Edward H. Hon, MD (1917-2006): A scientist, inventor, academician and the pioneer for the development of electronic fetal heart rate monitoring.

AIMS: To describe the professional life of Edward H. Hon, MD, and the course of his academic career for the development of electronic fetal heart rate (FHR) monitoring. METHODS: Review of archives at the Loma Linda University related to Dr Hon's early education and medical school training, his postgraduate training at Yale University, his faculty appointments at Yale University, University of Southern California and his research accomplishment related to electronic FHR monitoring. RESULTS: Primarily, Dr Hon advanced the clinical application of the electronic FHR monitoring, particularly during labor and delivery. Dr Hon also defined significance of FHR patterns based on years of clinical studies and astute observations. CONCLUSION: Currently, electronic FHR monitoring, during pregnancy and labor/delivery, has a universal application. Dr Hon's research contribution on FHR monitoring, and its impact for the welfare of mother and her unborn child, is well recognized.

Early Blood Transfusion and Resolution of Disseminated Intravascular Coagulation Associated with Massive Subgaleal Hemorrhage.

A male infant delivered to a primipara woman following vacuum applications. He was vigorous at birth, with small caput and scalp bruising. His head was enlarging; he became pale with respiratory distress. Subgaleal hemorrhage (SGH) was suspected. His hematocrit was noted to be 26.2 percent prior to transfusion of O, Rh-negative blood (40 mL/kg). Moderate disseminated intravascular coagulation (DIC) was noted at 12 hours of age. Posttransfusion of fresh frozen plasma (FFP), his condition became stable, and DIC gradually resolved. Head magnetic resonance imaging did not show intracranial hemorrhage. Although one episode of seizures was noted, electroencephalogram was normal. With the application of obstetric vacuum, we recommend that the neonatal health care professionals frequently evaluate the infant's condition. In light of developing fluctuant subgaleal fluid associated with pallor, anemia, metabolic acidosis, and respiratory distress, immediate blood transfusion is warranted. In the presence of DIC, transfusion of FFP is beneficial.

Medical care of children during the golden age of Islamic medicine.

During the Sassanid Empire in Persia (226-652 AD), there was a renaissance of humanistic sciences, including medicine, in the city of Gondi-Shapur. When the Islamic center of power moved to Baghdad in about 750 AD, physicians of Gondi-Shapur, including the dean of the medical school (a Nestorian Christian), gradually moved to Baghdad constructing hospitals and medical schools. Aided by the Persian and Nestorian Christians, the Islamic civilization ushered in what is considered to be the Golden Age of Islam from the 8th to 13th century AD. During this period, there were remarkable achievements in humanistic sciences including medicine by many physicians/authors whose medical textbooks were used for centuries in burgeoning medical schools in Europe. The medical texts written during the Golden Age of Islamic Medicine contain sections and chapters about the clinical conditions, diseases and medical care of children. It was during this era that the first treatise was written on the diseases of children and their care. This essay will describe, in brief, the writings about the conditions and diseases of children and their medical care, by three prominent Persian physicians of the Golden Age of Islamic Medicine: 1) Abubakr Muhammad Ibn Zakaria Razi, Rhazes (865-925 AD); 2) Ali ibn-al-Abbas al-Majusi or Haly Abbas (949-994 AD); and 3)  Abu Ali al-Husayn ibn Abd Allah ibn Sina or Avicenna (980-1037 AD).

Capillary blood draws in the NICU: the use of the Innovac quick-draw whole blood collection system versus traditional capillary blood draws.

