Surfactant phosphatidylcholine half-life and pool size measurements in premature baboons developing bronchopulmonary dysplasia

Because minimal information is available about surfactant metabolism in bronchopulmonary dysplasia, we measured half-lives and pool sizes of surfactant phosphatidylcholine in very preterm baboons recovering from respiratory distress syndrome and developing bronchopulmonary dysplasia, using stable isotopes, radioactive isotopes, and direct pool size measurements. Eight ventilated premature baboons received (2)H-DPPC (dipalmitoyl phosphatidylcholine) on d 5 of life, and radioactive (14)C-DPPC with a treatment dose of surfactant on d 8. After 14 d, lung pool sizes of saturated phosphatidylcholine were measured. Half-life of (2)H-DPPC (d 5) in tracheal aspirates was 28 +/- 4 h (mean +/- SEM). Half-life of radioactive DPPC (d 8) was 35 +/- 4 h. Saturated phosphatidylcholine pool size measured with stable isotopes on d 5 was 129 +/- 14 micro mol/kg, and 123 +/- 11 micro mol/kg on d 14 at autopsy. Half-lives were comparable to those obtained at d 0 and d 6 in our previous baboon studies. We conclude that surfactant metabolism does not change during the early development of bronchopulmonary dysplasia, more specifically, the metabolism of exogenous surfactant on d 8 is similar to that on the day of birth. Surfactant pool size is low at birth, increases after surfactant therapy, and is kept constant during the first 2 wk of life by endogenous surfactant synthesis. Measurements with stable isotopes are comparable to measurements with radioactive tracers and measurements at autopsy

Single nucleotide polymorphisms in surfactant protein A1 are not associated with a lack of responsiveness to antenatal steroid therapy in a pregnant sheep model

Treatment with antenatal steroids (ANS) is standard practice for reducing the risk of respiratory distress in the preterm infant. Despite clear overall benefits when appropriately administered, many fetuses fail to derive benefit from ANS therapies. In standardized experiments using a pregnant sheep model, we have demonstrated that around 40% of ANS-exposed lambs did not have functional lung maturation significantly different from that of saline-treated controls. Surfactant protein A is known to play an important role in lung function. In this genotyping study, we investigated the potential correlation between polymorphisms in SFTPA1, messenger RNA and protein levels, and ventilation outcomes in animals treated with ANS. 45 preterm lambs were delivered 48 h after initial ANS therapy and 44 lambs were delivered 8 days after initial ANS therapy. The lambs were ventilated for 30 min after delivery. SFTPA1 mRNA expression in lung tissue was not correlated with arterial blood PaCO2 values at 30 min of ventilation in lambs delivered 48 h after treatment. SFTPA1 protein in lung tissue was significantly correlated with PaCO2 at 30 min of ventilation in lambs ventilated both 48 h and 8 days after ANS treatment. Six different single nucleotide polymorphisms (SNPs) in the Ovis aries SFTPA1 sequence were detected by Sanger Sequencing. No individual SNPs or SNP haplotypes correlated with alterations in PaCO2 at 30 min of ventilation or SFTPA1 protein levels in the lung. For the subset of animals analyzed in the present study, variable lung maturation responses to ANS therapy were not associated with mutations in SFTPA1

Betamethasone phosphate reduces the efficacy of antenatal steroid therapy and is associated with lower birth weights when administered to pregnant sheep in combination with betamethasone acetate

