA closure, severe RV hypertrophy and dysfunction, and marked right-to-left atrial shunting. Improvement occurred over 3 weeks with the neonate tolerating room air and a follow-up echocardiogram showing minimal atrial shunting and improved RV function. This report shows an association between MonaVie ingestion throughout pregnancy and prenatal DA closure resulting in cardiac dysfunction and pulmonary hypertension at birth.

    Title Pregnancy Modifies the Large Conductance Ca2+-activated K+ Channel and Cgmp-dependent Signaling Pathway in Uterine Vascular Smooth Muscle.
    Date July 2009
    Journal American Journal of Physiology. Heart and Circulatory Physiology
    Excerpt

    Regulation of uteroplacental blood flow (UPBF) during pregnancy remains unclear. Large conductance, Ca(2+)-activated K(+) channels (BK(Ca)), consisting of alpha- and regulatory beta-subunits, are expressed in uterine vascular smooth muscle (UVSM) and contribute to the maintenance of UPBF in the last third of ovine pregnancy, but their expression pattern and activation pathways are unclear. We examined BK(Ca) subunit expression, the cGMP-dependent signaling pathway, and the functional role of BK(Ca) in uterine arteries (UA) from nonpregnant (n = 7), pregnant (n = 38; 56-145 days gestation; term, approximately 150 days), and postpartum (n = 15; 2-56 days) sheep. The alpha-subunit protein switched from 83-87 and 105 kDa forms in nonpregnant UVSM to 100 kDa throughout pregnancy, reversal occurring >30 days postpartum. The 39-kDa beta(1)-subunit was the primary regulatory subunit. Levels of 100-kDa alpha-subunit rose approximately 70% during placentation (P < 0.05) and were unchanged in the last two-thirds of pregnancy; in contrast, beta(1)-protein rose throughout pregnancy (R(2) = 0.996; P < 0.001; n = 13), increasing 50% during placentation and approximately twofold in the remainder of gestation. Although UVSM soluble guanylyl cyclase was unchanged, cGMP and protein kinase G(1alpha) increased (P < 0.02), paralleling the rise and fall in beta(1)-protein during pregnancy and the puerperium. BK(Ca) inhibition not only decreased UA nitric oxide (NO)-induced relaxation but also enhanced alpha-agonist-induced vasoconstriction. UVSM BK(Ca) modify relaxation-contraction responses in the last two-thirds of ovine pregnancy, and this is associated with alterations in alpha-subunit composition, alpha:beta(1)-subunit stoichiometry, and upregulation of the cGMP-dependent pathway, suggesting that BK(Ca) activation via NO-cGMP and beta(1) augmentation may contribute to the regulation of UPBF.

    Title Metabolism and Synthesis of Arginine Vasopressin in Conscious Newborn Sheep.
    Date October 2008
    Journal American Journal of Physiology. Endocrinology and Metabolism
    Excerpt

    Arginine vasopressin (AVP) is an important regulator of cardiovascular homeostasis in the fetus, but its role after birth is unclear. Although infused AVP increases mean arterial pressure (MAP) during the 1st mo after birth, pressor responses are unchanged, suggesting that vascular responsiveness is also unchanged. Alternatively, this could reflect increases in AVP metabolic clearance rate (MCR(AVP)). However, newborn AVP metabolism and synthesis are poorly studied. Therefore, we examined the pressor responses to infused AVP and the pattern of circulating AVP, AVP production rate (PR(AVP)), and MCR(AVP) in conscious newborn sheep (n = 5) at 9-38 days after birth. Basal MAP rose and heart rate (HR) fell during the study period (P < or = 0.02), while circulating AVP was unchanged (P > 0.1), averaging 3.01 +/- 0.86 pg/ml. Infused AVP elicited steady-state responses at 10-40 min, increasing plasma AVP and MAP and decreasing HR (P < 0.001). Although pressor responses were unchanged between 9 and 38 days, the rise in MAP correlated with increases in plasma AVP (R = 0.47, P = 0.02, n = 24). MCR(AVP) was unchanged throughout the 1st mo (P > 0.2), averaging 205 +/- 17 ml.kg(-1).min(-1), and was associated with an elevated PR(AVP), 973 +/- 267 pg.kg(-1).min(-1), which also was unchanged (P > 0.1). After birth, MCR(AVP) and PR(AVP) are elevated, probably accounting for the stable plasma AVP levels. The former is also likely to account for the stable pressor responses to infused AVP during the 1st mo. The reason for the elevated PR(AVP) is unclear but may relate to increases in vascular volume associated with postnatal growth.

    Title Interrater Reliability and Effect of State on Blood Pressure Measurements in Infants 1 to 3 Years of Age.
    Date September 2008
    Journal Pediatrics
    Excerpt

    OBJECTIVE: The objective of this study was to determine the interrater variability and effect of state on systolic blood pressure measurements in infants </=3 years of age. METHODS: Study 1 examined interrater variability, determined by interclass correlation coefficient for 2 raters, and the effect of state on systolic blood pressure measurements in infants at 1, 2, and 3 years. Study 2 examined the variability of duplicate systolic blood pressure measurements by a single rater determined by interclass correlation coefficient and effect of state in 120 infants at 1, 2, and 3 years. Systolic blood pressure was defined as the Doppler-amplified sound corresponding to the first Korotkoff sound using a sphygmomanometer with appropriate cuff size. State was scored as follows: 1, sleeping; 2, awake and calm; 3, awake and fussy/restless; and 4, awake and vigorously crying/screaming. RESULTS: In study 1, the overall interclass correlation coefficient for systolic blood pressure was 0.81 and decreased when state varied between raters. When compared with a calm state 1 and/or 2 at both measurements, noncalm state 3 and/or 4 at both measurements was associated with an increase in systolic blood pressure. Although state was similar in infants born at </=36 and >36 weeks' gestational age, the former had a systolic blood pressure 13.0 +/- 14 mm Hg greater than the 50th centile for age and gender versus 2.4 +/- 12 mmHg for those >36 weeks' gestation. In study 2, the interclass correlation coefficient for repeated measurements by a single rater was 0.85, and noncalm state at both measurements was associated with an elevated systolic blood pressure. CONCLUSIONS: Systolic blood pressure can be accurately measured in the first 3 years after birth, but state modifies systolic blood pressure and must be determined at the time of measurement. Infants born at </=36 weeks' estimated gestational age may be at risk for an elevated systolic blood pressure, but this requires additional study.

    Title Meconium Increases Type 1 Angiotensin Ii Receptor Expression and Alveolar Cell Death.
    Date March 2008
    Journal Pediatric Research
    Excerpt

    The pulmonary renin-angiotensin system (RAS) contributes to inflammation and epithelial apoptosis in meconium aspiration. It is unclear if both angiotensin II receptors (ATR) contribute, where they are expressed and if meconium modifies subtype expression. We examined ATR subtypes in 2 wk rabbit pup lungs before and after meconium exposure and with and without captopril pretreatment or type 1 receptor (AT1R) inhibition with losartan, determining expression and cellular localization with immunoblots, RT-PCR and immunohistochemistry, respectively. Responses of cultured rat alveolar type II pneumocytes were also examined. Type 2 ATR were undetected in newborn lung before and after meconium instillation. AT1R were expressed in pulmonary vascular and bronchial smooth muscle and alveolar and bronchial epithelium. Meconium increased total lung AT1R protein approximately 3-fold (p = 0.006), mRNA 29% (p = 0.006) and immunostaining in bronchial and alveolar epithelium and smooth muscle, which were unaffected by captopril and losartan. Meconium also increased AT1R expression >3-fold in cultured type II pneumocytes and caused concentration-dependent cell death inhibited by losartan. Meconium increases AT1R expression in newborn rabbit lung and cultured type II pneumocytes and induces AT1R-mediated cell death. The pulmonary RAS contributes to the pathogenesis of meconium aspiration through increased receptor expression.

    Title Insulin Resistance in Hispanic Large-for-gestational-age Neonates at Birth.
    Date November 2007
    Journal The Journal of Clinical Endocrinology and Metabolism
    Excerpt

    CONTENT: Intrauterine exposure to maternal diabetes and large size at birth are known risk factors for the subsequent development of insulin resistance and metabolic syndrome. Although Hispanic youth have been shown to have a high prevalence of metabolic syndrome, it is unknown whether metabolic abnormalities and a predisposition for glucose intolerance are present at birth. OBJECTIVE: The objective of the study was to determine whether abnormalities in insulin sensitivity exist at or soon after birth in large-for-gestational-age neonates born to Hispanic women with and without gestational diabetes. DESIGN/PATIENTS/SETTING: Forty-two term Hispanic neonates were enrolled for cross-sectional studies at 24-48 h after birth and included nine large-for-gestational-age neonates delivered of women with gestational diabetes (large-for-gestational-age-IDM), 12 large-for-gestational-age but not IDM neonates, 11 poorly grown (at the fifth to 10th percentile), and 10 appropriate-for-gestational-age neonates. Insulin sensitivity and secretion were measured by shortened fasting iv glucose tolerance test. MAIN OUTCOME MEASURE: Insulin sensitivity index was measured within 48 h of birth. RESULTS: Neonates were studied at 36 +/- 11 h postnatally, and all groups were euglycemic at the time of study. However, insulin sensitivity was significantly lower (P < 0.05, ANOVA) in large-for-gestational-age-IDM [3.0 +/- 0.7 (sem) mU/liter.min] and large-for-gestational-age-non-IDM (2.2 +/- 0.4 mU/liter.min) cohorts in comparison with poorly grown (5.0 +/- 0.7 mU/liter.min) and appropriate-for-gestational-age controls (5.4 +/- 0.8 mU/liter.min). Insulin secretion did not differ between groups. CONCLUSIONS: Reduced insulin sensitivity is present soon after birth in Hispanic large-for-gestational-age neonates born to mothers with and without gestational diabetes, demonstrating the onset of insulin resistance before birth and evidence of altered fetal programming.

    Title The Renin-angiotensin System in Conscious Newborn Sheep: Metabolic Clearance Rate and Activity.
    Date October 2007
    Journal Pediatric Research
    Excerpt

    The role of the renin-angiotensin system (RAS) in regulating newborn mean arterial blood pressure (MAP) and tissue blood flow remains unclear. Although postnatal MAP increases, vascular responsiveness to infused angiotensin II (ANG II) is unchanged, possibly reflecting increased metabolic clearance rate of ANG II (MCR(ANG II)). To address this, we examined MAP, heart rate, plasma ANG II and renin activity (PRA), and MCR(ANG II) in conscious postnatal sheep (n = 9, 5-35 d old) before and during continuous systemic ANG II infusions to measure MCR (ANG II). Postnatal MAP increased (p < 0.02), whereas plasma ANG II decreased from 942 +/- 230 (SEM) to 471 +/- 152 and 240 +/- 70 pg/mL at <10 d, 10-20 d, and 21-35 d postnatally (p = 0.05), respectively. Despite high plasma ANG II, PRA remained elevated, averaging 6.70 +/- 1.1 ng/mL.h throughout the postnatal period, but decreased 35% (p = 0.01) during ANG II infusions. MCR(ANG II) decreased approximately sixfold after birth and averaged 115 mL/min.kg during the first month. Circulating ANG II is markedly increased after birth, reflecting placental removal, high fetal MCR(ANG II), and enhanced RAS activity. Although circulating ANG II decreases as MAP increases, MCR(ANG II) is unchanged, suggesting decreased ANG II production. Persistent vascular smooth muscle (VSM) AT2 receptor subtype (AT2R) expression after birth may modify the hypertensive effects of ANG II postnatally.

    Title Vascular Development in Early Ovine Gestation: Carotid Smooth Muscle Function, Phenotype, and Biochemical Markers.
    Date August 2007
    Journal American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
    Excerpt

    Vascular smooth muscle (VSM) maturation is developmentally regulated and differs between vascular beds. The maturation and contribution of VSM function to tissue blood flow and blood pressure regulation during early gestation are unknown. The carotid artery (CA) contributes to fetal cerebral blood flow regulation and well being. We studied CA VSM contractility, protein contents, and phenotype beginning in the midthird of ovine development. CAs were collected from early (88-101 day of gestation) and late (138-150 day; term = day 150) fetal (n = 14), newborn (6-8 day old; n = 7), and adult (n = 5) sheep to measure forces in endothelium-denuded rings with KCl, phenylephrine, and ANG II; changes in cellular proteins, including total and soluble protein, actin and myosin, myosin heavy chain isoforms (MHC), filamin, and proliferating cell nuclear antigen; and vascular remodeling. KCl and phenylephrine elicited age- and dose-dependent contraction responses (P < 0.001) at all ages except early fetal, which were unresponsive. In contrast, ANG II elicited dose responses only in adults, with contractility increasing greater than fivefold vs. that shown in fetal or neonatal animals (P < 0.001). Increased contractility paralleled age-dependent increases (P < 0.01) in soluble protein, actin and myosin, filamin, adult smooth muscle MHC-2 (SM2) and medial wall thickness and reciprocal decreases (P < 0.001) in nonmuscle MHC-B, proliferating cell nuclear antigen and medial cellular density. VSM nonreceptor- and receptor-mediated contractions are absent or markedly attenuated in midgestation and increase age dependently, paralleling the transition from synthetic to contractile VSM phenotype and, in the case of ANG II, paralleling the switch to the AT(1) receptor. The mechanisms regulating VSM maturation and thus blood pressure and tissue perfusion in early development remain to be determined.

    Title Prevalence of Spontaneous Closure of the Ductus Arteriosus in Neonates at a Birth Weight of 1000 Grams or Less.
    Date May 2006
    Journal Pediatrics
    Excerpt

    OBJECTIVE: Ductus arteriosus (DA) closure occurs within 96 hours in >95% of neonates >1500 g in birth weight (BW). The prevalence and postnatal age of spontaneous ductal closure in neonates < or =1000 g in BW (extremely low birth weight [ELBW] neonates) remain unclear, as does the incidence of failure to close with indomethacin. Therefore, we prospectively examined the prevalence, postnatal age, and clinical variables associated with spontaneous DA closure, occurrence of persistent patent DA, and indomethacin failure in ELBW neonates. METHODS: Neonates delivered at Parkland Memorial Hospital from February 2001 through December 2003 were studied. Those with congenital heart defects or death <10 days postnatally were excluded. Echocardiograms were performed 48 to 72 hours postnatal and every 48 hours until 10 days postnatally. RESULTS: We studied 122 neonates with BW of 794 +/- 118 (SD) g and estimated gestational age (EGA) of 26 +/- 2 weeks. Spontaneous permanent DA closure occurred in 42 (34%) neonates at 4.3 +/- 2 days postnatally, with 100% closure by 8 days. These neonates were more mature, less likely to have received antenatal steroids or have hyaline membrane disease (HMD; 52% vs 79%), and more likely to be growth restricted (31% vs 5%) and delivered of hypertensive women. Using regression analysis, EGA and absence of antenatal steroids and HMD predicted ductal closure. Ten (8%) neonates with early DA closure reopened and required medical/surgical closure. Eighty neonates had persistent patent DA; 7 were surgically ligated, and 5 remained asymptomatic, with 4 of 5 closing after 10 days postnatally. Sixty-eight (85%) received indomethacin at 6.2 +/- 4 days postnatally; 41% failed therapy and had no distinguishing characteristics. CONCLUSIONS: Spontaneous permanent DA closure occurs in >34% of ELBW neonates and is predicted by variables related to maturation, for example, EGA and an absence of HMD, whereas indomethacin failure could not be predicated.

    Title Large-conductance Ca2+-dependent K+ Channels Regulate Basal Uteroplacental Blood Flow in Ovine Pregnancy.
    Date March 2006
    Journal Journal of the Society for Gynecologic Investigation
    Excerpt

    OBJECTIVES: The mechanisms regulating basal uteroplacental blood flow (UBF) and the greater than 30-fold increase observed in normal pregnancy remain unclear. Although vascular growth contributes in early gestation, vasodilation accounts for the exponential rise seen in the last third of pregnancy. Large conductance potassium channels (BK(Ca)) are expressed in uterine vascular smooth muscle (VSM), but the extent of their role in regulating UBF in pregnancy is unclear. Therefore, we determined if BK(Ca) regulate basal UBF during ovine pregnancy. METHODS: Studies were performed at 113 to 127 days and 135 to 150 days of gestation in eight pregnant ewes instrumented with uterine artery flow probes and uterine arterial and venous catheters. Tetraethylammonium chloride (TEA), a BK(Ca)-specific inhibitor at less than 1.0 mM, was infused intra-arterially into the pregnant uterine horn over 60 minutes to achieve levels of 0.001-0.35 mM while continuously monitoring UBF, arterial pressure (MAP), and heart rate (HR). Uterine arterial and venous blood was collected simultaneously to measure uterine cyclic guanosine monophosphate (cGMP) synthesis. RESULTS: Intra-arterial TEA dose-dependently decreased basal UBF in the early (R = 0.81, n = 36, P <.001) and late (R = 0.72, n = 31, P <.001) study periods without altering contralateral UBF, MAP, and HR. The IC(50) was 0.2 mM and basal UBF decreased >or=80% at 0.35 mM in both periods. Although UBF fell greater than 40% at estimated plasma TEA levels of 0.3 mM, uterine arterial cGMP was unchanged, uterine venous cGMP rose, and uterine cGMP synthesis was unchanged; therefore, upstream events associated with BK(Ca) activation were unaffected by blockade. CONCLUSIONS: These are the first data demonstrating that BK(Ca) are essential in the maintenance of basal UBF in the last third of ovine pregnancy.

    Title Estrogen Regulates {beta}1-subunit Expression in Ca(2+)-activated K(+) Channels in Arteries from Reproductive Tissues.
    Date October 2005
    Journal American Journal of Physiology. Heart and Circulatory Physiology
    Excerpt

    Daily estradiol-17beta (E(2)beta) increases basal uterine blood flow (UBF) and enhances acute E(2)beta-mediated increases in UBF in ovariectomized nonpregnant ewes. The acute E(2)beta-mediated rise in UBF involves vascular smooth muscle (VSM) large-conductance Ca(2+)-activated K(+) channels (BK(Ca)). BK(Ca) consist of pore-forming alpha-subunits and regulatory beta(1)-subunits that modulate channel function and E(2)beta responsiveness. It is unclear whether E(2)beta also alters subunit expression and thus channel density and/or function, thereby contributing to the rise in basal UBF and enhanced UBF responses that follow daily E(2)beta. Therefore, we examined BK(Ca) subunit expression by using reverse transcription-PCR and immunoblot analysis of arterial VSM from reproductive and nonreproductive tissues and myometrium from ovariectomized nonpregnant ewes after daily E(2)beta (1 microg/kg iv) or vehicle without or with acute E(2)beta (1 microg/kg). Tissue distribution was determined by immunohistochemistry. Acute E(2)beta did not alter alpha- or beta(1)-subunit expression in any tissue (P > 0.1). Daily E(2)beta also did not affect alpha-subunit mRNA or protein in any tissue (P > 0.1) or mesenteric arterial VSM beta(1)-subunit. However, daily E(2)beta increased uterine and mammary arterial VSM beta(1)-subunit mRNA by 32% and 83% (P < 0.05), uterine VSM protein by 30%, and myometrial beta(1)-subunit mRNA and protein by 74% (P < or = 0.005). Immunostaining of uterine arteries, myometrium, and intramyometrial arteries paralleled immunoblot analyses for both subunits. Although BK(Ca) density is unaffected by daily and acute E(2)beta, daily E(2)beta increases beta(1)-subunit in proximal and distal uterine arterial VSM. Thus prolonged E(2)beta exposure may alter BK(Ca) function, estrogen responsiveness, and basal vascular tone and reactivity in reproductive arteries by modifying alpha:beta(1) stoichiometry.

    Title Effects of Systemic and Local Phenylephrine and Arginine Vasopressin Infusions in Conscious Postnatal Sheep.
    Date September 2005
    Journal Pediatric Research
    Excerpt

    Mean arterial pressure (MAP) increases after birth, however, the mechanisms remain unclear. Systemic angiotensin II (ANG II) infusions increase MAP in newborn sheep, but the direct effects of ANG II on peripheral vascular resistance (PVR) are minimal. Thus, its systemic pressor effects may reflect release of other pressor agents, e.g. alpha-agonists and/or AVP, suggesting they contribute to postnatal regulation of MAP and PVR. To address this, we performed studies in conscious sheep at 7-14, 15-21, and 22-35 d postnatal, infusing phenylephrine (PE) or AVP systemically or intra-arterially into the hindlimb while measuring MAP, heart rate (HR), and femoral blood flow (FmBF). Basal MAP and FmBF rose, whereas HR and femoral vascular resistance (FmVR) fell (p < or = 0.03) during the first month postnatal. Although systemic PE and AVP dose dependently increased MAP and FmVR and decreased FmBF and HR (p < 0.001, ANOVA) at all ages, responses were not age dependent. Notably, increases in FmVR exceeded increases in MAP, and responses to PE appeared to exceed AVP (p < 0.05). Hindlimb infusions of both agents decreased FmBF and increased FmVR dose dependently (p < 0.001, ANOVA) at all ages without altering MAP or HR. These responses also were not age dependent. Unlike ANG II, PE and AVP directly increase PVR in newborn sheep. Moreover, FmVR increases more than MAP at all doses, suggesting these agonists may contribute to postnatal MAP regulation and could mediate the effects of systemic ANG II on postnatal MAP.

    Title Vessel-specific Regulation of Angiotensin Ii Receptor Subtypes During Ovine Development.
    Date May 2005
    Journal Pediatric Research
    Excerpt

    Umbilical and systemic responses to angiotensin II differ in term fetal sheep, and peripheral vascular responses are attenuated or absent before and after birth. These observations may reflect developmental differences in angiotensin II receptor (AT) subtypes in vascular smooth muscle (VSM). Studies of AT subtype ontogeny and regulation are generally limited to the aorta, which may not be extrapolated to other arteries, and neither is completely described during ovine development. We therefore characterized VSM AT subtype expression and regulation throughout an extended period of development in umbilical and carotid artery and aorta from fetal (85-146 d gestation), postnatal (5-23 d), and adult sheep, measuring AT(1) and AT(2) mRNA and protein and performing immunohistochemistry. Parallel increases in umbilical AT(1) mRNA and protein began early in gestation and continued to term, and although AT(2) mRNA was unchanged, protein levels decreased >90% at term. Fetal carotid AT(1) mRNA was <40% of adult values and unchanged before birth; however, AT(1) protein rose >2-fold at term. After birth, AT(1) mRNA increased to 85% of adult values and was associated with another 2-fold rise in protein. In contrast, carotid AT(2) mRNA and protein fell in parallel throughout development and were barely detectable in the newborn and the adult. Immunostaining was consistent with observations in both arteries. A third pattern occurred in aortic VSM. The ontogeny of AT subtype expression and regulation is vessel specific, with changes in umbilical VSM beginning very early in development. Although the mechanisms that regulate mRNA and protein expression are unclear, these changes parallel differences in VSM maturation and function and local blood flow.

    Title Hospital Survival of Very-low-birth-weight Neonates from 1977 to 2000.
    Date September 2004
    Journal Journal of Perinatology : Official Journal of the California Perinatal Association
    Excerpt

    OBJECTIVE: To determine patterns of survival for very low birth weight (VLBW, birth weight 501 to 1500 g) neonates over 23 years. STUDY DESIGN: Data for 4873 VLBW neonates born from 1977 to 2000 were divided into five epochs. The primary outcome was survival to hospital discharge. Birth weight-specific survival rates were estimated by race and gender for each epoch. Presence of comorbidities and congenital anomalies, delivery mode, and provision of artificial ventilation were investigated to determine whether they could explain observed survival patterns. RESULTS: From 1977 to 1995, survival increased from 50.2% to 81.0% as the proportion of VLBW neonates receiving artificial ventilation rose from 59.0% to 80.9%. Survival was unchanged between 1990 to 1995 and 1996 to 2000. Black females maintained a survival advantage over the entire study period. Survival improved for neonates with congenital anomalies over time, but had little impact on race/gender survival patterns. Survival patterns also could not be explained by comorbidity status, delivery mode, or access to artificial ventilation. CONCLUSION: The survival advantage of VLBW black females persists and remains unexplained.

    Title Are Complete Blood Cell Counts Useful in the Evaluation of Asymptomatic Neonates Exposed to Suspected Chorioamnionitis?
    Date August 2004
    Journal Pediatrics
    Excerpt

    OBJECTIVE: Chorioamnionitis complicates 1% to 10% of pregnancies and increases the risk of neonatal infection. Women with chorioamnionitis receive intrapartum antibiotics, often resulting in inconclusive neonatal blood cultures. Peripheral neutrophil values are used frequently to assist in the diagnosis of neonatal infection and to determine duration of antibiotics; we sought to determine the utility of this approach. METHODS: A prospective observational study was performed in 856 near-term/term neonates who were exposed to suspected chorioamnionitis. Each received antibiotics for 48 hours unless clinical infection or positive blood cultures occurred. Peripheral neutrophils were measured serially and analyzed using the reference ranges of Manroe et al; an additional analysis of only the initial neutrophil values used the normal ranges of Schelonka et al. Results of neutrophil analyses were not used to determine duration of therapy. Fifty percent of asymptomatic neonates were seen postdischarge to ascertain recurrent infection. Local patient charges were examined. RESULTS: Ninety-six percent of neonates were asymptomatic and had negative cultures, and antibiotics were discontinued at 48 hours. A total of 2427 neutrophil counts were analyzed. Although abnormal neutrophil values were more frequent in infected or symptomatic neonates, 99% of asymptomatic neonates had > or = 1 abnormal value. The specificity and negative predictive values for abnormal neutrophil values ranged between 0.12 and 0.95 and 0.91 and 0.97, respectively; sensitivity was 0.27 to 0.76. Significant differences in interpretation of the initial neutrophil values were noted, depending on the normal values used. Follow-up was performed for 373 asymptomatic neonates until 3 weeks' postnatal age. Eight required rehospitalization; none had evidence of bacterial infection. If neutrophil values had been used to determine duration of antibiotics, then local costs would have increased by 76,000 dollars to 425,000 dollars per year. CONCLUSIONS: Single or serial neutrophil values do not assist in the diagnosis of early-onset infection or determination of duration of antibiotic therapy in asymptomatic, culture-negative neonates who are > or = 35 weeks' gestation and are delivered of women with suspected chorioamnionitis.

    Title Angiotensin Ii Mediates Uterine Vasoconstriction Through Alpha-stimulation.
    Date July 2004
    Journal American Journal of Physiology. Heart and Circulatory Physiology
    Excerpt

    Intravenous angiotensin II (ANG II) increases uterine vascular resistance (UVR), whereas uterine intra-arterial infusions do not. Type 2 ANG II (AT(2)) receptors predominate in uterine vascular smooth muscle; this may reflect involvement of systemic type 1 ANG II (AT(1)) receptor-mediated alpha-adrenergic activation. To examine this, we compared systemic pressor and UVR responses to intravenous phenylephrine and ANG II without and with systemic or uterine alpha-receptor blockade and in the absence or presence of AT(1) receptor blockade in pregnant and nonpregnant ewes. Systemic alpha-receptor blockade inhibited phenylephrine-mediated increases in mean arterial pressure (MAP) and UVR, whereas uterine alpha-receptor blockade alone did not alter pressor responses and resulted in proportionate increases in UVR and MAP. Although neither systemic nor uterine alpha-receptor blockade affected ANG II-mediated pressor responses, UVR responses decreased >65% and also were proportionate to increases in MAP. Systemic AT(1) receptor blockade inhibited all responses to intravenous ANG II. In contrast, uterine AT(1) receptor blockade + systemic alpha-receptor blockade resulted in persistent proportionate increases in MAP and UVR. Uterine AT(2) receptor blockade had no effects. We have shown that ANG II-mediated pressor responses reflect activation of systemic vascular AT(1) receptors, whereas increases in UVR reflect AT(1) receptor-mediated release of an alpha-agonist and uterine autoregulatory responses.