PURPOSE: (1) To determine the rate of damaged and discarded capillary blood draws in the NICU; (2) to compare the rate of damaged and discarded samples between traditional capillary blood draws and the Innovac Quick-Draw device; (3) to determine whether in-service training for nurses on capillary blood draws decreased the rate of damaged and discarded blood samples. DESIGN: During Phase I of the study, the rate of capillary blood draws by the traditional method was determined. At the completion of Phase I, the manufacturer provided in-service training to senior nurses in the NICU with the use of the Innovac Quick-Draw device. Additional in-service training was also provided for the traditional capillary blood draw technique. Within a month of in-service training, an openly randomized study (Phase II) was carried out comparing traditional versus Innovac device capillary blood draws. SAMPLE: All infants admitted to the NICU between June 2008 and June 2009 were eligible to be in the study. There were no exclusion criteria based on weight, gestational age, or gender because the sampling method was the only variable being assessed. Phase I lasted two months, whereas Phase II lasted approximately four months. MAIN OUTCOME VARIABLE: Occurrence of damaged capillary samples with the Innovac device versus the traditional method. RESULTS: In Phase I, the rate of damaged and discarded samples was 10 percent (28/278). In Phase II, the rate of damaged and discarded samples for traditional and Innovac device was 7.2 percent and 10 percent, respectively. Comparisons between traditional and Innovac for different type of samples were as follows: complete blood count, 11.0 percent (12/104) vs. 13.4 percent (14/104); serum electrolytes, 6.4 percent (6/94) vs. 9.5 percent (9/95); C-reactive protein, 5.7 percent (4/70) vs. 8.0 percent (5/62); and liver panel, 5.3 percent (7/131) vs. 8.3 percent (9/108). There were no statistically significant differences of damaged and discarded samples for the overall or individual sample type comparisons.

Biomolecular effects of JB1 (an IGF-I peptide analog) in a rat model of oxygen-induced retinopathy.

Low-serum IGF-I levels at birth is a risk factor for the development of retinopathy of prematurity in extremely LBW infants. We tested the hypothesis that JB1 (an IGF-I analog) prevents oxygen-induced retinopathy in our rat model. Neonatal rats were exposed to 50% oxygen with brief, clustered, hypoxic (12%) episodes from birth to P14. The pups were treated with s.c. injections of 1) JB1 (1 µg/d) on P1, P2, and P3 (JB1x3); 2) JB1 (1 µg/d) on alternate days from P1 to P13 (JB1x7); or 3) equivalent volume saline. Control littermates were raised in room air (RA) with all conditions identical except for inspired O2. Groups were analyzed after hyperoxia/hypoxia (H/H) cycling at P14 or allowed to recover in RA until P21. Systemic and ocular VEGF, soluble VEGFR-1, and IGF-I; retinal vasculature; and gene profile of retinal angiogenesis were assessed. JB1x3 was more effective with associated increases in sVEGFR-1 and decreased retinal pathologies than JB1x7. We conclude that early short-term exposure to systemic JB1 treatment normalizes retinal abnormalities seen with H/H cycling, an effect that may involve sVEGFR-1.

Effects of combined hyperoxia and cyclooxygenase inhibition in neonatal rat lungs.

We examined the hypothesis that persistent pulmonary hypertension of the newborn (PPHN) associated with ibuprofen is due to alterations in biochemical and molecular regulators of oxidative stress and NO signaling. Newborn rats breathing 50% O2 or room air from the first day of life (P1), received early IP injections of: 1) indomethacin (0.2 mg/kg) on P1 and 0.1 mg/kg on P2 and P3; 2) ibuprofen (10 mg/kg) on P1 and 5 mg/kg on P2 and P3; or 3) saline on P1, P2 and P3, then euthanized on P4; or late treatment on P4, P5 and P6, then euthanized on P7. Lung biomarkers for oxidative stress (8- epi-PGF2a), DNA damage (8-hydroxy-2'-deoxyguanosine) and pulmonary hypertension (ET-1, big ET-1, and total NO) were assessed. Despite timing of the dose and oxygen exposure, both drugs resulted in increased alveolar size. Both drugs had no beneficial effects on oxidative stress. Indomethacin treatment in O2 resulted in higher pulmonary levels of 8-epi-PGF2alpha which was associated with downregulation of most antioxidant genes with early treatment and overexpression of GPX5 and 6 with late treatment. Early and late ibuprofen treatment suppressed hyperoxia-induced NOx production and downregulated iNOS. Postponing treatment had no significant beneficial effects on biomolecular regulators of oxidative stress and NO signaling. The effect of ibuprofen on pulmonary NOx may explain in part, the transient PPHN seen in ibuprofen-treated preterm infants.

