Thomas N. George

The effect of inhaled nitric oxide therapy on bleeding time and platelet aggregation in neonates

The effect of inhaled nitric oxide (iNO) on bleeding time and platelet aggregation was studied in nine newborn infants with resolving pulmonary hypertension. Infants treated with iNO at 40 ppm for 30 minutes had bleeding times that were nearly twofold longer than those obtained 24 hours after iNO was discontinued. iNO had no effect on in vitro platelet aggregation studies.

Transient surfactant protein B deficiency in a term infant with severe respiratory failure

A 38-day-old male infant with persistent pulmonary hypertension and respiratory failure since birth was found to have a complete absence of surfactant protein B (SP-B) along with an aberrant form of SP-C in his tracheal aspirate fluid, findings consistent with the diagnosis of hereditary SP-B deficiency. Surprisingly, SP-B and SP-B messenger ribonucleic acid were present in lung biopsy tissue. However, DNA sequence analysis demonstrated a point mutation in exon 5 of one of the SP-B gene alleles. The infants mother was found to be a carrier of this mutation. The infants other SP-B allele did not differ from the published DNA sequence for the SP-B gene. We conclude that this patient had a transient deficiency of SP-B, in contrast to that of previously described infants with irreversible respiratory failure caused by hereditary SP-B deficiency. We recommend that infants with suspected SP-B deficiency have serial analysis of tracheal fluid samples for both SP-B and SP-C before lung biopsy, along with genetic analysis for the known SP-B mutations. We speculate that the new mutation found in one of this patients SP-B genes was in part responsible for the transient deficiency of SP-B.

Regulation of surfactant protein gene expression by retinoic acid metabolites

Surfactant-associated proteins (SP) play an important role in the function of pulmonary surfactant. We have previously shown that SP-B mRNA is increased whereas SP-A and SP-C mRNA are decreased by all-trans-retinoic acid(RA) in a dose-dependent manner in human fetal lung explants. All-trans-RA binds primarily to the retinoic acid receptors (RARs) and 9-cis-RA binds primarily to the retinoid X receptors (RXRs). Because the fetal lung contains RXRs, we hypothesized that 9-cis-RA regulates surfactant protein gene expression in lung epithelial cells. H441 human lung adenocarcinoma cells, which synthesize SP-A and SP-B mRNA and protein, were treated with either all-trans-RA or 9-cis-RA(10-10 to 10-6 M) for 24 h. Neither all-trans-RA nor 9-cis-RA had an effect on SP-A mRNA levels in the H441 cells. All-trans-RA (10-6 M) significantly increased SP-B mRNA levels in the H441 cells and 9-cis-RA had a smaller, not statistically significant effect. Human fetal lung explants were treated with 9-cis-RA for 6 d. 9-cis-RA did not significantly increase SP-B mRNA levels, significantly inhibited SP-A mRNA levels at all concentrations tested, and significantly inhibited SP-C mRNA levels at 10-6 M in the human fetal lung explants. Both all-trans-RA(10-6 M) and 9-cis-RA (10-6 M) significantly increased SP-B protein levels in the human fetal lung explants. Together, these results are suggestive that all-trans-RA directly regulates SP-B gene expression in human pulmonary epithelial cells. In addition, the inhibitory effect of all-trans-RA and 9-cis-RA on SP-A mRNA levels in pulmonary epithelial cells is probably an indirect effect mediated by other cell types present in fetal lung tissue.

Mechanism of all trans-retinoic acid and glucocorticoid regulation of surfactant protein mRNA

The surfactant proteins (SPs) are required for the normal function of pulmonary surfactant, a lipoprotein substance that prevents alveolar collapse at end expiration. We characterized the effects of cortisol and all trans-retinoic acid (RA) on SP-A and SP-B gene expression in H441 cells, a human pulmonary adenocarcinoma cell line. Cortisol, at 10-6M, caused a significant inhibition of SP-A mRNA to levels that were 60-70% of controls and a five- to sixfold increase in the levels of SP-B mRNA. RA alone (10-6M) had no effect on SP-A mRNA levels and modestly reduced the inhibitory effect of cortisol. RA alone and the combination of cortisol and RA both significantly increased SP-B mRNA levels. RA had no effect on the rate of SP-A gene transcription or on SP-A mRNA stability. Cortisol alone and the combination of cortisol and RA significantly inhibited the rate of SP-A gene transcription but had no effect on SP-A mRNA half-life. RA at 10-6 M had no effect on the rate of SP-B gene transcription but prolonged SP-B mRNA half-life. Cortisol alone and the combination of cortisol and RA caused a significant increase in the rate of SP-B gene transcription and also caused a significant increase in SP-B mRNA stability. We conclude that RA has no effect on SP-A gene expression and increases SP-B mRNA levels by an effect on SP-B mRNA stability and not on the rate of SP-B gene transcription. In addition, the effects of the combination of RA and cortisol were generally similar to those of cortisol alone.The surfactant proteins (SPs) are required for the normal function of pulmonary surfactant, a lipoprotein substance that prevents alveolar collapse at end expiration. We characterized the effects of cortisol and all trans-retinoic acid (RA) on SP-A and SP-B gene expression in H441 cells, a human pulmonary adenocarcinoma cell line. Cortisol, at 10(-6) M, caused a significant inhibition of SP-A mRNA to levels that were 60-70% of controls and a five- to sixfold increase in the levels of SP-B mRNA. RA alone (10(-6) M) had no effect on SP-A mRNA levels and modestly reduced the inhibitory effect of cortisol. RA alone and the combination of cortisol and RA both significantly increased SP-B mRNA levels. RA had no effect on the rate of SP-A gene transcription or on SP-A mRNA stability. Cortisol alone and the combination of cortisol and RA significantly inhibited the rate of SP-A gene transcription but had no effect on SP-A mRNA half-life. RA at 10(-6) M had no effect on the rate of SP-B gene transcription but prolonged SP-B mRNA half-life. Cortisol alone and the combination of cortisol and RA caused a significant increase in the rate of SP-B gene transcription and also caused a significant increase in SP-B mRNA stability. We conclude that RA has no effect on SP-A gene expression and increases SP-B mRNA levels by an effect on SP-B mRNA stability and not on the rate of SP-B gene transcription. In addition, the effects of the combination of RA and cortisol were generally similar to those of cortisol alone.

