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Do neonatal androgen levels affect antibody production?
158
Abstracts
The Journal of Pediatrics January 1980
19.8 + 1.1 /~g/dl at one hour and then remained between 16.0 _+ 1.3 and 16.8 _+ 1.3 ~g/dl until sacrifice. The mean serum [T4] was significantly greater in the Tcinfused F compared to the S-infused F throughout the 72-hour infusion period. The mean lung tissue protein and DNA concentrations, protein/DNA ratios, and tracheal fluid L/S ratios were similar in the S- and T4-infused F. Histologic examination of the S-infused F lung tissue revealed areas of mature lung and areas of hypercellularity and thickened septae compatible with the canalicular stage of development. The T4-infused F lung tissue was homogenous in its mature state of development. CONCLUSION Administration of low doses of T~ to the euthyroid ovine F at 130 days gestation appears to affect the mesenchymal portion of the lung and accelerate alveolarization but not to accelerate surfactant maturation.
Prostaglandin treatment of infants with cyanotic congenital heart disease G. William Henry,* Roger A. Hurwitz, Donald A. Girod, M.D., Randall L, Caidwell, M.D., and Harold King, M.D., Indianapolis, Ind. Neonates with severe obstruction to pulmonary blood flow may depend on persistence of a patent ductus arteriosus for the maintenance of adequate systemic oxygenation. Since February, 1977, 19 such infants have received a prostaglandin E (PGE 0 infusion in an attempt to preserve ductal patency. The PGE~, administered by scalp vein, was begun at age 24 hours to 9 days, and duration varied from 5 hours to intermittently over 13 days.
Table III
Prior to PGE1 Initial post-PGE1 Maximum post-PGE1
Mean Pa,,~ (mm Hg)
Range (mm Hg)
25 52 63
14-32 31-125 31-125
Dosages ranged from 0.025 to 0.3 /~g/kg/minute. All 19 infants had a marked rise in arterial Po._, (Pa%) (Table llI). The difference between Pa% prior to PGEI and during the PGE, was highly significant (P < 0.001). No other cardiovascular side effects such as systemic hypotension or arrhythmias were noted. Systemic side effects included mild pyrexia in 5, seizures in 2 (both were febrile; one had hypomagnesemia and sever~ hypocalcemia), and occasional flushing. There were no deaths prior to or during the 26 surgical procedures. Ten infants have survived for 3 to 19 months. This study indicates that PGE1, administered by peripheral vein, is effective in maintaining duetal patency in neonates with severe right ventricular outflow obstruction.
Hepatic cholestasis associated with parentera! nutrition in infancy: Incidence and clinical utility of liver function tests Richard Inwood,* Rita Vileisis,* and Carl E. Hunt, Chicago, Ill. Parenteral nutrition (PN) is extensively used in critically ill neonates and infants. Hepatic dysfunction with cholestasis is a now well-recognized complication whose etiology and management are still controversial. Total and direct bilirubin (TB and DB), serum glutamic oxalacetic and glutamic pyruvic transaminases (SGOT and SGPT), and alkaline phosphatase (ALP) were measured weekly to better define the incidence and proper management of infants undergoing PN in the Neonatal 1CU at Children's Memorial Hospital. All infants received Aminosyn, glucose, and Intralipid, according to our standard protocol. During a 9-month period, 8 of the 42 infants who received PN developed hepatic cholestasis as defined by a DB _> 2.0 mg/dl. No infant on PN for < 14 days developed cholestasis, whereas 35% (8/23) on prolonged PN (~> 14 days) developed cholestasis. Cholestatic (Ch) infants had significantly shorter gestations and lower birth weights (P < 0.05) than noncholestatic (NCh) infants on prolonged PN. The duration of exposure to PN was similar for Ch and NCh infants on prolonged PN. SGOT and SGPT did not rise preceding the onset of cholestasis. Although ALP values became significantly higher in Ch infants versus NCh infants at one week prior to onset of cholestasis, there was no significant difference in ALP values at time of onset. Thus, there is no apparent benefit to measuring SGOT, SGPT, and ALP prior to onset of cholestasis. The etiology of PN-associated cholestasis has not yet been clarified. Nevertheless, in all patients the abnormal fiver function values progressively returned to normal after PN was discontinued.
