c-abl is required for the development of hyperoxia-induced retinopathy.

The requirement for the nonreceptor tyrosine kinase c-abl in the pathogenesis of retinopathy of prematurity (ROP) was examined using the mouse model for ROP and c-abl-deficient mice. Hyperoxia-induced retinal neovascularization was observed in wild-type and heterozygous mice but animals that were homozygous null for c-abl did not develop a vasoproliferative retinopathy in response to hyperoxia. Two gene products, endothelin-1 (ET-1) and vascular endothelial growth factor (VEGF), have been implicated in the pathogenesis of ROP. The mRNA expression of ET-1 and VEGF was assessed in mice maintained in normoxia and in hyperoxia-exposed mice. ET-1 mRNA levels were unchanged in wild-type mice throughout the hyperoxia treatment, suggesting that ET-1 mRNA expression is not regulated by the increase in inspired oxygen. In wild-type mice maintained in room air, VEGF mRNA levels rose threefold from postnatal day 6 (P6) to P17. When wild-type mice were treated with the hyperoxia regimen, a fivefold decrease in VEGF mRNA expression was observed from P7 to P16. However, retinal VEGF expression in hyperoxia-treated homozygous null mice did not decrease and remained at control levels. These data suggest that c-abl is required for the hyperoxia-induced retinal neovascularization and hyperoxia-induced decrease in VEGF mRNA levels.

Influence of clinical status on the association between plasma total and unbound bilirubin and death or adverse neurodevelopmental outcomes in extremely low birth weight infants.

OBJECTIVES: To assess the influence of clinical status on the association between total plasma bilirubin and unbound bilirubin on death or adverse neurodevelopmental outcomes at 18-22 months corrected age in extremely low birth weight infants. METHOD: Total plasma bilirubin and unbound bilirubin were measured in 1101 extremely low birth weight infants at 5 +/- 1 days of age. Clinical criteria were used to classify infants as clinically stable or unstable. Survivors were examined at 18-22 months corrected age by certified examiners. Outcome variables were death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death prior to follow-up. For all outcomes, the interaction between bilirubin variables and clinical status was assessed in logistic regression analyses adjusted for multiple risk factors. RESULTS: Regardless of clinical status, an increasing level of unbound bilirubin was associated with higher rates of death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss and death before follow-up. Total plasma bilirubin values were directly associated with death or neurodevelopmental impairment, death or cerebral palsy, death or hearing loss, and death before follow-up in unstable infants, but not in stable infants. An inverse association between total plasma bilirubin and death or cerebral palsy was found in stable infants. CONCLUSIONS: In extremely low birth weight infants, clinical status at 5 days of age affects the association between total plasma bilirubin and death or adverse neurodevelopmental outcomes at 18-22 months of corrected age. An increasing level of UB is associated a higher risk of death or adverse neurodevelopmental outcomes regardless of clinical status. Increasing levels of total plasma bilirubin are directly associated with increasing risk of death or adverse neurodevelopmental outcomes in unstable, but not in stable infants.

Expanding bubbles in Orion A: [C II] observations of M42, M43, and NGC 1977.

