Rolf R. Engel

Low thyroid hormones and respiratory-distress syndrome of the newborn. Studies on cord blood.

To investigate the relation between thyroid function and respiratory-distress syndrome we determined thyroid hormone in cord serum from 39 term and 120 premature newborns. In groups matched for gestational age (33 to 37 weeks) and body length, after exclusion of newborns with birth asphyxia, maternal diabetes and delivery by cesarean section, the newborns with respiratory distress syndrome had significantly lower cord tri-iodothyronine index, higher ratio of thyroxine to tri-iodothyronine and higher thyrotropin concentration than those without syndrome (P less than 0.05 or less). Conversely, the frequency and severity of respiratory-distress syndrome were higher in newborns who had low cord tri-iodothyronine and thyroxine concentration, low free tri-iodothyronine index and high thyrotropin levels. These observations show an association between low thyroid activity at birth and respiratory-distress syndrome and are in accord with animal studies showing accelerated lung maturation due to thyroxine administration.

Thyroid function in preterm infants with respiratory distress syndrome

Thyroid function was evaluated in premature infants 30 to 35 weeks EGA with severe RDS and was compared to that of healthy control subjects of similar EGA. The infants with RDS had significantly lower serum levels of T3, T4, and FT4I during the first 60, 90, and 30 days, respectively, and had elevated T3UR during the first 10 days. The mean (+/- SD) postdelivery TSH peak was lower in the RDS group (32.8 +/- 9.6 muU/ml) than in the control group (60.9 +/- 21.8 muU/ml; P less than 0.005). After TRH injection the increment in serum TSH was inversely related to the basal FT4I in the control infants but not in the infants with RDS.

Influence of Amylase Assay Technique on Renal Clearance of Amylase-Creatinine Ratio

The influence of amylase assay technique on the renal amylase/creatinine clearance measurement was determined by analysis of serum and urine specimens obtained from 10 normal subjects. CAm/CCr averaged 2.19 +/- 0.18% with a saccharogenic technique, 1.52 +/- 0.2% with an iodometric technique, and 0.80 +/- 0.08% with a chromogenic technique. Each of these values differed significantly (P less than 0.05) from the other two. Recovery studies were carried out by adding partially purified human salivary or pancreatic amylase to human newborn serum or urine (which contain minimal endogenous amylase). Equal amylase activity was recovered from serum and urine by the saccharogenic technique whereas recovery from urine was less than 50% of that from serum using the iodometric and chromogenic techniques. The accuracy of the chromogenic technique is markedly improved by the addition of albumin to the urine assay system. Although it appears that only the saccharogenic method provides an accurate estimate of CAm/CCr, each assay technique distinguished the elevated CAm/CCr of patients with pancreatitis from the normal range established for that technique. Accurate clinical interpretation of CAm/CCr measurment requires knowledge of the amylase assay technique used.

Tin protoporphyrin inhibits carbon monoxide production in adult mice.

ABSTRACT: We studied the effect of tin protoporphyrin, a potent inhibitor of heme oxygenase (EC 1.14.99.3), on carbon monoxide (CO) production in mature mice. Measurements of CO production provide a sensitive, noninvasive means of quantitating heme catabolism. CO accumulation in the gas space of closed chambers was decreased by about 25% for mice treated with two 50 nmol/g doses of tin protoporphyrin as compared to saline-treated controls. Calculated rates of CO production were 0.28 ± 0.07 and 0.40 ± 0.05 nmol-g-1h-1 for mice injected with tin protoporphyrin and saline, respectively (p < 0.01). When hemin (125 nmol/g) was administered to simulate hemolysis, CO production increased markedly in both saline- and tin protoporphyrin-treated mice. However, the rate of CO production in tin protoporphyrin-treated mice was only 44% that of saline-treated animals (p < 0.0001). These studies demonstrate that tin protoporphyrin inhibits heme catabolism in both the basal- and heme-loaded states and confirm that this inhibition is at the heme oxygenase step in the heme to bilirubin pathway.

