Akihiko Noguchi

Multicenter controlled trial comparing high-frequency jet ventilation and conventional mechanical ventilation in newborn infants with pulmonary interstitial emphysema

One hundred forty-four newborn infants with pulmonary interstitial emphysema were stratified by weight and severity of illness, and randomly assigned to receive treatment with high-frequency jet ventilation (HFJV) or rapid-rate conventional mechanical ventilation (CV) with short inspiratory time. If criteria for treatment failure were met, crossover to the alternate ventilatory mode was permitted. Overall, 45 (61%) of 74 infants met treatment success criteria with HFJV compared with 26 (37%) of 70 treated with CV (p less than 0.01). Eighty-four percent of patients who crossed over from CV to HFJV initially responded to the new treatment, and 45% ultimately met success criteria on HFJV. In contrast, only 9% of those who crossed over from HFJV to CV responded well to CV (p less than 0.01), and the same 9% ultimately met success criteria (p less than 0.05). Therapy with HFJV resulted in improved ventilation at lower peak and mean airway pressures, as well as more rapid radiographic improvement of pulmonary interstitial emphysema, in comparison with rapid-rate CV. Survival by original assignment was identical. When survival resulting from rescue by the alternate therapy in crossover patients was excluded, the survival rate was 64.9% for HFJV, compared with 47.1% for CV (p less than 0.05). The incidence of chronic lung disease, intraventricular hemorrhage, patent ductus arteriosus, airway obstruction, and new air leak was similar in both groups. We conclude that HFJV, as used in this study, is safe and is more effective than rapid-rate CV in the treatment of newborn infants with pulmonary interstitial emphysema.

The influence of the wider use of surfactant therapy on neonatal mortality among blacks and whites

BACKGROUND Surfactant therapy reduces morbidity and mortality among premature infants with the respiratory distress syndrome (RDS). Fetal pulmonary surfactant matures more slowly in white than in black fetuses, and therefore RDS is more prevalent among whites than among blacks. We reasoned that the increased use of surfactant after its approval by the Food and Drug Administration (FDA) in 1990 might have reduced neonatal mortality more among whites than among blacks. METHODS We merged vital-statistics information for all 1563 infants with very low birth weights (500 to 1500 g) born from 1987 through 1989 or in 1991 and 1992 to residents of St. Louis with clinical data from the four neonatal intensive care units in the St. Louis area; we then compared neonatal mortality during two periods, one before and one after the FDAs approval of surfactant for clinical use (1987 through 1989 and 1991 through 1992). RESULTS The use of surfactant increased by a factor of 10 between 1987 through 1989 and 1991 through 1992. The neonatal mortality rate among all very-low-birth-weight infants decreased 17 percent, from 220.3 deaths per 1000 very-low-birth-weight babies born alive (in 1987 through 1989) to 183.9 per 1000 (in 1991 through 1992; P = 0.07). This decrease was due to a 41 percent reduction in the mortality rate among white newborns with very low birth weights (from 261.5 per 1000 to 155.5 per 1000; P = 0.003). In contrast, among black infants, the mortality rate for very-low-birth-weight infants did not change significantly (195.6 per 1000 and 196.8 per 1000). The relative risk of death among black newborns with very low birth weights as compared with white newborns with similar weights was 0.7 from 1987 through 1989 and 1.3 from 1991 through 1992 (P = 0.02). The differences in mortality were not explained by differences in access to surfactant therapy, by differences in mortality between black and white infants who received surfactant, or by differences in the use of antenatal corticosteroid therapy. CONCLUSIONS After surfactant therapy for RDS became generally available, neonatal mortality improved more for white than for black infants with very low birth weights.

Development and Testing of New Screening Method for Keratan Sulfate in Mucopolysaccharidosis IVA

Mucopolysaccharidosis IVA (MPS IVA), a progressive lysosomal storage disease, causes skeletal dysplasia through excessive storage of keratan sulfate (KS). We developed an ELISA-sandwich assay that used a MAb specific to KS. Forty-five blood and 59 urine specimens from MPS IVA patients (ages 1–65 y) were analyzed to determine whether KS concentration is a suitable marker for early diagnosis and longitudinal assessment of disease severity. Blood specimens were obtained from patients categorized as phenotypically severe (n = 36) and milder (n = 9). Urine specimens were also analyzed from patients categorized as severe (n = 56) and milder (n = 12), respectively. Blood KS levels (101–1525 ng/mL) in MPS IVA patients were two to eight times higher than those in age-matched controls (15–323 ng/mL). It was found that blood KS level varied with age and clinical severity. Blood KS levels in both MPS IVA and controls peaked between 5 and 10 y of age (mean, 776 versus 234 ng/mL, respectively). Blood levels in severe MPS IVA were 1.5 times higher than in the milder form. In contrast to blood, urine KS levels in both MPS IVA and controls peaked between 1 and 5 y (15.3 versus 0.26 mg/g creatinine), and thereafter declined with age. Urine KS level also varied with age and clinical severity, and the severe MPS IVA phenotype was associated with 6.7 times greater urine KS excretion than the milder one. These findings indicate that the new assay for blood or urine KS may be suitable for early diagnosis and longitudinal assessment of disease severity in MPS IVA.