Do neonatal androgen levels affect antibody productiJn? Jean F. Kenny and Pamela C. Pangburn,* Pittsburgh, Pa., and Sioux Falls, S. D. The reasons that male infants are more susceptible to infections in early infancy, particularly with gram-negative bacteria, remain obscure. Although data suggest that postpubertal levels of estrogen (E) in females may enchance immunity, levels of E in male and female infants are low and insignificantly different. Recent data, however, show marked sex differences in serum concentrations (C) of testosterone (T) in infancy, with levels in males of 0 to 3 months ranging from 350 to 2,000 pg/ml, and those in females of the same age from 50 to 100 pg/ml. To determine what effects these C of T might have on numbers of anti-bacterial antibody-producing cells (APC), spleen cell suspensions from outbred male Swiss mice, injected with 3 x 10~' heat-killed Escherichia coli 3 days before, were incubated in vitro with C of T ranging from 5 to 5,000 pg/ml. After 24 hours, numbers of anti-E.coli APC as determined in an agar-gel were compared for T-treated and untreated (U) portions of the same suspension. At 50 pg/ml, 21 of 27 (77%) of the T-treated suspensions had increased numbers of APC over the U
Volume 96 Number 1
(P = 0.003). The mean number of 1,280 APC/spleen for T-treated was 45% greater than that of the U. By contrast, at 500 pg/ml and above, APC were significantly reduced; at 500 pg/ml 27 of 36 suspensions had fewer APC than U (P = 0.002). T-treated suspensions averaged 42% fewer. Comparable studies show that at C of estradiol (E0 of 500 to 5,000 pg/ml and of progesterone (P) of 500 pg to 50 ng/ml, increases in APC occur, but at C of 50 ng/ml and 500 ng/ml of these hormones respectively, APC are reduced. Thus, T, E~, and P enhance at lower C and suppress numbers of APC at higher C. On a molar basis, T is the most potent hormone, with its effects at the lowest C. Findings suggest that serum levels o f T in male infants may suppress, whereas those in female infants may enhance, the proliferation and/or differentiation of antibacterial APC.
Characteristics of insulin binding to human fetal and rat myocardial membranes James Stevens,* and J.A. Whitsett* (Introduced by R. Tsang), Cincinnati, Ohio The effects o f insulin on tissue metabolism are regulated by its interaction with insulin receptors present in the plasma membranes o f numerous tissues. Previous studies have demonstrated that insulin is involved in the regulation of myocardial metabolism; however, little is known about possible insulin receptors in this tissue, especially in the neonatal period. In the present study insulin receptor activity was characterized in the human neonatal heart obtained at autopsy and compared with those demonstrated in purified membrane fractions of rat myocardium. Membrane fractions were prepared by differential and sucrose gradient centrifugafion from 5 neonatal myocardial samples obtained immediately post mortem. Insulin receptor activity was determined by ~~ binding assessed by Millipore filtration. Binding was linearly related to membrane protein 50 to 500/~g and was dependent on time, l~sI-iodoinsulin concentrations, and temperature. Scatchard analysis of the binding demonstrated by curvilinear plot suggested negative cooperativity in both fetal and adult samples. Marked insulin degradation activity was noted in samples of human heart at 20 ~ and 37 ~ but was much less at 0 ~ Myocardial plasma membranes were purified by sucrose gradient centrifugation and found to be sixfold enriched in adenylate cyclase, 5'nucleotidase and to have specific insulin binding. The human neonatal heart is rich in insulin receptors and contains marked insulin degrading capacity, suggesting an important role for insulin in the developing myocardium.