543 EFFECT OF RACE AND OTHER VARIABLES ON TRANSCUTANEOUS BILIRUBINOMETRY

A non-invasive device for measuring cutaneous bilirubin has been evaluated on newborn infants to assess the effect of race, serum albumin level, site of measurement, breast feeding, and phototherapy. More than 560 comparisons between the Minolta transcutaneous bilirubinmeter (Pediatrics 65:195) and conventional serum bilirubin determinations (A.O. Bilirubinometer) confirmed Yamanouchi and Luceys report (Ped. Res. 14:604) of a correlation coefficient near 0.9, P <.001. Phototherapy produced a pronounced decrement in the correlation, apparently by reducing cutaneous bilirubin levels and increasing melanin pigmentation. Both of these effects of phototherapy were circumvented by placing an opaque patch on a skin site between measurements. Formula-fed black (n = 32), Oriental (n = 24), and white (n = 47) babies all had similar slopes (1.0), but the background signal was progressively higher for the darker races and phototherapy augmented this rise in the intercept. Native Americans (n = 24) had a lower slope (0.55) but a higher intercept than the other races. Surprisingly, the correlation coefficient for each of the other three racial groups was higher for bottle-fed (n = 103) than for breast-fed (n = 137) infants. As predicted, the ratio of skin to serum bilirubin level was inversely related to the serum albumin concentration for formula-fed infants (P <0.05) which raises the question of whether skin or serum measurements provide a better index of critical CNS levels.

Carbon monoxide generation from hydrocarbons at ambient and physiological temperature: a sensitive indicator of oxidant damage?

This paper shows that a variety of carbon-containing materials (wool, cotton, wood, paper, latex, Tygon) release CO during incubation at ambient temperature. This CO production was enhanced by aerobic versus anaerobic incubation, increasing temperature, and exposure to fluorescent light. CO production from glucose solutions was enhanced by alkaline pH or prior boiling or autoclaving and reduced by the presence of superoxide dismutase or catalase. We conclude that a variety of materials are constantly undergoing oxidation at ambient or physiological temperature as evidenced by the release of CO. Measurements of this CO production could provide a simple, rapid and sensitive means of assessing oxidative damage.

LOW THYROID ACTIVITY IN PREMATURES WITH RDS

Thyroid function was compared in prematures with RDS (PROS) and healthy prematures (controls) with EGA from 30 to 37 weeks, to determine how long the reported differences in cord blood persist. Compared to controls, PRDS had lower serum T4, T3 and free T4 index (FT4I) during the first 20 days. Sick prematures without RDS had Intermediate values.TSH at 1 to 3 hrs was lower in 6 PRDS (22.1 ± 4.1 μU/ml)** than In 9 controls (53.6 ± 6.4 μU/ml). TSH and FT4I were lowest tn PRDS with birth asphyxia, suggesting that early stress depresses these hormones. Injection of TRH increased TSH in 4 PRDS, ruling out pituitary unresponsiveness. It is important to determine whether early depression of thyroid function has adverse consequences, since 4 prematures with low T4 and T3 had symptomatic improvement (less apnea, better intestinal motllity and weight gain) in association with temporary T4 or T3 administration.