    Title Estrogen Selectively Up-regulates Enos and Nnos in Reproductive Arteries by Transcriptional Mechanisms.
    Date February 2004
    Journal Journal of the Society for Gynecologic Investigation
    Excerpt

    OBJECTIVE: To determine the mechanism(s) whereby daily and acute estradiol-17beta (E(2)beta) exposure modifies endothelium-derived nitric oxide synthase (eNOS) and vascular smooth muscle (VSM) neuronal nitric oxide synthase (nNOS) in reproductive and nonreproductive arteries and to localize NOS isoform expression within the vessel wall. METHODS: Oophorectomized nonpregnant ewes received E(2)beta (1 microg/kg per day) or no E(2)beta for 5-6 days or acute E(2)beta (1 microg/kg) on day 6-7 with or without daily E(2)beta. Uterine, mammary, mesenteric, and femoral arteries were collected at completion of each study, adventitia were removed, and samples were frozen and stored at -80C. After separating endothelium and VSM, NOS isoform mRNA was measured using reverse transcription-polymerase chain reaction. VSM nNOS protein was determined by Western analysis. RESULTS: Basal eNOS and nNOS mRNA was greatest (P <.02) in reproductive artery endothelium and VSM, respectively. Daily E(2)beta was required for maximum uterine vascular responses to acute E(2)beta and was associated with increased reproductive artery endothelial eNOS mRNA (>1.5-fold, P <.02) and uterine VSM nNOS mRNA (>2.5-fold, P <.003) and protein (21%, P <.05). Acute E(2)beta in the presence and absence of daily E(2)beta also increased uterine eNOS 68% and 28% (P =.01), respectively, within 90 minutes but did not affect VSM nNOS. Mammary eNOS increased 71% only after E(2)beta withdrawal; VSM nNOS was unchanged. Neither NOS isoform was altered in nonreproductive arteries by daily or acute E(2)beta. CONCLUSIONS: Basal eNOS and nNOS isoform expression is greatest in arteries from reproductive tissues, and isoform responses to E(2)beta are cell specific and transcriptionally regulated. Furthermore, optimal uterine vascular responses to acute E(2)beta exposure require daily E(2)beta exposure that enhances basal NOS expression and abundance.

    Title Progression of Autoimmune Thyroiditis in an Hiv-infected Woman on Haart.
    Date June 2003
    Journal The Aids Reader
    Excerpt

    Changes in immunoregulation, among other factors, may initiate or exacerbate autoimmune thyroiditis. Strikingly high titers of antithyroid peroxidase antibodies have been found in HIV-infected patients, and, according to some studies, these increase further as HIV disease progresses. The pathogenesis of autoimmune thyroiditis is not totally understood, but activated CD4+ cells predominate in the infiltrate and are believed to be central to the process. Some investigators have postulated that endocrinologic autoimmunity might result from incomplete or unbalanced immune restoration with highly active antiretroviral therapy (HAART). The case presented here suggests progression from euthyroid Hashimoto's thyroiditis to hypothyroidism after initiation of HAART.

    Title Differential Responses to Systemic and Local Angiotensin Ii Infusions in Conscious Postnatal Sheep.
    Date April 2003
    Journal Pediatric Research
    Excerpt

    Angiotensin II (ANG II) increases blood pressure (MAP) via specific ANG II receptors (AT) and is considered important in regulating MAP after birth. In adult animals, AT(1) receptors predominate in vascular smooth muscle (VSM) and mediate vasoconstriction. In newborn sheep, AT(2) receptors, which do not mediate vasoconstriction, predominate in vascular smooth muscle until 2 wk postnatal when they are replaced by AT(1). Thus, the mechanisms whereby ANG II increases MAP after birth are unclear. We examined the effects of ANG II on femoral vascular resistance (FmVR) and blood flow (FmBF) in serial studies of newborn sheep (n = 7) at 7-14 d, 15-21 d, and 22-35 d. Animals had femoral catheters implanted for systemic ANG II infusions and cardiovascular monitoring, and a flow probe was implanted on the contralateral artery proximal to the superficial saphenous artery, which contained a catheter for intra-arterial ANG II infusions. Studies were performed using a range of systemic and intra-arterial ANG II doses. Systemic ANG II increased MAP dose-dependently at all ages (p < 0.001); however, responses were not age dependent. FmBF rose dose dependently at 7-14 d (p < 0.001) and was unchanged at older ages. FmVR was unaffected at 7-14 d, but values increased dose dependently at 15-21 d and 22-3 5d (p < 0.001), although never exceeded relative increases in MAP. Local ANG II did not alter MAP, FmBF, or FmVR at any age. Although systemic ANG II increases MAP and FmVR dose dependently after birth, ANG II-induced vasoconstriction is attenuated. Furthermore, intra-arterial ANG II does not alter FmVR in the absence of systemic responses, suggesting incomplete vascular smooth muscle AT(1) expression, stimulation of local ANG II antagonists, or ANG II-mediated release of another vasoconstrictor.

    Title Mechanisms Modulating Estrogen-induced Uterine Vasodilation.
    Date March 2003
    Journal Vascular Pharmacology
    Excerpt

    Estrogen, a potent vasodilator, has its greatest effects in reproductive tissues, e.g., increasing uterine blood flow (UBF) 5- to 10-fold within 90 min after a bolus dose. High-conductance potassium channels and nitric oxide (NO) contribute to the uterine responses, but other factors may be involved. We examined the role of ATP-dependent (ATP-sensitive) and voltage-gated (Kv) potassium channels and new protein synthesis in ovariectomized ewes with uterine artery flow probes, infusing intraarterial inhibitors glibenclamide (GLB; KATP), 4-aminopyridine (4-AP; Kv) or cycloheximide, respectively, into one uterine horn before and/or after systemic estradiol-17 beta (E2 beta, 1 microgram/kg i.v.). E2 beta alone increased UBF > 5-fold and heart rate by 10-25% (P < .01) within 90 min; mean arterial pressure (MAP) was unaffected. GLB did not alter basal hemodynamic parameters or responses to E2 beta. Basal UBF and heart rate were unaffected by 4-AP, but MAP increased by 10% and 25% at 30 and 120 min of infusion (P < .01), respectively. Although E2 beta-induced rises in UBF were unaffected in the control uterine horn, 4-AP dose-dependently inhibited UBF responses in the infused horn (R = .83, P = .003, n = 10). Cycloheximide not only dose-dependently inhibited UBF responses (R = .57, P = .01, n = 18) and increases in uterine cGMP secretion, 23.4 +/- 10.7 versus 340 +/- 60 pmol/min (P < .001), but also decreased UBF by 50% and cGMP by approximately 90% at the time of maximum UBF. Mechanisms modulating estrogen-induced uterine vasodilation involve signaling pathways that include NO, smooth muscle cGMP, smooth muscle potassium channels and new protein synthesis.

    Title Medical Privacy and Medical Research.
    Date May 2002
    Journal The New England Journal of Medicine
    Title Autoantibodies to Ia-2 and Gad65 in Patients with Type 2 Diabetes Mellitus of Varied Duration: Prevalence and Correlation with Clinical Features.
    Date October 2001
    Journal Endocrine Practice : Official Journal of the American College of Endocrinology and the American Association of Clinical Endocrinologists
    Excerpt

    OBJECTIVE: To determine the prevalence of autoantibodies to IA-2 (IA-2Ab) and glutamic acid decarboxylase (GADAb) in type 2 diabetes, their relationship to disease duration, and their importance in management decisions. METHODS: We undertook a study of 101 patients with type 2 diabetes (defined as nonketotic hyperglycemia at diagnosis) of varied duration (median, 4 years). Results were compared with those from 36 patients with type 1 diabetes also of varied duration (median, 2 years). IA-2Ab and GADAb were measured by radioligand-binding assays with use of in vitro-synthesized, 35S-labeled antigens. RESULTS: Of the 101 patients with type 2 diabetes, 20 (20%) were positive for GADAb; only 4 of these 20 were positive for IA-2Ab. In comparison, 75% of patients with type 1 diabetes were positive for GADAb, IA-2Ab, or both (P<0.0001). The coincidence of IA-2Ab positivity in GADAb-positive patients with type 2 diabetes was significantly lower than in patients with type 1 diabetes (20% versus 73%, respectively; P = 0.002). All four IA-2Ab- and GADAb-positive patients with type 2 diabetes required insulin and were younger than those positive for GADAb alone (P = 0.018). GADAb positivity in patients with type 2 diabetes was highly associated with insulin requirement (P = 0.004), with an odds ratio of 5.8 in predicting insulin dependence. Among patients with type 2 diabetes receiving insulin therapy, disease duration was significantly shorter (P = 0.025) and body mass index was significantly lower (P<0.001) in GADAb-positive versus GADAb-negative patients. In contrast to type 1 diabetes, in which GADAb values were negatively correlated with disease duration (r = -0.34; P = 0.044), no significant correlation with disease duration was observed in type 2 diabetes (r = -0.166; P = 0.48). CONCLUSION: Irrespective of duration of disease, measurement of IA-2Ab and GADAb can help to identify those patients with type 2 diabetes most likely to require insulin therapy.

    Title Mechanisms Regulating Angiotensin Ii Responsiveness by the Uteroplacental Circulation.
    Date October 2001
    Journal American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
    Excerpt

    Pregnancy is associated with increases in cardiac output and uterine blood flow (UBF) and a fall in systemic vascular resistance. In ovine pregnancy, UBF rises from approximately 3% of cardiac output to approximately 25% at term gestation, reflecting a >30-fold rise in UBF by term. This increase in UBF supports exponential fetal growth during the last trimester and maintains fetal well-being by providing excess oxygen and nutrient delivery. These hemodynamic changes are associated with numerous hormonal changes, including increases in placental steroid hormones and enhanced activation of the renin-angiotensin and sympathetic nervous systems, all of which are believed to modulate systemic and uterine vascular adaptation and vascular reactivity. Systemic pressor responses to infused ANG II are attenuated in normotensive pregnancies and the uteroplacental vasculature is even less sensitive, suggesting development of mechanisms to maintain basal UBF and permit the rise in UBF necessary for fetal growth and well-being. The effects of ANG II on the uteroplacental vasculature are reviewed, and the mechanisms that may account for attenuated vascular sensitivity are examined, including ANG II metabolism, vascular production of antagonists, ANG II-receptor subtype expression, and the role of indirect mechanisms.

    Title Ca(2+)-activated K(+) Channels Modulate Basal and E(2)beta-induced Rises in Uterine Blood Flow in Ovine Pregnancy.
    Date July 2001
    Journal American Journal of Physiology. Heart and Circulatory Physiology
    Excerpt

    Uterine blood flow (UBF) increases >30-fold during ovine pregnancy. During the last trimester, this reflects vasodilation, which may be due to placentally derived estrogens. In nonpregnant ewes, estradiol-17 beta (E(2)beta) increases UBF >10-fold by activating nitric oxide synthase and large conductance calcium-dependent potassium channels (BK(Ca)). To determine whether BK(Ca) channels modulate basal and E(2)beta-induced increases in UBF, studies were performed in near-term pregnant ewes with uterine artery flow probes and catheters for intra-arterial infusions of tetraethylammonium (TEA), a selective BK(Ca) channel antagonist at <1 mM, in the absence or presence of E(2)beta (1 microg/kg iv). Uterine arteries were collected to measure BK(Ca) channel mRNA. TEA (0.15 mM) decreased basal UBF (P < 0.0001) 40 +/- 8% and 55 +/- 7% (n = 11) at 60 and 90 min, respectively, and increased resistance 175 +/- 48% without affecting (P > 0.1) mean arterial pressure (MAP), heart rate, or contralateral UBF. Systemic E(2)beta increased UBF 30 +/- 6% and heart rate 13 +/- 1% (P < or = 0.0001, n = 13) without altering MAP. Local TEA (0.15 mM) inhibited E(2)beta-induced increases in UBF without affecting increases in heart rate (10 +/- 4%; P = 0.006). BK(Ca) channel mRNA was present in uterine artery myocytes from pregnant and nonpregnant ewes. Exponential increases in ovine UBF in late pregnancy may reflect BK(Ca) channel activation, which may be mediated by placentally derived estrogens.

    Title Vascular Medicine and Osteopathic Medicine: Treating the Whole Patient.
    Date December 2000
    Journal The Journal of the American Osteopathic Association
    Excerpt

    Education and instruction in the care of the patient with peripheral vascular diseases is, at best, fragmented during the first years of medical training. Attention to the issues of peripheral arterial, venous, and lymphatic disorders deserves a more formal approach with respect to physician education, patient evaluation and treatment, knowledge and application of various diagnostic modalities, and involvement of our physician colleagues in complementary disciplines. The vascular medicine internist is an invaluable resource in these areas. The aging of our general population will lead to an increase in manifest peripheral vascular disease within our patient population. Having received additional comprehensive training in the management of the complex patient with peripheral vascular disease, the vascular medicine internist may serve as a complete resource for their care.

    Title Maturation of Ovine Uterine Smooth Muscle During Development and the Effects of Parity.
    Date November 2000
    Journal Journal of the Society for Gynecologic Investigation
    Excerpt

    OBJECTIVES: To characterize changes in myometrial contractile proteins and myosin heavy chain (MHC) isoforms during ovine fetal and neonatal development and after pregnancy. We hypothesized that ovine myometrium demonstrates progressive cellular differentiation and maturation which begins in utero and extends into the postnatal period, and that pregnancy causes further cellular alterations. METHODS: Myometrium was obtained from female fetal (72- to 140-days of gestation, n = 19; term = approximately 145 days), postnatal (1 day to 3 months, n = 25), and parous noncycling nonpregnant (n = 9) sheep to measure total and soluble proteins, actin, MHC, and MHC isoforms. Contractile proteins were analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and expression of 200-kD MHC isoforms were determined with Western immunoblots. RESULTS: The contents of total and soluble proteins and actin and total myosin gradually increase (P <.003) during ovine development. Although the contribution of smooth-muscle 204-kD MHC increased (P <.001) from 23 +/- 8% of total MHC at <100 days of gestation to 75 +/- 2% 3 to 4 months postnatally, the 200-kD species fell proportionately. Before birth, MHC-B, a fetal isoform, is the predominant 200-kD protein; postnatally, it is replaced by SM2, demonstrating a switch from a synthetic to a mature contractile smooth-muscle phenotype. Pregnancy is associated with further increases in actin contents and redistribution of the contents of the 204-kD and SM2 MHC isoforms. CONCLUSIONS: Although the fetal and postnatal uterus has no known functional demand, ovine myometrial differentiation and maturation begin in the midtrimester and continue throughout the postnatal period. Thus, changes in smooth-muscle phenotype occur prenatally, as evidenced by a switch from MHC-B to SM2, which may signal completion of organ development and preparation for adult function. Pregnancy results in further modifications in myometrial proteins.

    Title Determinants of Blood Pressure in Very Low Birth Weight Neonates: Lack of Effect of Antenatal Steroids.
    Date November 2000
    Journal Early Human Development
    Excerpt

    OBJECTIVES: To define the range of normal blood pressures (BP) for very low birth weight (VLBW;</=1500 g) neonates and to study perinatal variables affecting BP measurements after birth, including the effects of antenatal steroids. STUDY DESIGN: Antenatal steroids were rarely administered at Parkland Memorial Hospital before May 1994, permitting us to establish a cohort of VLBW neonates exposed to antenatal steroids [n=70, 1166+/-253 (S.D.) g, and 28.7+/-2.1 weeks] who were matched with neonates delivered during the prior year (n=46, 1100+/-241 g, 28.9+/-1.8 weeks). Maternal and neonatal charts were abstracted for pertinent data, and neonatal BP measurements (determined directly when an arterial catheter was available or indirectly by the oscillometric method) were extracted every 3 h for the first 12 h and every 6 h until 72 h postnatal. RESULTS: Antenatal steroids did not affect BP immediately after birth or for the subsequent 72 h postnatal. Therefore, data from all neonates </=1500 g were combined and the pattern of BP change over 72 h postnatal assessed. Systolic, diastolic and mean BP increased (P<0.001) 33%, 44% and 38%, respectively, during the first 72 h. Although neonates weighing </=1000 g and 1001-1500 g demonstrated gradual increases (P<0.001) in systolic, diastolic and mean BP by 72 h, values were consistently lower (P<0.01) in neonates </=1000 g. Of interest, only 11 neonates (9.5%) were treated for clinical hypotension. CONCLUSIONS: In VLBW neonates antenatal steroids do not modify BP measurements either immediately after birth or the 30-40% rise occurring in the first 72 h postnatal. Further, BP is developmentally regulated and is gestationally and birth weight dependent. These data provide additional insight into assessing the need for treating hypotension.

    Title Calcium-activated Potassium Channels and Nitric Oxide Coregulate Estrogen-induced Vasodilation.
    Date August 2000
    Journal American Journal of Physiology. Heart and Circulatory Physiology
    Excerpt

    Nitric oxide synthase (NOS) contributes to estradiol-17beta (E(2)beta)-induced uterine vasodilation, but additional mechanisms are involved, and the cellular pathways remain unclear. We determined if 1) uterine artery myocytes express potassium channels, 2) E(2)beta activates these channels, and 3) channel blockade plus NOS inhibition alters E(2)beta-induced uterine vasodilation. Studies of cell-attached patches identified a 107 +/- 7 pS calcium-dependent potassium channel (BK(Ca)) in uterine artery myocytes that rapidly increased single-channel open probability 70-fold (P < 0.05) after exposure to 100 nM E(2)beta through an apparent cGMP-dependent mechanism. In ovariectomized nonpregnant ewes (n = 11) with uterine artery flow probes and catheters, local BK(Ca) blockade with tetraethylammonium (TEA; 0.05-0.6 mM) dose dependently inhibited E(2)beta-induced uterine vasodilation (n = 37, R = 0.77, P < 0.0001), with maximum inhibition averaging 67 +/- 11%. Mean arterial pressure (MAP) and E(2)beta-induced increases (P </= 0.001) in heart rate (13%) and contralateral uterine blood flow (UBF, approximately 5-fold) were unaffected. Local NOS inhibition plus BK(Ca) blockade, using submaximal doses of nitro-L-arginine methyl ester (5 mg/ml) and TEA (0.3 mM), did not alter basal UBF but completely inhibited ipsilateral E(2)beta-induced uterine vasodilation without affecting MAP and E(2)beta-induced increases in contralateral UBF and heart rate. Acute E(2)beta-mediated uterine vasodilation involves rapid activation of uterine artery BK(Ca) and NOS, and the pathway for their interaction appears to include activation of guanylyl cyclase.

    Title Regulation of Types I and Iii Nos in Ovine Uterine Arteries by Daily and Acute Estrogen Exposure.
    Date July 2000
    Journal American Journal of Physiology. Heart and Circulatory Physiology
    Excerpt

    Nitric oxide contributes to estrogen-mediated uterine vasodilation; however, the nitric oxide synthases (NOS) involved and their location within uterine arteries are incompletely documented. We investigated the effects of repetitive daily and acute estradiol-17beta (E(2)beta) exposure on uterine hemodynamics and NOS abundance and localization in uterine arteries from nonpregnant ovariectomized ewes receiving daily intravenous E(2)beta (1 microg/kg, n = 5) or no E(2)beta (n = 7) for 5 days to determine NOS abundance, cGMP contents, and NOS immunohistochemistry. Daily E(2)beta increased basal and E(2)beta-mediated rises in uterine blood flow (UBF) 36 and 43% (<0.01), respectively, calcium-dependent NOS activity 150% (P < 0.02) in endothelium-intact and -denuded ( approximately 40% of total NOS) arteries, and cGMP contents 39% (P < 0.05). Endothelial (eNOS) was detected in luminal endothelium, whereas neuronal NOS (nNOS) protein was only in the media. A second group of ewes received E(2)beta (1 microg/kg iv) for 4 days and acute intravenous E(2)beta (n = 8) or vehicle (n = 4) on day 5. UBF rose 5.5-fold (P < 0.001) 115 min after E(2)beta, at which time only endothelium-derived calcium-dependent NOS activity increased 30 +/- 13% (P < 0.05). Daily E(2)beta enhances basal and E(2)beta-mediated increases in UBF, which parallel increases in endothelium-derived eNOS and smooth muscle-derived nNOS. Acute E(2)beta, however, selectively increases endothelium-derived eNOS.

    Title Maturational Differences Between Vascular and Bladder Smooth Muscle During Ovine Development.
    Date June 2000
    Journal American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
    Excerpt

    Maturation rates of vascular and visceral smooth muscle (SM) during ovine development were compared by quantifying contractile protein, myosin heavy chain (MHC) isoform contents, and contractile properties of aortas and bladders from female fetal (n = 19) and postnatal (n = 21) sheep. Actin, myosin, and protein contents rose progressively throughout development in both tissues (P </= 0.003); however, expression patterns differed. During the last trimester, i. e., 101-130 days (term approximately 145 days), bladder actin and MHC contents were approximately twofold greater (P < 0.04) than those in the aorta. Although the fractional content of 204-kDa SM1 MHC in the bladder decreased from 74 +/- 3% at midgestation to 48 +/- 2% 3 mo postnatal, the aorta exhibited an increase from 30 +/- 2% to 65 +/- 2%. Bladder MHC (MHC-B) migrating at 200 kDa contained only SM2 throughout development. In contrast, 200-kDa MHC in the aorta was predominantly nonmuscle MHC-B at midgestation, which was gradually replaced by SM2 as development progressed. Along with its early expression of SM2, bladder muscle obtained maximal stress generating capacity (1.7 x 10(5) N/m(2)) by term gestation, whereas the aorta exhibited no contractions until after birth. We conclude that whereas aortic SM maturation is delayed until after birth, bladder SM matures biochemically and functionally during prenatal development, thus supporting early requirements for micturition.

    Title Angiotensin Ii Indirectly Vasoconstricts the Ovine Uterine Circulation.
    Date April 2000
    Journal American Journal of Physiology. Regulatory, Integrative and Comparative Physiology
    Excerpt

    The uterine vasculature of women and sheep predominantly expresses type 2 ANG II receptors that do not mediate vasoconstriction. Although systemic ANG II infusions increase uterine vascular resistance (UVR), this could reflect indirect mechanisms. Thus we compared systemic and local intra-arterial ANG II infusions in six near-term pregnant and five ovariectomized nonpregnant ewes to determine how ANG II increases UVR. Systemic ANG II dose-dependently (P > 0.001) increased arterial pressure (MAP) and UVR and decreased uterine blood flow (UBF) in pregnant and nonpregnant ewes; however, nonpregnant responses exceeded pregnant (P < 0.001). In contrast, local ANG II infusions at rates designed to achieve concentrations in the uterine circulation comparable to those seen during systemic infusions did not significantly decrease UBF in either group, and changes in MAP and UVR were absent or markedly attenuated. When MAP rose during local ANG II, which only occurred with doses > or =2 ng/ml, increases in MAP were delayed more than twofold compared with responses during systemic ANG II infusions and always preceded decreases in UBF, resembling that observed during systemic ANG II infusions. These observations demonstrate attenuated uterine vascular responses to systemic ANG II during pregnancy and suggest that systemic ANG II may increase UVR through release of another potent vasoconstrictor(s) into the systemic circulation.

    Title A Population-based Study of Congenital Diaphragmatic Hernia: Impact of Associated Anomalies and Preoperative Blood Gases on Survival.
    Date October 1999
    Journal Journal of Pediatric Surgery
    Excerpt

    BACKGROUND/PURPOSE: Although neonatal care has improved over the past 20 years, mortality rate with congenital diaphragmatic hernia (CDH) remains 50% to 60%, possibly reflecting differences in management or selection biases. The authors determined the incidence, outcome, effect of coexisting anomalies, and prognostic indicators for neonates with CDH in a single inborn population older than 13 years. METHODS: Forty-three neonates with CDH, those symptomatic within the first 6 hours of life, were identified using a validated neonatal database and diagnosis coding data from medical records among 180,643 live inborn neonates delivered at Parkland Memorial Hospital between 1983 and 1995. Charts were reviewed for prenatal history, demographic variables, presence of coexisting malformations, preoperative arterial blood gases, surgical findings, and outcome. Survival to hospital discharge was the primary outcome variable. RESULTS: The incidence of CDH was 1 in 4,200 live births; overall survival rate was 51%. Thirty-two (74%) neonates underwent surgical repair, often at less than 8 hours of life; postoperative mortality rate was 31%. Eighteen (42%) had coexisting major anomalies or chromosomal abnormalities. Eighty percent of neonates with isolated CDH survived, whereas 89% with CDH and associated defects died. Nonsurvivors had lower birth weights and Apgar scores, were more acidotic, and had more severe respiratory compromise. When best preoperative pH was > or = 7.25 or PaCO2 < or = 50 mm Hg, 80% of neonates survived. CONCLUSION: In this inborn population-based review of neonatal CDH between 1983 and 1995, the best predictors of survival were the presence or absence of other anomalies and the best preoperative PaCO2 and pH.

    Title Ontogeny of Vascular Angiotensin Ii Receptor Subtype Expression in Ovine Development.
    Date June 1999
    Journal Pediatric Research
    Excerpt

    Angiotensin II (ANG II) increases arterial pressure in fetal sheep and may modulate cardiovascular adaptation before and after birth. The type 1 angiotensin II receptor (AT1R) predominates in adult vascular smooth muscle (VSM) and mediates vasoconstriction. In contrast, AT2R predominate in fetal tissues and are not known to mediate contraction. Although sheep are commonly used to study cardiovascular development, the ontogeny and distribution of VSM ATR subtypes is unknown. We examined ATR binding characteristics and subtype expression across the umbilicoplacental vasculature and in aorta, carotid, and mesenteric arteries from fetal (n = 44; 126-145 d gestation) and postnatal (n = 65; 1-120 d from birth) sheep using plasma membranes from tunica media and tissue autoradiography. Binding density (Bmax) was similar throughout the umbilicoplacental vasculature (p = 0.5), but only external umbilical arteries and veins and primary placental arteries expressed AT1R, whereas subsequent placental branches and fetal placentomes expressed only AT2R. Systemic VSM Bmax and binding affinity did not change significantly during development (p > 0.1). Fetal systemic VSM, however, expressed only AT2R, and binding was insensitive to GTPgammaS. Transition to AT1R in systemic VSM began 2 wk postnatal and was completed by 3 mo. Before birth, umbilical cord vessels are the primary site of AT1R expression in fetal sheep, and AT2R seem to predominate in systemic VSM until 2-4 wk postnatal.

    Title Differential Development of Umbilical and Systemic Arteries. Ii. Contractile Proteins.
    Date November 1998
    Journal The American Journal of Physiology
    Excerpt

    In fetal sheep, umbilical responsiveness to ANG II exceeds systemic vascular responsiveness. Fetal systemic vascular smooth muscle (VSM) exhibits an immature phenotype with decreased contractile protein contents, low 200-kDa myosin heavy chain (MHC) SM2, and significant nonmuscle MHC-B expression, whereas umbilical VSM phenotype is incompletely described. We tested the hypothesis that differences in vascular responsiveness could reflect dissimilarities in VSM phenotype. Actin, MHC, MHC isoforms, and active stresses were compared in strips of femoral arteries and aorta from near-term fetal (n = 12) and adult (n = 12) sheep to those in external and intra-abdominal umbilical arteries. Actin contents in fetal femoral artery and aorta were less (P </= 0.006) than in external umbilical artery (7.37 +/- 1.4 and 7.53 +/- 0.7 vs. 21.6 +/- 2.2 microg/mg wet wt, respectively) as were MHC contents (3.17 +/- 0.4 and 2.84 +/- 0. 3 vs. 7.16 +/- 0.7, respectively). Whereas 204- and 200-kDa MHC were expressed equally in fetal systemic arteries, umbilical and adult arteries predominantly expressed the 204-kDa isoform (SM1); only fetal systemic VSM expressed MHC-B. Fetal systemic artery stresses and myosin light chain phosphorylation were less than those in umbilical and adult arteries (P < 0.001). Compared with umbilical and adult arteries, fetal systemic VSM is biochemically and functionally immature and thus umbilical VSM demonstrates precocious maturation resembling adult VSM in protein expression and function.

    Title Circulating Neutrophils in Septic Preterm Neonates: Comparison of Two Reference Ranges.
    Date September 1998
    Journal Pediatrics
    Excerpt

    OBJECTIVE: To study the effect of sepsis on circulating neutrophils in very low birth weight neonates and to assess the usefulness of recently revised reference ranges for circulating neutrophils in the diagnosis of sepsis in this population by comparison with previously reported reference ranges. METHODS: Neutrophil parameters (absolute total neutrophils, absolute total immature neutrophils, and the immature:total neutrophil proportion) were analyzed retrospectively in 202 sepsis episodes in 192 neonates (birth weight = 1055 +/- 246 g, X +/- SD; estimated gestational age = 29 +/- 2 weeks) between birth and 30 days of age. The percentage of values lying outside the reference ranges reported recently by Mouzinho et al and previously by Manroe et al were compared. To more accurately assess possible differences in specificity between the two reference ranges, neonates with early-onset group B streptococcal infection (n = 19) were compared with a matched control group (n = 51) using conditional logistic regression. RESULTS: Greater sensitivity was observed using the previous reference ranges of Manroe et al over the entire study period (0 to 720 hours) both for the initial and the second complete blood count (CBC). The previous reference ranges also were more sensitive than the revised ranges for the initial CBC at 0 to 72 and at 73 to 720 hours and for infections attributable to coagulase-negative staphylococci. However, specificity in neonates without group B streptococcal infection was significantly greater with the revised reference ranges compared with those of Manroe et al (initial CBC, 73% vs 45%; serial CBCs, 59% vs 10%). CONCLUSION: The observed differences in sensitivities may be of limited clinical significance because very low birth weight infants often are begun on antibiotic therapy regardless of laboratory values. However, the striking differences in specificity using the revised reference ranges suggest that these ranges may be clinically useful in determining length of antimicrobial therapy in infants in whom cultures remain sterile.