CONTEXT: The Orion Molecular Cloud is the nearest massive-star forming region. Massive stars have profound effects on their environment due to their strong radiation fields and stellar winds. Stellar feedback is one of the most crucial cosmological parameters that determine the properties and evolution of the interstellar medium in galaxies. AIMS: We aim to understand the role that feedback by stellar winds and radiation play in the evolution of the interstellar medium. Velocity-resolved observations of the [C II] 158µm fine-structure line allow us to study the kinematics of UV-illuminated gas. Here, we present a square-degree-sized map of [C II] emission from the Orion Nebula complex at a spatial resolution of 16″ and high spectral resolution of 0.2kms-1, covering the entire Orion Nebula (M42) plus M43 and the nebulae NGC 1973, 1975, and 1977 to the north. We compare the stellar characteristics of these three regions with the kinematics of the expanding bubbles surrounding them. METHODS: We use [C II] 158µm line observations over an area of 1.2deg2 in the Orion Nebula complex obtained by the upGREAT instrument onboard SOFIA. RESULTS: The bubble blown by the O7V star θ 1 Ori C in the Orion Nebula expands rapidly, at 13kms-1. Simple analytical models reproduce the characteristics of the hot interior gas and the neutral shell of this wind-blown bubble and give us an estimate of the expansion time of 0.2 Myr. M43 with the B0.5V star NU Ori also exhibits an expanding bubble structure, with an expansion velocity of 6kms-1. Comparison with analytical models for the pressure-driven expansion of H II regions gives an age estimate of 0.02 Myr. The bubble surrounding NGC 1973, 1975, and 1977 with the central B1V star 42 Orionis expands at 1.5kms-1, likely due to the over-pressurized ionized gas as in the case of M43. We derive an age of 0.4 Myr for this structure. CONCLUSIONS: We conclude that the bubble of the Orion Nebula is driven by the mechanical energy input by the strong stellar wind from θ 1 Ori C, while the bubbles associated with M43 and NGC 1977 are caused by the thermal expansion of the gas ionized by their central later-type massive stars.

Predictors of death or bronchopulmonary dysplasia in preterm infants with respiratory failure.

OBJECTIVES: To identify the variables that predict death/physiologic bronchopulmonary dysplasia (BPD) in preterm infants with severe respiratory failure. STUDY DESIGN: The study was a secondary analysis of data from the NICHD Neonatal Research Network trial of inhaled nitric oxide (iNO) in preterm infants. Stepwise logistic regression models and Classification and Regression Tree (CART) models were developed for the outcome of death or physiologic BPD (O(2) at 36 weeks post-menstrual age). RESULT: Death and/or BPD was associated with lower birth weight, higher oxygen requirement, male gender, additional surfactant doses, higher oxygenation index and outborn status, but not the magnitude of response in PaO(2) to iNO. The positive predictive value of the CART model was 82% at 95% sensitivity. CONCLUSIONS: The major factors associated with death/BPD were an increased severity of respiratory failure, lower birth weight, male gender and outborn status, but not the magnitude of initial response to iNO.

Inhaled nitric oxide in infants >1500 g and <34 weeks gestation with severe respiratory failure.

OBJECTIVE: Inhaled nitric oxide (iNO) use in infants >1500 g, but <34 weeks gestation with severe respiratory failure will reduce the incidence of death and/or bronchopulmonary dysplasia (BPD). STUDY DESIGN: Infants born at <34 weeks gestation with a birth weight >1500 g with respiratory failure were randomly assigned to receive placebo or iNO. RESULTS: Twenty-nine infants were randomized. There were no differences in baseline characteristics, but the status at randomization showed a statistically significant difference in the use of high-frequency ventilation (P=0.03). After adjustment for oxygenation index entry strata, there was no difference in death and/or BPD (adjusted relative risk (RR) 0.80, 95% confidence interval (CI) 0.43 to 1.48; P=0.50), death (adjusted RR 1.26, 95% CI 0.47 to 3.41; P=0.65) or BPD (adjusted RR 0.40, 95% CI 0.47 to 3.41; P=0.21). CONCLUSIONS: Although sample size limits our ability to make definitive conclusions, this small pilot trial of iNO use in premature infants >1500 g and <34 weeks with severe respiratory failure suggests that iNO does not affect the rate of BPD and/or death.

[Cii] emission from L1630 in the Orion B molecular cloud.