Serum cortisol and dehydroepiandrosterone sulfate responses to adrenocorticotropin stimulation in premature infants.

Summary: ACTH stimulation tests were performed in 15 premature infants in a serial fashion at the ages of 5-10 days and 27-31 days. Six of the 15 had subsequent ACTH stimulation tests at 6-8 weeks and/or 12-13 weeks. The pre- and post-ACTH serum cortisol and dehydroepiandrosterone sulfate (DHAS) levels were determined by radioimmunoassay. The mean basal levels of cortisol, 55 ng/ml, and DHAS, 4108 ng/ml, were significantly higher (P< 0.05 and P < 0.025, respectively) at 5-10 days than those of 24 ng/ml and 1858 ng/ml, respectively, at 27-31 days. The mean net change (Δ) of cortisol after ACTH at 5-10 days, 95 ng/ml, increased significantly to 148 ng/ml at 27-31 days. However, ΔDHAS did not differ significantly between the two periods (1514 ng/ml vs. 972 ng/ml). Therefore, ΔDHAS/Δcortisol was lower (P < 0.05) at 27-31 days than at 5-10 days. No further significant changes were observed after 4 weeks of age in the levels of the two steroids. There was little correlation of basal levels between cortisol and DHAS, nor between Δcortisol and ΔDHAS at any age period we studied. There were four infants whose mothers had prenatal steroid treatment for the prevention of hyaline membrane disease and their values were not different from the other infants.Speculation: Increased responsiveness of cortisol to ACTH at 1 month of age may suggest that there is increasing 3β-hydroxysteroid dehydrogenase in the neonatal adrenal gland in this period. The well maintained DHAS responsiveness to ACTH until 3 months of age, however, implies that there is a persistence of fetal corticosteroidogenic pathways through the first months of life.

Identification of a common mutation in mucopolysaccharidosis IVA: correlation among genotype, phenotype, and keratan sulfate

AbstractMucopolysaccharidosis IVA (MPS IVA) is a lysosomal storage disorder caused by the deficiency of N-acetylgalactosamine-6-sulfate sulfatase (GALNS). Mutation screening of the GALNS was performed by genomic PCR and direct sequence analyses in 20 MPS IVA patients from Latin America. In this study, 12 different gene mutations including nine unreported ones were identified in 16 severe and four attenuated patients and accounted for 90.0% of the unrelated mutant alleles. The gene alterations were missense mutations except one insertion. Six recurrent mutations, p.A75G, p.G116S, p.G139S, p.N164T, p.R380S, and p.R386C, accounted for 5.0, 10.0, 5.0, 7.5, 5.0, and 32.5% of the unrelated mutant alleles, respectively. The p.R386C mutation was identified in all Latin American populations studied. Eleven mutations correlated with a severe form, while one mutation, p.R380S, was associated with an attenuated form. MPS IVA patients had an elevation of urine and plasma keratan sulfate (KS) concentrations compared with those of the age-matched control. KS concentrations in severe patients were higher than those in attenuated patients. These data provide evidence for extensive allelic heterogeneity and presence of a common mutation in Latin American patients. Accumulation of mutations with clinical description and KS concentration will lead us to predict clinical severity of the patient more precisely.

Developmental Changes of Tropoelastin Synthesis by Rat Pulmonary Fibroblasts and Effects of Dexamethasone

ABSTRACT: Lung elastin is an important extracellular structural protein and it has been postulated that it plays a regulatory role in alveolar formation. To study the developmental regulation of elastin gene expression, we examined the tropolastin (TE) production in primary culture of rat pulmonary fibroblasts (RPF). We found that developmental changes in elastin production as assessed by TE synthesis and 3.6-kb TE mRNA levels were similar for RPF and whole tissue except those results from iate gestation animals, with peak elastin expression occurring 7 d postnatally with a decline out to 21 d. At late gestation (20 d), TE mRNA was barely detectable in RPF but clearly detectable TE mRNA in the whole tissue, indicating that there are elastogenic cells other than RPF in the tissue at this age. When TE-producing cells were treated with dexamethasone, there was a dose-dependent stimulation of TE synthesis with the maximum response at 10-9 to 10-7 M. Interestingly, dexamethasone had no stimulatory effect on cells from late gestation animals. The developmental window of elastin synthesis in this RPF model between late gestation and 21 d postnatal seems to correlate with the reported period of secondary alveolar formation, and thus we speculate that RPF elastogenic activity reflects that of the alveolar wall. (Pediatr Res 28: 379–382, 1990)

Age-Related Changes in the Adrenergic Control of Glycogenolysis in Rat Liver: The Significance of Changes in Receptor Density