    Title Differential Development of Umbilical and Systemic Arteries. I. Ang Ii Receptor Subtype Expression.
    Date April 1998
    Journal The American Journal of Physiology
    Excerpt

    In fetal sheep umbilical responses to angiotensin II (ANG II) exceed those by systemic vasculature. Two ANG II receptors (AT) exist, AT1 and AT2, but only AT1 mediates vasoconstriction in adult tissues. Thus differences in reactivity could reflect differences in subtype expression. Using competitive radioligand binding assays, we demonstrated AT1 predominance in umbilical arteries and AT2 in femoral arteries. Steady-state responses to intravenous ANG II (0.229-1.72 micrograms/min) were studied in 16 fetuses with umbilical and/or femoral artery flow probes without and with local AT1 (L-158,809) or AT2 (PD-123319) blockade. ANG II dose dependently (P < 0.001) increased umbilical resistance more than arterial pressure (MAP) while decreasing umbilical blood flow. Femoral vascular resistance also increased dose dependently (P = 0.02), but responses were less than umbilical (P = 0.0001) and paralleled increases in MAP; blood flow was unaffected. Cumulative local doses of L-158,809 (125 micrograms) inhibited all responses (P < 0.001); however, 1,000 micrograms of the AT2 antagonist had no effect. Plasma renin activity (PRA) was unaltered by local AT1 blockade, whereas PRA doubled (P = 0.001) after systemic infusion of only 50 micrograms of the AT1 antagonist and remained elevated. Differences in umbilical and femoral vascular responses to ANG II are in large part due to differences in AT subtype expression. Furthermore, in fetal sheep the ANG II negative feedback on PRA is mediated by AT1 receptors, and it is substantially more sensitive to receptor blockade than the vasculature.

    Title Estrogen Acutely Stimulates Nitric Oxide Synthase Activity in Fetal Pulmonary Artery Endothelium.
    Date September 1997
    Journal The American Journal of Physiology
    Excerpt

    Estrogen (E) has nitric oxide (NO)-mediated effects in certain vascular beds, and fetal E levels rise acutely with parturition, suggesting that E may be involved in NO-mediated pulmonary vasodilation at birth. We tested the hypothesis that E acutely stimulates NO synthase (NOS) activity in ovine fetal pulmonary artery endothelial cells (PAEC) by measuring L-[3H]arginine conversion to L-[3H]citrulline in intact cells. NOS activity in the presence of 17 beta-estradiol (E2 beta) rose in a dose-dependent manner, increasing 70-100%, with a threshold concentration of 10(-10) M. This effect was detectable within 5 min of E2 beta exposure, and the maximal response was comparable to that obtained with acetylcholine, which had a threshold concentration of 10(-8) M. Ca2+ removal completely inhibited E2 beta-stimulated NOS activity, and activity with E2 beta and the Ca2+ ionophore A-23187 was not additive. In addition, the expression of the endothelial isoform of NOS (eNOS) was not altered, and the inducible and neuronal NOS isoforms were not detected by immunoblot analysis. These findings indicate that E2 beta acutely stimulates eNOS by Ca2+ influx. Furthermore, E2 beta-stimulated NOS activity was fully inhibited by the E receptor (ER) antagonists tamoxifen and ICI-182,780, and ER mRNA expression was evident in reverse transcription-polymerase chain reaction assays. Thus E acutely stimulates eNOS activity in fetal PAEC via the activation of endothelial ER and increases in intracellular Ca2+.

    Title Brain Does Not Utilize Low Density Lipoprotein-cholesterol During Fetal and Neonatal Development in the Sheep.
    Date February 1997
    Journal Journal of Lipid Research
    Excerpt

    Several lines of evidence have suggested that central nervous system development and function depend upon a supply of cholesterol that comes from low density lipoproteins (LDL-C). These studies test this hypothesis directly by measuring in vivo the uptake of LDL-C in nine regions of the central nervous system at five different stages of development in the fetal and neonatal sheep. The concentration of LDL-C in the plasma decreased from 49 mg/dl in the fetus 90 days before birth (-90 days) to only 10 mg/dl at -13 days. By 17 days postnatal this value increased to nearly 60 mg/dl. Throughout the period of development between -90 days (very early fetus) and 17 days (late neonatal animal) the weight of the brain increased 32-fold (from 2.3 to 73.6 g) and the content of cholesterol rose 100-fold (from 8.6 to 876 mg), yet there was no detectable LDL-C uptake in any of nine areas of the central nervous system at any stage of development (clearances of < 2 microliters/h per g). This was true even in the -90 day fetus prior to closure of the blood brain barrier. In contrast, LDL-C clearance by the adrenal gland increased dramatically (from 91 to 348 microliters/h per g) as it also did in the liver (from 36 to 85 microliters/h per g) during fetal development. These studies strongly suggest, therefore, that cholesterol carried in LDL plays little or no role in the process of sterol acquisition during brain development or in cholesterol turnover in the mature central nervous system. Changes in circulating LDL-C concentration, therefore, should have no effect on brain function.

    Title Nitric Oxide Contributes to Estrogen-induced Vasodilation of the Ovine Uterine Circulation.
    Date January 1997
    Journal The Journal of Clinical Investigation
    Excerpt

    Estradiol-17beta (E2beta), a potent vasodilator, has its greatest effects on the uterine vasculature, blood flow (UBF) increasing > or = 10-fold. The mechanism(s) responsible for E2beta-induced vasodilation is unclear. We determined if nitric oxide (NO)-induced increases in cGMP modulate estrogen-induced increases in UBF, and if cyclooxygenase inhibition modifies E2beta responses. Nonpregnant (n = 15) and pregnant (n = 8) ewes had flow probes implanted on main uterine arteries and catheters in branches of the uterine vein and artery bilaterally for blood sampling and infusion of the NO synthase inhibitor L-nitro-arginine methyl ester (L-NAME), respectively. In nonpregnant ewes E2beta (1 microg/kg) caused parallel increases (P < 0.001) in UBF (15+/-3 to 130+/-16 ml/min) and uterine cGMP secretion (23+/-10 to 291+/-38 pmol/min); uterine venous cGMP also rose (4.98+/-1.4 to 9.43+/-3.2 pmol/ml; P < 0.001). Intra-arterial L-NAME partially inhibited increases in UBF dose-dependently (r = 0.66, n = 18, P < 0.003) while completely inhibiting cGMP secretion (P = 0.025). Indomethacin, 2 mg/kg intravenously, did not alter E2beta-induced responses. After E2beta-induced increases in UBF, intraarterial L-NAME partially decreased UBF dose dependently (r = 0.73, n = 46, P < 0.001) while inhibiting cGMP secretion (178+/-48 to 50+/-24 pmol/min; n = 5, P = 0.006); both were reversed by L-arginine. In pregnant ewes, E2beta increased UBF and venous cGMP (9.1+/-0.96 to 13.2+/-0.96 pmol/ml, P < 0.01); however, intraarterial L-NAME decreased basal cGMP secretion 66% (P = 0.02), but not UBF. Acute estrogen-induced increases in UBF are associated with NO-dependent increases in cGMP synthesis, but other mechanisms may also be involved. However, vasodilating prostanoids do not appear to be important. In ovine pregnancy NO is not essential for maintaining uteroplacental vasodilation.

    Title Understanding Obesity: the Interaction of Diet, Genetics, and Hormones.
    Date December 1996
    Journal Cleveland Clinic Journal of Medicine
    Title Alterations in Myometrial Stress During Ovine Pregnancy and the Puerperium.
    Date October 1996
    Journal The American Journal of Physiology
    Excerpt

    Substantial alterations occur in female reproductive tissues to ensure the successful outcome of and recovery from pregnancy. Although sheep have been widely used to study several aspects of pregnancy, little information is available regarding alterations in myometrial function. We therefore characterized the alterations that occur in ovine myometrial stress-generating capacity and examined mechanisms that might account for these changes. Length-force relations were determined for longitudinal myometrial strips from nonpregnant (n = 6), pregnant (n = 11; 67-140 days gestation), and postpartum (n = 6) ewes. Active stress (force per cross-sectional area) was calculated at optimal length for maximal force as determined from length-force relations. Stimulation by 65 mM KCl resulted in 3.5 times greater stress in strips from late-pregnant vs. nonpregnant ewes, 1.20 +/- 0.16 vs. 0.34 +/- 0.04 x 10(5) N/m2 (+/- SE; P < 0.05), respectively. Responses returned to values seen in strips from nonpregnant ewes within 2 wk postpartum. Increases in stress were not associated with differences in the phosphorylated myosin light-chain fraction or the amount of smooth muscle bundles. Although basal prostacyclin production was 15-fold greater in myometrium from nonpregnant vs. pregnant ewes (222 +/- 28 vs. 14.9 +/- 2.0 pg.mg wet wt-1.h-1), cyclooxygenase inhibition did not potentiate stress responses in strips from nonpregnant animals. However, smooth muscle contents of actin (26.0 +/- 1.8 vs. 19.1 +/- 2.2 micrograms/mg wet wt) and myosin heavy chain (5.5 +/- 0.4 vs. 2.0 +/- 0.3 microgram/mg wet wt) were greater (P < 0.04) in myometrium from late-pregnant vs. nonpregnant ewes. Myometrial growth during ovine pregnancy is associated with reversibly augmented contractile properties that appear to primarily reflect increased cellular contents of contractile proteins.

    Title Tissue Specific Expression of Vascular Smooth Muscle Angiotensin Ii Receptor Subtypes During Ovine Pregnancy.
    Date October 1996
    Journal The American Journal of Physiology
    Excerpt

    Uteroplacentral responses to infused angiotensin II (ANG II) are less than those elicited by systemic vasculature. This does not reflect ANG II receptor (AT) downregulation but may reflect differences in AT-receptor subtypes expressed. We examined AT-receptor subtypes in smooth muscle (SM) from uterine (UA), mesenteric, renal, and mammary arteries and aorta from nulliparous (n = 12), pregnant (n = 18; 105-140 days, term = 145 days), postpartum (n = 5; 6-9 days after delivery), and nonpregnant parous (n = 14) ewes by assessing displacement of 125I-labeled ANG II binding by [Sar1, Ile8]ANG II (AT1 and AT2), losartan (AT1) PD-123319 (AT2), and CGP-42112A (AT2). AT2 receptors accounted for 75-90% of total binding in UA. Except for mammary arteries, other arteries expressed only AT1 receptors. Receptor subtype expression was not altered by reproductive state in any artery studied. With the use of autoradiography, AT2 receptors appear to predominate in media of small intramyometrial arteries, whereas AT1 receptors predominate in the luminal portion. We therefore determined which subtype mediates endothelium-derived ANG II-induced increases in UA PGI2 synthesis during pregnancy. ANG II (0.05 microM) increased PGI2 synthesis 62%, from 214 +/- 13 to 346 +/- 23 pg.mg-1.h-1 (P < 0.05). Losartan (1.0 microM) inhibited the rise in PGI2 (257 +/- 24 vs. 238 +/- 25 pg.mg-1.h-1), whereas 1.0 microM PD-123319 had no effect (231 +/- 23 vs. 337 +/- 31 pg.mg-1.h-1; P < 0.05). AT2 receptors do not mediate ANG II-induced vasoconstriction, thus differences in uteroplacental and systemic sensitivity to ANG II may reflect predominance of AT2 receptors in UASM and ANG II-induced increases in UA prostacyclin synthesis by endothelial AT1 receptors.

    Title Endothelial Vasodilator Production by Uterine and Systemic Arteries. I. Effects of Ang Ii on Pgi2 and No in Pregnancy.
    Date September 1996
    Journal The American Journal of Physiology
    Excerpt

    Uterine vasculature is less responsive than systemic vasculature to angiotensin II (ANG II)-induced vasoconstriction. We hypothesized that pregnancy augments basal and ANG II-stimulated endothelial prostacyclin (PGI2) and/or nitric oxide (NO) production, which locally increase vascular smooth muscle (VSM) adenosine 3',5'-cyclic monophosphate (cAMP) and guanosine 3',5'-cyclic monophosphate (cGMP), respectively. Uterine (UA) and systemic arteries (SA) from pregnant (P) and nonpregnant (NP) sheep were incubated with isobutylmethylxanthine. Basal PGI2, cAMP, and cGMP production was 2.4-, 1.6-, and 5.9-fold greater (P < 0.01) in UA from P vs. NP sheep; endothelium removal lowered (P < 0.05) values 69, 44, and 88%. Basal SA PGI2 and cAMP, but not cGMP, also were elevated by pregnancy. Indomethacin (Indo; 100 microM) decreased PGI2 and cAMP, but not cGMP production; N omega-nitro-L-arginine methyl ester (L-NAME; 10 microM) and methylene blue (MB, 10 microM) only decreased cGMP. Basal UA, but not SA, NO synthase activity (conversion of [3H]arginine to [3H]citrulline), was 1.8-fold higher in pregnancy and decreased (P < 0.01) after endothelium removal and with L-NAME. ANG II (50 nM) increased PGI2 (86%) and cAMP (56%) production only in UA from P sheep (P < 0.05); this was abolished by endothelium removal or Indo. ANG II also increased (P < 0.01) cGMP production by UA from both groups but only by SA from P ewes; this was absent in denuded, L-NAME-, or MB-treated vessels. Stimulation of VSM cGMP production with sodium nitroprusside (50 microM) was inhibited by MB, but not L-NAME or endothelium removal. In pregnancy, endothelial PGI2 and NO production are enhanced and may contribute to attenuated ANG II vasoconstriction via VSM cAMP and cGMP.

    Title Smooth Muscle Myosin Heavy Chain Isoforms Are Developmentally Regulated in Male Fetal and Neonatal Sheep.
    Date February 1996
    Journal Pediatric Research
    Excerpt

    Adult vascular smooth muscle expresses 204-kD (SM1) and 200-kD (SM2) myosin heavy chain (MHC) isoforms. Fetal vascular smooth muscle expresses another 200-kD isoform, MHC-B, that appears to be developmentally regulated. The ontogeny of expression of these MHC isoforms in vascular and nonvascular smooth muscles is not fully understood and may differ. In the present report we examined the ontogeny of these isoforms in aortic and bladder smooth muscle from male fetal (n = 12, 119-140-d gestation; term 145 +/- 5 d) and neonatal (n = 12, 1-33 d) sheep. Tissues were analyzed for total and soluble protein contents. Actin, MHC, and MHC isoforms were analyzed by SDS-PAGE using 3-20% and 4% polyacrylamide gels, respectively. The expression of the adult and fetal 200-kD MHC isoforms were determined by Western analysis. Between 119 d gestation and 33 d neonatal, age-dependent increases (p < 0.02) occurred in bladder actin (16 +/- 0.8 versus 22 +/- 1.4 micrograms/mg of wet weight), MHC (6.5 +/- 0.2 versus 9.7 +/- 1.1) and both soluble (71 +/- 2.9 versus 92 +/- 6.3) and total protein (78 +/- 3.9 versus 103 +/- 5.5). Aortic smooth muscle actin (8.5 +/- 0.7 versus 17 +/- 1.1), MHC (3.1 +/- 0.4 versus 5.2 +/- 0.5), and soluble (44 +/- 2.3 versus 61 +/- 3.0) and total protein (87 +/- 5.8 versus 108 +/- 3.2) also increased (p < 0.01). Aortic SM1 increased (r = 0.79, p < 0.001) during this time, whereas expression of the 200-kD MHC fell (r = -0.79, p < 0.001). In contrast, bladder SM1 fell (r = -0.88, p < 0.001) as the 200-kD MHC rose (r = 0.88, p < 0.001). The type of 200-kD MHC isoform expressed also differed between tissue types; bladder expressed SM2 and little or no MHC-B throughout this phase of development, whereas fetal aorta appeared to express primarily MHC-B, which decreased as adult SM2 expression rose after birth. Expression of smooth muscle proteins and MHC isoforms are developmentally regulated and tissue-dependent, the latter perhaps reflecting developmental differences in organ growth and/or function.

    Title Angiotensin Ii Receptor Characteristics and Subtype Expression in Uterine Arteries and Myometrium During Pregnancy.
    Date February 1996
    Journal The Journal of Clinical Endocrinology and Metabolism
    Excerpt

    The uteroplacental vasculature is less sensitive to angiotensin II (ANG II)-induced vasoconstriction than the systemic vasculature. Although the mechanism(s) responsible is unclear, uterine arteries (Ua) may demonstrate ANG II receptor (AT receptors) down-regulation or expression of AT2 receptors, which do not mediate vasoconstriction. We determined AT receptor binding characteristics and subtype expression in Ua from normotensive pregnant (n = 14; 38 +/- 0.5 weeks gestation) and nonpregnant (n = 28) women. Comparative studies were performed with myometrium, a nonvascular smooth muscle. We measured binding density (Bmax) and affinity (Kd) in plasma membrane preparations employing radioligand binding. Receptor subtypes were assessed by inhibiting [125I]ANG II binding with specific antagonists. During pregnancy, the Ua Bmax and Kd were unchanged (P > 0.1; 221 +/- 36 vs. 159 +/- 27 fmol/mg protein and 0.8 +/- 0.1 vs. 0.9 +/- 0.1 nmol/L, respectively). However, myometrial Bmax decreased 92% (580 +/- 129 vs. 44 +/- 7 fmol/mg protein; P < 0.001), and Kd rose 4-fold (1.5 +/- 0.4 to 6.0 +/- 0.6 nmol/L; P < 0.001). AT1/AT2 expression averaged 15%/85% in Ua from nonpregnant and pregnant women, whereas in myometrium, values were 10%/90% and 60%/40%, respectively. In myometrium from laboring women (n = 8), force (1.38 +/- 0.14 to 1.59 +/- 0.12 x 10(4) N/m2; P < 0.04) and contractile frequency (0.038 +/- 0.05 to 0.116 +/- 0.014 contractions/min; P < 0.001) increased with 10(-5) mol/L ANG II and were abolished by AT1 receptor inhibition. Myometrium from nonpregnant women (n = 3) was unresponsive, and AT2 inhibition did not alter responses. In nonpregnant women, AT2 receptors predominate in Ua and myometrium. Although Ua AT receptors are unaltered during pregnancy, myometrial Bmax decreases, reflecting decreases in the expression of AT2 >> AT1 receptors and differential receptor regulation.

    Title Neonatal Neutrophil Values in Low Birthweight Preterm Infants.
    Date February 1996
    Journal American Journal of Perinatology
    Title The Small for Gestational Age Infant: Accelerated or Delayed Pulmonary Maturation? Increased or Decreased Survival?
    Date May 1995
    Journal Pediatrics
    Excerpt

    OBJECTIVE. Small for gestational age (SGA) neonates have been considered to have accelerated pulmonary maturation and thus a lower risk for respiratory distress syndrome (RDS) than appropriate for gestational age (AGA) neonates. This, however, has not been thoroughly examined. Therefore, we compared SGA infants with AGA infants of the same gestational age (GA) with respect to risk of RDS, respiratory failure, or death. POPULATION. An indigent population born in a large county hospital. METHODS. Multivariate analyses were performed controlling for GA alone or for GA, race, sex, and congenital anomalies. Because the proper method to identify SGA infants is unclear, we performed separate analyses using different GA estimates (obstetric or pediatric) and intrauterine growth grids (hospital-specific grids or grids for a healthy, geographically-defined population). RESULTS. SGA infants did not fare better than AGA infants in any analysis. SGA infants had significantly increased risk in some analyses of RDS and in almost all analyses of respiratory failure or death. The risk associated with being SGA was generally comparable to that associated with male sex or White race. CONCLUSION. The concept that intrauterine growth retardation accelerates lung maturation and improves outcome is not supported in comparisons of SGA and AGA infants of the same GA, sex, and race. This widely accepted concept deserves critical re-evaluation.

    Title Band Neutrophil Counts in Neonates.
    Date March 1995
    Journal The Journal of Pediatrics
    Title Comparison of Ang Ii in Fetal and Pregnant Sheep: Metabolic Clearance and Vascular Sensitivity.
    Date March 1995
    Journal The American Journal of Physiology
    Excerpt

    Fetal sheep appear less responsive to infused angiotensin II (ANG II) than pregnant ewes. This may reflect a greater fetal metabolic clearance rate (MCRANGII) and thus lower plasma ANG II levels. We therefore determined fetal MCRANGII, half-life (T1/2), and placental removal of ANG II. Fetal sheep (n = 13; 113-139 days of gestation) received 0.573-5.73 micrograms ANG II/min iv for 30 min while arterial pressure and heart rate were monitored. Serial blood samples were obtained before and during a 30-min infusion to measure ANG II and calculate MCRANGII and after stopping the infusion to determine T1/2. MCRANGII was similar across gestation and at doses < or = 2.29 micrograms/min (683 +/- 49 vs. 74 +/- 5 ml.min-1.kg-1 for adults) but was 30-40% lower with 5.73 micrograms ANG II/min (494 +/- 57 ml.min-1.kg-1, P < 0.05). T1/2 was 15-21 s. Fetal placental ANG II removal averaged 87 +/- 3 vs. 20 +/- 6% for uteroplacental removal; this was unaffected by dose and was linear with plasma ANG II levels, and saturation was not evident. Plasma ANG II levels rose proportionally with infusion rate and did not change significantly over time; thus fetal plasma ANG II concentrations can be predicted from MCRANGII. Measured and predicted ANG II levels at each infusion rate and time point were similar: r = 0.87, slope = 0.87 (P < 0.001). At equivalent predicted plasma ANG II levels fetal and maternal pressor responses were similar (P > 0.1); however, increases in umbilical vascular resistance exceeded those in uteroplacental vascular resistance (P < 0.03). Fetal MCRANGII is approximately 10-fold greater than maternal, partially reflecting the extensive capacity of ANG II removal by the placental circulation. Contrary to previous conclusions, fetal-maternal pressor sensitivity to ANG II does not differ, whereas the placental vasculature is more sensitive to ANG II than the uteroplacental circulation.

    Title Surfactant Protein A and Saturated Phosphatidylcholine in Respiratory Distress Syndrome.
    Date December 1994
    Journal American Journal of Respiratory and Critical Care Medicine
    Excerpt

    We measured surfactant protein A (SP-A) by ELISA using a rabbit antihuman SP-A polyclonal antibody and saturated phosphatidylcholine (SPC) by thin-layer chromatography in sequential tracheal fluid samples obtained from 16 preterm neonates without lung disease and 37 with respiratory distress syndrome (RDS). SP-A and SPC were lower in neonates with RDS than in control infants (1.0 +/- 0.1 versus 8.9 +/- 2.2 ng SP-A/microgram protein [p < 0.0001] and 0.20 +/- 0.05 versus 0.70 +/- 0.19 mumol SPC/mg protein [p < 0.01], respectively). Initial SP-A concentrations correlated inversely with severity of RDS (r = 0.45, p < 0.01) but did not correlate with initial SPC levels. Significant increases in SP-A were detectable within 12 to 24 h after birth in neonates with RDS. Further increases occurred subsequently and were similar for neonates treated with either a synthetic (Exosurf) or a modified natural (Survanta) surfactant. Using two-dimensional gel electrophoresis, SP-A in tracheal fluid obtained during the early and recovery phases of RDS exhibited lesser degrees of posttranslational modification than SP-A forms from control neonates. Administration of Exosurf or Survanta resulted in comparable increases in SPC in tracheal fluid. Preterm neonates with RDS seem to have an immature SP-A metabolism that persists for several days after birth. The type of surfactant used does not modify the recovery of SP-A or SPC in tracheal fluid from infants with RDS.

    Title Angiotensin Ii Metabolic Clearance Rate and Pressor Responses in Nonpregnant and Pregnant Women.
    Date October 1994
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVES: Normal pregnancy is associated with reduced pressor dose-responses to infused angiotensin II. We tested the hypotheses that alterations in the metabolic clearance rate and the half-life of angiotensin II account for reduced pressor dose-responses during gestation and that angiotensin II increases circulating levels of vasodilatory prostaglandins I2 and E2 relative to thromboxane A2. STUDY DESIGN: Eleven nonpregnant and 37 pregnant (30 +/- 0.3 weeks' gestation, mean +/- SE) women were infused with angiotensin II (3.11 to 22.36 ng/min.kg) for 15 minutes, and blood was obtained to evaluate steady-state immunoreactive plasma angiotensin II and eicosanoid concentrations. RESULTS: Angiotensin II pressor responses were dose dependent in all groups and reduced in pregnant women (p < 0.001). Basal immunoreactive plasma angiotensin II concentrations were 2.7-fold greater (p < 0.001) in pregnant versus nonpregnant women. Plasma levels reached steady state by 5 minutes of infusion, and at similar angiotensin II concentrations the increase in blood pressure was greater in nonpregnant versus pregnant women (p < 0.001). The angiotensin II metabolic clearance rate and half-life were similar in nonpregnant and pregnant women: metabolic clearance rate = 85 +/- 10 versus 68 +/- 3 ml/min.kg, respectively (p = 0.130), and half-life = 48 and 49 seconds, respectively. Plasma prostaglandin I2 (6-keto-prostaglandin F1 alpha) prostaglandin E2, and thromboxane B2 levels in pregnant women were unaffected by angiotensin II infusions. CONCLUSION: Neither changes in angiotensin II metabolism nor angiotensin II-induced increases in plasma levels of prostaglandin I2, prostaglandin E2, or the prostaglandin I2/thromboxane A2 ratio appear responsible for the decreased pressor response sensitivity to infused angiotensin II observed during normal human pregnancy.

    Title Revised Reference Ranges for Circulating Neutrophils in Very-low-birth-weight Neonates.
    Date July 1994
    Journal Pediatrics
    Excerpt

    OBJECTIVE. Healthy very-low-birth-weight neonates (VLBW, < or = 1500 g) exhibit a high incidence of neutropenia according to Manroe's reference ranges for neutrophil indices. Since these reference ranges may be inappropriate for VLBW neonates, we determined the reference ranges for circulating peripheral neutrophils in VLBW neonates between birth and 28 days of age. METHODS. Serial, timed peripheral white blood cell counts (n = 1788) were prospectively obtained between birth and 28 days from 193 inborn, VLBW neonates delivered between January 1 and December 31, 1990. Data were divided into neutrophil counts obtained prior to (n = 630) and after (n = 1158) 60 hours of age. After excluding counts from neonates with perinatal and/or neonatal complications, values from "normal" neonates were compared to Manroe's reference ranges. Where indicated new ranges were developed. RESULTS. Although immature neutrophil (ATI) and immature:total neutrophil (I:T) values were within Manroe's reference ranges (P > .1) throughout the neonatal period, 67% of total neutrophil values (ATN) obtained prior to 60 hours of age were outside (P < .001) and 95% were considered neutropenic. Newly developed ATN reference ranges for VLBW neonates have a wider range of distribution compared to Manroe's results, primarily reflecting a decrease in the lower boundary. ATN values between 61 hours and 28 days also differed (P < .001), and new ranges had upper and lower boundaries of 6000 and 1100/mm3, respectively. Maternal hypertension was associated with neonatal neutropenia (P < .001) without abnormalities of ATI or I:T prior to day 3 of life; however, neutrophilia predominated after day 7. Between birth and 28 days > 70% of ATN values were abnormal in neonates with apnea, neutrophilia occurring in > 90% of counts; I:T values, however, were normal between 61 hours and 28 days. CONCLUSIONS. Normal preterm VLBW neonates have ATN reference ranges that differ significantly from that for larger, older neonates, demonstrating the effects of development on neutrophil dynamics. The predictability of neonatal infection using these new reference ranges requires additional study.