CONTEXT: L1630 in the Orion B molecular cloud, which includes the iconic Horsehead Nebula, illuminated by the star system σ Ori, is an example of a photodissociation region (PDR). In PDRs, stellar radiation impinges on the surface of dense material, often a molecular cloud, thereby inducing a complex network of chemical reactions and physical processes. AIMS: Observations toward L1630 allow us to study the interplay between stellar radiation and a molecular cloud under relatively benign conditions, that is, intermediate densities and an intermediate UV radiation field. Contrary to the well-studied Orion Molecular Cloud 1 (OMC1), which hosts much harsher conditions, L1630 has little star formation. Our goal is to relate the [Cii] fine-structure line emission to the physical conditions predominant in L1630 and compare it to studies of OMC1. METHODS: The [Cii] 158 µm line emission of L1630 around the Horsehead Nebula, an area of 12' × 17', was observed using the upgraded German Receiver for Astronomy at Terahertz Frequencies (upGREAT) onboard the Stratospheric Observatory for Infrared Astronomy (SOFIA). RESULTS: Of the [Cii] emission from the mapped area 95%, 13 L⊙, originates from the molecular cloud; the adjacent Hii region contributes only 5%, that is, 1 L⊙. From comparison with other data (CO(1-0)-line emission, far-infrared (FIR) continuum studies, emission from polycyclic aromatic hydrocarbons (PAHs)), we infer a gas density of the molecular cloud of nH ∼ 3 · 103 cm-3, with surface layers, including the Horsehead Nebula, having a density of up to nH ∼ 4 · 104 cm-3. The temperature of the surface gas is T ∼ 100 K. The average [Cii] cooling efficiency within the molecular cloud is 1.3 · 10-2. The fraction of the mass of the molecular cloud within the studied area that is traced by [Cii] is only 8%. Our PDR models are able to reproduce the FIR-[Cii] correlations and also the CO(1-0)-[Cii] correlations. Finally, we compare our results on the heating efficiency of the gas with theoretical studies of photoelectric heating by PAHs, clusters of PAHs, and very small grains, and find the heating efficiency to be lower than theoretically predicted, a continuation of the trend set by other observations. CONCLUSIONS: In L1630 only a small fraction of the gas mass is traced by [Cii]. Most of the [Cii] emission in the mapped area stems from PDR surfaces. The layered edge-on structure of the molecular cloud and limitations in spatial resolution put constraints on our ability to relate different tracers to each other and to the physical conditions. From our study, we conclude that the relation between [Cii] emission and physical conditions is likely to be more complicated than often assumed. The theoretical heating efficiency is higher than the one we calculate from the observed [Cii] emission in the L1630 molecular cloud.

Barriers to enrollment in a randomized controlled trial of hydrocortisone for cardiovascular insufficiency in term and late preterm newborn infants.

OBJECTIVE: To analyze reasons for low enrollment in a randomized controlled trial (RCT) of the effect of hydrocortisone for cardiovascular insufficiency on survival without neurodevelopmental impairment (NDI) in term/late preterm newborns. STUDY DESIGN: The original study was a multicenter RCT. Eligibility: ⩾34 weeks' gestation, <72 h old, mechanically ventilated, receiving inotrope. Primary outcome was NDI at 2 years; infants with diagnoses at high risk for NDI were excluded. This paper presents an analysis of reasons for low patient enrollment. RESULTS: Two hundred and fifty-seven of the 932 otherwise eligible infants received inotropes; however, 207 (81%) had exclusionary diagnoses. Only 12 infants were randomized over 10 months; therefore, the study was terminated. Contributing factors included few eligible infants after exclusions, open-label steroid therapy and a narrow enrollment window. CONCLUSION: Despite an observational study to estimate the population, very few infants were enrolled. Successful RCTs of emergent therapy may require fewer exclusions, a short-term primary outcome, waiver of consent and/or other alternatives.

Cocaine-stimulated endothelin-1 release is decreased by angiotensin-converting enzyme inhibitors in cultured endothelial cells.