Hormonal influences of early postnatal indomethacin and ibuprofen in neonatal rats.

OBJECTIVE: Indomethacin and ibuprofen are administered to preterm neonates for symptomatic patent ductus arteriosus. The drugs suppress prostaglandins (PGs) which modulate growth and secretion of various hormones. We examined the hypothesis that early postnatal indomethacin and ibuprofen influence growth and GH-IGF-I-insulin and HPA axes in neonatal rats. DESIGN: Rat pups received IP injections of saline (Sal) on P1, P2, and P3; 10mg/kg ibuprofen on P1 followed by 5mg/kg on P2 and P3; or 0.2mg/kg indomethacin on P1 followed by 0.1mg/kg on P2 and P3. Serum and hepatic GH, GHBP and IGF-I; and serum corticosterone and insulin levels were determined. RESULTS: Ibuprofen suppressed somatic growth in the sucking rats, but the effect was transient, resolving by P14. Indomethacin had an opposite, latent effect on body weight and liver to body weight ratios in weanling rats. Both indomethacin and ibuprofen had profound hormonal effects that differed in magnitude and timing. Indomethacin resulted in a sustained elevation in corticosterone levels at P21, while ibuprofen increased serum and hepatic GH levels. Both drugs suppressed GHBP in serum at P7 and P14; and liver at P4 and P7, but a rebound increase in serum GHBP was noted at P21 with Ibuprofen only. Both drugs increased serum IGF-I at P7. The effect remained sustained with indomethacin. CONCLUSIONS: These results provide evidence for an involvement of PGs in the regulation of growth as well as the GH-IGF and HPA axes. Therefore, early postnatal exposure to PG inhibitors may further exacerbate postnatal growth restriction and ability to cope with stress.

Soluble vascular endothelial growth factor receptor 1 in tracheal aspirate fluid of preterm neonates at birth may be predictive of bronchopulmonary dysplasia/chronic lung disease.

OBJECTIVE: We tested the hypothesis that soluble vascular endothelial growth factor receptors are involved in the development of bronchopulmonary dysplasia/chronic lung disease. PATIENTS AND METHODS: Neonates with a birth weight of < or =1500 g and/or < or =30 weeks' gestation, with respiratory failure, requiring O(2) and mechanical ventilation within 24 hours, were eligible. Tracheal aspirate fluid samples were collected from 65 neonates before surfactant and/or assisted mechanical ventilation (baseline), at 3 and 7 days after birth, and weekly thereafter until extubation. Samples were analyzed for total vascular endothelial growth factor, soluble vascular endothelial growth factor receptor 1 and 2 levels and compared in infants with bronchopulmonary dysplasia/chronic lung disease (n = 31) versus those with no bronchopulmonary dysplasia/chronic lung disease (n = 34). RESULTS: Mean gestational age and birth weight were lower in infants with bronchopulmonary dysplasia/chronic lung disease. At baseline, vascular endothelial growth factor levels in the tracheal aspirate fluid were significantly lower, whereas soluble vascular endothelial growth factor receptor 1 levels were higher in the bronchopulmonary dysplasia/chronic lung disease infants compared with infants with no bronchopulmonary dysplasia/chronic lung disease. Vascular endothelial growth factor levels progressively increased from baseline to 4 weeks in all of the infants developing bronchopulmonary dysplasia/chronic lung disease. Conversely, soluble vascular endothelial growth factor receptor 1 declined in both groups from baseline to 5 weeks of age. Similarly, soluble vascular endothelial growth factor receptor 2 declined from baseline to 5 weeks in the control infants, but there were significant increases at 3 and 4 weeks in infants developing bronchopulmonary dysplasia/chronic lung disease. CONCLUSIONS: We speculate that low vascular endothelial growth factor levels in tracheal aspirate fluid, concurrent with elevated soluble vascular endothelial growth factor receptor 1 levels on the first day of life, are biological markers for the development of bronchopulmonary dysplasia/chronic lung disease in very low birth weight infants requiring O(2) and assisted mechanical ventilation.