Background Antenatal corticosteroid (ACS) therapy is standard of care for women at imminent risk of preterm labour. Despite this, much remains to be understood regarding an optimal (maximum benefit, minimal risk of side effects) ACS dosing strategy. Although conveying overall benefit when given to the right patient at the right time, ACS treatment efficacy is highly variable, and is not risk-free. Building on earlier findings, we hypothesized that when administered in combination with slow-release betamethasone acetate, betamethasone phosphate and the high materno-fetal betamethasone concentrations it generates are redundant for fetal lung maturation. Objective Using an established sheep model of prematurity and post-natal ventilation of the preterm lamb, we aimed to compare the pharmacodynamic effects of a low-dose treatment with betamethasone acetate only against a standard dose of betamethasone phosphate and betamethasone acetate as recommended by the American College of Obstetricians and Gynaecologists for women at risk of imminent preterm delivery between 24 and 35+6 weeks’ gestation. Methods Ewes carrying a single fetus at 122±1 d gestational age (term=150d) were randomized to receive either: i) maternal intramuscular injections of sterile saline (the Saline Negative Control Group, n=12), ii) two maternal intramuscular injections of 0.25 mg/kg betamethasone phosphate + acetate spaced by 24h (the Beta-P+Ac Group, n=12); or iii) two maternal intramuscular injections of 0.125 mg/kg betamethasone acetate spaced by 24h (the Beta-Ac Group, n=11). Fetuses were surgically delivered 48h after treatment initiation and ventilated for 30 minutes to determine functional lung maturation. Fetuses were euthanized after ventilation and lung were collected for analysis using quantitative polymerase chain reaction and western blot assays. Fetal plasma ACTH levels were measured in the cord blood samples taken at delivery. Results Preterm lambs were defined as either ACS treatment responders or non-responders using an arbitrary cut-off, being a PaCO2 level at 30 minutes of ventilation being more extreme than two standard deviations from the mean value of the normally-distributed Saline Control Group values. Relative to Saline Control Group animals, both ACS treatment group animals showed significantly improved lung physiological responses (blood gas and ventilation data) and had a biochemical signature (mRNA and surfactant protein assays) consistent with functional maturation. However, the Beta-Ac Group had a significantly higher treatment response rate than the Beta-P+Ac Group. These physiological results were strongly correlated to the amount of surfactant protein A. Birth weight was lower in Beta-P+Ac Group and the fetal HPA axis was supressed to a greater extent in the Beta-P+Ac Group. Conclusion Low dose ACS therapy solely employing Beta-Ac was sufficient for fetal lung maturation. The elevated materno-fetal betamethasone concentrations associated with the co-administration of betamethasone phosphate did not additionally improve lung maturation, but were associated with greater HPA axis suppression, a lower ACS treatment response rate, and lower birth weight – outcomes not desirable in a clinical setting. These data warrant a clinical investigation of sustained, low-dose ACS treatments that avoid high materno-fetal betamethasone exposures

Accelerator measurements of magnetically-induced radio emission from particle cascades with applications to cosmic-ray air showers

For fifty years, cosmic-ray air showers have been detected by their radio emission. We present the first laboratory measurements that validate electrodynamics simulations used in air shower modeling. An experiment at SLAC provides a beam test of radio-frequency (RF) radiation from charged particle cascades in the presence of a magnetic field, a model system of a cosmic-ray air shower. This experiment provides a suite of controlled laboratory measurements to compare to particle-level simulations of RF emission, which are relied upon in ultra-high-energy cosmic-ray air shower detection. We compare simulations to data for intensity, linearity with magnetic field, angular distribution, polarization, and spectral content. In particular, we confirm modern predictions that the magnetically induced emission in a dielectric forms a cone that peaks at the Cherenkov angle and show that the simulations reproduce the data within systematic uncertainties.Comment: 5 pages, 7 figure

Variability in the efficacy of a standardized antenatal steroid treatment is not due to maternal or fetal plasma drug levels. Evidence from a sheep model of pregnancy.

Background Antenatal steroids (ANS) are standard of care for women judged to be at imminent risk of preterm delivery. Worldwide, there is significant variation in ANS dosing strategy, selection for treatment criteria, and agent choice. This, combined with very limited optimization of ANS use per se means that treatment efficacy is highly variable and the rate of respiratory distress syndrome is decreased perhaps as little as 40%. In some cases, ANS use is associated with limited benefit and potential harm. Objective We hypothesized that individual differences in maternal and fetal steroid exposure would contribute to observed variability in ANS treatment efficacy. Using a chronically catheterized sheep model of pregnancy, we aimed to explore the relationship between materno-fetal steroid exposure and ANS treatment efficacy as determined by functional lung maturation in preterm lambs undergoing ventilation. Methods Ewes carrying a single fetus had surgery to catheterize a fetal and maternal jugular vein at 119 days’ gestation. Animals recovered for 24h before being randomized to either: i) a single maternal intramuscular injection (IM) of 2ml saline (Negative Control Group, n=10); or ii) a single maternal IM of 0.25mg/kg betamethasone phosphate + acetate (ANS Group, n=20). Serial maternal and fetal plasma samples were collected from each animal over 48h before fetuses were delivered and ventilated for 30 minutes. Total and free plasma betamethasone concentration was measured by mass spectrometry. Fetal lung tissue was collected for analysis using quantitative polymerase chain reaction. Results One animal of the Control Group and one animal from the ANS Group had did not complete their treatment protocol and were removed from analyses. Animals in the ANS Group were divided into a Responder (n=12/19) Sub-Group and a Non-Responder Sub-Group (n=7/19) using a cut-off of a PaCO2 at 30 minutes ventilation within 2SD of the mean value from saline-treated Negative Control Group animals. While ANS improved fetal lung maturation in the undivided ANS group, and in the Responder Sub-Group both physiologically (blood gas and ventilation related data) and biochemically (mRNA expression related to fetal lung maturation), these values were not improved relative to saline-treated Control Group animals in the ANS Non-Responder Sub-Group. Interestingly, no differences in betamethasone distribution, clearance, or protein binding were identified between the ANS Responder and Non-Responder Sub-Groups. Conclusion This study correlated individual materno-fetal steroid exposures with preterm lung maturation as determined by pulmonary ventilation. Herein, approximately 40% of preterm lambs exposed to antenatal steroids had lung maturation not significantly different to saline-treated Control Group animals. These non-responsive animals received maternal and fetal betamethasone exposures identical to animals that had a significant improvement in functional lung maturation. These data suggest that the efficacy of ANS therapy is not solely determined by materno-fetal drug levels, and that individual fetal or maternal factors may play a role in determining treatment outcomes in response to glucocorticoid-driven signaling