    Title Blood Pressure in Low Birth Weight Infants After Dexamethasone.
    Date June 1994
    Journal European Journal of Pediatrics
    Title Distribution of Unsaturated Fatty Acids in Phospholipids of Arteries from Nonpregnant, Pregnant and Fetal Sheep.
    Date April 1994
    Journal Prostaglandins, Leukotrienes, and Essential Fatty Acids
    Excerpt

    Normal ovine pregnancy is associated with elevated levels of circulating vasodilator prostaglandins (PGs) and increases in PG production by uterine and systemic arteries. We hypothesized that the availability of fatty acid substrate may regulate PG production in vasculature from nonpregnant, pregnant and fetal sheep. In pregnant sheep, levels of arachidonic acid (20:4 omega 6), the immediate PG precursor, were significantly lower in phospholipids from uterine versus systemic (renal) arteries. Although linoleic acid (18:2 omega 6), the primary arachidonic acid precursor, was elevated (p < 0.001) in uterine arteries during pregnancy, levels in systemic arteries were decreased. Levels of omega 3 polyunsaturated fatty acids (PUFAs) also were increased (p < 0.001) in both uterine and systemic arteries during pregnancy. In fetal-placental arteries, the levels of arachidonic and linoleic acid were 50 and 90% less, respectively, than that in maternal arteries. We conclude that during ovine pregnancy vascular prostanoid production may be regulated, in part, by the availability of fatty acid precursors.

    Title Systemic and Uterine Responses to Chronic Infusion of Estradiol-17 Beta.
    Date December 1993
    Journal The American Journal of Physiology
    Excerpt

    Human and ovine pregnancies are associated with increases in plasma levels of estrogens and angiotensin II (ANG II), cardiac output (CO), blood volume (BV), and uterine blood flow (UBF), as well as attenuated ANG II pressor responses. We hypothesized that, in nonpregnant animals, prolonged estradiol-17 beta (E2 beta) treatment would reproduce these endocrine and hemodynamic alterations. Nonpregnant ovariectomized ewes (n = 5) received 5 microgram E2 beta/kg iv followed by 220 micrograms/day for 14 days. Plasma E2 beta increased from 36 +/- 6 to 269 +/- 79 (SE) pg/ml (P < 0.05) during E2 beta treatment, returning to control values 4 days posttreatment. By 3 days of E2 beta, mean arterial pressure (MAP) and systemic vascular resistance (SVR) fell 9 +/- 1 and 29 +/- 1%, whereas heart rate (HR) and CO increased 20 +/- 5 and 26 +/- 1% (P < 0.05). Stroke volume (SV), BV, and plasma volume were unchanged until 7 days of E2 beta, with values rising 17 +/- 5, 13 +/- 3, and 14 +/- 4, respectively (P < 0.05). Although MAP remained similarly depressed (-11 +/- 1%) during week 2 of E2 beta, SVR decreased further (-37 +/- 3%) and was associated with additional increases (P < 0.05) in CO to 44 +/- 5%, reflecting rises in SV (21 +/- 2%) but not HR. Increases in BV correlated with rises in CO (r = 0.55) and SV (r = 0.64) but not HR (r = -0.04).(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Myometrial Angiotensin Ii Receptor Subtypes Change During Ovine Pregnancy.
    Date December 1993
    Journal The Journal of Clinical Investigation
    Excerpt

    Although regulation of angiotensin II receptor (AT) binding in vascular and uterine smooth muscle is similar in nonpregnant animals, studies suggest it may differ during pregnancy. We, therefore, examined binding characteristics of myometrial AT receptors in nulliparous (n = 7), pregnant (n = 24, 110-139 d of gestation), and postpartum (n = 21, 5 to > or = 130 d) sheep and compared this to vascular receptor binding. We also determined if changes in myometrial binding reflect alterations in receptor subtype. By using plasma membrane preparations from myometrium and medial layer of abdominal aorta, we determined receptor density and affinity employing radioligand binding; myometrial AT receptor subtypes were assessed by inhibiting [125I]-ANG II binding with subtype-specific antagonists. Compared to nulliparous ewes, myometrial AT receptor density fell approximately 90% during pregnancy (1,486 +/- 167 vs. 130 +/- 16 fmol/mg protein) and returned to nulliparous values > or = 4 wk postpartum; vascular binding was unchanged. Nulliparous myometrium expressed predominantly AT2 receptors (AT1/AT2 congruent to 15%/85%), whereas AT1 receptors predominated during pregnancy (AT1/AT2 congruent to 80%/20%). By 5 d postpartum AT1/AT2 congruent to 40%/60%, and > 4 wk postpartum AT2 receptors again predominated (AT1/AT2 congruent to 15%/85%). In studies of ANG II-induced force generation, myometrium from pregnant ewes (n = 10) demonstrated dose-dependent increases in force (P < 0.001), which were inhibited with an AT1 receptor antagonist. Postpartum myometrial responses were less at doses > or = 10(-9) M (P < 0.05) and unaffected by AT2 receptor antagonists. Vascular and myometrial AT receptor binding are differentially regulated during ovine pregnancy, the latter primarily reflecting decreases in AT2 receptor expression. This is the first description of reversible changes in AT receptor subtype in adult mammals.

    Title Prediction of the Severity of Meconium Aspiration Syndrome.
    Date August 1993
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: Meconium aspiration syndrome is associated with increased neonatal morbidity and mortality. We sought to determine whether the need for neonatal mechanical ventilation or prolonged ventilation (> or = 3 days) was predictable from antepartum, intrapartum, and immediate neonatal events. STUDY DESIGN: Between 1987 and 1989, 8003 of 43,906 (18%) live infants had meconium-stained amniotic fluid; 82 of these infants had clinical and radiographic evidence of meconium aspiration, and of these 82, 39 (48%) required mechanical ventilation. Predictors of ventilation or prolonged ventilation were determined by means of stepwise logistic regression. RESULTS: Predictors of neonatal ventilation included fetal tachycardia, interval from meconium detection to delivery, low 5-minute Apgar score, respiratory distress necessitating intubation in the delivery suite, and delivery by cesarean section. Sensitivity was 72%, and specificity was 64%; the model was incorrect in 32% of the cases. Predictors of prolonged ventilation were ominous fetal heart rate tracing, umbilical arterial pH < 7.20, birth weight > 90th percentile, nulliparity, and Apgar score > 4 at 1 minute and < or = 6 at 5 minutes. Sensitivity was 67%, and specificity was 91%; prolonged ventilation was incorrectly predicted in 17% of the cases. CONCLUSIONS: Use of these models to determine the need for mechanical ventilation or prolonged ventilatory assistance will enhance identification of infants at risk of severe meconium aspiration and will lead to early transfer to the neonatal intensive care unit for intense observation and management.

    Title Calcium Modulation of Endothelium-derived Prostacyclin Production in Ovine Pregnancy.
    Date July 1993
    Journal Endocrinology
    Excerpt

    Refractoriness to angiotensin-II (ANG II)-induced vasoconstriction is greater in the uteroplacental vs. systemic vascular beds during pregnancy, possibly reflecting enhanced uterine artery prostacyclin production. We determined the role(s) of calcium and calcium channels in regulating basal and ANG II-induced vascular prostacyclin production in uterine and omental (systemic) arteries obtained from pregnant (P) and nonpregnant (NP) ewes. To evaluate the endothelial contribution to basal and stimulated prostacyclin production, arteries with and without endothelium also were incubated in the absence and presence of 50 nM ANG II, 5 microM A23187, or 5 microM arachidonate. Basal prostacyclin production by intact and denuded uterine and systemic arteries was P > NP (P < 0.05), plus in intact arteries, production fell approximately 33% in calcium-free Krebs-Henseleit and 5 microM EGTA. Although basal prostacyclin production by P and NP uterine and NP systemic arteries was unaffected by 5 microM verapamil, P systemic artery synthesis fell 41% (P < 0.05). P uterine artery prostacyclin production increased similarly with ANG II (61%) and A23187 (78%) in the presence of calcium (2 mM), whereas NP uterine arteries responded only to A23187 (71%). Verapamil inhibited ANG II-induced increases in prostacyclin synthesis by P uterine arteries. Neither calcium removal nor verapamil altered prostacyclin responses to arachidonate (5 microM). The endothelium accounted for approximately 68% of basal prostacyclin production by all arteries studied and for 100% of ANG II-induced increases by P uterine arteries (P < 0.01). A23187 and arachidonate increased both endothelial and smooth muscle prostacyclin production (P < 0.01). During ovine pregnancy, extracellular calcium entry via activation of potential-gated calcium channels are involved in modulating basal vascular prostacyclin production as well as ANG II-induced increases in uterine artery production. Furthermore, the endothelium is the primary source of basal vascular prostacyclin synthesis and the sole source of ANG II-stimulated increases by uterine arteries during pregnancy.

    Title Ontogeny of Angiotensin Ii Vascular Smooth Muscle Receptors in Ovine Fetal Aorta and Placental and Uterine Arteries.
    Date June 1993
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    OBJECTIVE: Our purpose was to determine if differences in angiotensin II vascular smooth muscle receptor binding account for the attenuated fetal placental and systemic responses to infused angiotensin II relative to maternal responses and for the differences between umbilical and fetal systemic responses. STUDY DESIGN: Using plasma membranes prepared from the medial layer of fetal aorta, fetal placental artery, and maternal uterine artery obtained between 107 and 134 days of ovine gestation (n = 17), we measured and compared angiotensin II receptor binding density (in femtomoles per milligram of protein) and affinity (in nanomoles per liter) in radioligand binding studies with iodine 125-angiotensin II. Maternal and fetal plasma angiotensin II were also compared. RESULTS: A single class of high-affinity receptor was identified in all arteries. Although the binding density was similar at < 100 and > 130 days for fetal aorta (388 +/- 87 [SE] vs 262 +/- 56), placental artery (319 +/- 95 vs 235 +/- 54), and uterine artery (46 +/- 6 vs 50 +/- 13), values for fetal arteries exceeded those for uterine arteries (p < or = 0.018) in spite of higher fetal plasma angiotensin II (74 +/- 18 vs 30 +/- 8 pg/ml, p < 0.01). Affinity did not differ between arteries and, except for fetal aorta (1.4 +/- 0.2 vs 2.1 +/- 0.4, r = 0.49, p = 0.045), was unchanged during late gestation. CONCLUSION: Differences between fetal and maternal responses and fetal placental and systemic responses to infused angiotensin II in sheep do not reflect alterations in total angiotensin II vascular smooth muscle receptor binding density or affinity.

    Title Evaluation of a Continuous Thermodilution Cardiac Output Catheter.
    Date January 1993
    Journal Asaio Journal (american Society for Artificial Internal Organs : 1992)
    Excerpt

    The authors evaluated a thermodilution catheter designed to continuously measure cardiac output (CO). A 10 cm long surface heating element is positioned in a Swan-Ganz catheter corresponding to a right atrial-ventricular site. Heat is repetitively deposited into flowing blood in a unique, pseudorandom binary form. Small temperature fluctuations are sensed with a high performance thermistor and correlated with the heat input pattern, from which CO is determined. Seven adult sheep were anesthetized and instrumented for both continuous and standard cold bolus injection thermodilution (COM1) flow measurements. Heart rate and blood volume were adjusted to vary CO from 1.5 to 13.2 L/min. Continuous measurements correlated well with triplicate COM1 determinations (Sy,x = 0.56, r = 0.967) that improved with experience (Sy,x = 0.38, r = 0.99 for the last three animals). The surface heat transfer coefficient was measured in water (catheter parallel to flow). Results agreed well with a standard cylinder-in-crossflow correlation. The right ventricle heating element surface temperature was predicted for several CO and heating combinations. Worst case results yielded a 5.8 degrees C surface temperature elevation, suggesting that thermally induced damage is unlikely. Results suggest this catheter provides accuracy at least comparable to that of standard cold bolus injection methods, with no heat induced damage to blood.

    Title Role of Angiotensin Ii and Alpha-adrenergic Receptors During Estrogen-induced Vasodilation in Ewes.
    Date December 1992
    Journal The American Journal of Physiology
    Excerpt

    Estradiol-17 beta (E2 beta) produces uterine and systemic vasodilation in nonpregnant ewes without altering mean arterial pressure (MAP). Mechanisms responsible for maintaining MAP and thus uterine blood flow (UBF) may include activation of the renin-angiotensin and/or adrenergic systems. We therefore investigated the effects of systemic blockade of angiotensin II (ANG II) and/or alpha-adrenergic receptors in nonpregnant, castrated ewes, using saralasin (Sar) and/or phentolamine (Phen) in the presence or absence of intravenous E2 beta (1.0 microgram/kg). In nonestrogenized ewes neither antagonist alone had substantial cardiovascular effects; however, Sar + Phen decreased systemic vascular resistance (SVR) 20 +/- 7.4% (SE) and increased heart rate (HR) 50 +/- 19% (P < 0.01); MAP and UBF were unaffected. Following E2 beta treatment SVR fell 17 +/- 2.4% (P < 0.01), UBF increased more than fourfold, and MAP was unchanged. Compared with E2 beta alone, Phen + E2 beta decreased SVR 42 +/- 4.7%, and MAP fell 11 +/- 1.8% (P < 0.05) despite 40-50% increases in HR and cardiac output (P < 0.05). Responses to Sar + E2 beta were similar to E2 beta alone, except for a fall in MAP, whereas responses to Sar + Phen + E2 beta resembled those of Phen + E2 beta. E2 beta-induced uterine vasodilation was unaltered by Sar and/or Phen. During E2 beta-induced vasodilation, MAP is maintained by enhanced activation of the alpha-adrenergic and renin-angiotensin systems; however, uterine vascular responses to E2 beta are independent of both systems and perfusion pressure.

    Title Vasoconstrictor-induced Secretion of Anp in Fetal Sheep.
    Date October 1992
    Journal The American Journal of Physiology
    Excerpt

    Fetal secretion of atrial natriuretic peptide (ANP) increases during volume expansion and hypoxia. It is unknown whether this is associated with alterations in right atrial pressure (RAP) or distension and whether increases in ANP secretion reflect effects of specific vasopressors. To address this we studied fetal sheep (n = 13) at 125-140 days gestation, infusing either angiotensin II (ANG II; 0.023-5.73 micrograms/min) or the alpha-agonist phenylephrine (Phen; 0.031-7.64 micrograms/min) while monitoring mean arterial pressure (MAP), RAP, heart rate, and amniotic sac pressure. Arterial blood was obtained before and at 5 min of infusion to measure ANP, blood gases, and pH; umbilical venous blood was collected to determine placental clearance of ANP. ANG II caused dose-dependent increases in MAP and plasma ANP (P less than 0.05), whereas Phen caused dose-dependent increases in MAP, but ANP rose only with the highest dose (40 +/- 12%). delta MAP and delta RAP were highly correlated for Phen (r = 0.74, P = 0.002) and ANG II (r = 0.90, P less than 0.001), but for both agents the increase in delta RAP was proportionately greater than delta MAP, and increases in plasma ANP were greater per millimeter mercury rise in RAP than that observed with MAP. Increases in ANP were associated with a dose-dependent rise in hematocrit, suggesting decreases in intravascular volume. There was no fetal placental clearance of ANP. As in adults, ANG II- and alpha-agonist-induced fetal ANP secretion appears to primarily reflect increases in RAP and thus right atrial distension.

    Title Effect of Maternal Hypertension on Neonatal Neutropenia and Risk of Nosocomial Infection.
    Date October 1992
    Journal Pediatrics
    Excerpt

    Neonatal neutropenia occurs in approximately 50% of newborns delivered by women with pregnancy-induced hypertension. It is thought to be transient, independent of birth weight and gestational age, and unassociated with significant risks, including infection. It recently was suggested that neonatal neutropenia occurs primarily in smaller, younger neonates, is related to the severity of pregnancy-induced hypertension, and importantly, may be associated with an increased risk for nosocomial infection. We examined these points in a large inborn population in consecutive years, performing retrospective (n = 110, 1989) and prospective (n = 151, 1990) studies in low birth weight (less than or equal to 2200 g) neonates delivered by women with pregnancy-induced hypertension. Overall, 40% to 50% of neonates studied developed neonatal neutropenia, and they were younger and smaller (P less than .01) than non-neutropenic neonates. In the prospective study, neutropenic neonates were more likely to have mothers with severe pregnancy-induced hypertension (P less than .001), and the incidence of neonatal neutropenia was primarily among neonates less than 30 weeks of gestation and less than 1500 g birth weight, approximately 80% vs 35% to 45% in older, larger neonates or infants (P less than .001). Although nosocomial infection occurred more frequently among the group of neutropenic neonates in the prospective study (P less than .02), the incidence was similar to that in matched non-neutropenic controls delivered of normotensive women. Thrombocytopenia (less than 100,000/mm3) was not more frequent in neutropenic neonates.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Uterine Prostaglandin Production in Ovine Pregnancy: Effects of Angiotensin Ii and Indomethacin.
    Date August 1992
    Journal The American Journal of Physiology
    Excerpt

    The ovine and human uteroplacental vascular beds are more refractory to angiotensin II (ANG II)-induced vasoconstriction than the systemic vasculature. ANG II increases in vitro prostacyclin (PGI2) production by uterine but not omental arteries from pregnant sheep. Thus vasodilator prostaglandins may account for this difference in vascular responsiveness. We measured uterine and systemic eicosanoid production and hemodynamic responses in pregnant sheep before and during intravenous ANG II (1.15 and 11.5 micrograms/min). ANG II caused dose-related increases in arterial pressure and systemic and uterine vascular resistance (P less than 0.05). PGI2 metabolite (6-keto-PGF1 alpha) in the uterine vein rose from 166 +/- 70 (SE) to 223 +/- 114 and 631 +/- 323 pg/ml, respectively (P less than 0.05), and arterial levels increased from 67 +/- 24 to 145 +/- 78 and 312 +/- 173 pg/ml, respectively (P less than 0.05). Basal uterine venoarterial differences of 6-keto-PGF1 alpha were 99 +/- 43 pg/ml and increased during 11.5 micrograms ANG II/min to 295 +/- 181 pg/ml (P less than 0.05) but not during 1.15 micrograms/min (64 +/- 30 pg/ml). Responses were similar in gravid and nongravid uterine horns. Unilateral uterine prostaglandin inhibition with indomethacin did not alter basal uterine blood flow or systemic responses to ANG II (0.573-11.5 micrograms/min); however, ipsilateral uterine prostaglandin production fell and uterine vasoconstrictor responses increased (P less than 0.05). During ovine pregnancy ANG II increases uterine PGI2 production. PGI2 appears in part to attenuate ANG II-induced uterine vasoconstriction.

    Title Reliability of Birth Certificate Reporting of Congenital Anomalies.
    Date June 1992
    Journal American Journal of Perinatology
    Excerpt

    Birth certificates comprise an important source of data on the prevalence of genetic conditions and for monitoring possible teratogens in the population. Investigators have found wide variability (12 to 100%) in the accuracy of reporting. In a large public hospital, of those congenital anomalies detected at birth, only 5.4% were recorded on the birth certificate. This is one of the lowest rates ever reported. An underreporting correction factor may be applied if congenital anomalies are distributed randomly with respect to reporting status, and the rate of reporting is sufficient to comprise a valid sample for estimating a correction factor (that is, 20% or more reported). In this study, factors such as numbers or types of anomalies, race, infant birthweight, or estimated gestational age did not significantly influence the rate of birth certificate reporting. Thus, our data satisfied the first but not the second criterion for derivation of a correction factor. In conducting epidemiologic studies, birth certificate data should be used with: (1) great caution; (2) a system of validation with the medical record to estimate the degree of underreporting and to derive a correction factor; and (3) a priori knowledge that underreporting of congenital anomalies on this document is highly prevalent.

    Title Chloral Hydrate Toxicity in a Term Infant.
    Date June 1992
    Journal Developmental Pharmacology and Therapeutics
    Excerpt

    Chlorate hydrate is commonly used for neonatal sedation, but blood levels are infrequently monitored, reflecting an underemphasis of acute toxic effects. This report describes a case of chloral hydrate toxicity in a term infant with cardiac, renal, neurologic, bladder and gastrointestinal dysfunction. The effects of exchange transfusion are described as well as pharmacokinetics.

    Title Symptomatic Patent Ductus Arteriosus in Very-low-birth-weight Infants: 1987-1989.
    Date April 1992
    Journal Early Human Development
    Excerpt

    Symptomatic patent ductus arteriosus (sPDA) may occur in up to 50% of very-low-birth-weight (VLBW, less than or equal to 1500 g) infants. We reported a 16% incidence in 1979-1980 in a totally inborn population, demonstrating the importance of early fluid management. Although survival of VLBW infants, especially those less than 1000 g, has increased, sPDA has not been carefully re-examined. Therefore, we sought to determine if the incidence, morbidity, treatment, or risk factors for sPDA had changed in this population. Between January 1, 1987 and December 31, 1989 all VLBW infants with sPDA surviving greater than 72 h (119/636) were identified and compared to matched controls (n = 70). Incidence and onset of sPDA were 19% and 10 +/- 6 days (+/- S.D.), respectively, the former increasing from 8% to 33% between 1251-1500 g and 500-750 g, respectively (P less than 0.001). Fluid and colloid administration were similar in sPDA and control infants. sPDA was associated with the occurrence of chronic lung disease (18% vs 7%, P = 0.005) and intracranial hemorrhage (53% vs 21%, P less than 0.001). Using stepwise logistic regression analysis we were unable to create a model that accurately predicted sPDA. Medical management and indomethacin were unsuccessful in 66% and 25%, respectively, of infants so treated; 43% required surgical ligation. Although survival of VLBW infants has increased, our incidence of sPDA remains low, with greater than 80% of infants demonstrating spontaneous closure when fluid and colloid administration are judiciously used.

    Title Intraobserver and Interobserver Reliability in Assessment of Neonatal Cranial Ultrasounds.
    Date April 1992
    Journal Early Human Development
    Excerpt

    Intraobserver and interobserver reliability in assessing neonatal cranial ultrasounds for periventricular-intraventricular hemorrhage (PVH-IVH) is not well studied; therefore, studies were designed to address this. For intraobserver reliability 180 cranial ultrasounds (360 hemispheres) were randomly selected from greater than 2000 ultrasounds and read twice by one radiologist in a blinded fashion. Ninety-eight percent were interpreted identically; of the 2% reinterpreted differently, all were initially abnormal but normal on the second reading. The least agreement occurred when interpreting ventricular size. Only four infants (1.1%) were placed in an unfavorable prognostic category (grades III and IV) on the first reading and a favorable prognostic category on the second interpretation (no bleed, grades I and II). To determine interobserver reliability, 20 sonograms were interpreted by eight independent observers representing five institutions. Using the multiple rater kappa kappa statistic, we determined interobserver agreement on overall impression (normal vs. abnormal), presence and extent of PVH-IVH (i.e. grade), presence of residual cyst, and ventricular dilatation. Greatest degree of agreement occurred when determining normal vs. abnormal, residual cyst, no bleed, and grades III and IV PVH-IVH. Poorest agreement occurred when reading grades I and II PVH-IVH and ventricular dilatation. After condensing interpretations of cranial ultrasounds into two prognostic categories, i.e. favorable (no bleed, grades I and II) and unfavorable (grades III and IV), there was excellent agreement among the observers.

    Title Angiotensin Ii Vascular Smooth-muscle Receptors Are Not Down-regulated in Near-term Pregnant Sheep.
    Date January 1992
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    Normal human and ovine pregnancies are associated with elevated plasma angiotensin II levels and refractoriness to the vasoconstrictor effects of infused angiotensin II, which is greater in the ovine uteroplacental vascular bed than in the systemic vasculature. It remains unclear whether this refractoriness reflects alterations in angiotensin II vascular smooth-muscle receptor density or affinity. We examined the angiotensin II vascular smooth-muscle receptor in nonpregnant (n = 12) and near-term pregnant (130 +/- 3 days [mean +/- SD], n = 10) sheep, comparing binding characteristics on plasma membranes prepared from the medial layer of aorta, mesenteric artery, and uterine artery. Plasma angiotensin II levels were increased threefold to fourfold (p less than 0.001) in pregnant ewes. A single class of high-affinity angiotensin II vascular smooth-muscle receptor was identified in each type of artery. Receptor density was similar in nonpregnant and pregnant mesenteric artery (92 +/- 21 vs 103 +/- 40 fmol/mg protein, respectively), aorta (186 +/- 29 vs 220 +/- 46 fmol/mg protein), and uterine artery (59 +/- 20 vs 77 +/- 20 fmol/mg protein) tissue. Receptor affinity also was unchanged during pregnancy. Because changes in the density and affinity of the angiotensin II vascular smooth-muscle receptor were not observed in near-term pregnant ewes, the attenuated vasoconstrictor responses seen during pregnancy do not reflect receptor down-regulation or decreased affinity.

    Title Effects of Acute Hypercapnia on Maternal and Fetal Vasopressin and Catecholamine Release.
    Date December 1991
    Journal Pediatric Research
    Excerpt

    Although fetal asphyxia, i.e. hypoxemia, acidosis, and hypercapnia, increases plasma arginine vasopressin (AVP) greater than 40-fold, hypoxemia and metabolic acidosis occurring independently cause only 5-fold and 2-fold increases, respectively. To determine the effects of hypercapnia on AVP release, we examined the effects of acute hypercapnia on AVP secretion in six pregnant sheep and their fetuses at 135 +/- 4 d (chi +/- SD), exposing the ewe successively to room air, 30% O2, 30% O2 plus 10% CO2, 30% O2, and room air, and monitoring uterine blood flow, as well as maternal and fetal mean arterial pressure, heart rate, arterial blood gases, and plasma AVP and catecholamines. Oxygen exposure had no effect on the ewe or fetus. During O2 plus CO2 exposure, the ewes and fetuses developed hypercapnia in the absence of hypoxia, arterial CO2 tension increasing to 8.38 +/- 0.87 kPa (62.9 +/- 6.5 mm Hg) and 10.0 +/- 0.61 kPa (75.2 +/- 4.6 mm Hg) (p less than 0.001), respectively, at 30 min of exposure. Although fetal heart rate and mean arterial pressure were unchanged, maternal values rose 61 and 30% (p less than 0.001), respectively. At 30 min of O2 + CO2 exposure, maternal norepinephrine increased from 2.23 +/- 0.74 to 8.52 +/- 3.97 nmol/L (p = 0.15) and fetal epinephrine increased from 0.27 +/- 0.10 to 2.271 +/- 0.90 nmol/L (p = 0.01); plasma AVP was not significantly increased in the ewe or fetus, although levels rose from approximately 45 to 127 +/- 48 and 137 +/- 64 pmol/L (p = 0.10), respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Stress Hormones and Acid-base Status of Human Fetuses at Delivery.
    Date July 1991
    Journal The Journal of Clinical Endocrinology and Metabolism
    Excerpt

    The relationship of plasma concentrations of arginine vasopressin (AVP), ACTH, cortisol, and PRL in the human fetus to mode of delivery and acid-base status has been investigated in 91 term pregnancies consisting of 4 groups based on mode of delivery, type of anesthesia, and use of ephedrine prophylaxis for maternal blood pressure control. Infants delivered vaginally after uncomplicated labors had higher umbilical cord plasma concentrations of AVP, ACTH, and cortisol than infants delivered without labor. Use of ephedrine, an alpha-agonist, during regional anesthesia was associated with elevated plasma AVP and ACTH concentrations compared to those in women receiving general anesthesia. At the time of delivery, 12 infants had acidemia (pH less than 7.20), as judged by pH of umbilical arterial blood. Their plasma AVP, ACTH, and cortisol levels did not differ from those of infants delivered by uncomplicated vaginal delivery, but were greater than those of infants delivered by cesarean section under general anesthesia. Moreover, in infants with acidemia, plasma concentrations of AVP and ACTH were significantly correlated, but PRL levels were unaffected by mode of delivery or acidemia. Elevated umbilical cord plasma concentrations of AVP, ACTH, and cortisol characterize term vaginal deliveries and are associated with intrauterine stress, demonstrating activation of the fetal hypothalamic-pituitary-adrenal axis and suggesting that AVP is important in ACTH release in the human fetus; however, PRL does not appear to be an important stress hormone.