A tribute to Zakariya Razi (865 - 925 AD), an Iranian pioneer scholar.

The resurgence of Islamic Civilization in the Near East in the 7th century AD and its expansion to Persian Empire and Westward provided opportunities of access Persian, Hellenic, and Roman writings in philosophy and medicine. Based on their observations and experiences, Islamic physician-philosophers expanded upon those writings and at times challenged them. Among these physician-philosophers admiring and challenging Galen was Zakariya Razi described as the greatest physician of Islam and Medieval Ages.A search of electronic and written materials about early Islamic Medicine was carried out focusing on Persian physician-philosophers Zakariya Razi. Abu Bakr Mohammad Ibn Zakariya al-Razi, known in the West as Rhazes, was born in 865 AD in the ancient city of Rey, Near Tehran. A musician during his youth he became an alchemist. He discovered alcohol and sulfuric acid. He classified substances as plants, organic, and inorganic. At age 30, he undertook the study of medicine. He was a prolific writer with more than 184 texts in medicine attributed to him with 40 of them currently available. Among them are Kitab al-Mansoori, Kitab al-Hawi, and Kitab al -Judari wa al-Hasabah. The latter is the first scientific description for the recognition and differentiation of smallpox and measles. The Bulletin of the World Health Organization of May 1970 pays tribute to Razi by stating "His writings on smallpox and measles show originality and accuracy, and his essay on infectious diseases was the first scientific treatise on the subject". Razi established qualifications and ethical standards for the practice of medicine. Zakariya Razi was not only one of the most important Persian physician-philosophers of his era, but for centuries his writings became fundamental teaching texts in European medical schools. Some important aspects of his contributions to medicine are reviewed.

Percutaneously inserted central catheter for total parenteral nutrition in neonates: complications rates related to upper versus lower extremity insertion.

OBJECTIVE: The objective of this study was to compare the complication rates of upper versus lower extremity percutaneously inserted central catheters used for total parenteral nutrition in neonates. METHODS: During a 48-month study period, 396 neonates were identified as having had percutaneously inserted central venous catheters. A total of 370 catheters were inserted from the upper and 107 from the lower extremity. Data retrieved and analyzed were birth weight, gestational age, age at placement, duration in place, duration of total parenteral nutrition, type of infusates, catheter-related bloodstream infection, phlebitis, leakage, occlusion, necrotizing enterocolitis, intraventricular hemorrhage, serum creatinine, liver function tests, and length of hospitalization. RESULTS: The median birth weight and gestational age were 940 g and 28 weeks. The rate of catheter-related bloodstream infection was 11.6% for the upper and 9.3% in the lower extremity catheters. The most common organism was coagulase-negative Staphylococcus for both upper and lower extremity catheters and significantly higher with catheters from the upper extremity. Lower extremity catheters were in place longer, and the time from insertion to complication was also longer. The rate of cholestasis was higher for the upper extremity catheters. Multiple regression analysis showed that the most significant contributor to cholestasis was duration of time the catheters were in place and the duration of total parenteral nutrition administration. Receiver operating characteristics curve demonstrated higher sensitivity for duration of catheters in predicting cholestasis with duration of total parenteral nutrition being more specific. CONCLUSION: Lower extremity percutaneously inserted central venous catheters had lower rates of catheter-related bloodstream infection, longer time to first complication, and lower cholestasis despite longer duration of total parenteral nutrition. When possible, lower extremity inserted catheters should be used for the administration of total parenteral nutrition.