The Next Linear Collider machine protection system

The Next Linear Collider (NLC) electron and positron beams are capable of damaging the linac accelerating structure and beamline vacuum chambers during an individual aberrant accelerator pulse. Machine protection system (MPS) considerations, outlined in this paper, have an impact on the engineering and design of most machine components downstream of the damping ring injector complex. The MPS consists of two functional levels. The first is a system that provides a benign, single bunch, low intensity, high emittance beam that will be used for commissioning and at any time that the integrity or the settings of the downstream component are in doubt. This level also provides for the smooth transition back and forth between high power operation and the benign diagnostic pilot bunch operation. The pilot bunch parameters in the main linac are estimated on the basis of the expected stress in the accelerator structure copper. Beam tests have been done at the SLAC linac to examine the behaviour of the copper at the damage stress threshold. Typical pilot beam parameters (compared with nominal) are: 10 times reduced intensity, 10 times increased horizontal emittance and 1000 times increased vertical emittance, resulting in a reduction in charge density of 105. The second level is the primary protection against a single aberrant pulse. It’s goal is to reduce the possibility that a substantial transverse field changes the trajectory of the high power beam from one pulse to the next. All devices that could produce such a field are 1) monitored by a fast response network and 2) have deliberately slowed response times. A ‘maximum allowable interpulse difference ’ is evaluated for each such device as well as the beam trajectory monitors in each interpulse period.

Early Respiratory Management of Respiratory Distress Syndrome in Very Preterm Infants and Bronchopulmonary Dysplasia: A Case-Control Study

BACKGROUND: In the period immediately after birth, preterm infants are highly susceptible to lung injury. Early nasal continuous positive airway pressure (ENCPAP) is an attempt to avoid intubation and may minimize lung injury. In contrast, ENCPAP can fail, and at that time surfactant rescue can be less effective. OBJECTIVE: To compare the pulmonary clinical course and outcome of very preterm infants (gestational age 25–32 weeks) with respiratory distress syndrome (RDS) who started with ENCPAP and failed (ECF group), with a control group of infants matched for gestational age, who were directly intubated in the delivery room (DRI group). Primary outcome consisted of death during admission or bronchopulmonary dysplasia (BPD). RESULTS: 25 infants were included in the ECF group and 50 control infants matched for gestational age were included in the DRI group. Mean gestational age and birth weight in the ECF group were 29.7 weeks and 1,393 g and in the DRI group 29.1 weeks and 1,261 g (p = NS). The incidence of BPD was significantly lower in the ECF group than in the DRI group (4% vs. 35%; P<0.004; OR 12.6 (95% CI 1.6–101)). Neonatal mortality was similar in both groups (4%). The incidence of neonatal morbidities such as severe cerebral injury, patent ductus arteriosus, necrotizing enterocolitis and retinopathy of prematurity, was not significantly different between the two groups. CONCLUSION: A trial of ENCPAP at birth may reduce the incidence of BPD and does not seem to be detrimental in very preterm infants. Randomized controlled trials are needed to test whether early respiratory management of preterm infants with RDS plays an important role in the development of BPD