DOES HEME OXYGENASE ACTIVITY DEPEND ON THE VINYL SUBSTITUENTS OF HEME

Since cytochrome c and myoglobin are heme proteins, we tested the assumption that their catabolism contributes to endogenous CO production(Vco). Adult mice were injected with NaHCO3 solution or this solution containing equimolar amounts of myoglobin, cytochrome c, freshly dissolved hematin or hematin stored for 24 and 48 hrs. After the injection, each mouse was placed in a glass chamber from which gas was sampled at 4 and 23 hrs. Within 4 hrs of injecting myoglobin or freshly prepared hematin, the Vco was 2 to 4 fold greater than for control mice. Tin protoporphyrin prevented most of this rise in Vco suggesting that heme oxygenase mediated the reaction. In contrast, Vco 4 hrs after injecting either cytochrome c or stored hematin was indistinguishable from control mice. However between 4 to 23 hrs Vco increased and was comparable to myoglobin or fresh hematin treated animals. The cytochrome c heme differs from myoglobin or hemoglobin only in that the 2 vinyl groups are covalently linked to cysteine. Storage of hematin also alters these vinyl groups (NEJM 315:235, 1986). While these in vivo studies suggest that heme cleavage at the α methene bridge requires 2 vinyl groups on the adjacent pyrrole rings, in vitro studies (J Biol Chem 257:9944, 1982) suggest alternative explanations. The delayed increase in Vco from cytochrome c and aged hematin suggests either slow conversion to compounds that are cleaved by heme oxygenase or excretion and CO formation by enteric bacteria.

255 AN ADVENTAGEOUS ASYMMETRY IN THE BURSTING PRESSORE OF FETAL MEMBRANES

The association between prematurity and early rupture of amniotie membranes prompted studies of the tensile strength and elastic limit of human fetal membranes. Chorio-amniotic membranes were obtained from 14 uncomplicated, term pregnancies at the time of elective, repeat C-section. None of the mothers had been in labor, all of them had intact membranes prior to the section, and all of the infants were normal. Multiple sites were sampled from each amniotie sac by mounting samples between two circular surfaces (O.D. 3 cm) with a central tapered round hole (diameter 0.45 cm). Progressive increases in the pressure provided by a tank of compressed nitrogen were plotted by a X-Y plotter against the displacement of a rod by the stretched membrane up to the point of bursting.Human membranes had marked (>3 fold) variability in bursting pressure and elastic limit as compared to synthetic membranes of silicone or polyethylene polymer. There was a positive correlation between the pressure and the elastic limit at the point of bursting for samples of amnion (r=.53, p<10−6), chorion (r=.53, p<10−6) and the intact bilayer of the two membranes together (r=.27, p<10−6) but not for the synthetic membranes. The combination of amnion and chorion was about 7% stronger (p <.003) when pressure was applied from the fetal side as opposed to the maternal surface, although the bursting pressure of amnion or chorion alone was independent of the direction from which it was applied.

ASYMPTOMATIC HYPOGAMMAGLOBULINEMIA IN A MOTHER PRESENTING AS NEONATAL MENINGITIS IN TWO SIBLINGS

The unusual occurrence of group B streptococcal (GBS) disease in siblings lead to immune studies of a boy who mimicked his older sister in developing septicemia and meningitis from GBS by the 4th day of life. His serum IgG level was only 40 mg%. His IgM was 36 and IgA was < 7. Maternal levels were all low: IgG 40, IgM 36, IgA 14 and IgE<10 mg%.Despite 14 days of penicillin and intravenous immunoglobulins, the boys GBS (type Ic) meningitis recurred within 3 days with fever and a rise in the CSF leukocyte count from 20 to 2,025. He recovered completely during 2 more weeks of antibiotic Tx and at 7 months his Ig levels are normal. His sister had neonatal septicemia, meningitis, septic arthritis, and pneumonia which responded to 32 days of Tx. At 3 years, she is healthy with normal Ig levels: IgG 761, IgM 113, and IgA 62 mg%.The mother is healthy and has not had excess infections. GBS (type Ic) was also recovered from her vagina. She was unresponsive to rubella immunization. She has low levels of IgA in saliva: 2 mg%, and breast milk: 3 mg%. Her panhypogammaglobulinemia is associated with normal numbers of B cells that have IgA, IgG, and IgM surface markers. Her lymphocytes had a normal in vitro response to phytohemagglutinin, Concanavalin A, and pokeweed mitogen.This unique family emphasizes the importance of passive immunity in protecting newborns against GBS and it suggests that serious bacterial infections in neonates should prompt inquiry into the mothers immune competence.