Effects of brief, clustered versus dispersed hypoxic episodes on systemic and ocular growth factors in a rat model of oxygen-induced retinopathy.

Oxygen fluctuation patterns in preterm infants who develop retinopathy of prematurity (ROP) are varied and poorly represented in animal models. We examined the hypothesis that clustered (CL) episodes of hypoxia during hyperoxia results in a more severe form of oxygen-induced retinopathy (OIR) than dispersed episodes. Rat pups were exposed to alternating cycles of 1) 50% O2 with three CL episodes of 12% O2 every 6 h; or 2) 50% O2 with one episode of 12% O2 every 2 h, for 7 (P7) or 14 (P14) days postnatal age. Pups were killed after hyperoxia, or placed in room air (RA) until P21. RA littermates were killed at P7, P14, and P21. Systemic and ocular vascular endothelial growth factor (VEGF), soluble VEGFR-1 (sVEGFR-1), insulin-like growth factor I (IGF-I), and growth hormone were examined. All hyperoxia-exposed retinas had evidence of neovascularization. Animals in the CL group had a more severe form of OIR at P21 evidenced by vascular tufts, leaky vessels, retinal hemorrhage, and vascular overgrowth. These characteristics were associated with low body weight; high systemic and ocular VEGF; and low systemic and high ocular sVEGFR-1 and IGF-I. These data suggest that preterm infants who experience CL fluctuations in Pao2 during supplemental O2 therapy are at a higher risk for severe ROP.

Early postnatal ibuprofen and indomethacin effects in suckling and weanling rat kidneys.

The use of indomethacin in preterm newborn infants with symptomatic patent ductus arteriosus is associated with compromised renal function. Ibuprofen has been shown to be as effective as indomethacin with fewer renal side effects. We examined the hypothesis that early postnatal ibuprofen has less adverse effects on neonatal rat renal prostanoids, COX-2 expression, and angiotensin II than indomethacin. Newborn rats received IP injections of human therapeutic doses of ibuprofen or indomethacin on the first 3 days of life. Control rats were treated with equivalent volume saline. Kidneys were assessed in suckling and weanling rats for prostanoids, COX-2 expression, and angiotensin II. In suckling rats, indomethacin suppressed PGE(2) and COX-2 expression, and increased PGF(2alpha), whereas ibuprofen increased COX-2 and angiotensin II. Although both NSAIDs suppressed 6-ketoPGF(1alpha) and TxB(2) levels in suckling rats, the effect was sustained in weanling rats with indomethacin. Our findings demonstrate that indomethacin exhibits more potent suppressive effects on renal COX-2 and vasodilator prostanoids which are important regulators of renal development and function. These long-term, sustained effects may explain in part, why indomethacin exerts more severe adverse renal effects than ibuprofen, when administered during early postnatal life.

Effects of antenatal betamethasone on maternal and fetoplacental matrix metalloproteinases 2 and 9 activities in human singleton pregnancies.

BACKGROUND: A single course of antenatal betamethasone is administered to women at risk of preterm labor to advance fetal lung maturation. Matrix metalloproteinases (MMPs) are collagen-degrading enzymes that remodel extracellular matrix components during lung development. We tested the hypothesis that the effects of betamethasone on fetal lung maturation involve changes in MMP activity. METHODS: We conducted a prospective, observational pilot study of three groups of singleton pregnancies. Group 1 (n = 21) was composed of women who were antenatally treated with a single course of betamethasone and who delivered < 37 weeks of gestation, group 2 (n = 7) was composed of matched untreated women who delivered < 37 weeks of gestation, and group 3 (n = 15) was composed of untreated women who delivered > 37 weeks of gestation. Maternal blood, mixed cord blood, and placental samples were collected at the time of delivery for MMP-2 and MMP-9 activity and tissue inhibitor of metalloproteinases (TIMP)-1 and -2 levels. RESULTS: MMP-2 activity was significantly higher in the maternal, placental, and fetal compartments in group 1 compared with group 2 (p < .05). TIMP-2 levels were lower in groups 1 and 2 compared with group 3. Maternal TIMP-2 levels were higher (p < 0.003), whereas fetal TIMP-1 (p < .01) and MMP-9 to TIMP-1 ratios (p < .05) were lower when delivery was delayed more than 2 weeks following betamethasone treatment. CONCLUSION: We conclude that elevated MMP-2 activity in the maternal and fetoplacental compartments may suggest a mechanism, in part, for betamethasone-induced fetal lung maturation.