Carbohydrate-deficient glycoprotein syndrome type 1 with profound thrombocytopenia and normal phosphomannomutase and phosphomannose isomerase activities

We report siblings with a variant of carbohydrate-deficient glycoprotein syndrome, type 1 (CDGS1), characterized by normal phosphomannomutase and phosphomannose isomerase activities, severe thrombocytopenia, and respiratory compromise. Each infant died after a course of intensive care, suggesting that infants with CDGS1 and normal phosphomannomutase and phosphomannose isomerase activities may have a more severe CDGS1 phenotype.

Non-immune hydrops fetalis caused by herpes simplex virus type 2 in the setting of recurrent maternal infection

We report a case of non-immune hydrops fetalis (NIHF) caused by herpes simplex virus type 2 (HSV-2) in an infant whose mother had recurrent HSV-2 infection. In spite of prematurity, severe disseminated infection and hydrops, the infant survived and was neurologically intact. HSV-2-induced NIHF is extremely rare, particularly in the setting of recurrent maternal infection, and this case is, to our knowledge, the first report of a surviving infant. HSV-2 should be considered in the differential diagnosis of NIHF and early initiation of empiric acyclovir therapy is recommended in this setting, pending the results of virologic diagnostic tests.

Insulin and Lung Development

Infants of diabetic mothers have an elevated incidence of respiratory distress syndrome of the newborn (RDS), a disease which is caused by pulmonary surfactant deficiency associated with inadequate numbers of differentiated alveolar type II cells in the lung (1,2). Pulmonary surfactant, which functions to reduce surface tension at the air-alveolar interface, is made up of glycerophospholipids (approx 80% by weight), cholesterol (approx 10%) and the surfactant-associated proteins (approx 10%) (3). The fetus of the diabetic mother tends to have high serum glucose and insulin levels as a result of maternal hyperglycemia (4). Robert et al. (1) first advanced the hypothesis that high levels of insulin might delay lung development in the fetus of the gestational diabetic woman. In this chapter, we will review the literature concerning the effects f maternal diabetes, glucose, and, in particular, insulin on fetal lung development.

The effect of inhaled nitric oxide (iNO) on bleeding time and platelet aggregation in neonates. † 886

The effect of inhaled nitric oxide (iNO) on bleeding time and platelet aggregation in neonates. † 886

Variation in the Phototherapy Practices and Irradiance of Devices in a Major Metropolitan Area

Background: Phototherapy (PT) is widely used to prevent and treat severe hyperbilirubinemia and its associated risks for both acute and chronic bilirubin encephalopathy. Intensive PT, recommended for inpatient treatment of hyperbilirubinemia in term and near-term infants, is defined as having a spectral irradiance of ≥30 μW/cm2/nm. Objectives: We aimed to assess local PT practices by measuring the irradiance of PT devices in local neonatal intensive care units and newborn nurseries. Methods: The irradiance footprint, including maximum irradiance at the center of the footprint, of 39 PT devices in 7 area hospitals was measured according to current practice in these facilities. Results: The mean ± SD (range) footprint irradiance was 20.7 ± 5.8 (8.8-29.4) μW/cm2/nm. The mean ± SD maximum irradiance at the footprint center for all devices at a mean clinically used treatment distance of 33.1 ± 9.3 (25.5-60.0) cm was 27.8 ± 7.0 (14.7-42.0) μW/cm2/nm. Sixty-two percent of the devices did not meet the minimum recommended spectral irradiance for intensive PT. For the sites without irradiance-based protocols, the maximum irradiance of the devices (n = 33) at the treatment distances was 25.8 ± 6.1 μW/cm2/nm. Conclusions: Despite established PT guidelines, local protocols and practices vary. Based on an assessment of 7 local hospitals, intensive PT was suboptimal for 62% of devices. Straightforward changes, such as decreasing the distance between an infant and the light source and establishing a consistent irradiance-based protocol, could substantially improve the quality of the intervention.

Neonatal Respiratory Failure Caused by Congenital Diffuse Intrinsic Pontine Glioma.

The authors present a case of diffuse intrinsic pontine glioma presenting in a newborn with stridor and respiratory distress that progressed to respiratory failure. Magnetic resonance imaging (MRI) of the brain revealed findings compatible with the diagnosis of diffuse intrinsic pontine glioma. The family pursued palliative care and postmortem examination confirmed WHO grade III astrocytoma.