OBJECTIVE: The primary aim was to determine the action of pathophysiologically relevant cocaine concentrations (10(-7)-10(-5) M) on endothelin-1 (ET-1) release from cultured endothelial cells under various cellular conditions. Further aims were to evaluate the effect of angiotensin-converting enzyme inhibitors on cocaine-treated endothelial cells, to assess their potential for inhibition of ET-1-stimulated release. METHODS: Endothelin-1 release into the media was evaluated by radioimmunoassay under basal conditions and after 24 h treatment of endothelial cells with cocaine hydrochloride (HCl), or cocaine HCl and ACE inhibitors, captopril and lisinopril. The effect of serum and plasma under these conditions was also investigated. RESULTS: Cocaine HCl stimulated ET-1 release in a dose response fashion that was independent of plasma or serum factors. Furthermore, cocaine-stimulated ET-1 release was inhibited by administration of angiotensin-converting enzyme inhibitors captopril and lisinopril. CONCLUSIONS: These findings suggest that cocaine can directly stimulate endothelial cells to release ET-1 and that the observed increase is independent of serum or plasma factors. Furthermore, cocaine-stimulated endothelin-1 release appears to be mediated at least in part by the angiotensin system. These observations provide a framework for understanding the cellular mechanisms involved in cocaine-induced vasoconstriction.

Serial aEEG recordings in a cohort of extremely preterm infants: feasibility and safety.

OBJECTIVE: Amplitude-integrated electroencephalography (aEEG) monitoring is increasing in the neonatal population, but the safety and feasibility of performing aEEG in extremely preterm infants have not been systematically evaluated. STUDY DESIGN: Inborn infants 23(0/7) to 28(6/7) weeks gestation or birth weight 401 to 1000 g were eligible. Serial, 6-h aEEG recordings were obtained from first week of life until 36 weeks postmenstrual age. Adverse events were documented, and surveys evaluated the impact of the aEEGs on routine care. Success of performing aEEGs according to protocol and aEEG quality were assessed. RESULT: A total of 102 infants were enrolled, with 755 recordings performed. 83% of recordings were performed according to schedule, and 96% were without adverse event. Bedside nurses reported no interference with routine care for 89% of recordings. 92% of recordings had acceptable signal quality. CONCLUSION: Serial aEEG monitoring is safe in preterm infants, with few adverse events and general acceptance by nursing staff.

Candida sepsis and association with retinopathy of prematurity.

OBJECTIVE: To assess the association of Candida sepsis with retinopathy of prematurity (ROP) in extremely low birth weight infants. METHODS: We prospectively identified 253 infants admitted to the Critical Care Nursery at Georgetown University Hospital with birth weights

Nasal continuous positive airway pressure facilitates extubation of very low birth weight neonates.

A prospective randomized trial was performed in 58 neonates comparing nasal continuous positive airway pressure (NCPAP) vs oxyhood following extubation of neonates weighing less than 1 kg. All neonates had been ventilated for the treatment of respiratory distress syndrome for at least 24 hours and weighed less than 1 kg at the time of extubation. Clinical criteria for elective extubation included improving pulmonary status, fraction of inspired oxygen (FIO2) less than or equal to 0.35, mean airway pressure less than or equal to 7 cm H2O, ventilator rate less than or equal to 20 breaths per minute, and weight at least 80% of birth weight. Informed consent was obtained and neonates were randomized to NCPAP or oxyhood following extubation. Success was defined as remaining free of additional ventilatory support for at least 5 days. Failure criteria included FIO2 greater than or equal to 0.60 to maintain pulse oximetry greater than or equal to 93%, PaCO2 greater than or equal to 60 mm Hg, pH less than or equal to 7.23, or moderate to severe apnea. Results demonstrate that 22 (76%) of 29 neonates were successfully extubated to NCPAP while only 6 (21%) of 29 were successfully extubated to oxyhood (P less than .0001). There were no differences in baseline characteristics between the two groups. Of the 23 neonates who failed oxyhood, 21 were then given a trial of NCPAP and 58% (12/21) remained extubated. Data indicate that using selected clinical criteria for elective extubation of neonates weighing less than 1 kg, NCPAP facilitates successful extubation.

Captopril improves retinal neovascularization via endothelin-1.