Vaginal versus oral indomethacin in a rabbit model for non-infection-mediated preterm birth: an alternate tocolytic approach.

OBJECTIVE: We examined the hypotheses that vaginal indomethacin is more effective for prolonging gestation, and mediates its tocolytic actions via changes in cervical matrix metalloproteinase (MMP) activity, compared to oral. STUDY DESIGN: Pregnant rabbits induced with mifepristone received oral or vaginal indomethacin; or oral or vaginal vehicle once daily for 2 days. Premature delivery, fetal ductus arteriosus, and cervical MMP activity were assessed. RESULTS: Vaginal indomethacin delayed delivery >72 hours in 100% of the rabbits, extending gestation to 28.2 +/- 0.5 (P < .01) versus 26.4 +/- 0.3, 25.8 +/- 0.5, and 26.5 +/- 0.3 days, for vaginal placebo, oral indomethacin, and oral vehicle, respectively. Fetal ductus arteriosus was patent in all groups. Vaginal indomethacin decreased MMP-1, -8, and -9 activities and increased TIMP-1 levels in the cervix. CONCLUSION: Vaginal indomethacin is more effective than oral for prolonging gestation in the rabbit. Its tocolytic effects may be mediated, in part, by alterations in cervical MMP activity.

Influence of a single course of antenatal betamethasone on the maternal-fetal insulin-IGF-GH axis in singleton pregnancies.

OBJECTIVE: We examined the hypothesis that a single course of antenatal betamethasone influences the maternal-fetal insulin-IGF-GH axis. DESIGN: A prospective, observational, pilot study consisting of four groups of pregnant women: (I) received betamethasone and delivered <2 weeks post treatment; (II) received betamethasone and delivered >2 weeks post treatment; (III) untreated women who delivered <37 weeks (preterm controls); (IV) untreated women who delivered >37 weeks (term controls). Maternal and mixed umbilical cord blood was collected at delivery and analyzed for insulin, glucose, IGF-I, IGF-II, IGFBP-1, IGFBP-3, GH, and GHBP. RESULTS: Betamethasone increased maternal insulin, glucose and IGF-I levels without affecting IGFBPs. In the fetal compartment, betamethasone treatment was associated with a delayed suppressive effect on GH and a sustained suppressive effect on IGF-II levels. There were no differences in infant size or neonatal morbidities between patients who delivered <2 weeks or >2 weeks post betamethasone treatment. In Group IV, birth weight correlated positively with cord IGF-I levels (r2=0.41, p=0.0098) and negatively with cord IGFBP-1 levels (r2=0.51, p=0.0039), and ponderal index correlated negatively with cord IGFBP-1 levels (r2=0.27, p<0.05). CONCLUSIONS: A single course of antenatal betamethasone influences the maternal-fetal insulin-IGF-GH axis, particularly fetal IGF-II levels, without measurable anthropometric changes at birth. Whether these effects have implications beyond the neonatal period remains to be determined.

Comparative effects of early postnatal ibuprofen and indomethacin on VEGF, IGF-I, and GH during rat ocular development.