    Title Protein Kinase C in Uterine and Systemic Arteries During Ovarian Cycle and Pregnancy.
    Date April 1991
    Journal The American Journal of Physiology
    Excerpt

    Elevated uterine blood flow is associated with increases in local estrogen-to-progesterone ratios during the follicular phase of the ovarian cycle and late pregnancy. Because protein kinase C (PKC) activation increases arterial tone, decreased PKC activity may mediate vasodilation. Therefore, we determined uterine (UA) and systemic artery (SA, omental) PKC activity (pmol.mg protein-1.min-1) during the follicular (n = 6), early luteal (n = 4), and late luteal (n = 3) phases of the sheep ovarian cycle, and at 110 +/- 3 (n = 4) and 130 +/- 1 (n = 8) (+/- SE) days of ovine gestation. The stage of the ovarian cycle was verified by the presence of follicles (high estrogen) or corpora lutea (high progesterone) on the ovary and by plasma estrogen and progesterone concentrations. UA-PKC activity (pmol.mg protein-1.min-1) during the follicular phase was 100 +/- 18 and increased progressively to 155 +/- 28 during the early luteal phase and to 219 +/- 37 (P less than 0.05) during the late luteal phase; SA-PKC activity was unchanged. A local utero-ovarian relationship was observed, i.e., UA-PKC activity was lower (P less than 0.001) in UA ipsilateral to ovaries with only follicles (105 +/- 14) when compared with UA adjacent to ovaries with corpora lutea (224 +/- 26), which was similar to SA-PKC activity (184 +/- 35). UA-PKC activity fell from 344 +/- 70 at 110 days to 109 +/- 12 at 130 days gestation (P less than 0.05); SA-PKC activity was unchanged. During the ovarian cycle and latter one-third of ovine pregnancy, increased estrogen production is associated with decreased UA-PKC activity; thus local ovarian and placental steroids may alter PKC activity, thereby regulating UA tone and blood flow.

    Title Angiotensin Ii and Alpha-agonist. Iii. In Vitro Fetal-maternal Placental Prostaglandins.
    Date February 1991
    Journal The American Journal of Physiology
    Excerpt

    In fetal sheep, angiotensin II, but not phenylephrine, increases umbilical venous concentrations of prostaglandin E2 (PGE2) and prostacyclin (PGI2); however, their source(s) is unknown. We sought to determine the tissue source(s) of this increase in prostanoids and to compare responses in fetal and maternal tissues. Fetal placental arteries (PA) and veins (PV), mesenteric arteries (MA) and cotyledons, and maternal caruncles and uterine arteries (UA) from eight pregnant ewes [127 +/- 3 (SE) days] were incubated (37 degrees C, 1 h) in Krebs-Henseleit (95% O2-5% CO2) with or without angiotensin II, phenylephrine, or norepinephrine (5 x 10(-10) and 5 x 10(-8) M). Basal PGE2 production exceeded PGI2 in PA, cotyledons, and caruncles (P less than 0.05), whereas PGE2 less than PGI2 only in UA; production of both prostanoids was greatest in MA with 34.8 +/- 5.0 and 27.4 +/- 3.7 pg.micrograms protein-1.h-1, respectively (P less than 0.001). Caruncles produced little of either prostanoid. Angiotensin II increased PA PGE2 production from 6.5 +/- 1.5 to 8.4 +/- 3.0 and 10.8 +/- 4.5 pg.micrograms-1.h-1 (P = 0.001) and PGI2 from 3.3 +/- 0.5 to 5.5 +/- 1.5 (P less than 0.05) and 3.7 +/- 0.9 pg.micrograms-1.h-1; PV PGE2 rose from 4.5 +/- 1.1 to 9.0 +/- 3.5 and 7.9 +/- 2.3 pg.micrograms-1.h-1 (P less than 0.05); PV PGI2 was unchanged. Angiotensin II increased UA PGE2 from 1.5 +/- 0.3 to 3.4 +/- 1.2 (P less than 0.05) and 2.4 +/- 0.8 pg.micrograms-1.h-1 and PGI2 from 8.7 +/- 1.0 to 12.4 +/- 2.2 and 16.2 +/- 5.2 (P less than 0.05) pg.micrograms-1.h-1. Angiotensin II had no effect on MA, cotyledonary, or caruncular prostanoids. alpha-Agonist had no effect on any tissue examined. In fetal sheep, angiotensin II-induced increases in PGI2 and PGE2 are likely of vascular origin.

    Title Neonatal Intracranial Hemorrhage: Ii. Risk Factor Analysis in an Inborn Population.
    Date January 1991
    Journal Early Human Development
    Excerpt

    The ability to predict the occurrence of neonatal periventricular-intraventricular hemorrhage (PVH-IVH) would be useful in the design of clinical trials to prevent its occurrence. Therefore, data were collected from 463 consecutive infants less than or equal to 1500 g birth weight delivered between March 1, 1982 and February 28, 1985. This large population made it feasible to divide the infants into two groups, using one group to develop a model predictive of ICH and the second group to test the validity of the model. Infants were randomly grouped by sex, race, gestational age, birth weight, month of birth, mortality, and incidence and grade of worst PVH-IVH. In Group A (n = 232), respiratory distress syndrome, ventilator therapy, PaCO2 greater than or equal to 60 mmHg, PO2 less than or equal to 40 mmHg greater than or equal to 2 h, lower 1- and 5-min Apgar scores, lower pediatric estimation of gestational age, and pneumothorax were significantly associated with PVH-IVH by univariant analyses (chi 2, P less than 0.03). Multivariant discriminant analysis performed on Group A revealed that pneumothorax, cesarean section, PaCO2, and ventilator therapy were most predictive of PVH-IVH, but sensitivity was 55% and specificity 78%. Applying the model to Group B, sensitivity decreased to 21% while specificity rose to 93%. Logistic regression, which takes into account non-normally distributed variables, did not improve predictability.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Neonatal Intracranial Hemorrhage: I. Changing Pattern in Inborn Low-birth-weight Infants.
    Date January 1991
    Journal Early Human Development
    Excerpt

    Many reports of the occurrence of periventricular-intraventricular hemorrhage (PVH-IVH) are biased by the inclusion of both inborn and outborn infants. To obviate this selection bias we examined a large inborn population of low-birth-weight infants to determine if the incidence of PVH-IVH changed over a 3-year interval from March, 1982 through February, 1985. Serial cranial ultrasonography was performed in 463 consecutive infants of birth weight less than or equal to 1500 g who survived for more than 8 h. The incidence of PVH-IVH decreased from 31.5% and 29.3% in years 1 and 2, respectively, to 23.7% in year 3 (P less than 0.05). The latter reflected a fall in the incidence of grades III and IV PVH-IVH, but no change in the incidence of grades I and II. This observation was not attributable to changes in mortality, the distribution of infants by birth weight and estimated gestational age in each year of the study, or infants excluded from the analysis. Contrary to most reports, 21.9% of all PVH-IVH during the 3 years were first diagnosed after 14 days postnatal age and were predominantly grade I. These results document not only a change in the epidemiology of PVH-IVH in an inborn population, but also the importance of serial cranial ultrasonography beyond the first week of life.

    Title Low-dose Aspirin. Ii. Relationship of Angiotensin Ii Pressor Responses, Circulating Eicosanoids, and Pregnancy Outcome.
    Date January 1991
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    Forty pregnant women (28 to 32 weeks' gestation) were given low-dose aspirin therapy (81 mg/day) from the time of enrollment until delivery; circulating eicosanoid levels and angiotensin II pressor responses were measured before and after 1 week of aspirin therapy. Subsequent clinical outcome was correlated with these results. All women had significant reductions in serum and plasma thromboxane B2 levels with aspirin treatment (p less than 0.01). Eleven women who remained sensitive to the pressor effects of angiotensin II (effective pressor dose less than 10 ng/kg/min) after 1 week of low-dose aspirin treatment exhibited significant decreases (p less than 0.05) in plasma 6-keto-prostaglandin F1 alpha (264 +/- 119 vs 161 +/- 31 pg/ml, mean +/- SD) and prostaglandin E2 (476 +/- 174 vs 351 +/- 112 pg/ml) levels. In contrast, patients who were either nonsensitive (refractory) to angiotensin II (n = 18; greater than or equal to 10 ng/kg/min) before aspirin or became nonsensitive after aspirin administration (n = 11) had no change in either plasma 6-keto-prostaglandin F1 alpha or prostaglandin E2 concentrations. The occurrence of pregnancy-induced hypertension was 100% in the women who remained angiotensin II sensitive during aspirin therapy as compared with 36% and 39% in the other two groups (x2 = 16.14; p less than 0.001). Thus during low-dose aspirin therapy a failure to develop refractoriness to infused angiotensin II is associated with a nonselective inhibition of eicosanoids and the almost certain development of pregnancy-induced hypertension. These observations may reflect a basic defect in vascular adaptation to pregnancy.

    Title Failure to Recognize Fetal Alcohol Syndrome in Newborn Infants.
    Date October 1990
    Journal American Journal of Diseases of Children (1960)
    Excerpt

    A clinically distinct constellation of major and minor anomalies, termed the fetal alcohol syndrome, occurs among infants whose mothers abuse alcohol during pregnancy. In addition, significantly higher rates of pregnancy complications, including perinatal deaths and fetal growth retardation, occur among these women and their offspring. We studied the medical records of 40 infants born to 38 alcohol abusers and the frequency of characteristics associated with fetal alcohol syndrome. Physical examinations of 6 infants revealed primary features consistent with a diagnosis of fetal alcohol syndrome. Postnatal growth and development were very poor in 17 (50%) of 34 liveborn alcohol-exposed infants. The diagnosis of fetal alcohol syndrome did not appear in the medical records of any of these infants despite the fact that the mothers' obstetric records included a history of alcohol abuse during pregnancy. This finding emphasizes the importance of good communication between obstetric and pediatric medical staff at this hospital, particularly when providing care for pregnant women and newborn infants at high risk for complications due to maternal alcohol or other drug abuse.

    Title Protein Content and Myosin Light Chain Phosphorylation in Uterine Arteries During Pregnancy.
    Date October 1990
    Journal The American Journal of Physiology
    Excerpt

    During pregnancy, the ovine uterine artery changes from a low- to a high-stress artery. We investigated the hypotheses that the increased stress reflects alterations in vessel wall cellularity, smooth muscle cell contractile protein contents, or activation properties. Uterine artery diameter increased during pregnancy, whereas the fractional cellular composition and thickness of the muscularis were unchanged. Results of morphometry suggest that vessel growth is associated with cell elongation. Uterine arteries from pregnant ewes had greater protein contents than those from nonpregnant ewes (104 vs. 69 mg/g, respectively); there were corresponding increases in the absolute cellular contents of actin and myosin. While the fraction of light chain phosphorylated in response to phenylephrine was unaltered, the total amount of myosin light chain phosphorylated per gram wet weight increased significantly during pregnancy. In addition, the distribution of myosin heavy chain isoforms was also altered during pregnancy. The increased stress observed in the uterine artery during ovine pregnancy reflects, in part, increases in cellular contractile protein concentrations associated with hypertrophy.

    Title Angiotensin Ii and Alpha-agonist. I. Responses of Ovine Fetoplacental Vasculature.
    Date September 1990
    Journal The American Journal of Physiology
    Excerpt

    During ovine pregnancy the uteroplacental vasculature is less responsive to angiotensin II (ANG II)-induced vasoconstriction than the systemic vasculature, whereas responses to alpha-agonists are just the opposite. Comparisons of fetal systemic and placental vascular responses to these agents are not well described, nor have they been compared with maternal responses. We determined steady-state responses to fetal infusions (5-7 min) of ANG II (0.023-5.73 micrograms/min) and phenylephrine (PHEN, 0.031-7.64 micrograms/min), continuously monitoring mean arterial pressure (MAP), heart rate (HR), and umbilical blood flow (UmBF). Although both vasoconstrictors caused dose-dependent increases in MAP and umbilical vascular resistance (UmVR), responsiveness (delta MAP and delta UmVR) to ANG II (mol/min) was 35- to 60-fold greater than to PHEN. ANG II caused dose-dependent decreases in UmBF (2-48%); PHEN had minimal effects except at the highest dose, UmBF decreasing only 18%. Although patterns of fetal responses of MAP, UmBF, and UmVR to ANG II resembled maternal responses of MAP and uterine blood flow and uterine vascular resistance, the former were greatly attenuated. Similar observations were made with PHEN for UmBF and UmVR but not MAP. ANG II is a more potent fetal systemic and placental vasoconstrictor than PHEN; however, compared with those of the mother the responses are attenuated. Moreover, the fetoplacental vascular bed appears unresponsive to alpha-adrenergic stimulation, possibly reflecting a mechanism for maintaining UmBF when plasma catecholamines are elevated.

    Title Angiotensin Ii and Alpha-agonist. Ii. Effects on Ovine Fetoplacental Prostaglandins.
    Date September 1990
    Journal The American Journal of Physiology
    Excerpt

    The fetoplacental vasculature is more sensitive to angiotensin II (ANG II) than to alpha-agonists, possibly reflecting their differing effects on vascular prostaglandin (PG) production. To examine this we studied in fetal sheep (123-138 days) the effects of ANG II (n = 7; 0.057, 1.15, and 5.73 micrograms/min) and phenylephrine (PHEN, n = 7; 0.306, 1.53, and 7.64 micrograms/min) on mean arterial pressure (MAP), heart rate (HR), and simultaneous measurements of umbilical arterial and venous PGE2, 6-keto-PGF1 alpha (PGI2) and thromboxane B2 (TxB2) concentrations. ANG II increased MAP and decreased HR dose dependently (P less than 0.05). Basal umbilical venous plasma PGE2 levels exceeded PGI2 (P less than 0.001) and increased during ANG II infusions from 502 +/- 63 to 516 +/- 113, 647 +/- 188, and 1,968 +/- 541 pg/ml (mean +/- SE, P less than 0.05), as did venous-arterial concentration differences (129 +/- 26 to 179 +/- 47, 244 +/- 58, and 1,287 +/- 507 pg/ml, respectively; P less than 0.05). ANG II also increased umbilical venous PGI2 levels from 110 +/- 13 to 116 +/- 24, 144 +/- 46, and 680 +/- 147 pg/ml (P less than 0.01) and the venous-arterial concentration difference from 3 +/- 6 to 20 +/- 16, 41 +/- 27, and 405 +/- 122 pg/ml (P less than 0.05), respectively. ANG II had no effect on plasma TxB2, and no umbilical venous-arterial concentration differences existed. Although PHEN increased MAP and decreased HR, plasma eicosanoid concentrations were unaltered. The fetus is more sensitive to ANG II than PHEN; however, only ANG II increased placental PGE2 and PGI2 production.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Why Use Indomethacin?
    Date July 1990
    Journal Pediatrics
    Title Limited Effectiveness of Triple Dye in Preventing Colonization with Methicillin-resistant Staphylococcus Aureus in a Special Care Nursery.
    Date June 1990
    Journal The Pediatric Infectious Disease Journal
    Title Uteroplacental Production of Eicosanoids in Ovine Pregnancy.
    Date April 1990
    Journal Prostaglandins
    Excerpt

    Dramatic cardiovascular alterations occur during normal ovine pregnancy which may be associated with increased prostaglandin production, especially of uteroplacental origin. To study this, we examined (Exp 1) the relationships between cardiovascular alterations, e.g., the rise in uterine blood flow and fall in systemic vascular resistance, and arterial concentrations of prostaglandin metabolites (PGEM, PGFM and 6-keto-PGF1 alpha) in nonpregnant (n = 4) and pregnant (n = 8) ewes. To determine the potential utero-placental contribution of these eicosanoids in pregnancy, we also studied (Exp 2) the relationship between uterine blood flow and the uterine venous-arterial concentration differences of PGE2, PGF2 alpha, PGFM, 6-keto-PGF1 alpha, and TxB2 in twelve additional late pregnant ewes. Pregnancy was associated with a 37-fold increase in uterine blood flow and a proportionate (27-fold) fall in uterine vascular resistance (p less than 0.01). Arterial concentrations of PGEM were similar in nonpregnant and pregnant ewes (316 +/- 19 and 245 +/- 38 pg/ml), while levels of PGFM and PGI2 metabolite 6-keto-PGF1 alpha were elevated 23-fold (31 +/- 14 to 708 +/- 244 pg/ml) and 14-fold (12 +/- 4 to 163 +/- 78 pg/ml), respectively (p less than 0.01). Higher uterine venous versus uterine arterial concentrations were observed for PGE2 (397 +/- 36 and 293 +/- 22 pg/ml) and 6-keto-PGF1 alpha (269 +/- 32 and 204 +/- 32 pg/ml), p less than 0.05, but not PGF2 alpha or TxB2. Although PGFM concentrations appeared to be greater in uterine venous (1197 +/- 225 pg/ml) as compared to uterine arterial (738 +/- 150 pg/ml) plasma, this did not reach significance (0.05 less than p less than 0.1). In normal ovine pregnancy arterial levels of PGI2 are increased, which may in part reflect increased uteroplacental production. Moreover the gravid ovine uterus also appears to produce PGE2 and metabolize PGF2 alpha.

    Title Prenatal Care Evaluation and Cohort Analyses.
    Date February 1990
    Journal Pediatrics
    Excerpt

    The value of prenatal care has been obscured by multiple factors, including the limitations of birth certificate data, large socioeconomic disparities between women who seek prenatal care and those who do not, and the "preterm delivery bias", ie, the reduced pregnancy duration and opportunity for prenatal care among women who give birth prematurely. Perinatal mortality and morbidity (neonatal intensive care unit admission; ventilator therapy) were carefully assessed in an indigent population (28,838 deliveries at Parkland Memorial Hospital). To avoid the preterm delivery bias, a cohort of all women whose pregnancy reached a specific week of gestation was identified and their prenatal care status (zero vs one or more visits) by that week was related to pregnancy outcome. Separate cohorts were defined at 26, 30, 34, 38, and 42 weeks. Prenatal care was associated with improved pregnancy outcomes in only the 34-, 38-, and 42-week cohorts (P less than .01). Findings suggest substantial benefit from prenatal care after 30 weeks' gestation but not from early prenatal care. Unfortunately, it may not be possible to assess prenatal care accurately in observational studies even if cohort analyses are used. Clinical trials are needed to assess the effects of strategies for increasing or improving prenatal care, especially in early pregnancy.

    Title Oxytocin Stimulates Glucagon and Insulin Secretion in Fetal and Neonatal Sheep.
    Date November 1989
    Journal Endocrinology
    Excerpt

    In adults of several species arginine vasopressin (AVP) and oxytocin (OT) stimulate pancreatic secretion of immunoreactive plasma glucagon (IRG). In fetal sheep AVP is an important stress hormone and may be simultaneously secreted with OT; however, their effects on IRG secretion are not known. We sought to determine if AVP and/or OT affected pancreatic IRG secretion in fetal and neonatal sheep. Either AVP or OT was infused for 30 min in chronically catheterized fetal and neonatal sheep, obtaining peripheral arterial and/or portal venous blood samples before; 10, 15, and 30 min during; and 15, 30, and 60 min after infusion for measurements of blood gases, hematocrit, IRG, immunoreactive plasma insulin (IRI) and plasma glucose. AVP did not affect IRG or IRI in fetal sheep (mean +/- SE, 133 +/- 1 days gestation), but small increases occurred in portal venous blood of lambs (2-49 days old). In contrast, OT (4.6 +/- 0.3 mU/min.kg; n = 12) increased fetal plasma IRG from 72 +/- 5 to 86 +/- 6 and 97 +/- 7 pg/ml (P less than 0.001) and IRI from 16 +/- 2 to 20 +/- 3 and 20 +/- 2 microU/ml (P less than 0.02) at 15 and 30 min, respectively; 157 +/- 11 microU OT/min.kg had no effect. In lambs (2-49 days old), 3.0 mU OT/min.kg increased arterial (n = 15) IRG from 139 +/- 19 to 367 +/- 43 and 483 +/- 76 pg/ml (P less than 0.01) and portal IRG (n = 8) from 167 +/- 39 to 341 +/- 72 and 502 +/- 148 pg/ml (P less than 0.01), respectively. Arterial and portal IRI also rose (P less than 0.01) from 36 +/- 4 to 82 +/- 12 and 105 +/- 32 microU/ml and from 29 +/- 5 to 65 +/- 13 and 51 +/- 7 microU/ml, respectively. Glucose was unchanged in all experiments. In fetal and neonatal sheep, AVP has minimal effects on IRG and IRI release. In contrast, OT increases both substantially; furthermore, there is a difference in fetal and neonatal responsiveness. OT may be important in modulating glucagon and insulin secretion during and after parturition.

    Title Alcohol Abuse During Pregnancy: Changes in Frequency in a Large Urban Hospital.
    Date October 1989
    Journal Obstetrics and Gynecology
    Excerpt

    The reported frequency of alcohol abuse during pregnancy was studied in a large urban public hospital in Dallas, Texas. During 1977-1980, 5602 pregnant women were surveyed and 0.7% (95% confidence interval 0.6-0.8%) reported abusing alcohol during pregnancy. In 1987, 1.4% (95% confidence interval 1.3-1.5%) of 1032 pregnant women, who were surveyed before delivery, reported alcohol abuse according to the same definition used 10 years earlier. The increase in the frequency of reported alcohol abuse during pregnancy between 1977-1980 and 1987 is statistically significant (P less than .05).

    Title Prolactin Levels in Umbilical Cord Blood of Human Infants: Relation to Gestational Age, Maternal Complications, and Neonatal Lung Function.
    Date October 1989
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    The ontogeny of serum prolactin and its relation to several variables, especially lung function, in 543 neonates was studied. Umbilical cord serum prolactin levels rose between 24 and 42 weeks' gestation, correlating significantly (p less than 0.001) with gestational age (r = 0.44) and birth weight (r = 0.32). Among infants of similar ages, however, there was no variation in serum prolactin level as a function of birth weight, sex, Apgar scores, or delivery method. Infants of women with pregnancy-induced hypertension had higher than normal prolactin levels; infants of diabetic women had normal prolactin levels. At 31.5 to 37 weeks' gestation, infants who developed respiratory distress syndrome had lower serum prolactin levels than those whose lung function was normal or else was abnormal from causes other respiratory distress syndrome. The risk for respiratory distress syndrome was higher in newborns whose prolactin level was low (10th percentile) than in infants whose prolactin level was high (90th percentile). These results are suggestive that prolactin may play a role in fetal lung maturation.

    Title Ovine Placental Steroid 17 Alpha-hydroxylase/c-17,20-lyase, Aromatase and Sulphatase in Dexamethasone-induced and Natural Parturition.
    Date October 1989
    Journal The Journal of Endocrinology
    Excerpt

    Parturition in the sheep is preceded by an abrupt alteration in placental steroid metabolism causing a shift from progesterone to oestrogen production. This change is believed to be a consequence of the preparatum rise in cortisol in the fetal circulation and involves increases in activities of the enzymes steroid 17 alpha-hydroxylase (cytochrome P-450(17) alpha), steroid C-17,20-lyase, and possibly aromatase and steroid sulphatase. The activity levels have been determined of steroid 17 alpha-hydroxylase, aromatase and steroid sulphatase in placental microsomes in late pregnancy, dexamethasone-induced labour and in natural labour at term. Over the gestational period of 118-140 days, basal levels of placental aromatase were relatively constant (mean value (+/- S.E.M.) of 5.6 +/- 0.5 pmol/min per mg microsomal protein (n = 10]. Pregnenolone and progesterone 17 alpha-hydroxylase activities were undetectable (less than 0.5 pmol/min per mg microsomal protein (n = 7]. In six animals in labour induced with infusion of dexamethasone into the fetus, placental aromatase activity increased to a value of 14.0 +/- 1.0 pmol/min per mg protein; placental pregnenolone 17 alpha-hydroxylase, measured in four of the animals, also increased to 453 +/- 77 pmol/min per mg microsomal protein. In five animals in natural spontaneous labour with vaginal delivery, aromatase activity was 26.7 +/- 5.2 pmol/min per mg microsomal protein and pregnenolone 17 alpha-hydroxylase activity was 141 +/- 14 pmol/min per mg microsomal protein. Steroid sulphatase activity was barely detectable (less than 1.5 pmol/min per mg microsomal protein) during late pregnancy, dexamethasone-induced labour or natural parturition.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Uterine and Nonuterine Vascular Responses to Angiotensin Ii in Ovine Pregnancy.
    Date August 1989
    Journal The American Journal of Physiology
    Excerpt

    The uteroplacental vasculature is more refractory to angiotensin II (ANG II) than the systemic vasculature as a whole. To ascertain the differences in responses between reproductive and nonreproductive tissues that account for this, we infused ANG II (0.573, 5.73, and 11.5 micrograms/min) in pregnant sheep (137 +/- 5 days of gestation) and monitored arterial pressure (MAP), heart rate, and uterine blood flow (UBF); cardiac output and regional blood flows were measured with radiolabeled microspheres. Dose-dependent changes in MAP, UBF, and systemic (SVR) and uterine (UVR) vascular resistance occurred (P less than 0.05); systemic responses exceeded uterine (P less than 0.05), except with 11.5 micrograms/min, when % delta UVR = % delta SVR, % delta UVR greater than % delta MAP, and UBF fell 29%. Although a dose-dependent rise in placental resistance occurred, blood flow was unaffected except at 11.5 micrograms ANG II/min, falling 16.8 +/- 3.5% (P = 0.059). In contrast, endometrial perfusion decreased 68 +/- 4.2 and 81 +/- 1.8% (P less than 0.01) with 5.73 and 11.5 micrograms ANG II/min, respectively. Myometrial responses were intermediate, thus placental flow increased from 75 to greater than 90% of total UBF. Adipose, renal, and adrenal glands were extremely sensitive to ANG II, with blood flows decreasing maximally at 0.573 micrograms/min (P less than 0.05). Maximum adipose vascular resistance occurred at 0.573 micrograms/min, greater than 400% (P less than 0.001), exceeding responses in all tissues (P less than 0.05). The placenta is less responsive to ANG II than other uterine and most nonreproductive tissues, resulting in preferential maintenance of uteroplacental perfusion and protecting the fetus from the effects of this vasoconstrictor.

    Title Alterations in Vascular Smooth Muscle Contractility During Ovine Pregnancy.
    Date June 1989
    Journal The American Journal of Physiology
    Excerpt

    During pregnancy, sheep develop attenuated systemic and uterine vascular responsiveness to alpha-adrenergic stimulation. To determine whether this reflects altered vascular smooth muscle function, we studied the responsiveness of smooth muscle isolated from systemic and uterine arteries to KCl and phenylephrine. Uterine, renal, and carotid arteries were collected from nonpregnant, pregnant (131 +/- 2 days, +/- SD), and late postpartum (144 +/- 4 days) ewes; endothelium was removed and open rings were hung for measurement of isometric force. There were no differences in concentration-response relationships nor maximal stresses generated to phenylephrine between nonpregnant, pregnant, and late postpartum states for carotid or renal arteries. However, the 50% maximal concentration for phenylephrine of uterine arteries in the nonpregnant state (2.8 +/- 0.9 x 10(-6) M) was greater than the pregnant state (0.76 +/- 0.05 x 10(-6) M). Moreover, uterine arteries from pregnant sheep generated significantly more stress than those from nonpregnant sheep (2.2 +/- 0.23 vs. 0.73 +/- 0.23 x 10(6) dyn/cm2, P less than 0.01). The attenuated systemic and uterine vascular responses associated with pregnancy do not result from diminished adrenergic sensitivity or contractile capability of arterial smooth muscle. In contrast, there is increased stress-generating capacity of uterine arterial smooth muscle during pregnancy, which is reversed during the postpartum period.

    Title Local and Systemic Estradiol-17 Beta: Effects on Uterine and Systemic Vasodilation.
    Date May 1989
    Journal The American Journal of Physiology
    Excerpt

    Systemic estradiol-17 beta (E2 beta) administration increases uterine blood flow (UBF), cardiac output (CO), heart rate (HR), and plasma renin activity (PRA). We sought to determine if the E2 beta-induced systemic responses were dependent on the observed uterine responses. Nonpregnant, ovariectomized ewes (n = 5) received 3 micrograms E2 beta into both uterine arteries followed 120 min later by systemic E2 beta, 1 microgram/kg. At 120 min after local E2 beta, UBF increased from 26 +/- 5 to 161 +/- 21 ml/min (P less than 0.05); uterine vascular resistance (UVR) decreased 83 +/- 2.5% (P less than 0.05); and systemic parameters were unchanged. At 120 min after systemic E2 beta, UBF remained elevated and CO had increased gradually from 4.4 +/- 0.2 to 5.5 +/- 0.32 l/min (26 +/- 3.4%, P less than 0.05), reflecting a 37 +/- 3.9% (P less than 0.05) increase in HR; mean arterial pressure (MAP) remained unchanged. The increased CO was associated with a 20 +/- 3.1% (P less than 0.05) fall in systemic vascular resistance (SVR), with % delta SVR less than % delta UVR (P less than 0.05). Base-line PRA and angiotensin II, 1.31 +/- 0.2 ng.ml-1.h-1 and 10.3 +/- 2.1 pg/ml, respectively, were unchanged by local E2 beta; systemic E2 beta caused increases to 3.56 +/- 0.51 ng.ml-1.h-1 (P less than 0.05) and 34.1 +/- 11.3 pg/ml (P less than 0.05), respectively. E2 beta-induced uterine hyperemia occurs independent of its systemic effects and is not responsible for systemic cardiovascular alterations, and the relative uterine vascular responses exceed systemic responses.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Endocrine Maturation and Lung Function in Premature Neonates of Women with Diabetes.
    Date April 1989
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    Because respiratory distress syndrome may result, in part, from a hormonal deficiency in the developing fetus, we investigated the endocrine millieu of 28 infants of women with diabetes who were delivered prematurely (34 to 37 weeks of gestation). The umbilical serum concentrations of estrone, estradiol, estriol, cortisol, and prolactin in infants of women with diabetes who developed respiratory distress syndrome (n = 6) were lower than those in infants of women with diabetes who had normal lung function. Serum hormone levels in age-matched newborns of normal women were higher than those in the infants of women with diabetes with respiratory distress syndrome but were not different than those in the infants of women with diabetes with normal lung function. Plasma glucose levels were highest in women whose neonates developed respiratory distress syndrome. An inverse correlation existed between maternal glucose levels and lecithin-sphingomyelin ratios in amniotic fluid. Thus diabetes occasionally results in significantly delayed maturation of the fetal endocrine milieu. In these instances, delayed fetal lung maturation is a frequent occurrence. Moreover, both phenomena may be related to the extent of diabetic control during pregnancy.