PURPOSE: The purpose of this study was to determine the effect of an angiotensin converting enzyme inhibitor, captopril, on oxygen-induced retinopathy (OIR) in the mouse. Endothelin-1 (ET-1) expression is assessed in a mouse model of OIR. METHODS: OIR was produced in C57BL6 mice. Captopril (0.5mg/kg/d SC) was given from P7 (post natal day 7) for 5 days. Retinopathy was assessed by a retinal scoring system and by quantification of extra retinal neovascular nuclei on retinal sections at P17 to P20. The expression of ET-1 was determined using a reverse transcriptase polymerase chain reaction. RESULTS: Pups treated with captopril during hyperoxia had a lower median retinopathy score of 4.5 (25th, 75th quartile: 3, 6.4) compared with animals exposed to hyperoxia alone with median score 9.5 (25th, 75th quartile: 7.1, 10.4; P < 0.001). The pups treated with captopril during hyperoxia had significant reduction in number of nuclei extending beyond the inner limiting membrane (15.8 +/- 16.7, mean +/- SD) when compared with the animals exposed to hyperoxia only (50.4 +/- 28.0; P < 0.01). ET-1 expression in the retina increased 4.1-fold from P7 to P12 and a 1.9-fold increase from P12 to P17. Overall, there was an 8-fold increase in ET-1 expression from P7 to P17. Hyperoxia increased ET-1 expression by 2.1-fold at P12 over room air-reared animals. At P17, there was a 2.9-fold increase in retinal ET-1 expression when compared with room air. At P17, there was a 6.2-fold suppression in ET-1 expression in captopril-treated animals when compared with the oxygen only-treated animals. CONCLUSIONS: Captopril reduces retinal neovascularization in a mouse model of oxygen-induced retinopathy. ET-1 expression is increased from P7 to P17, altered by hyperoxic exposure and relative hypoxic recovery and modulated by captopril in a mouse model of OIR.

Dexamethasone and critical effect of timing on retinopathy.

PURPOSE: Administration of corticosteroids soon after birth has been reported to have deleterious, protective, and no effect on retinopathy of prematurity. Conflicting results may be due to timing of corticosteroid administration. The goal of this study was to determine effects of pretreatment and late dexamethasone on retinopathy in a mouse model. METHODS: The C57BL6 mouse model of oxygen-induced retinopathy (by placing animals in 75% oxygen from postnatal days 7 through 12) was used to create retinal neovascularization. Dexamethasone at 0.5 mg/kg per day was administered from day 1 through day 5 in the pretreatment group. The late-treatment group received 5 days of dexamethasone at the same dose beginning on day 12. Mice were killed at days 17 through 20, and retinal vasculature was assessed by a retinal scoring system of wholemount preparation after high-molecular-weight fluorescein-labeled dextran perfusion. In addition, retinal neovascularization was assessed by quantification of extraretinal neovascular nuclei in retinal sections. Statistical significance was defined as P: < 0.05 and was determined by the Kruskal-Wallis test, Mann-Whitney test, and Student's t-test. RESULTS: Oxygen-exposed animals that received treatment with dexamethasone before oxygen exposure had an improvement in retinopathy, with a median score of 6 (5,7; 25th,75th quartiles) compared with 10 (8,11) in the untreated oxygen-exposed (P: < 0.05). The group treated late (after oxygen exposure) with dexamethasone had a median score of 10 (9,11). Pretreatment reduced extraretinal vascularization, when assessed by quantification of neovascular nuclei, to a mean +/- SEM of 19 +/- 9, significantly less than in the untreated oxygen-exposed group (55 +/- 12; P: < 0.05). No difference was observed in the late-treatment group when compared with the untreated oxygen-exposed group. Significant growth retardation, indicated by body weight, was observed in the pretreatment (P: < 0.01) and late-treatment (P: < 0. 05) groups when compared with the control group. CONCLUSIONS: Timing of dexamethasone administration was critical to the inhibition of development of retinopathy in the mouse model. Degree of growth retardation, measured by body weight, also appeared to be time dependent. These data may explain the different results of clinical observations with respect to corticosteroid treatment, timing, and development of retinopathy.

Squalamine improves retinal neovascularization.