PURPOSE: Ibuprofen and indomethacin are nonselective prostaglandin synthetase inhibitors that have been shown to improve oxygen-induced retinopathy in mice. Vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF)-I, and growth hormone (GH) are potent growth factors involved in retinal development. This study was conducted to examine and compare the effects of early postnatal ibuprofen and indomethacin on ocular and systemic VEGF, IGF-I, and GH during rat ocular development. METHODS: Newborn rats were treated with intraperitoneal injections of low and high doses of ibuprofen or indomethacin at birth (postnatal day [P]1) and on P2 and P3. A control group received equivalent volumes of saline. At P14, vitreous fluid, retinal homogenates, and serum were analyzed for VEGF, IGF-I, and GH protein levels. Retinal mRNA expression of VEGF splice variants (VEGF188, VEGF164, VEGF120), VEGF receptors (VEGFR-1, VEGFR-2, Npn-1, Npn-2), and pigment epithelium-derived factor (PEDF) were also examined. RESULTS: Animals treated with high-dose ibuprofen had significantly lower somatic growth and higher serum and vitreous IGF-I levels. High-dose ibuprofen decreased retinal VEGF levels and retinal VEGF164, VEGF120, and VEGFR-2 transcripts, resulting in a significant increase in the cecal period in 87% of rats at P14. Both indomethacin doses suppressed retinal VEGF164 transcripts without affecting VEGF receptors. CONCLUSIONS: Ibuprofen may be more effective than indomethacin for suppression of retinal VEGF signaling, suggesting a possible therapy for retinal neovascularization. However, deficits in somatic growth concurrent with higher systemic IGF-I levels suggests decreased IGF-I bioactivity. These adverse effects should be considered.

Ontogeny of VEGF, IGF-I, and GH in neonatal rat serum, vitreous fluid, and retina from birth to weaning.

PURPOSE: Vascular endothelial growth factor (VEGF), insulin-like growth factor (IGF)-I, and growth hormone (GH) are major regulators of physical growth, as well as normal and pathologic retinal development. Ocular tissues are protected by the blood-ocular barrier. This study was conducted to test the hypothesis that the ontogenic profiles of VEGF, IGF-I, and GH in the rat serum, vitreous fluid, and retina are compartment specific, and that the vitreous is a reservoir for retinal growth factors. METHODS: Sprague-Dawley rat pups were killed at birth (postnatal day [P]0) and at P7, P14, and P21. At death, serum, vitreous fluid, and retinal homogenates were analyzed for ontogeny of VEGF, IGF-I, and GH. RESULTS: VEGF levels were 10 times higher in the vitreous than in serum at all stages of development. Vitreous and serum VEGF levels progressively declined, with lowest concentrations at P21. Retinal VEGF levels increased with the highest concentration at P21. IGF-I levels in the vitreous decreased from P7 through P21. IGF-I levels in serum and retinal homogenates increased with advancing postnatal age. Although IGF-I levels were four times higher in the vitreous than in the retina at P0, equilibration was achieved at P21. GH levels in the vitreous were 10 times lower than serum levels, were decreased at P14 and P21, and remained unchanged from P0 through P21 in the retina. CONCLUSIONS: VEGF and IGF-I act in concert to promote retinal development with the vitreous fluid as a reservoir. The ontogenic profiles of VEGF, IGF-I and GH in the serum and ocular compartments are specific. These differences should be considered when therapies for ROP are proposed.

Maternal and feto-placental prostanoid responses to a single course of antenatal betamethasone.

We tested the hypothesis that antenatal betamethasone alters prostanoid levels in the maternal and feto-placental compartments. Forty-three singleton pregnancies were studied. Group I were women treated with a single course of antenatal betamethasone and who delivered <37 weeks gestation; Group II were untreated women who delivered <37 weeks; and Group III were untreated women who delivered >38 weeks. Maternal and mixed cord blood; and placental samples were collected at delivery and analyzed for PGE2, PGF(2alpha), 6-ketoPGF(1alpha), and TxB2 levels. Antenatal betamethasone decreased maternal PGE2 levels with concomitant increases in the feto-placental compartment. Umbilical cord TxB2 levels in the treated group were significantly lower than the non-treated pre-term and term groups resulting in a higher 6-ketoPGF(1alpha):TxB2 ratio. Considering the regulatory role of PGE2 and PGI2 in fetal lung development and neonatal transition homeostasis, these results suggest a mechanism, at least in part, for the beneficial effects of antenatal steroids on fetal lung maturation and neonatal cardio-pulmonary homeostasis at birth.