    Title The Concentration of the 35-kda Surfactant Apoprotein in Amniotic Fluid from Normal and Diabetic Pregnancies.
    Date February 1989
    Journal Pediatric Research
    Excerpt

    A specific, enzyme-linked immunoabsorbent assay was used to determine the concentration of the 35,000 mol wt surfactant apoprotein (SP-A) in samples of amniotic fluid obtained from nondiabetic (n = 358) and diabetic (n = 29) women. The enzyme-linked immunoabsorbent assay was performed with rabbit antibodies directed against SP-A present in lavage fluid from a patient with alveolar proteinosis. Amniotic fluid SP-A concentrations increased as a function of gestational age, from less than 3 micrograms/ml at 30-31 wk to 24 micrograms/ml at 40-41 wk, and were positively correlated with the lecithin to sphingomyelin ratio (p less than 0.01). SP-A concentrations also increased as a function of gestational age in shake test positive samples (p less than 0.05), but were unchanged in shake test-negative samples. There was no difference in the surfactant apoprotein concentration of male compared with female fetuses at any gestational age. In amniotic fluid obtained from 20 diabetic women, SP-A levels were significantly less than in nondiabetic pregnancies that were matched for gestational age and sex of the fetus (p less than 0.05). The SP-A concentrations in amniotic fluids obtained from nine women who were diabetic and hypertensive and from 10 hypertensive women were not different from matched controls. The relationships described above were valid whether the SP-A concentration was expressed per mg protein or per ml amniotic fluid. These data are suggestive that the concentration of amniotic fluid SP-A is decreased in diabetic pregnancies.

    Title Low-dose Aspirin. I. Effect on Angiotensin Ii Pressor Responses and Blood Prostaglandin Concentrations in Pregnant Women Sensitive to Angiotensin Ii.
    Date December 1988
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    Decreased incidence of proteinuric hypertension after low-dose aspirin therapy is hypothesized to be a consequence of selective thromboxane A2 inhibition and sparing of prostacyclin. This study was designed to ascertain if low-dose aspirin therapy (81 mg/day for 1 week) alters vascular refractoriness to angiotensin II and the prostacyclin/thromboxane A2 ratio in pregnant women sensitive to angiotensin II (n = 17). Low-dose aspirin increased the effective pressor dose of angiotensin II from 5.9 +/- 2.4 to 10.2 +/- 5.5 ng/kg/min (p less than 0.01, mean +/- SD). Platelet-derived serum thromboxane B2 (a metabolite of thromboxane A2), a measure of therapy compliance, decreased from 1804 +/- 1771 to 132 +/- 206 pg/ml (p less than 0.01). Plasma thromboxane B2 decreased from 130 +/- 107 to 19 +/- 12 pg/ml (p less than 0.01). Inhibition was not selective because 6-keto-prostaglandin F1 alpha (a metabolite of prostacyclin) also decreased from 243 +/- 90 to 163 +/- 90 pg/ml (p = 0.039) and prostaglandin E2 was reduced from 155 +/- 67 to 95 +/- 40 pg/ml (p = 0.014). Decreases in thromboxane B2, however, were significantly greater (75% +/- 19%) than decreases in 6-keto-prostaglandin F1 alpha (21% +/- 33%) or prostaglandin E2 (29% +/- 36%); thus the 6-keto-prostaglandin F1 alpha/thromboxane B2 ratio increased from 3.1 +/- 2.0 to 12.4 +/- 9.9 (p less than 0.01). Although low-dose aspirin increases the effective pressor dose of angiotensin II, it does not return to normal pregnancy values. This observation is consistent with the hypothesis that this represents only a partial selective prostaglandin inhibition.

    Title Intrapartum Treatment of Acute Chorioamnionitis: Impact on Neonatal Sepsis.
    Date October 1988
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    In a study of 312 women with acute chorioamnionitis, 152 women received antibiotics before delivery, 90 received antibiotics after cord clamping, and 70 did not receive antibiotics. Antibiotics were administered during labor rather than after cord clamping if delivery was not imminent. Although endometritis developed more frequently in the patients receiving antibiotics after cord clamping, the difference was not statistically significant (5.6% versus 3.9%, difference not significant). There were two cases of verified sepsis in the group of infants (35 weeks) born to mothers receiving intrapartum antibiotics and there were eight cases in the no antibiotics group (p = 0.06). More importantly, in neonates greater than or equal to 35 weeks' gestational age, there was a significant difference in the frequency of positive blood cultures for group B streptococci (0/133 versus 8/140, p less than 0.05). We conclude that administration of antibiotics to the mother during labor may result in a decreased incidence of neonatal sepsis.

    Title The Regulation of Ovine Placental Steroid 17 Alpha-hydroxylase and Aromatase by Glucocorticoid.
    Date August 1988
    Journal Molecular Endocrinology (baltimore, Md.)
    Excerpt

    Parturition in the pregnant sheep is preceded by an abrupt alteration in placental steroid metabolism causing a shift from progesterone to estrogen production. This change is believed to be a consequence of the prepartum rise in cortisol in the fetal circulation and involves increases in activities of the enzymes steroid 17 alpha-hydroxylase (cytochrome P-450(17)alpha), steroid C-17,20-lyase, and possibly aromatase. We have investigated the activity levels of aromatase and 17 alpha-hydroxylase in placental microsomes in late pregnancy and dexamethasone-induced labor. Over the gestational period of 118-140 days basal levels of placental aromatase were relatively constant [mean value (+/- SD) of 5.6 +/- 1.6 pmol min-1 mg microsomal protein-1 (n = 10)]. Steroid 17 alpha-hydroxylase activity was undetectable [less than 0.5 pmol min-1 mg microsomal protein-1 (n = 7)]. In six animals in labor induced with infusion of dexamethasone into the fetus, placental aromatase activity had a mean value of 14.0 +/- 2.5 pmol min-1 mg protein-1; placental steroid 17 alpha-hydroxylase, measured in four of the animals, had a mean (+/- SD) activity of 319 +/- 58 pmol min-1 mg microsomal protein-1. Immunoblotting of placental microsomal preparations with specific antibodies to cytochrome P-450(17)alpha and NADPH-cytochrome P-450-reductase indicated that the glucocorticoid-induced activity of 17 alpha-hydroxylase was associated with increased content of cytochrome P-450(17)alpha. Northern blotting with a cDNA probe for cytochrome P-450(17)alpha showed that glucocorticoid increased the levels of mRNA for the enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Mechanisms for Attenuated Pressor Responses to Alpha-agonists in Ovine Pregnancy.
    Date August 1988
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    Attenuated pressor responses to angiotensin II and alpha-agonists normally occur during ovine pregnancy; however, for alpha-agonists it is not known to what extent this reflects alterations in cardiac output. We therefore compared peripheral and cardiac responses to alpha-agonists in pregnant (n = 6) and nonpregnant (n = 6) sheep, measuring mean arterial pressure, heart rate, and cardiac output before and during steady-state dose responses to norepinephrine (0.458 to 45.84 micrograms/min) and phenylephrine (1.29 to 129 micrograms/min). Both alpha-agonists caused dose-dependent increases in mean arterial pressure and systemic vascular resistance, more so in nonpregnant than pregnant sheep (p less than 0.01), and decreases in cardiac output and heart rate (p less than 0.01). In both nonpregnant and pregnant sheep the percent change in systemic vascular resistance generally exceeded the percent change in mean arterial pressure, reflecting decreases in cardiac output; however, at equivalent increases in percent change in mean arterial pressure and percent change in systemic vascular resistance, the fall in the percent change in cardiac output was greatest in pregnant sheep (p less than 0.05). Also, at similar increases in mean arterial pressure the percent change in heart rate was greatest in pregnant sheep (p less than 0.01). In contrast to angiotensin II, the attenuated pressor responses to alpha-agonists observed during ovine pregnancy are partly a result of reflex decreases in cardiac output mediated mainly through falls in heart rate.

    Title Preeclampsia: a Review of the Role of Prostaglandins.
    Date August 1988
    Journal Obstetrics and Gynecology
    Title Increased Fetal Secretion of Acth and Cortisol by Arginine Vasopressin.
    Date April 1988
    Journal The American Journal of Physiology
    Excerpt

    In the fetus, arginine vasopressin (AVP) has been considered a "stress" hormone with primarily cardiovascular effects. In adult animals, AVP also has substantial endocrine effects, e.g., acting as a corticotropin-releasing factor, an effect not clearly demonstrated in the fetus. Therefore we examined this action of AVP in fetal sheep [135 +/- 1 (SE) days gestation] during a 30-min vasopressin infusion (12 mU/min) while monitoring mean arterial pressure (MAP) and heart rate (HR). Blood samples were obtained before, 15 and 30 min during, and 30 and/or 60 min after the infusion. During vasopressin infusion (n = 11), MAP increased (P less than 0.01), whereas HR fell (P less than 0.01). Plasma AVP increased from 2.32 +/- 0.22 to 84 +/- 6.8 and 89 +/- 10 microU/ml (P less than 0.001), whereas adrenocorticotropin (ACTH) rose from 18.0 +/- 2.4 to 27.7 +/- 3.7 and 43.4 +/- 8.0 pg/ml (P less than 0.05) and cortisol from 1.81 +/- 0.36 to 3.48 +/- 0.56 and 3.97 +/- 0.57 micrograms/dl (P less than 0.005) at 15 and 30 min, respectively. Although neither basal nor AVP-induced ACTH increases changed over the period of gestation studied, base-line cortisol concentrations and the absolute rise in ACTH-stimulated cortisol release increased as gestation progressed, demonstrating increased adrenal sensitivity to ACTH. As in adults, AVP stimulates fetal pituitary secretion of ACTH, providing evidence for another role for AVP in fetal adaptation.

    Title An Analysis of Potential Biases in the Loss of Indigent Infants to Follow-up.
    Date April 1988
    Journal Early Human Development
    Excerpt

    Loss to follow-up is a major problem in indigent inner-city populations. We evaluated a large, well-described, inborn indigent population of high-risk infants (HRI) and control infants (CI) to assess possible selection biases in loss to follow-up at one year adjusted age. Serial clinic visits, phone calls, and letters and payment of $20.00 for attending at 1 year was used to minimize patient loss. Yet, the 1 year loss rate was high, and among HRI, greater for ventilator-treated infants greater than 1500 g birthweight (71/114; 62%) than for ventilator-treated very-low-birthweight (VLBW; less than 1500 g) infants (39/108; 36%) or non-ventilated VLBW infants (62/145; 43%) (P less than 0.05). Multivariate analyses indicated that those lost to follow-up were at no greater risk of a poor outcome on the basis of prenatal and perinatal medical and socioeconomic findings than were those in the same risk group (HRI or CI) or subgroup of HRI who were examined at 1 year. In a review of hospital records, similar rates of hospitalization and neurologic problems during infancy were identified for HRI examined and HRI lost to follow-up. The identification of such morbidity during infancy may be less complete for HRI lost to follow-up than for those examined. Thus, the high frequency of deficits observed in follow-up evaluation of indigent HRI is unlikely to result from loss of unaffected infants.

    Title Failure to Detect a Stimulatory Effect of Estradiol-17 Beta on Ovine Fetal Lung Maturation.
    Date November 1987
    Journal Pediatric Research
    Excerpt

    It has been reported that estradiol-17 beta (E2) stimulates rat and rabbit fetal lung maturation; however, E2 was not directly administered to the fetus in these experiments. Therefore, we used the chronically instrumented fetal sheep to study the effects of 14 days of continuous E2 infusion on fetal lung maturation. Animals were instrumented on days 104-106 of gestation, then infused with either saline or E2 (100 micrograms/day) from 111 to 127 days of gestation. Fetal plasma concentrations of E2, estrone, and cortisol, and tracheal fluid phosphatidylcholine:sphingomyelin ratios and phosphatidylcholine flux were measured daily in E2-infused (n = 8) and saline-infused (n = 6) control animals. At 127 days of gestation, fetuses were sacrificed and lung tissue samples obtained for biochemical and morphological analyses. Plasma E2 levels rose from 0.045 +/- 0.001 (mean +/- SE) to 7.45 +/- 5.31 ng/ml (p less than 0.05) in E2-infused animals whereas levels remained less than 0.06 ng/ml in saline-infused animals. Plasma estrone concentrations also were significantly elevated by E2 infusion. Plasma cortisol concentrations increased from 0.58 +/- 0.08 to 0.88 +/- 0.40 microgram/dl in E2-treated fetuses during the last week of infusion whereas values in control animals were unchanged. The ratio of acetone-precipitated phosphatidylcholine to sphingomyelin and the flux of acetone-precipitated phosphatidylcholine in tracheal fluid were not affected by E2 infusion. Fetal lung tissue phospholipid content was also unaffected by E2 infusion. Furthermore, there was no consistent effect of E2 infusion on the histological structure of the fetal lung tissue as determined by morphometric methods.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Ovine Placental Aromatase: Studies of Activity Levels, Kinetic Characteristics and Effects of Aromatase Inhibitors.
    Date October 1987
    Journal Journal of Steroid Biochemistry
    Excerpt

    We have measured microsomal steroid aromatase activity in the fetal component of ovine placental cotyledons collected from pregnant ewes between 124 days and 127 days of gestation. Aromatase activity was determined by quantifying the [3H]water by-product when [1 beta-3H(N)] androstenedione was used as substrate. The mean microsomal aromatase activity (+/- SD) was 5.7 +/- 2.2 pmol.min-1.mg protein-1 (n = 12) and was 9% of the aromatase activity of human placental microsomes [mean (+/- SD) of 66.1 +/- 25.0 pmol.min-1.mg protein-1 (n = 7)]. The apparent Km for ovine placental aromatase for androstenedione, at pH 7.4 and 37 degrees C, was 50 nM while the Vmax was 20.6 pmol.min-1.mg protein-1. The respective concentrations effecting 50% inhibition of ovine placental aromatase activity (the I50) for econazole, 4-hydroxyandrostenedione, imazalil, miconazole, ketoconazole and aminoglutethimide were 0.03, 0.05, 0.15, 0.50, 5.0 and 5.5 microM. The order of relative potencies were similar to those obtained for human placental aromatase. Ketoconazole and aminoglutethimide were approx 10 times more potent inhibitors of the sheep enzyme relative to the human. Aromatase activity was not confined to the microsomal fraction of ovine placental tissue but was distributed throughout all the particulate subcellular fractions. The proportionally high activity of the tissue homogenate (1.75 pmol.min-1.mg protein-1) is suggestive that in the last third of pregnancy, aromatase is not rate limiting with regard to placental estrogen production. It would appear, therefore, that the major factor regulating placental estrogen synthesis in ovine pregnancy is the availability of substrate.

    Title Ontogeny of Adrenal Steroid Hydroxylases: Evidence for Camp-independent Gene Expression.
    Date June 1987
    Journal Molecular and Cellular Endocrinology
    Excerpt

    Total RNA from normal and anencephalic human fetal adrenals was examined by blot analysis for transcripts encoding P-450scc, P-450(11) beta, P-450(17) alpha, P-450C21 and adrenodoxin using bovine cDNA clones specific for these different enzymes. The specific contents of RNA encoding these components of the adrenocortical steroidogenic pathway were found to be similar in both types of adrenal tissue. Likewise, immunoblot analysis showed comparable concentrations of P-450scc, P450(17) alpha and adrenodoxin protein to be present in adrenal tissues from normal and anencephalic human fetuses. Immunoblot analysis of homogenates of fetal sheep adrenals of increasing gestational age (85-145 days) showed constant levels of P-450scc and P-450(11) beta, but increasing P-450(17) alpha content, especially near term. Both sheep fetuses prior to 136 days gestational age and human anencephalic fetuses are known to have extremely low circulating levels of immunoreactive ACTH as well as very low adrenal adenylate cyclase activity. Thus, it is concluded that factors other than pituitary ACTH which operate independent of adenylate cyclase activation are required for the initial expression (imprinting) of steroid hydroxylase genes.

    Title Ontogeny of Unconjugated Estriol in Fetal Blood and the Relation of Estriol Levels at Birth to the Development of Respiratory Distress Syndrome.
    Date June 1987
    Journal Pediatric Research
    Excerpt

    Unconjugated estriol (E3) was quantified in serum of umbilical cord blood of 533 newborn infants, 360 of whom were delivered between 23 and 37 wk of gestation. Serum E3 levels rose (F = 7.71, p less than 0.0001) as a function of gestational age; the mean concentration of E3 at 37.5-42 wk of gestation (105 ng/ml, n = 173) was significantly higher than that in serum of newborns delivered at 23-28 wk of gestation (63 ng/ml, n = 33). Umbilical cord serum levels of E3 were significantly higher among newborns delivered vaginally between 31.5 and 42 wk of gestation than among newborns delivered by cesarean section (p less than 0.005). Although serum E3 levels correlated highly (p less than 0.0001) to newborn weight throughout the entire period of gestation, there was no relationship of newborn weight to umbilical serum E3 levels within a given gestational period. Also, the umbilical serum levels of E3 in male infants were similar to those of female infants at each gestational age. Significant changes in umbilical serum levels of E3 as a function of gestational age were not observed among newborns (n = 90) who developed respiratory distress syndrome (RDS). The mean umbilical serum concentration of E3 in newborns delivered at 34.5-37 wk of gestation who developed RDS were significantly lower (p less than 0.01) than that in similar aged newborns whose lung function was normal.(ABSTRACT TRUNCATED AT 250 WORDS)

    Title Vasopressin and Catecholamine Secretion During Metabolic Acidemia in the Ovine Fetus.
    Date February 1987
    Journal Pediatric Research
    Excerpt

    It has been suggested that the substantial rise in fetal plasma arginine vasopressin (AVP) during intrauterine hypoxia/asphyxia reflects decreases in PaO2 and/or pHa; however, the components of these "stresses," i.e. PO2, PCO2, and pH, have not been controlled. Recently, only modest increases in fetal AVP secretion were seen during hypoxia independent of changes in pH and PCO2. Since the independent effects of metabolic acidosis on fetal AVP secretion are unknown, we induced acute metabolic acidemia in fetal sheep at 137 +/- 4 (mean +/- SD) days gestation with 1 M NH4Cl, while monitoring mean arterial pressure, heart rate, PaO2, PaCO2, pHa, plasma osmolality, and blood concentrations of electrolytes, AVP, dopamine, norepinephrine, and epinephrine. Mean arterial pressure, PaO2, PaCO2, and plasma osmolality and sodium were unchanged; pHa decreased from 7.37 +/- 0.01 to 7.04 +/- 0.05 (p less than 0.05) during NH4Cl and did not return to control levels until 24 h later. AVP increased from 2.85 +/- 0.23 to 5.26 +/- 1.11 microU/ml (p less than 0.05) at the time of maximum acidosis, correlating with the fall in pHa (r = -0.67, (p = 0.001); however, after stopping NH4Cl, AVP returned to baseline levels although pHa remained less than 7.15. In control studies using the same osmolar load, volume, and rate of infusion, AVP levels were unchanged. Only epinephrine was significantly (p less than 0.05) elevated during acidosis, but did not correlate with pHa or plasma AVP. Marked metabolic acidemia appears to have little or no effect on fetal AVP secretion, and fetal catecholamine secretion is variable.

    Title Fetal Pulmonary Development and Abnormalities of Amniotic Fluid Volume.
    Date February 1987
    Journal Seminars in Perinatology
    Title Disappointing Follow-up Findings for Indigent High-risk Newborns.
    Date January 1987
    Journal American Journal of Diseases of Children (1960)
    Excerpt

    Indigent populations have received little attention in neonatal follow-up studies. We conducted "blinded" evaluations one year past term for 204 indigent high-risk infants who were ventilator treated or had a very low birth weight (VLBW) (less than or equal to 1500 g) and 85 healthy term controls from families similar to those of the high-risk infants. Marked developmental delay (Bayley Mental Developmental Index, less than 70) or gross motor abnormality occurred in 2% of controls, 27% of VLBW infants, 33% of ventilator-treated infants, and 39% of ventilator-treated VLBW infants. Despite considerable effort to prevent attrition, 43% of high-risk survivors were unavailable for follow-up at the one-year visit. Even if all of these infants were assumed to be normal, the incidence of developmental delay exceeded that in 11 of 12 recent studies. Indigent high-risk infants deserve considerable follow-up attention because of their high rate of attrition and developmental delay.

    Title Systemic and Uterine Responses to Alpha-adrenergic Stimulation in Pregnant and Nonpregnant Ewes.
    Date November 1986
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    Attenuated systemic pressor responses to infused angiotensin II characterize normal human and ovine pregnancy; moreover, uterine vascular refractoriness is greater than that of the systemic vasculature overall. It remains unclear whether this generalized refractoriness also pertains to other vasoconstrictors; therefore we studied simultaneous systemic and uterine responses to alpha-agonists in pregnant (n = 6) and nonpregnant (n = 6) sheep. Mean arterial pressure, heart rate, uterine blood flow, and cardiac output were measured before and during infusions of norepinephrine (0.456 to 45.84 micrograms/min) and phenylephrine (1.29 to 129 micrograms/min). Both alpha-agonists caused dose-dependent increases (p less than 0.01) in mean arterial pressure and systemic vascular resistance and decreases in cardiac output (p less than 0.01) in nonpregnant and pregnant animals; however, nonpregnant pressor responses exceeded pregnant ones. Nonpregnant ewes also had greater decreases in uterine blood flow (p less than 0.05) and increases in uterine vascular resistance (p less than 0.05); furthermore, increases in uterine vascular resistance exceeded those of systemic vascular resistance in both groups (p less than 0.01). Attenuated uterine and systemic responses to alpha-agonists characterize normal ovine pregnancy; however, in contrast to the results with angiotensin II, the uterine vascular bed is substantially more responsive to alpha-agonists than the systemic vasculature overall.

    Title A Prospective Comparison of Selective and Universal Electronic Fetal Monitoring in 34,995 Pregnancies.
    Date September 1986
    Journal The New England Journal of Medicine
    Excerpt

    We investigated the effects of using intrapartum electronic fetal monitoring in all pregnancies, as compared with using it only in cases in which the fetus is judged to be at high risk. Predominant risk factors included oxytocin stimulation of labor, dysfunctional labor, abnormal fetal heart rate, or meconium-stained amniotic fluid. This prospective alternate-month clinical trial took place over a 36-month period during which 34,995 women gave birth. In alternate months, either 7 (for "selective monitoring") or 19 (for "universal monitoring") fetal monitors were made available in the labor and delivery unit. During the "selective" months, 6420 of 17,409 women (37 percent) were electronically monitored, as compared with 13,956 of 17,586 women (79 percent) during the "universal months." Universal monitoring was associated with a small but significant increase in the incidence of delivery by cesarean section because of fetal distress, but perinatal outcomes as assessed by intrapartum stillbirths, low Apgar scores, a need for assisted ventilation of the newborn, admission to the intensive care nursery, or neonatal seizures were not significantly different. We conclude that not all pregnancies, and particularly not those considered at low risk of perinatal complications, need continuous electronic fetal monitoring during labor.

    Title Brainstem Auditory Evoked Potentials in Very-low-birth-weight Neonates with Intracranial Hemorrhage.
    Date September 1986
    Journal Early Human Development
    Excerpt

    A study was conducted in very-low-birth-weight (VLBW) neonates to correlate structural damage to the central nervous system due to intracranial hemorrhage (ICH) with electrophysiological function of the lower auditory system as measured by brainstem auditory evoked potentials (BAEP). BAEP testing of 61 VLBW neonates was completed at 36 weeks conceptional age. BAEP Wave III and V latencies significantly increased with increasing severity of ICH. Although significant at conventional levels (P less than 0.05), these correlations were of modest size. Furthermore, after adjusting for the effects of birthweight, hypoxia, lowest pH and associated pCO2 the correlation between ICH and BAEP was reduced in magnitude and no longer significant. Thus, there is little evidence that ICH shortly after birth affected functioning of the auditory brainstem pathways in VLBW neonates at 36 weeks conceptional age.

    Title Urinary Arginine Vasopressin: Pattern of Excretion in the Neonatal Period.
    Date March 1986
    Journal Pediatric Research
    Excerpt

    The pattern of arginine vasopressin (AVP) secretion in the immediate neonatal period is unclear. Plasma concentrations of AVP are reflected by its urinary excretion, thus providing a noninvasive method for studying the pattern of AVP release in the neonate. In these studies, we determined the pattern of urinary AVP excretion (microU/mg creatinine) during the first 2-4 days after birth in 78 neonates, 53 of whom had various prenatal and/or neonatal complications. In well term (n = 12) and preterm (n = 13) infants mean urinary AVP excretion decreased gradually during the first 24-36 h after birth. Although term and preterm infants with perinatal asphyxia had highest initial levels of urinary AVP (greater than 200 microU/mg creatinine) and a significant negative correlation with the 1-min Apgar score was obtained, their pattern of excretion was similar to respective controls. After delivery, elevated values for urinary AVP excretion were found among infants with neonatal courses complicated by intracranial hemorrhage, hypoxic encephalopathy, and pneumothorax. Urine osmolality did not correlate linearly with urinary AVP levels, but rather attained a maximum value of approximately 400 mosmol/kg at urinary AVP levels less than 200 microU/mg creatinine and then plateaued. It is concluded that the decrease in urinary AVP excretion observed soon after birth generally reflects diminution of the hypersecretion of AVP during parturition; neonates with evidence of intrapartum asphyxia initially have increased urinary AVP excretion; however, the pattern of excretion is similar to normal infants. During the neonatal period insults such as pneumothorax and intracranial hemorrhage may cause hypersecretion of this hormone.

    Title The Relationship Between Abortion in the First Pregnancy and Development of Pregnancy-induced Hypertension in the Subsequent Pregnancy.
    Date February 1986
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    The relation between pregnancy-induced hypertension and reproductive history was assessed in 29,484 women receiving obstetric care at Parkland Memorial Hospital. The incidence of pregnancy-induced hypertension was 25.4% in primigravid women, somewhat lower (22.3%) in women whose only previous pregnancy terminated in abortion, and much lower (10%) in women who carried two or more successive pregnancies to viability.

    Title Fetal Responses to Maternal Infusions of Angiotensin Ii.
    Date February 1986
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    It is unclear whether the fetus is affected by maternal infusions of angiotensin II; therefore we studied maternal and fetal responses (n = 9) to angiotensin II (1.15, 2.29, 11.5 micrograms/min) infused 5 minutes into the vena cava of chronically instrumented sheep (129 to 137 days of gestation) while monitoring PO2, PCO2, pH, heart rate, uterine blood flow, and arterial and umbilical venous pressures. Pregnant sheep demonstrated expected dose-related increases in mean arterial pressure and decreases in uterine blood flow (p less than 0.05). Increases in fetal mean arterial pressure also correlated with the maternal dose of angiotensin II (r = 0.77, p less than 0.001). Fetal heart rate appeared to increase with 2.29 micrograms/min; however, bradycardia was observed with 11.5 micrograms/min (p less than 0.05) and was associated with decreased PaO2, 19.0 +/- 1.0 to 14.3 +/- 1.4 mm Hg (p less than 0.05), increased PaO2 (p less than 0.05), and decreased umbilical venous PO2, 31.4 +/- 2.3 to 27.0 +/- 1.9 mm Hg. The decreases in PO2 correlated with decreases in uterine blood flow (r = 0.60, p less than 0.002, and r = 0.75, p less than 0.005, respectively). Nevertheless, changes in fetal mean arterial pressure also occurred in the absence of altered fetal oxygenation; thus decreased uterine blood flow and fetal oxygenation alone cannot explain the fetal cardiovascular responses. It is suggested that angiotensin II or an active metabolite may cross the ovine placenta.