PURPOSE: Modalities for inhibiting neovascularization may be one avenue to the development of effective therapies for retinopathy. The effect of squalamine, an antiangiogenic amino sterol, on oxygen-induced retinopathy (OIR) was assessed in a mouse model. METHODS: OIR was induced in C57BL6 mice by a 5-day exposure to 75% oxygen from postnatal day (P)7 through P12. Squalamine (25 mg/kg, subcutaneous)treated animals received either daily doses for five days from P12 to P16 or one dose just after removal from oxygen on P12. Each set of animals was killed at P17 to P21. Retinopathy was assessed with a retinopathy scoring system evaluation of retinal wholemounts and by quantification of neovascular nuclei on retinal sections. RESULTS: Animals receiving 5 days of squalamine after a 5-day exposure to oxygen had total retinopathy scores (expressed as median score with 25th and 75th quartiles in parentheses) of 4(3, 5) versus oxygen-only-reared animals with scores of 8(7, 9; P < 0.001). Animals reared in room air and animals exposed to squalamine only had similar retinopathy scores: 1(1, 2) and 1(0, 2). Oxygen-reared animals receiving single-dose squalamine also showed improvement, with a median retinopathy score of 4(4, 6.75) versus oxygen-only-reared animals with median retinopathy score of 9(7, 10; P < 0.001). There was a decreased number of neovascular nuclei extending beyond the inner limiting membrane on retinal sections in animals treated with 5 days (P < 0.01) and 1 day (P < 0.001) of squalamine. CONCLUSIONS: Squalamine significantly improved retinopathy and may be a novel agent for effective treatment of ocular neovascularization.

Antenatal dexamethasone and decreased severity of retinopathy of prematurity.

OBJECTIVE: To assess risk factors associated with the development of retinopathy of prematurity (ROP) in an urban population. DESIGN: Observational cohort study. SETTING: Bellevue Hospital Center, a regional perinatal referral center in New York City. PATIENTS: Surviving inborn infants with birth weight less than 1250 g undergoing an ophthalmologic screening examination. MAIN OUTCOME MEASURES: Screening examination results for ROP were obtained. Additional data included birth weight, gestational age, maternal factors, and common neonatal diagnoses and exposures. RESULTS: Sixty-three infants were included in the analysis. Mean +/- SD birth weight was 981+/-179 g and mean gestational age was 27.8+/-2.4 weeks. Infants whose mothers received antenatal dexamethasone developed significantly less ROP that was stage 2 or higher than infants without a history of antenatal dexamethasone exposure--8.7% (2/23) vs 35% (14/40), respectively (P=.04). Birth weight, gestational age, respiratory distress syndrome, bronchopulmonary dysplasia, and patent ductus arteriosus were also significantly associated with the development of ROP that was stage 2 or higher. After controlling for these confounders by multiple logistic regression analysis, antenatal dexamethasone administration was associated with a significantly decreased risk of development of ROP stage 2 or higher (adjusted odds ratio [OR], 0.14; 95% confidence interval [CI], 0.02-0.93). The association was stronger when the analysis was restricted to the 36 infants who were 24 to 28 weeks of gestational age (adjusted OR, 0.02; 95% CI, 0.00-0.76). CONCLUSION: Antenatal dexamethasone administration appears to be associated with a decreased incidence of development of ROP of stage 2 or higher in this urban population.

Hyperoxia stimulates endothelin-1 secretion from endothelial cells; modulation by captopril and nifedipine.