ABSTRACT: The present study examined the developmental changes in the adrenergic control of glycogenolysis in the rat model. A relatively new β-adrenergic radioligand, 125I-iodocyanopindolol (ICP), was examined in binding assays with rat liver plasma membrane (LPM). ICP demonstrated both a higher specificity and a greater affinity for β-adrenergic receptors than any previously available β- adrenergic radioligand used to study rat LPM. Utilizing this new ligand it was found that β-adrenergic receptor density decreased from 114 ± 4 fmol mg-1 in newborn LPM to 19 ± 3 fmol mg-1 in adult male LPM. In contrast α-adrenergie receptor density examined using 3H-prazosin increased from 161 ± 14 fmol mg-1 in the newborn to 554 ± 59 fmol mg-1 in the adult male. The results of ICP displacement assays employing various β2-adrenergic agonsists and antagonists indicated that ICP binding sites were β2-adrenergic receptors. Both guanosine triphosphate and its nonhydrolyzabie synthetic analog guanylyl-imidodiphosphate lowered the affinity of epinephrine for ICP binding sites similarly in newborn and adult LPM. Thus the coupling of receptor to guanine nucleotide regulatory protein appeared to be the same in both age groups examined. In isolated hepatocytes glycogen phosphorylase activation was mediated by β2-adrenergic stimuli in the newborn and predominantly a-adrenergic stimuli in the aduit male. These results suggest that the change in glycogen phosphorylase activation from β- to predominantly α-adrenergic mechanisms seen with maturation is related to changes in receptor density.

IGF-I stimulates tropoelastin synthesis in neonatal rat pulmonary fibroblasts

ABSTRACT: We have examined the effect of IGF-I on tropoelastin (TE) synthesis in cultured rat neonatal pulmonary fibroblasts, because this growth factor has been shown to stimulate TE synthesis in vascular smooth muscle cells. IGF-I stimulated TE and total protein synthesis in a dose-dependent manner even when cells were cultured in the medium supplemented with 0.5% FCS. The maximal stimulation was at IGF-I concentration 500 ng/mL and was an increase of 86 ± 14 and 35 ± 5% for TE and estimated total protein synthesis, respectively. There was a corresponding 95 ± 20% increase in the TE mRNA/β-actin mRNA ratio assessed by densitometry of the Northern blot analysis. At this low concentration of FCS, however, there was neither TE stimulation by dexamethasone alone nor in combination with IGF-I. We conclude that IGF-I stimulation of TE synthesis may occur in cells other than vascular smooth muscle cells and that there is no additive stimulation by glucocorticoids.

Effect of Catheter Dwell Time on Risk of Central Line–Associated Bloodstream Infection in Infants

BACKGROUND AND OBJECTIVE: Central venous catheters in the NICU are associated with significant morbidity and mortality because of the risk of central line–associated bloodstream infections (CLABSIs). The purpose of this study was to determine the effect of catheter dwell time on risk of CLABSI. METHODS: Retrospective cohort study of 13 327 infants with 15 567 catheters (93% peripherally inserted central catheters [PICCs], 7% tunneled catheters) and 256 088 catheter days cared for in 141 NICUs. CLABSI was defined using National Health Surveillance Network criteria. We defined dwell time as the number of days from line insertion until either line removal or day of CLABSI. We generated survival curves for each week of dwell time and estimated hazard ratios for CLABSI at each week by using a Cox proportional hazards frailty model. We controlled for postmenstrual age and year, included facility as a random effect, and generated separate models by line type. RESULTS: Median postmenstrual age was 29 weeks (interquartile range 26–33). The overall incidence of CLABSI was 0.93 per 1000 catheter days. Increased dwell time was not associated with increased risk of CLABSI for PICCs. For tunneled catheters, infection incidence was significantly higher in weeks 7 and 9 compared with week 1. CONCLUSIONS: Clinicians should not routinely replace uninfected PICCs for fear of infection but should consider removing tunneled catheters before week 7 if no longer needed. Additional studies are needed to determine what daily maintenance practices may be associated with decreased risk of infection, especially for tunneled catheters.

Tropoelastin gene expression in the rat pulmonary vasculature: a developmental study.

ABSTRACT: The elastic laminae in a vessel provide resilience to its wall. In perinatal and adult rats, we used in situ hybridization to localize the mRNA for tropoelastin (TE) in endothelial cells, medial smooth muscle cells, and adventitial fibroblasts of pulmonary arteries and veins to determine the contribution of these cells to laminae formation. We found that 1) all three cell types are elastogenic but for each the ontogenic pattern is different, 2) signal in the artery is strongest in the late fetal lung, 5) postnatally TE expression decreases first in the outer medial smooth muscle cells, and 4) the pattern of expression in arteries differs from that in veins. In the d 19 fetus, the signal for TE mRNA was higher in arteries than in veins. In the immediate postnatal period, the arterial signal declined, whereas the signal in veins increased. By postnatal d 21, the arterial TE signal per cell had significantly decreased to an intensity lower than that in veins. In the adult rat lung, no TE mRNA was detected by in situ hybridization. The reciprocal alterations in TE expression in pulmonary arteries and veins may suggest a response to the postnatal change in pulmonary blood pressure. We speculate that because all three cell types are potentially elastogenic they may all play a role in the remodeling that occurs after vascular injury.