    Title In Vitro Prostacyclin Production by Ovine Uterine and Systemic Arteries. Effects of Angiotensin Ii.
    Date February 1986
    Journal The Journal of Clinical Investigation
    Excerpt

    Normal pregnancy is associated with reduced systemic pressor responses to infused angiotensin II (ANG II); furthermore, the uterine vascular bed is even less responsive to vasoconstriction by ANG II than the systemic vasculature overall. The mechanism(s) for this refractoriness remains unknown. To determine if vessel production of prostacyclin may be responsible, uterine and omental artery segments were obtained from four groups of sheep, nonpregnant (NP), pregnant (P; 131 +/- 4 d), early postpartum (2.2 +/- 0.4 d), and late postpartum (16 +/- 2 d), and incubated in Krebs-Henseleit alone or with ANG II in the absence or presence of Saralasin. Prostacyclin was measured as 6-keto-prostaglandin F1 alpha (6-keto-PGF1 alpha). Synthesis of 6-keto-PGF1 alpha was de novo, since aspirin inhibited its formation. P and early uterine arteries produced more 6-keto-PGF1 alpha than NP and late vessels (P less than 0.05): 386 +/- 60 (X +/- SE) and 175 +/- 23 vs. 32 +/- 5 and 18 +/- 4 pg/mg X h, respectively. A similar relationship was observed for omental arteries: 101 +/- 14 and 74 +/- 14 vs. 36 +/- 10 and 22 +/- 4 pg/mg X h, respectively. Furthermore, synthesis by arteries from P and early animals was greater in uterine than omental vessels (P less than 0.05); this was not observed in NP or late vessels. ANG II increased 6-keto-PGF1 alpha production 107 +/- 20% and 92 +/- 16% in P and early uterine arteries only; the threshold dose was between 5 X 10(-11) and 5 X 10(-9) M ANG II. This ANG II-induced increase in 6-keto-PGF1 alpha by uterine arteries was inhibited by Saralasin, which by itself had no effect. During pregnancy, the reduced systemic pressor response to ANG II and the even greater refractoriness of the uterine vascular bed may be reflective of vessel production of the potent vasodilator, prostacyclin. Furthermore, in the uterine vasculature, this antagonism may be potentiated by specific ANG II receptor-mediated increases in prostacyclin.

    Title Incidence and Risk Factors for Symptomatic Patent Ductus Arteriosus Among Inborn Very-low-birth-weight Infants.
    Date January 1986
    Journal Early Human Development
    Excerpt

    The incidence of symptomatic patent ductus arteriosus (sPDA) in very-low-birth-weight infants has been reported almost exclusively from referral centers. Moreover, the incidence has varied considerably. We prospectively evaluated the incidence and risk factors of sPDA in a totally inborn population of infants less than or equal to 1500 g birth weight (n = 120) receiving conservative fluid management and examined the role of echocardiography in predicting sPDA before clinical signs are evident. The incidence of sPDA was relatively low (16%) and the age at onset was relatively late (mean +/- S.E. = 14.7 +/- 3.0 days) when compared to prior reports. Echocardiographic changes preceded physical and radiographic findings of sPDA. Fluid volume within the range administered to our infants was unrelated to the occurrence of sPDA. However, risk factors identifiable within 24 h of birth were defined: obstetric estimate of gestational age, race, mean fluid volume intake in the initial 24 h, and early treatment with volume expanders. From these risk factors, 79% of infants with sPDA and 79% without sPDA could be predicted by stepwise discriminant function analyses. These findings may be employed in studies needed to assess the benefit of early surgical or pharmacologic therapy for infants at highest risk for sPDA.

    Title Systemic and Uterine Responsiveness to Angiotensin Ii and Norepinephrine in Estrogen-treated Nonpregnant Sheep.
    Date November 1985
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    Pregnancy is associated with uterine and systemic vasodilation and reduced vascular reactivity to angiotensin II and perhaps norepinephrine. The uteroplacental vasculature is relatively refractory to angiotensin II but very sensitive to norepinephrine. To investigate the possible role of the high levels of estrogen in pregnancy mediating these hemodynamic changes, we examined systemic and uterine vascular responsiveness to angiotensin II and norepinephrine in eight chronically instrumented nonpregnant sheep treated with 17 beta-estradiol. In these animals, 17 beta-estradiol produced significant systemic and uterine vasodilation without changing arterial pressure; cardiac output increased from 5.3 +/- 0.3 to 6.7 +/- 0.4 L/min, and uterine blood flow increased from 26 +/- 3 to 218 +/- 13 ml/min (mean +/- SE). Treatment with 17 beta-estradiol reduced the increases in systemic vascular resistance produced by angiotensin II and norepinephrine by 25% and 35%, respectively. After 17 beta-estradiol treatment, the uterine vascular responses were compared to the systemic vascular responses; the uterine responses to angiotensin II were only half the systemic responses, whereas the uterine responses to norepinephrine were six times greater than the systemic responses and were associated with decreases in uterine blood flow of 35% to 40%. These hemodynamic features of nonpregnant sheep treated with estrogen are strikingly similar to previous observations in sheep during pregnancy.

    Title Isolation and Propagation of a Human Enteric Coronavirus.
    Date September 1985
    Journal Science (new York, N.y.)
    Excerpt

    Coronavirus-like particles were found by electron microscopy in stools from infants with necrotizing enterocolitis. Stool samples from these infants as well as control specimens were passaged in cultures of human fetal intestinal organs. Two samples yielded virus-like particles and these have now been passaged 14 times (HEC 14). Gradient-purified HEC 14 strains had typical coronavirus morphology on electron microscopy and contained five major proteins with molecular sizes ranging from 190 to 23 kilodaltons. Infants with necrotizing enterocolitis developed specific antibody to the viral antigens between the acute and convalescent stages of the disease, as shown by examining serum specimens by single radial hemolysis, immunoenzymatic assay, and Western immunoblotting. No cross-reactivity was shown with other coronavirus strains tested, or with the newly isolated viruses of the Breda-Berne group, responsible for calf or horse diarrhea.

    Title Cerebral Vascular Responses to Tolazoline Infusions in the Piglet.
    Date August 1985
    Journal Early Human Development
    Excerpt

    Ventilated piglets were studied to determine the effects of intravenous tolazoline infusions during hypoxia on the cerebral circulation and to assess whether cerebral responses reflect tolazoline-induced alterations in the systemic vasculature. We measured cerebral blood flow (CBF), cardiac output (CO), mean arterial pressure (MAP) and cerebral arteriovenous differences of O2 content during normoxia, isocapnic hypoxia (FiO2 14%), and hypoxia (FiO2 14%) with infusions of either saline (n = 7) or tolazoline (n = 10). Hypoxia alone resulted in comparable cardiovascular alterations in both groups. During hypoxia + saline MAP remained stable, but decreased during hypoxia + tolazoline, reflecting reductions in systemic vascular resistance (SVR) and variable changes in CO (reductions in 4 piglets, increases in 6). In both groups CBF rose during hypoxia alone and remained elevated during hypoxia with saline or tolazoline. Cerebral O2 delivery, extraction and uptake were unchanged in both groups. Although mean CBF was similar during hypoxia with saline or tolazoline, CBF was variable during tolazoline, decreasing in 4 of 10 piglets; CBF never fell with saline. Tolazoline-induced changes in MAP correlated with CBF (r = 0.90, P less than 0.001) emphasizing the importance of MAP in maintaining CBF during hypoxia. Importantly, decreases in CBF also paralleled falls in CO. In the presence of a pressure-passive cerebral vasculature, the adequacy of increases in CO to offset tolazoline-induced reductions in SVR determines MAP and ultimately CBF. Thus, cerebral vascular responses to tolazoline infusions during hypoxia reflect tolazoline-induced systemic circulatory derangements.

    Title Metabolic Clearance of Angiotensin Ii in Pregnant and Nonpregnant Sheep.
    Date August 1985
    Journal The American Journal of Physiology
    Excerpt

    Reduced vascular responsiveness to infused angiotensin II (ANG II) has been observed during pregnancy. It has been proposed that infusions produce lower circulating concentrations of ANG II in pregnancy, due to an increase in the metabolic clearance rate of ANG II (MCRangii). We have evaluated the MCRangii and the arterial plasma concentrations of ANG II during constant infusions of 1.15 micrograms ANG II/min into chronically instrumented pregnant (n = 6) and nonpregnant (n = 9) sheep. Although the pressor responses were significantly less in the pregnant than in the nonpregnant sheep (17.5 +/- 0.5 vs. 34.9 +/- 3.2 mmHg, P less than 0.001), the values for MCRangii were not different: 56.2 +/- 6.3 ml X min-1 X kg-1 in nonpregnant and 55.9 +/- 4.3 ml X min-1 X kg-1 in pregnant sheep. The steady-state plasma ANG II concentrations during the infusions were slightly less in pregnant than in nonpregnant sheep (388 +/- 36 vs. 454 +/- 36 pg/ml); however, this difference would be responsible for only a 2-mmHg reduction in the pressor response. We conclude that the reduced pressor response to infused ANG II in pregnancy is not due to an increase in MCRangii nor to lower plasma ANG II concentrations.

    Title Neonatal Blood Cell Count in Health and Disease. Ii. Values for Lymphocytes, Monocytes, and Eosinophils.
    Date April 1985
    Journal The Journal of Pediatrics
    Excerpt

    The distribution of normal cell counts (the reference range) has been determined previously for circulating neutrophils in infants from birth to 28 days of age. We have determined the reference ranges for the absolute peripheral blood lymphocyte, monocyte, and eosinophil counts obtained from 393 infants in this same cohort. Furthermore, white blood cell counts were obtained from three groups of infants with perinatal complications previously shown to be associated with abnormal neutrophil values (ABO incompatibility, n = 82; maternal hypertension, n = 68; neonatal sepsis, n = 140) and compared with the derived reference ranges; significant alterations in the distribution of cell counts were found in each of these groups at different times. Our data provide reference ranges for lymphocyte, monocyte, and eosinophil counts in the neonatal period and evidence of the effect of specific perinatal events on these cell counts.

    Title Role of Alpha-receptors in Estrogen-induced Vasodilation in Nonpregnant Sheep.
    Date April 1985
    Journal The American Journal of Physiology
    Excerpt

    Estradiol-17 beta (E2) produces vasodilation in several systemic vascular beds, but most extensively in the nonpregnant uterus. It has been postulated that E2 induces this vasodilation via blockade of vascular alpha-adrenergic receptors. This hypothesis was tested in six chronically instrumented, nonpregnant sheep by comparing the systemic and uterine hemodynamic responses to intravenous E2, to an alpha-adrenergic receptor blocker, phentolamine, and to both agents given together. Uterine blood flow (UBF) increased significantly after E2 administration, from 20 +/- 7 to 233 +/- 37 (SE) ml/min. In contrast, phentolamine had no detectable effect on UBF or on the UBF response to E2 when both were given together. Similar contrasting responses were observed in the effects of E2 and/or phentolamine on the systemic vasculature. When responses to alpha-agonists were evaluated, there was no evidence of alpha-blockade following E2 despite the substantial vasodilation; in contrast, alpha-blockade was present during phentolamine administration when no vasodilation was noted. Therefore, we conclude that E2-induced vasodilation in chronically instrumented sheep is not mediated through blockade of vascular alpha-adrenergic receptors.

    Title Hemodynamic Effects of Indomethacin in Chronically Instrumented Pregnant Sheep.
    Date March 1985
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    Indomethacin administration has produced decreases in uteroplacental blood flow in several animal studies; therefore, it has been suggested that the maintenance of uterine blood flow is critically dependent on the continued synthesis of vasodilating prostaglandins. However, vasoconstriction following indomethacin administration may be due to mechanisms other than reduced prostaglandin synthesis. We administered indomethacin (2, 5, or 10 mg/kg) intravenously to seven unanesthetized sheep in late pregnancy and determined the time courses of the uteroplacental and systemic hemodynamic responses, comparing these to the concurrent changes in circulating prostaglandins. Indomethacin administration resulted in rapid increases in systemic and uteroplacental vascular resistance (80% to 100%) and mean arterial pressure (approximately 30%) and in decreases in systemic (approximately 30%) and uteroplacental (0% to 30%) blood flows within 5 minutes. Vasoconstriction was transient, however, and after 60 minutes there was no evidence of uterine or systemic vasoconstriction, although systemic and uterine plasma prostaglandin levels remained reduced for 180 minutes. Thus substantial inhibition of prostaglandin synthesis existed without evidence of concurrent systemic or uteroplacental vasoconstriction, suggesting that uterine blood flow is not directly dependent on maintained prostaglandin synthesis in unstressed pregnant sheep. Furthermore, the transient indomethacin-induced vasoconstriction may not be due to inhibition of prostaglandin synthesis.

    Title Neutropenia in High-risk Neonates.
    Date January 1985
    Journal The Journal of Pediatrics
    Excerpt

    To determine the usefulness of neutrophil values in diagnosing neonatal sepsis among infants at risk of neutropenia, we evaluated the pattern of sequential absolute total and immature neutrophil counts and the immature to total neutrophil (I:T) proportion over the first 5 days of life in infants with sepsis (n = 13), asphyxia neonatorum (n = 12), or delivered of mothers with pregnancy-induced hypertension (PIH) (n = 20), comparing values to references ranges previously reported by us. Neutropenia was initially present in 67% and 50% of infants with asphyxia and those whose mothers had PIH, respectively, and persisted through the first 3 postnatal days. In contrast, infants with sepsis were less likely to be neutropenic initially (38%), and neutropenia did not persist after 36 hours of age. Elevated values for the total immature neutrophil count and I:T proportion were much more likely to occur in infants with sepsis (46% and 61%, respectively) than in infants of mothers with PIH (4% and 12%) or those with asphyxia (13% and 22%). The importance of considering the perinatal history as well as the differential neutrophil count in the evaluation of neonatal neutropenia is demonstrated.

    Title Chloral Hydrate Toxicity in a Preterm Infant.
    Date December 1984
    Journal Pediatric Pharmacology (new York, N.y.)
    Excerpt

    Ventilator care in premature infants with hyaline membrane disease (HMD) may be complicated by episodes of irritability and "fighting" the respirator, resulting in significant hypoxemia. Neuromuscular blockade with pharmacologic agents such as pancuronium bromide is frequently used to manage this problem [Crone and Favorito, 1980]. This therapy results in the loss of important clinical signs, such as alterations in muscle tone and spontaneous movements, which are important in monitoring the critically ill newborn. As a result of these considerations, we occasionally have utilized the sedative-hypnotic effects of chloral hydrate to achieve adequate ventilation and oxygenation in these infants. We report, however, a case of a preterm infant who developed severe chloral hydrate toxicity after its administration as an adjunct to the treatment of HMD.

    Title Brain Blood Flow.
    Date August 1984
    Journal Pediatrics
    Title Vasopressin: Mediator of the Clinical Signs of Fetal Distress.
    Date June 1984
    Journal British Journal of Obstetrics and Gynaecology
    Title Maternal-infant Interactions at One-year Adjusted Age in Infants at Low- and High-risk As Newborns.
    Date May 1984
    Journal Early Human Development
    Excerpt

    To compare maternal-infant interactions in high- and low-risk groups, we observed infants who had required neonatal intensive care and otherwise similar infants with normal perinatal histories in a follow-up clinic at one year adjusted age. The developmental level as assessed by the Bayley Scales of Infant Development was significantly lower for the high-risk infants than for the control infants at one year of age. Principal component analyses were used to define interaction patterns in each of five situations. Principal component analyses allow a more meaningful analysis of interrelated maternal and infant behaviors than do standard statistical analyses and minimize the likelihood of misleading 'significant' findings resulting from multiple comparisons. Prior to being examined, mothers of control infants were more likely to adopt an 'en face' position, play with, comfort, talk to, and smile at their infants than were mothers of high-risk infants. Control infants were more likely to smile in return. These differences between control and high-risk mother-infant dyads disappeared when the infants' developmental level was statistically controlled. Group differences in maternal-infant interactions independent of the infants' developmental level were observed in only one situation (collection of blood). Specific medical risk factors had little relation to findings at one year. Maternal-infant interaction should be interpreted in relation to the postconceptional and developmental age as well as the postnatal age of the infant.

    Title Consideration of the Uteroplacental Circulation in Intrauterine Growth.
    Date May 1984
    Journal Seminars in Perinatology
    Title Estrogen-induced Refractoriness to the Pressor Effects of Infused Angiotensin Ii.
    Date March 1984
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    Estrogen may be important in the hemodynamic changes that develop during pregnancy; its role in the development of vascular refractoriness to the pressor effects of infused angiotensin II is unknown. We, therefore, examined the pressor responses to six doses of angiotensin II (0.115 to 5.73 micrograms/min) in unanesthetized, nonpregnant sheep both before and after treatment with either high-dose or low-dose 17 beta-estradiol (E2) and constructed dose-response curves. Although mean arterial pressure was unchanged after the infusion of E2, cardiac output rose 28% and systemic vascular resistance fell 19% (p less than 0.001). Infused angiotensin II resulted in dose-dependent rises in mean arterial pressure before and after E2; however, the pressor response after E2 was decreased 30% to 50%. Plasma renin activity rose from 1.15 +/- 0.09 ng/ml X hr to 2.57 +/- 0.39 and 3.21 +/- 0.61 ng/ml X hr with low-dose and high-dose E2, respectively (p less than 0.05). Acutely estrogenized nonpregnant sheep develop significant alterations in both the cardiovascular and the renin-angiotensin systems in addition to decreased pressor responsiveness to infused angiotensin II. Although our findings suggest that estrogen may be important in the development of the vascular refractoriness to angiotensin II seen in pregnancy, additional studies are needed to clarify the role of each E2-induced change.

    Title The Pressor Response to Angiotensin Ii: the Roles of Peripheral and Cardiac Responses in Pregnant and Nonpregnant Sheep.
    Date March 1984
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    A reduced pressor response to infused angiotensin II has been observed in pregnancy. Although this has been considered to reflect reduced sensitivity of the peripheral vasculature to angiotensin II, it has also been suggested that the reduced pressor response is due to a fall in cardiac output during infusion of angiotensin II in pregnancy. In the present study we investigated the hemodynamic responses to infused angiotensin II in chronically instrumented, pregnant and nonpregnant sheep. We measured changes in cardiac output and systemic vascular resistance and related these changes to the increase in mean arterial pressure. The response in systemic vascular resistance to angiotensin II was substantially reduced in pregnant sheep. During angiotensin II infusion cardiac output fell in both groups, but the effect of the fall in cardiac output in reducing the pressor response was greater in nonpregnant animals. Thus, it appears that the reduced pressor response to angiotensin II in pregnant sheep is due to reduced systemic vascular responsiveness and not to differences in cardiac output responses.

    Title Differences on Bayley's Infant Behavior Record for a Sample of High-risk Infants and Their Controls.
    Date December 1983
    Journal Child Development
    Excerpt

    3 groups of high-risk newborns and their controls were assessed at 92 weeks post-conceptional age using Bayley's Infant Behavioral Record (IBR). The 3 groups of high-risk infants were those who weighed 1,500 grams or less at birth and required no ventilator therapy, those weighing 1,500 grams or less at birth who required ventilator therapy, and newborns weighing more than 1,500 grams at birth who required ventilator therapy. Controls were healthy term infants matched for 7 socioeconomic and demographic variables. The first principal component of the IBR ratings for the 3 groups of high-risk infants and the controls were similar. All 3 groups of high-risk infants received less desirable IBR ratings on most items than their controls. In addition, there were some differences among high-risk groups; ventilated infants regardless of birth weight received the lowest ratings reflecting overall performance on the IBR, very low birthweight, ventilated newborns were more likely to receive ratings characterizing an overly active infant with a short attention span, and very low birth-weight, never-ventilated infants were most likely to be rated as happy but passive and delayed. The differences between the high-risk infants and controls in large part resulted from infants who were also delayed in terms of their mental and motor development.

    Title Effect of Hypertonic Saline on Vascular Responses to Angiotensin Ii in Pregnancy.
    Date November 1983
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    Refractoriness to infused angiotensin II is characteristic or normal human and ovine pregnancy; the mechanisms responsible are unclear. In this study, we sought to ascertain in gravid sheep whether hypertonic saline solution alters the vascular responses to angiotensin II, as in gravid women, and to compare the responses of the systemic and uteroplacental vasculature. Dose-response curves were determined. Mean arterial pressure and systemic vascular resistance increased in a dose-dependent fashion before and after hypertonic saline solution; responses were greater after hypertonic saline solution (p less than 0.01). Responses of cardiac output, heart rate, uterine vascular resistance, and uterine blood flow also were dose-dependent, but were unchanged after hypertonic saline solution. Plasma renin activity fell 45% after hypertonic saline solution. Treatment with hypertonic saline solution results in increased pressor responses to angiotensin II that are not a reflection of altered baroreceptor or chemoreceptor reflexes or of the response in the uteroplacental vascular bed. Rather, the increased systemic vascular responsiveness to angiotensin II after hypertonic saline solution appears to be a reflection of other mechanisms, such as alterations in vessel wall dynamics or receptor affinity.

    Title Perioperative Antimicrobials for Cesarean Delivery: Before or After Cord Clamping?
    Date August 1983
    Journal Obstetrics and Gynecology
    Excerpt

    To determine neonatal risk of exposure to intrapartum antimicrobials given to reduce maternal infection following cesarean delivery, 642 mother-infant pairs were evaluated. In 464, the mother was given an initial dose of antimicrobial(s) before cord clamping, whereas in the remaining 178 administration of these drugs was not begun until after delivery. Despite the facts that all infants were at equivalent risk for infection and that none were proved to have bacteremia, 28% of those exposed to intrapartum maternal antimicrobials were evaluated for sepsis whereas only 15% of those not exposed were evaluated (P less than .001). Excess hospital charges for infants in whom sepsis workup was initiated was $127 greater than that for infants not suspected of having sepsis (P less than .025). Of 305 women given three-dose perioperative antimicrobial therapy, 255 were given the initial dose before cord clamping and 24% experienced a subsequent uterine infection. This was not significant when compared with a uterine infection rate of 22% in 50 women in whom three-dose therapy was not initiated until after cord clamping. As maternal benefits that accrue from such intrapartum therapy are equivalent regardless of the timing of three-dose treatment, and as fetal exposure to these drugs has significant clinical and economic impacts, it is concluded that antimicrobials given to these women at high risk should be withheld until after cord clamping.

    Title Cardiovascular Effects and Clearance of Arginine Vasopressin in the Fetal Lamb.
    Date August 1983
    Journal The American Journal of Physiology
    Excerpt

    Increased fetal secretion of arginine vasopressin (AVP) occurs in association with complicated pregnancies, asphyxia, and meconium-stained amniotic fluid (AF); yet, the role of AVP in fetal homeostasis remains unclear. Using chronically instrumented, near-term lamb fetuses (n = 8), we have ascertained the cardiovascular responses to doses of AVP ranging from 1.94 to 8.73 mU/min, the clearance of AVP from plasma, and the occurrence of meconium release into AF during AVP infusions. AVP administration resulted in a dose-related rise in arterial pressure; although heart rate fell, the decline was not dose-related and occurred before the pressor response. Clearance of plasma AVP was 60 +/- 8.7 ml X kg-1 X min-1, and the half-time in plasma was 2.8 min. AVP was not cleared across the fetal placenta nor by fetal-maternal transport. However, the AF concentration of AVP rose fourfold after the infusion of AVP was stopped. Meconium release into AF occurred in fetuses infused with AVP at rates greater than or equal to 7.76 mU/min. AVP has hemodynamic effects that mimic fetal responses to intrauterine "stress" and may be causally associated with the fetal release of meconium into AF. Furthermore, plasma AVP is cleared in part by the fetal kidney.

    Title Diuresis and Respiratory Distress Syndrome: Physiologic Mechanisms and Therapeutic Implications.
    Date July 1983
    Journal The Journal of Pediatrics
    Excerpt

    Previous studies have suggested that spontaneous diuresis may be important to the recovery from respiratory distress syndrome in preterm infants. Daily quantification of fluid intake (1) and urine output (O) were recorded, and O/I and alveolar-arterial oxygen gradients (AaDO2) were determined for sequential eight-hour periods in 10 inborn premature infants with RDS. Sequential timed-urine-plasma collections were obtained during the first four days of life to evaluate the role of hormonal and vasoactive factors in the acute phase of RDS. Diuresis (O/I greater than 0.80) occurred at 25 to 32 hours, preceded any significant improvement in AaDO2 (which occurred at 57 to 64 hours), and was associated with a 6.2 +/- 1.4% decrease in body weight. Although there was no significant change in glomerular filtration rate, plasma AVP concentrations, or urinary excretion of AVP in the infants, there were significant decreases in both plasma concentrations and urinary excretion of 6-keto-PGF1 alpha (stable metabolite of prostacyclin) in sequential studies. These results suggest that changes in renal function or AVP may not be of primary importance in the diuresis associated with RDS, and that decreasing levels of prostacyclin, a prostaglandin that increases vascular permeability and lowers blood pressure, may have an important physiologic role.

    Title Mechanism of Arginine Vasopressin Release in the Sheep Fetus.
    Date September 1982
    Journal Pediatric Research
    Excerpt

    Maternal and fetal plasma concentrations of arginine vasopressin (AVP) during asphyxial and hypoxemic episodes were ascertained between 130 and 140 days of gestation in chronically catheterized sheep. During an acute asphyxial stress, i.e., decreased PaO2 and pHa and increased PaCO2, maternal AVP in plasma was unaltered, whereas fetal arterial plasma concentrations rose from 1.6-2.2 microunits/ml to 34-385 microunits/ml and were associated with massive expulsion of meconium into the amniotic fluid. Mild hypoxemia, induced while the mother breathed a gas mixture consisting of 85% nitrogen and 15% oxygen, did not affect either maternal or fetal plasma AVP concentrations. The use of 10% inspired oxygen resulted in 60% and 50% reductions in maternal and fetal PaO2, respectively (P less than 0.05). In this instance, the maternal plasma AVP levels were unchanged, whereas the fetal plasma AVP concentration rose from a mean of 2.61 +/- 0.14 (SE) to 10.2 +/- 2.59 microunits/ml (P less than 0.025) within 30 min. Expulsion of meconium into the amniotic fluid did not occur. No evidence or either fetal-maternal placental transfer or fetal-placental clearance of plasma AVP was obtained. Although hypoxemic stress resulted in an elevation of fetal plasma AVP concentration, it does not appear to be the sole factor responsible for AVP release during intrauterine stress. It is suggested that substantial elevations in fetal plasma AVP concentrations may play in integral role in the fetal expulsion of meconium into the amniotic fluid.

    Title Single-dose Penicillin Prophylaxis of Neonatal Group-b-streptococcal Disease.
    Date August 1982
    Journal Lancet
    Excerpt

    The efficacy of a single dose of aqueous penicillin G in preventing neonatal group-B streptococcal infections was demonstrated in a randomised study conducted over 41 months. 16 082 infant received a single dose of penicillin within one hour of delivery, and 15 976 infants who received tetracycline ophthalmic ointment served as the control group. Group-B streptococcal systemic infections were significantly less common in the penicillin-treated infants (0.6 vs 1.7 cases per 100 live birth, p = 0.004). The incidence of infection caused by penicillin-resistant pathogen was insignificantly increased in the penicillin group (2.2 vs 1.6 cases per thousand live birth, p = 0.32). this difference was accounted for almost completely by the events of the first 12 months of the study period when, for unexplained reasons, there was a considerable increase in the number of penicillin-resistant infections in the penicillin group (3.6 vs 1.4 cases per 1000 live births, p = 0.09). The mortality associated with penicillin-susceptible pathogens was higher in the control group (0.1 vs 0.4 per 1000 live births, p = 0.18). However, the mortality associated with penicillin-resistant pathogens was increased in the penicillin (0.4 vs 1.0 per 1000 live births, p = 0.06). The combined mortality rates for all pathogens were not significantly different (1.1 vs 0.7 per 1000 liver births, p = 0.27, for the penicillin and control groups, respectively) and were nearly equivalent when the excess number of deaths associated with penicillin-resistant infections in the penicillin group during the first study year was excluded from analysis. The incidence of gonococcal ophthalmia and conjunctivitis was unaffected by the use of intramuscular penicillin at birth.