PURPOSE: Retinopathy of prematurity (ROP) is a vasoproliferative condition that can result in severe visual impairment and blindness in preterm babies. Two conditions seen very early in radioimmunoassay (ROP) are vasoconstriction and vaso-obliteration. A potent vasoconstrictor secreted by endothelial cells is endothelin-1 (ET-1). Premature birth results in a relative systemic hyperoxia, compared to the in utero oxygen milieu. We tested the hypothesis that hyperoxia increases ET-1 expression as a possible mechanism for vasoconstriction in the retinal vasculature. METHODS: Bovine retinal endothelial cells and adrenal capillary endothelial cells were isolated and maintained in culture. Cells were exposed to control or hyperoxic culture conditions for 24 h, with and without addition of captopril and nifedipine. Media was collected and assayed for ET-1 by ROP. In addition, cell counts and secreted LDH assays were performed. RESULTS: Conditioned media from cultured bovine retinal and adrenal endothelial cells exposed to hyperoxic culture conditions for 24 h were found to have higher levels of ET-1 than conditioned media from normoxic control cells. Captopril (10(-6) M and 10(-4) M) and nifedipine (10(-6) M and 10(-4) M) inhibited ET-1 release from hyperoxia-exposed endothelial cells. Under normoxic conditions, ET-1 release was inhibited by 10(-4) M captopril or 10(-4) M nifedipine. CONCLUSIONS: These results demonstrate that (1) hyperoxia stimulates in vitro ET-1 secretion in bovine retinal and adrenal capillary endothelial cells, and (2) captopril and nifedipine downregulate ET-1 secretion under normoxic and hyperoxic culture conditions, in a dose-dependent fashion. We speculate that ET-1 may be involved in retinal vessel vasoconstriction seen early in the development of ROP. Further, ACE inhibitors and calcium-channel blocking agents, such as captopril and nifedipine, may provide an avenue for blocking vasoconstriction in ROP.

Diltiazem reduces retinal neovascularization in a mouse model of oxygen induced retinopathy.

PURPOSE: To assess the effect of diltiazem, a calcium channel blocking agent, on oxygen induced retinopathy (OIR) in a mouse model using neovascular nuclei quantitation and a quantitative scoring system based on examining fluorescein perfused retinal whole mount preparations. METHODS: The mouse model of oxygen induced retinopathy consisting of a 5 day exposure to 75% oxygen from postnatal day 7 to 12 was used to produce retinal neovascularization. Fluorescein conjugated dextran angiography of retinal vasculature was performed and retinal whole mounts were prepared to score features of retinopathy. The parameters that were scored in a masked fashion included blood vessel growth, blood vessel tuft formation, extra retinal neovascularization, degree of central vasoconstriction, retinal hemorrhage, and tortuosity of vessels. Diltiazem (0.05-0.5 mg/kg/day subcutaneously for five days) was administered to mice pups during exposure to oxygen to determine if calcium channel blockade altered retinopathy. In addition, quantification of retinal neovascular nuclei was performed in a masked fashion with periodic acid Schiff (PAS) staining of frozen eye sections. RESULTS: Animals that were exposed to hyperoxia for five days had a median (25th, 75th quartile) retinopathy score of 9 (8,11) versus control animals that had a retinopathy score of 1 (0,1) with p<0.001. Subscores for blood vessel growth, blood vessel tufts, extra-retinal neovascularization, central vasoconstriction, hemorrhage, and blood vessel tortuosity were all significantly different between control and treated animals. In addition, quantification of neovascular nuclei showed a significant increase in the number of nuclei extending beyond the inner limiting membrane into the vitreous in hyperoxic treated animals. Diltiazem at doses of 0.2 and 0.5 mg/kg/day improved the retinopathy as measured by the total retinopathy score [5 (4,6) and 4 (3.75,5.25), respectively]. The average number of extraretinal neovascular nuclei per retinal section (mean +/-standard deviation) was significantly decreased by diltiazem at doses of 0.2 and 0.5 mg/kg/day (31.4+/-18.8 and 20.9+/-6.9, respectively) when compared to hyperoxic treated animals (56.1+/-21.5). CONCLUSIONS: Diltiazem reduces oxygen induced retinopathy in the mouse as measured by a scoring system based on a retinal whole mount method of retinal neovascularization and by quantification of extra retinal neovascular nuclei.

Retinopathy of prematurity: lack of association with prenatal care.

