Correlation of placental pathology with the postoperative outcomes and white matter injury in preterm infants following necrotizing enterocolitis.

BACKGROUND: To determine the association of placental pathologic lesions with postoperative outcomes, survival, and white matter injury (WMI) in preterm infants with NEC. METHODS: A retrospective chart review of 107 neonates with NEC (Bell stage > IIa) from Jan 2013- June 2020 was completed. Demographic, clinical, and outcome data were compared between infants with or without placental pathologic lesions. RESULTS: In this cohort, 59/107 (55%) infants had medical NEC, and 48 (45%) had surgical NEC. The infants had a mean gestational age of 28.1±3.7 weeks and a birth weight of 1103±647 g. Maternal vascular malperfusion (82/107, 76.6%) and acute histological chorioamnionitis (42, 39.3%) were the most common pathological placental lesions. Acute histologic chorioamnionitis with fetal inflammatory response was more common in infants with surgical NEC vs. medical NEC (35.4% vs. 15.3%; p = 0.02). The NEC Infants with WMI on brain MRI scans had a significantly higher incidence of acute histological chorioamnionitis (52% vs. 27.8%; P = 0.04). No significant differences in mortality, length of stay and postoperative outcomes in neonates with and without acute histologic chorioamnionitis with fetal inflammatory response were noted. On unadjusted logistic regression, acute histologic chorioamnionitis without fetal inflammatory response was also associated with higher odds of WMI (OR 2.81; 95% CI 1.05-7.54; p = 0.039). CONCLUSION: Acute histological chorioamnionitis without fetal inflammatory response was associated with higher odds of WMI in infants with NEC, with no significant impact on mortality and other postoperative outcomes.

Early echocardiographic prediction of ductal closure in neonates ≤ 30 weeks gestation.

OBJECTIVE: To determine the accuracy of the patent ductus arteriosus:left pulmonary artery ratio (PDA:LPA) on echocardiogram (ECHO) at 3-day postnatal in predicting spontaneous PDA closure in neonates ≤ 30 weeks gestational age (GA). STUDY DESIGN: ECHOs were performed at 72 h to characterize PDA size as closed-to-small (PDA:LPA <0.5) or moderate-to-large (PDA:LPA ≥ 0.5) and at 10 days to determine spontaneous closure (defined as closed-to-small in the absence of medical and/or surgical treatment). Caretakers were blinded to results; treatment was based on standard care. Neonates were prospectively enrolled and stratified: <27 weeks (n=31) and 27 to 30 weeks (n=65). RESULT: Neonates <27 weeks with closed-to-small PDAs had 60% spontaneous closure vs 9% when moderate-to-large (positive predictive value (PPV) 60%, negative predictive value (NPV) 91%). Neonates 27 to 30 weeks had 95% spontaneous closure vs 27%, respectively (PPV 95%, NPV 73%). Inter-observer variability for the initial ECHO was 0.84. CONCLUSION: PDA size defined by PDA:LPA at 3 days postnatal in combination with GA predicts spontaneous PDA closure.

Prenatal closure of the ductus arteriosus and maternal ingestion of anthocyanins.

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.

Echocardiographic predictors of symptomatic patent ductus arteriosus in extremely-low-birth-weight preterm neonates.

OBJECTIVE: Identify echocardiographic parameters at or=1 indicated a large PDA, <1 but >or=0.5 moderate, and <0.5 small. Sensitivity, specificity, and positive predictive values (PPV) were determined for ELBW <27 weeks and >or=27 weeks gestational age. RESULT: Neonates with moderate to large PDA at

Severe neonatal hypoxic respiratory failure correlates with histological chorioamnionitis and raised concentrations of interleukin 6 (IL6), IL8 and C-reactive protein.

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 that are upregulated in the presence of placental inflammation. OBJECTIVE: To examine the relationship between histological 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 h and 30 h for cytokines and CRP, and at 72 h and 96 h for CRP. Placentas were examined for chorioamnionitis. The primary outcome was the administration of inhaled nitric oxide (iNO) therapy. Data were analysed using analysis of variance and chi(2) analysis. RESULTS: 32 neonates with hypoxic respiratory failure and 25 controls were enrolled. 14/32 (44%) neonates with HRF required iNO, 9/32 (28%) required high-frequency ventilation and 3/32 (9%) required ECMO; 2/32 (6%) died. Neonates with HRF had more than threefold higher cord levels of interleukin 8 (IL8) than the controls (p<0.05). At 6 h and 30 h, serum IL6, IL8 and CRP were > or =2.2-fold higher in neonates who received iNO (p<0.003). 23/32 (72%) infants with HRF had evidence of histological chorioamnionitis and/or funisitis compared with 5/25 (20%) controls (p<0.001). CONCLUSION: Severe HRF, as defined by the need for iNO, is associated with raised blood levels of proinflammatory mediators and increased occurrence of histological chorioamnionitis and funisitis, suggesting that inflammation contributes to the severity of hypoxic failure.

Autoantibodies to IA-2 and GAD65 in patients with type 2 diabetes mellitus of varied duration: prevalence and correlation with clinical features.

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.

Mechanisms regulating angiotensin II responsiveness by the uteroplacental circulation.

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.

Ca(2+)-activated K(+) channels modulate basal and E(2)beta-induced rises in uterine blood flow in ovine pregnancy.

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.

Vascular medicine and osteopathic medicine: treating the whole patient.

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.

Maturation of ovine uterine smooth muscle during development and the effects of parity.

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.

Determinants of blood pressure in very low birth weight neonates: lack of effect of antenatal steroids.

OBJECTIVES: To define the range of normal blood pressures (BP) for very low birth weight (VLBW;

Calcium-activated potassium channels and nitric oxide coregulate estrogen-induced vasodilation.

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

Regulation of types I and III NOS in ovine uterine arteries by daily and acute estrogen exposure.

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.

Maturational differences between vascular and bladder smooth muscle during ovine development.

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

Angiotensin II indirectly vasoconstricts the ovine uterine circulation.

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.

A population-based study of congenital diaphragmatic hernia: impact of associated anomalies and preoperative blood gases on survival.

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.

Ontogeny of vascular angiotensin II receptor subtype expression in ovine development.

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.

Progression of autoimmune thyroiditis in an HIV-infected woman on HAART.

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.

Differential development of umbilical and systemic arteries. II. Contractile proteins.

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

Differential development of umbilical and systemic arteries. I. ANG II receptor subtype expression.

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.