Impaired lung vascular endothelial growth factor in extremely premature baboons developing bronchopulmonary dysplasia/chronic lung disease.

BACKGROUND: Preterm infants exposed to O2 with mechanical ventilation often develop bronchopulmonary dysplasia (BPD), a form of chronic lung disease (CLD). The pathogenesis of BPD/CLD involves dysmorphic microvasculature and disrupted alveolarization. This may be due to impaired vascular endothelial growth factor (VEGF) and VEGF receptor expression. METHODS: To examine the ontogeny of VEGF and VEGF receptors in baboon lungs from 125 to 185 (term) days gestation and to determine whether exposure to O2 and mechanical ventilation alter these ontogenic profiles, we examined lung specimens from three O2-exposed groups: (1) animals delivered at 125 days gestation and exposed to O2 for 14 days as needed; (2) animals delivered at 140 days gestation and exposed to O2 for 10 days as needed; and (3) animals delivered at 140 days gestation and exposed to 100% O2 for 10 days. Lungs from gestational age-matched controls were also examined at 125, 140, 160, 175, and 185 (term) days. RESULTS: VEGF189 was the most abundant splice variant in the lungs at all stages of development. Extremely premature baboons developing BPD/CLD had higher lung VEGF121 messenger ribonucleic acid (mRNA) expression. However, transcripts for VEGF189, VEGF165, and VEGF receptors (Fms-like tyrosine kinase-1 [Flt-1], kinase-insert domain receptor [KDR]/fetal liver kinase-1 [Flk-1], and neuropilin 1) were suppressed in the BPD models. CONCLUSIONS: We conclude that impaired VEGF and VEGF receptor mRNA expression in lungs from extremely premature baboons developing BPD/CLD may contribute to dysmorphic microvasculature and disrupted alveolarization.

Effect of maternal administration of selective cyclooxygenase (COX)-2 inhibitors on renal size, growth factors, proteinases, and COX-2 secretion in the fetal rabbit.

BACKGROUND: Selective cyclooxygenase (COX)-2 inhibitors are currently being considered for management of preterm labor. COX-2 is an important regulator of fetal renal growth and function. Its inhibition may lead to congenital oligonephropathy. OBJECTIVES: We investigated whether maternal administration of a selective COX-2 inhibitor would adversely affect fetal renal growth. METHODS: Three groups of timed pregnant rabbits at 13 days gestation were examined. Group 1 received oral celecoxib (30 mg/kg/day) from 13 to 20 days gestation (Cel-A); group 2 received celecoxib from 13 to 28 days gestation (Cel-B), and group 3 received equivalent volumes of the vehicle from 13 to 28 days gestation. The fetuses were delivered by cesarean section at 29 days gestation. The kidneys were weighed and analyzed for vascular endothelial growth factor (VEGF) and its soluble receptors, matrix metalloproteinase (MMP)-2 and -9, tissue inhibitor of metalloproteinase (TIMP)-1 and -2, COX-2, and total cellular protein levels. Sections from the cortex and medulla were assessed histologically. RESULTS: Fetal kidney size was unaffected. VEGF levels were elevated in the Cel-B group. Soluble VEGF receptors, MMP-2, TIMP-1 and COX-2 levels remained unchanged. MMP-9 levels were suppressed in both treated groups, which resulted in significantly lower MMP-9/TIMP-1 ratios. Although TIMP-2 secretion was enhanced in the Cel-B group, MMP-2/TIMP-2 ratios were unaffected. No significant histological changes were detected. CONCLUSIONS: We conclude that maternal administration of therapeutic doses of celecoxib does not adversely affect fetal renal growth. MMP-9 is increased in various nephropathies, but may also have protective effects therefore its suppression by COX-2 inhibitors needs further study.