OBJECTIVES: The overall goal of this study was to prospectively assess risk factors for retinopathy of prematurity (ROP) in infants of birth weight <1250 g in an urban population at Bellevue Hospital Center, New York, New York. The hypothesis tested was that lack of prenatal care increases the incidence of ROP. METHODS: A consecutive sample of patients admitted to Bellevue Hospital Center's neonatal intensive care unit/special care nursery who weighed <1250 g at birth and survived until their ophthalmology screening examinations were included in the study. The main outcome measures were presence or absence of ROP and prenatal care. Additional relevant clinical information was collected on the patients. RESULTS: Ninety infants were evaluated. Sixty-one (68%) had ROP; 29 (32%) had no ROP. No differences in incidence or severity of ROP were detected with regard to prenatal care when the 2 groups were compared. In this population <1250 g, there were no differences in birth weight or gestational age with respect to prenatal care or lack of prenatal care. CONCLUSIONS: Lack of prenatal care was not associated with an increased risk for ROP in infants with birth weight <1250 g in this urban population.

Evolving blood pressure dynamics for extremely preterm infants.

OBJECTIVE: To examine changes in arterial blood pressure (ABP) after birth in extremely preterm infants. STUDY DESIGN: Prospective observational study of infants 23(0/7) to 26(6/7) weeks gestational age (GA). Antihypotensive therapy use and ABP measurements were recorded for the first 24 h. RESULT: A cohort of 367 infants had 18 709 ABP measurements recorded. ABP decreased for the first 3 h, reached a nadir at 4 to 5 h and then increased at an average rate of 0.2 mm Hg h(-1). The rise in ABP from hour 4 to 24 was similar for untreated infants (n=164) and infants given any antihypotensive therapy (n=203), a fluid bolus (n=135) or dopamine (n=92). GA-specific trends were similar. ABP tended to be lower as GA decreased, but varied widely at each GA. CONCLUSION: ABP increased spontaneously over the first 24 postnatal hours for extremely preterm infants. The rate of rise in ABP did not change with antihypotensive therapy.

Neurodevelopmental outcomes of extremely low birth weight infants with spontaneous intestinal perforation or surgical necrotizing enterocolitis.

OBJECTIVE: To determine if extremely low birth weight infants with surgical necrotizing enterocolitis have a higher risk of death or neurodevelopmental impairment and neurodevelopmental impairment among survivors (secondary outcome) at 18-22 months corrected age compared with infants with spontaneous intestinal perforation and infants without necrotizing enterocolitis or spontaneous intestinal perforation. STUDY DESIGN: Retrospective analysis of the Neonatal Research Network very low birth weight registry, evaluating extremely low birth weight infants born between 2000 and 2005. The study infants were designated into three groups: (1) spontaneous intestinal perforation without necrotizing enterocolitis; (2) surgical necrotizing enterocolitis (Bell's stage III); and (3) neither spontaneous intestinal perforation nor necrotizing enterocolitis. Multivariate logistic regression analysis was performed to evaluate the association between the clinical group and death or neurodevelopmental impairment, controlling for multiple confounding factors including center. RESULT: Infants with surgical necrotizing enterocolitis had the highest rate of death before hospital discharge (53.5%) and death or neurodevelopmental impairment (82.3%) compared with infants in the spontaneous intestinal perforation group (39.1 and 79.3%) and no necrotizing enterocolitis/no spontaneous intestinal perforation group (22.1 and 53.3%; P<0.001). Similar results were observed for neurodevelopmental impairment among survivors. On logistic regression analysis, both spontaneous intestinal perforation and surgical necrotizing enterocolitis were associated with increased risk of death or neurodevelopmental impairment (adjusted odds ratio 2.21, 95% confidence interval (CI): 1.5, 3.2 and adjusted OR 2.11, 95% CI: 1.5, 2.9, respectively) and neurodevelopmental impairment among survivors (adjusted OR 2.17, 95% CI: 1.4, 3.2 and adjusted OR 1.70, 95% CI: 1.2, 2.4, respectively). CONCLUSION: Spontaneous intestinal perforation and surgical necrotizing enterocolitis are associated with a similar increase in the risk of death or neurodevelopmental impairment and neurodevelopmental impairment among extremely low birth weight survivors at 18-22 months corrected age.