    Title Induction and Inhibition of Uterine Vasodilation by Catechol Estrogen in Oophorectomized, Nonpregnant Ewes.
    Date May 1982
    Journal Endocrinology
    Title Dilantin Toxicity in a Preterm Infant: Persistent Bradycardia and Lethargy.
    Date April 1982
    Journal The Journal of Pediatrics
    Title Effect of Angiotensin Ii on Uterine and Systemic Vasculature in Pregnant Sheep.
    Date October 1981
    Journal The Journal of Clinical Investigation
    Excerpt

    The response of uteroplacental blood flow (UBF) to angiotensin II is controversial. Moreover, the relationship of the uterine and systemic responses to infused angiotensin II is not well understood. Thus, in eight chronically instrumented, near-term pregnant sheep, we have determined the relationships between the dose and duration of constant systemic infusions of angiotensin II ([Val5] ANG II) and changes in UBF, uterine vascular resistance (UVR), mean arterial pressure (MAP), and systemic vascular resistance (SVR). [Val5] ANG II caused dose-dependent increases in UVR and MAP at all doses studied (P less than 0.05). The response in UBF was bidirectional, with increases at doses less than or equal to 1.15 microgram/min and decreases at greater than or equal to 2.29 micrograms/min (P less than 0.05). Increases in UBP occurred when the relative rise (delta) in MAP greater than delta UVR, whereas UBF was unchanged when delta MAP = delta UVR and decreased when delta MAP less than delta UVR. SVR also rose in a dose-dependent fashion (P less than 0.05); delta SVR was greater than delta UVR at doses less than or equal to 2.29 micrograms [Val5] ANG II/min (P less than 0.01). In studies of the effect of duration of [Val5] ANG II infusions, UBF increased at all doses during the 1st min, followed by stabilization at 4--5 min, with eventual decreases at doses greater than or equal to 2.29 micrograms/min and increases at doses less than 2.29 micrograms/min. The relationship between the changes in MAP and UVR to the response of UBF was as noted above. It is evident that (a) [Val5] NAG II is uterine vasoconstrictor, (b) changes in UBF are dependent upon relative changes in perfusion pressure and UVR, which in turn are dependent upon both the dose and duration of a [Val5] ANG II infusion, and (c) the uteroplacental vasculature is relatively refractory to the vasoconstricting effects of low doses of [Val5] ANG II.

    Title Effect of Volume Expansion on Pressor Response to Angiotensin Ii in Pregnant Ewes.
    Date August 1981
    Journal The American Journal of Physiology
    Excerpt

    Vascular refractoriness to infused angiotensin II (AII) characterizes normal human and ovine pregnancy. To ascertain whether the refractoriness in the gravid ewe is mediated by either endogenous plasma concentrations of renin and AII or vasomotor reflexes, effects of acute volume expansion (VE) on the pressor response to AII were studied in chronically instrumented nonpregnant and near-term pregnant sheep. Dose-response curves describing the pressor response (delta BP) were determined before and after infusions of 1.0 1 of isotonic saline (NS) or 0.5 1 of 10% dextran (D). In nonpregnant sheep, hematocrit (Hct) and plasma renin activity (PRA) fell in all animals after NS (n = 7) and D (n = 6) (P less than 0.005). After VE with NS and D, delta BP increased at each dose of AII (P less than 0.05). The pressor response to AII in pregnant sheep was not altered by NS although decreases in Hct and PRA were comparable to those in nonpregnant sheep. Baroreceptor responses were not altered. Vascular refractoriness to infused AII in pregnant sheep is not due primarily to changes in plasma concentrations of renin-AII but more likely to another factor, vessel wall refractoriness. In this respect, the ewe is similar to the human.

    Title Regional Blood Flows in Newborn Lambs During Endotracheal Continuous Airway Pressure and Continuous Negative Pressure Breathing.
    Date August 1981
    Journal Pediatric Research
    Excerpt

    Cardiovascular changes resulting from continuous distending alveolar pressure during endotracheal intubation (CPAP) and continuous negative pressure (CNP) were studied in two groups of healthy newborn lambs at 6 and 11 mm Hg and -6 and -11 mm Hg, respectively. Heart rate, left ventricular pressure, and arterial blood gases were unchanged in each group. Cardiac output decreased 16 and 15% at 6 and 11 mm Hg CPAP (P less than 0.05), respectively, whereas a fall of 9% occurred at both -6 and -11 mm Hg CNP (P greater than 0.05). Central venous pressure (mm Hg) rose from a control value of 7.0 +/- 1.4 (mean +/- S.E.) to 11 +/- 3.1 and 12 +/- 2.7 at 6 and 11 mm Hg CPAP (P less than 0.025), respectively, and decreased from a control of 7.7 +/- 0.7 to 5.8 +/- 0.5 at -6 mm Hg CNP and 4.8 +/- 1.3 at -11 mm Hg CNP (P less than 0.05). Jugular venous pressure also rose progressively with increasing CPAP (P less than 0.05), but was unchanged during CNP. Regional blood flow to the liver fell at both 6 and 11 mm Hg CPAP, whereas renal and gastrointestinal blood flows showed a tendency to decrease at 11 mm Hg CPAP. The removal of CPAP resulted in a prompt return of venous pressure, cardiac output, and regional blood flows to control values. Reductions in blood flows to the gastrointestinal tract at -6 mm Hg CNP and spleen at -11 mm Hg CNP were observed; blood flows returned toward control values when CNP was removed.

    Title The Chronically Instrumental Ewe: a Model for Studying Vascular Reactivity to Angiotensin Ii in Pregnancy.
    Date April 1981
    Journal The Journal of Clinical Investigation
    Excerpt

    Vascular refractoriness to the systemic pressor effects of angiotension II (AII) develops normally during human pregnancy. To ascertain if the ewe might provide a suitable animal model to study the mechanisms responsible for this response (unique to pregnancy) we studied this phenomenon in unanesthetized, chronically instrumented nonpregnant and pregnant sheep, 68-143 d gestation. In these studies dose-response curves were established for changes in both mean arterial pressure and uterine blood flow. The pressor response to continuous infusions of AII increases as a function of the dose of AII in both nonpregnant and pregnant animals (P less than 0.001), R = 0.943 and 0.879, respectively. However, the pregnant animals were refractory to the pressor effects of AII, requiring 0.016 microgram of AII/min per kg to elicit a 20 mm HG rise in mean arterial pressure, in contrast to 0.009 for nonpregnant animals. The slope and intercept for the regression lines are different at P less than 0.001. In pregnant animals the dose-response curve for uterine blood flow was also determined. Increases in uterine blood flow were observed at doses of AII less than 0.016 microgram/min per kg, while larger doses resulted in a progressively greater reduction in blood flow. It appears likely that the ewe may serve as an animal model suitable for the further study of the unique pregnancy-modified systemic and uteroplacental vascular responses elicited by AII.

    Title Effects of Fasting on Uterine Blood Flow and Substrate Uptake in Sheep.
    Date February 1981
    Journal The Journal of Nutrition
    Excerpt

    Twelve chronically instrumented late-gestation ewes fasted for 5 days were found to have a 25% decrease in total uterine blood flow and a 20% decrease in placental blood flow. Cardiac output was unchanged but was redistributed, as measured by radiolabeled microspheres, in a pattern similar to that produced by catecholamines. Fasting also was associated with hypoglycemia and altered whole blood amino acid concentrations. Uterine uptakes of glucose, oxygen, essential amino acids and glutamine, an important uterine and fetal nutrient, were decreased significantly during fasting. The increased hepatic blood flow and decreased arterial concentrations of glucogenic amino acids observed during fasting are consistent with a redistribution of maternal cardiac output to support maternal hepatic gluconeogenesis at the expense of nutrient supply to the gravid uterus.

    Title Responses of Reproductive and Nonreproductive Tissues to 17 Beta-estradiol During Ovine Puerperium.
    Date January 1981
    Journal The American Journal of Physiology
    Excerpt

    The responses of regional blood flows and cardiac output to the systemic infusion of 17 beta-estradiol (E2) (1 microgram/kg) were studied with radionuclide-labeled microspheres in 11 chronically instrumented ewes 1-12 days after lambing. Blood flow to the uterine myometrium, endometrium, and caruncles increased 818 +/- 212, 1,149 +/- 376, and 544 +/- 160% (mean +/- SE, P < 0.025), respectively, within 90 min after the infusion of E2. There was, however, in each of these tissues a progressive increase in the magnitude of the response to E2 stimulation as the puerperium progressed, not attaining changes expected in the prepregnant ewe until the 12th postpartum day. Significant vasodilation also occurred in the fallopian tubes, cervix, vagina, ovaries, mammary gland, skin, and thyroid gland. The magnitude of the blood flow response in the tubes, cervix, and vagina increased as the puerperium progressed. Cardiac output rose 17 +/- 10% (P < 0.05) after the infusion of E2. Although the ovine reproductive tissues are sensitive to estrogen-induced vasodilation throughout the puerperium, the magnitude of the responses progressively increase, suggesting that vascular reactivity in these tissues is changing and is not similar to that of the prepregnant animal.

    Title Single-dose Penicillin Prophylaxis Against Neonatal Group B Streptococcal Infections. A Controlled Trial in 18,738 Newborn Infants.
    Date November 1980
    Journal The New England Journal of Medicine
    Excerpt

    Neonatal Group B streptococcal infections may not respond to antimicrobial therapy and have been associated with case fatality rates of 50 per cent or greater. We evaluated the effect on colonization and disease rates of a single intramuscular dose of aqueous penicillin G given at birth in a prospectively controlled study of 18,738 neonates during a 25-month period. The colonization rate in the mothers was 26.6 per cent, with 50 per cent concordance in the untreated infants and 12.2 per cent in the penicillin-treated infants (P < 0.001). There was a significant decrease in the incidence of disease caused by all penicillin-susceptible organisms in the penicillin group (0.64 vs. 2.26 cases per thousand live births, P = 0.005). Disease caused by penicillin-resistant pathogens was increased in the penicillin-treated group during the first year of the study but was unaffected during the second year. Routine administration of parenteral penicillin at birth cannot be recommended until the effect on the incidence of disease caused by penicillin-resistant pathogens is fully defined.

    Title Phosphatidic Acid Phosphohydrolase and Phospholipids in Tracheal and Amniotic Fluids During Normal Ovine Pregnancy.
    Date November 1980
    Journal Pediatric Research
    Excerpt

    Samples of amniotic fluid and fetal tracheal fluid were obtained from 36 ovine pregnancies which were studied either acutely or chronically during the last two-thirds of gestation (65 to 149 days). The specific activity of phosphatidic acid phosphohydrolase (PAPase), disaturated lecithin (DS-L), total phospholipids (TLP) and the L/S ratio were assayed in the amniotic and tracheal fluids. There was a significant and progressive increase in the specific activity of PAPase in tracheal fluid beginning after 110 days, increasing from 66+/- 7 nmoles phosphate released X mg-1 protein x hour-1 (Mean +/- S.E.M.) less than or equal to 110 days, to 107 +/- 6 at 111 to 120 days, and to 277 +/- 70 at 131 to 144 days. The rise in PAPase specific activity was followed by a parallel rise in the DS-L fraction of the TPL (DS-L/TPL ratio), increasing from a DS-L/TPL ratio of 0.06 +/- 0.-1 in fetuses less than or equal to 120 days, to 0.29 +/- 0.06 at 121 to 130 days, and to 0.50 +/- 0.18 at 131 +/- 135 days. The PAPase specific activity and the L/S ratio in amniotic fluid did not change during pregnancy. Neonatal respiratory distress syndrome is the result of inadequate production of surface active material by the fetal and neonatal lung. The enzyme PAPase occupies a central role in the biosynthesis of the glycerophospholipids, and increases in the specific activity of PAPase in human amniotic fluid and in fetal rabbit lung tissue precede or are parallel with the increase in the L/S ratio and pulmonary surfactant synthesis, respectively. We have shown that this sequence is also demonstrable in ovine fetal tracheal fluid, thus providing an animal preparation in which the formation and regulation of surfactant biosynthesis during fetal lung maturation can be investigated in vivo.

    Title Ovine Fetoplacental Sulfoconjugation and Aromatization of Dehydroepiandrosterone.
    Date July 1980
    Journal Endocrinology
    Title The Neonatal Blood Count in Health and Disease. I. Reference Values for Neutrophilic Cells.
    Date November 1979
    Journal The Journal of Pediatrics
    Excerpt

    Reference ranges for absolute total neutrophils/mm3, absolute immature neutrophils/mm3, and the fraction of immature to total neutrophils (I:T proportion) during the first 28 days of life are developed from 585 peripheral blood counts obtained from 304 normal neonates and 320 counts obtained from 130 neonates with perinatal complications demonstrated to have no statistically significant effect on neutrophil dynamics. Perinatal factors other than bacterial disease which significantly alter neutrophil dynamics include maternal hypertension, maternal fever prior to delivery, hemolytic disease, and periventricular hemorrhage. The predictive value of these reference ranges in identifying bacterial disease in the first week of age varies with the neutrophil factor evaluated and the clinical setting. Neutropenia in the presence of respiratory distress in the first 72 hours had an 84% likelihood of signifying bacterial disease, whereas neutropenia in the presence of asphyxia had a 68% likelihood of signifying bacterial disease. An abnormal I:T proportion had an accuracy of 82% and 61%, respectively, in the same clinical settings. Elevations of either immature or total neutrophils were less specific. Interpretation of abnormal neutrophil factors must include consideration of both infectious and noninfectious perinatal events.

    Title Fetal Cervical Teratoma As a Cause of Polyhydramnios.
    Date October 1979
    Journal Pediatrics
    Title Atrial Tachy-arrhythmias Associated with Massive Edema in the Newborn.
    Date June 1979
    Journal Journal of Perinatal Medicine
    Title Circulatory Responses to Systemic Infusions of Estrone and Estradiol-17alpha in Nonpregnant, Oophorectomized Ewes.
    Date December 1978
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    Uterine arterial blood flow dose-response curves to systemic infusions of either estrone (E1) or estradiol-17alpha (E2alpha) were determined in ten oophorectomized, nonpregnant ewes. Maximum uterine blood flow occurred with 5 microgram per kilogram of E1 and greater than or equal to 20 microgram per kilogram of E2alpha. Total uterine blood flow measured with isotope-labeled microspheres rose more than tenfold following 30 microgram per kilogram of either estrogen, as did blood flow to the myometrium, endometrium, and uterine caruncles (p less than 0.05). Distribution of uterine blood flow was unaltered. Cervical and vaginal blood flows increased ten-to twenty-fold with E1 and E2alpha, while mammary gland blood flow rose 54 and 77 per cent. Significant increases in adrenal and thyroid blood flows were documented. The only significant decrease in blood flow occurred in the pancreas (- 13 percent; p less than 0.05) following E2alpha infusion. At the dose studied, E1 and E2alpha are potent vasodilators of reproductive tissues, especially the cervix and vagina. As they appear to be the major estrogens during ovine pregnancy, it is likely they participate in the preparation of these tissues for parturition.

    Title The Effect of Systemic Infusions of Dehydroisoandrosterone on the Distribution of Uterine Blood Flow in Ovine Pregnancy.
    Date April 1978
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    The effects of systemic infusions of dehydroisoandrosterone (6 mg.) on endogenous estrogen production and subsequent changes in regional blood flows and cardiac output were studied in six pregnant ewes at 105 to 128 days of gestation. Blood flows were measured with radionuclide-labeled microspheres. Plasma estrone concentrations increased from (mean +/- S.E.M.*) 27 +/- 2 to 117 +/- 13 pg. per mililiter, while estrodiol rose from 34 +/- 5 to 72 +/- 5 pg. per mililiter (p less than 0.05). Associated increases in blood flow occurred in endometrium, myometrium, and unimplanted uterine caruncles, while blood flow to the placental cotyledons was not significiantly changed. Perfusion was also increased in the Fallopian tubes, mammary gland, cervix, and vagina, the greatest fractional increase in blood flow occurring in the latter two, 387 and 456 per cent (p less than 0.005), respectively.

    Title The Estimation of Gestational Age: an Important Screening Technique.
    Date March 1978
    Journal Medical Record News
    Title The Differential Leukocyte Count in the Assessment and Outcome of Early-onset Neonatal Group B Streptococcal Disease.
    Date November 1977
    Journal The Journal of Pediatrics
    Excerpt

    The usefulness of the differential white blood cell count in distinguishing early-onset group B streptococcal disease from other causes of neonatal respiratory distress was studied in 45 infants with culture-proved infection. The initial diagnosis was hyaline membrane disease in 19 infants, wet lung syndrome 13, and other causes of respiratory distress in 13. Thirty-nine (87%) had abnormal absolute neutrophil counts, 25 with neutropenia and 14 with neutrophilia. The absolute immature neutrophil count was elevated in 19 infants (42%). Forty-one infants (91%) had an abnormal immature neutrophil to total neutrophil ratio. All infected infants were identified when both the absolute total neutrophil count and ratio were used. The differential white cell count appears to be a useful tool for screening infants presenting with respiratory distress in the first 48 hours of life and for separating early-onset group B streptococcal disease from other causes of neonatal respiratory distress.

    Title Uteroplacental Blood Flow and Estrogen Production Following Dehydroisoandrosterone Infusion.
    Date October 1977
    Journal Obstetrics and Gynecology
    Excerpt

    The effects of systemic infusions of dehydroisoandrosterone on uterine blood flow and the plasma concentration of estrogen in ovine pregnancy were studied in 7 pregnant ewes 52 to 128 days of gestation. Uterine blood flow increased 17.8% after a systemic infusion of dehydroisoandrosterone of 4.67 mg +/- 0.3. Maximum blood flows occurred 111 min +/- 5.8 after injection of dehydroisoandrosterone. The increase in flow (milliliter/minute) was greatest after 100 days of gestation. Plasma estrone concentrations increased from 67.9 pg/ml to 201 pg/ml, while estradiol rose from 42.6 pg/ml to 115 pg/ml (P less than 0.001). Estriol was not detected.

    Title Continuous Airway Pressure Breathing with the Head-box in the Newborn Lamb: Effects of Regional Blood Flows.
    Date July 1977
    Journal Pediatrics
    Excerpt

    Continuous airway pressure delivered by a head-box is an accepted means of treating clinical hyaline membrane disease. To investigate hemodynamic alterations resulting from its use, eight newborn lambs, 1 to 6 days of age, were studied at 6 and 11 mm Hg of positive pressure, while spontaneoulsy breathing room air. Organ blood flows and cardiac output were measured with 25 micron-diameter radioactive microspheres. Heart rate, left ventricular pressure, and arterial blood gases did not change during the study. Jugular venous pressures increased from 6.4 mm Hg to 18.6 and 24.2 mm Hg at 6 and 11 mm Hg, respectively (P less than .005). Cardiac output decreased approximately 20% at either intrachamber pressure setting. Renal blood flow fell 21% at 11 mm Hg. No significant changes in blood flow were found in the brain, gastrointestinal tract, spleen, heart, or liver when compared to control flows. Of particular interest was the finding of a 28% reduction in ocular blood flow at 6 mm Hg and 52% at 11 mm Hg. From these results, we conclude that substantial cardiovascular alterations may occur during the application of head-box continuous airway pressure breathing, including a significant reduction in ocular blood flow.

    Title Distribution of Cardiac Output in Ovine Pregnancy.
    Date April 1977
    Journal The American Journal of Physiology
    Excerpt

    Cardiac output and organ blood flows were measured in 6 nonpregnant and 24 pregnant ewes from 38 to 141 days of gestation employing radionuclide-labeled microspheres. From the nonpregnant state to term increases in cardiac output, from 73.7 +/- 4.6 ml/min-kg of maternal weight to 148 +/- 2.4 ml/min-kg, and heart rate, from 88.5 +/- 10.3 to 106 +/- 4.6 beats/min, were noted, while mean arterial blood pressure was unchanged. Near term, the blood flows to the uterus and mammary gland represented approximately 18% of cardiac output. The blood flow to nonreproductive organs increased from 76.6 +/- 6.8 ml/min-kg of nonreproductive tissue in the nonpregnant state to 132 +/- 3.5 ml/min-kg at 130-140 days' gestation (P less than 0.01). No significant changes in renal blood flow were detected.

    Title Circulatory Response to Systemic Infusion of Norepinephrine in the Pregnant Ewe.
    Date March 1977
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    Seven pregnant ewes from 100 to 137 days of gestation were infused with systemic doses of norepinephrine and uterine arterial flow dose-response curves were determined. A constant infusion of norepinephrine at a mean rate of 0.24 mug per minute per kilogram led to a 39.3 per cent decrease in total uterine arterial blood flow as measured with isotope-labeled microspheres while systemic pressure was unaltered. At this dose the reduction in endometrial blood flow (--64 per cent) was significantly greater than that in either the myometrium (--45 per cent) or placental cotyledons (--31 per cent) (p less than 0.005). Significant decreases in blood flow to small bowel, skeletal muscle, vagina, cervix. Fallopian tubes, kidneys, spleen, pancreas, and mammary gland were documented. There were no significant increases in blood flow. This study demonstrates that during the period or pregnancy studied, the overwhelming response to norepinephrine is vasoconstriction and that the vascular beds of all the tissues of pregnant uterus are sensitive to the alpha-adrenergic effects of norepinephrine.

    Title Letter: Questions on Theophylline.
    Date October 1976
    Journal Pediatrics
    Title Prenatal Diagnosis of Gastrointestinal Tract Obstruction.
    Date July 1976
    Journal Obstetrics and Gynecology
    Excerpt

    The diagnosis of possible duodenal atresia was made in a near-term fetus. The mother had developed polyhydramnios, and the fetus was found on sonography to have two communicating upper abdominal masses. It also failed to ingest contrast media after injection of radiopaque material into the amniotic sac. An esophageal atresia was found after delivery, in addition to the prenatally diagnosed duodenal atresia. The infant had a surgical repair 16 hours after delivery and survived.

    Title Effect of Estradiol-17beta on Blood Flow to Reproductive and Nonreproductive Tissues in Pregnant Ewes.
    Date May 1976
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    The effect of estradiol-17beta (1 mug per kilogram) on regional blood flow and cardiac output was studied by means of radionuclide-labeled microspheres in 6 nonpregnant and 13 pregnant ewes five to seven days after operation. Estradiol caused vasodilation in myometrium, endometrium, and placental cotyledons throughout pregnancy, but these responses were significantly less than the fifteenfold increase seen in the nonpregnant uterine tissues. Significant vasodilation also occurred in the ovaries, cervix, vagina, uterine tubes, mammary gland, skin, and adrenal glands of pregnant ewes. Cardiac output increased by 14%. No significant change in uterine oxygen consumption was associated with the increase in blood flow to the pregnant uterus.

    Title Effects of Epinephrine on Distribution of Blood Flow in the Pregnant Ewe.
    Date March 1976
    Journal American Journal of Obstetrics and Gynecology
    Excerpt

    Seven pregnant ewes ranging from 85 to 140 days of gestation were infused with systemic doses of epinephrine and uterine arterial flow dose-response curves were determined. With a constant systemic infusion of epinephrine at a mean rate of 0.29 +/- 0.03 mug/Kg.-min., and the radionuclide lebeled microsphere method to measure arterial blood flow, a 38.5 per cent decrease in total uterine arterial blood flow was demonstrated while systemic pressure was unaltered. At this dose the reduction in endometrial blood flow was significantly greater (-58.7 per cent) than that in either the myometrium (-36.9 per cent) or placental cotyledons (-34.5 per cent) (p less than 0.025 and less than 0.005, respectively). There also occurred a decrease in blood flow to the mammary gland and the pancreas, whereas increased in blood flow to the skeletal muscle, adipose tissue, and spleen were documented. It is evident from this study that during the period of ovine pregnancy investigated, the vascular bed of all tissues comprising the pregnant uterus, including the placental cotyledons, are sensitive to the vasoconstrictive effects of epinephrine.

    Title Growth of Uterine Oxygen and Glucose Uptakes During Pregnancy in Sheep.
    Date September 1975
    Journal Gynecologic Investigation
    Title Circulatory Changes in the Reproductive Tissues of Ewes During Pregnancy.
    Date September 1975
    Journal Gynecologic Investigation
    Title The L-s Ratio. Its Use in the Prediction of Respiratory Maturity in Infants.
    Date March 1974
    Journal Jama : the Journal of the American Medical Association
    Title Effect of Estrogens on the Uterine Blood Flow of Oophorectomized Ewes.
    Date May 1973
    Journal American Journal of Obstetrics and Gynecology
    Title Effect of Estradiol-17, on the Magnitude and Distribution of Uterine Blood Flow in Nonpregnant, Oophorectomized Ewes.
    Date May 1973
    Journal Pediatric Research
    Title On the Treatment of Fever.
    Date April 1971
    Journal The Journal of Pediatrics
    Title Necrotizing Enterocolitis.
    Date April 1971
    Journal Bulletin of the New York Academy of Medicine
    Title Intramural Intestinal Gas in Infants.
    Date August 1970
    Journal The New England Journal of Medicine
    Title Inactive Activists.
    Date July 1970
    Journal The New England Journal of Medicine
    Title Phototherapy of Neonatal Hyperbilirubinemia.
    Date March 1970
    Journal Pediatrics
    Title Cerebrospinal Fluid Sugar Determination.
    Date February 1970
    Journal The Journal of Pediatrics
    Title Severe Neonatal Hypoxic Respiratory Failure Correlates with Histologic Chorioamnionitis and Elevated Concentrations of Il-6, Il-8 and Crp.
    Date
    Journal Archives of Disease in Childhood. Fetal and Neonatal Edition
    Excerpt

    BACKGROUND: The mechanisms contributing to hypoxic respiratory failure (HRF) in term infants are multifactorial. Recent evidence suggests a potential pathogenetic role for inflammation. Nitric oxide (NO), a pulmonary vasodilator, is inhibited by inflammatory mediators which are upregulated in the presence of placental inflammation. OBJECTIVE: To examine the relationship between histologic chorioamnionitis and/or funisitis, serum concentrations of inflammatory mediators and severity of HRF. METHODS: Prospective observational study involving term neonates with HRF and normal controls. Blood samples were taken at birth from mixed cord blood, at 6 and 30 h for cytokines and CRP, and at 72 and 96h for CRP. Placentas were examined for chorioamnionitis. The primary outcome was the administration of inhaled nitric oxide (iNO) therapy. Data were analyzed by ANOVA and chi-square analysis. RESULTS: 32 neonates with hypoxic respiratory failure and 25 controls were enrolled. 14/32 (44%) neonates with HRF required iNO, 9/32(28%) hi-frequency ventilation and 3/32(9%) ECMO; 2/32 (6%) died. Neonates with HRF had >3-fold higher cord levels of IL-8 than controls (p<0.05). At 6 and 30h, serum IL-6, IL-8 and CRP were 2.2-fold higher in neonates who received iNO (p<0.003). 23/32 (72%) infants with HRF had evidence of histologic chorioamnionitis and/or funisitis compared to 5/25 (20%) controls (p<0.001). CONCLUSION: Severe hypoxic respiratory failure, as defined by the need for iNO, is associated with elevated blood proinflammatory mediators and increased occurrence of histologic chorioamnionitis and funisitis, suggesting that inflammation contributes to the severity of hypoxic failure.

    Title Large Conductance Ca2+--activated K+ Channels Contribute to Vascular Function in Nonpregnant Human Uterine Arteries.
    Date
    Journal Reproductive Sciences (thousand Oaks, Calif.)
    Excerpt

    Large conductance K( +) channels (BK(Ca)) are expressed in uterine artery (UA) smooth muscle from nonpregnant and pregnant sheep and contribute to the regulation of basal vascular tone and responses to estrogen and vasoconstrictors. To determine if BK(Ca) are expressed in women and contribute to UA function, we collected UA from nonpregnant women (n = 31) at elective hysterectomy and analyzed for subunit protein, localization with immunohistochemistry, and function using endothelium-denuded rings. UA expresses BK(Ca) alpha -, beta1- and beta2-subunit protein. KCl and phenylephrine (PE, an alpha(1)-agonist) caused dose-dependent vasoconstriction (P < .001), and UA precontracted with PE dose-dependently relaxed with sodium nitroprusside (SNP; P < .001).Tetraethylammonium chloride (TEA, 0.2-1.0 mM), a BK(Ca) inhibitor, dose-dependently increased resting tone (P = .004; 28% +/- 5.3% with 1.0 mM), enhanced PE-induced (10(-)(6) M) vasoconstriction (P < .04), and attenuated SNP-induced relaxation at 1.0 mM (P = .02). BK( Ca) are expressed in human UA and modulate vascular function by attenuating vasoconstrictor responses and contributing to nitric oxide-induced vasorelaxation.

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