Oxytocin and natriuresis in adult and newborn dogs L.I. Kleinman, R.O. Banks,* and R. Gorewit,* Cincinnati, OH and Ithaca, N.Y. Why do kidneys of adult animals but not newborns excrete a large sodium (Na) load? Can this be related to a natriuretic factor? Eleven newborn, 9 adult intact, and 18 adult hypophysectomized (HPX) dogs were volume expanded (8 to 10%) with isotonic saline. Prior to saline loading, fractional excretion of Na
Abstracts
15 9
(FENa) for all groups was similar. Following saline, FENa (%) was greater (P < 0.01) for intact adults (5s _+ 0.6) than for HPX adults (1.3 • 0.3) and puppies (2.8 + 0.7). When salineexpanded newborns and HPX adults were given oxytocin (8 to 10 mU/kg/minute) for two hours. FENa rose signficantly (P < 0.01) to 7.5 • 1.1 and 5.9 _+ 0.4, respectively. In salineexpanded HPX dogs, oxytocin produced a marked reduction in fractional free-water clearance but not fractional urine excretion, suggesting inhibition of Na reabsorption in the diluting segment of the Henle loop. Serum oxytocin levels were measured (radioimmunoassay) in 4 intact adult and 4 newborn dogs before and after saline expansion, tn adults prior to saline, serum oxytocin was 14.5 _+ 1.1/LU/ml and rose to 66.7 • 12.1 following saline. In newborns, oxytocin levels prior to saline were always < 10 ~U/ml. In three puppies with poor natriuretic response to saline, serum oxytocin did not change after saline. In one puppy with a marked natriuresis (FENa = 10.5%), serum oxytocin rose to > 100/zU/ml after saline. These results indicate that oxytocin is necessary for a good natriuretic response to saline loading and that the attenuated natriuretic response to saline loading in the newborn is related to lower serum oxytocin levels. Oxytocin appears to inhibit Na reabsorption in the Henle loop. (Supported in part by the American Heart Association.)
Pharmacokinetic analysis of dosedependent conversion of' cortisone to cortisol Win. H. Barr,* Thomas Aeeto, Jr.,* and John Rider* (Introduced by Jean F. Kenny), Buffalo, N. YI, Charlottesville, Va., and Sioux Falls, S. D., To determine the efficiency of conversion as a function of dose, relative amount of the biologically active metabolite of cortisone (E), hydroeortisone (F), available in systemic circulation was determined following the oral administration of 5 and 50 mg of E containing 1 to 6/~c 14c-E. Twenty-six studies were done: 8 well subjects; 7 children with adrenogenital syndrome; 5 with growth hormone deficiency; 2 with Crohn disease. Plasma concentrations of F were determined by liquid scintillation counting following TLC separation using silica gel HG-254 and a solvent system of methylene chloride-ethanol (90-10). Relative fraction of F which reaches the systemic circulation was estimated by using the area under the plasma concentration time curve normalized for differences in the radioactive dose and surface area of the subject (AUC'), AUC' values of F for 50 mg E given intravenously is only slightly greater than when 50 mg E was given orally, but the F to E ratio was much greater by the oral route, indicating a greater preponderance of the E to F conversion pathway during the absorptive phase. Mean normalized AUC values (in units of percent radioactive dose, l/minute) for5 and 50 mg dose were 283.5 (SD • 104.7) and 157.8 (SD _+ 80.6), respectively (P = < 0.001), indicating almost a 50% difference in conversion efficiencies at two doses. CONCLUSION Conversion o f E to F is dose dependent at 5 to 50 mg dosage range, apparently due to saturable enzymes in the gut and liver and/or saturable transcortin binding during the absorptive
Abstracts
The Journal of Pediatrics January 1980
19.8 + 1.1 /~g/dl at one hour and then remained between 16.0 _+ 1.3 and 16.8 _+ 1.3 ~g/dl until sacrifice. The mean serum [T4] was significantly greater in the Tcinfused F compared to the S-infused F throughout the 72-hour infusion period. The mean lung tissue protein and DNA concentrations, protein/DNA ratios, and tracheal fluid L/S ratios were similar in the S- and T4-infused F. Histologic examination of the S-infused F lung tissue revealed areas of mature lung and areas of hypercellularity and thickened septae compatible with the canalicular stage of development. The T4-infused F lung tissue was homogenous in its mature state of development. CONCLUSION Administration of low doses of T~ to the euthyroid ovine F at 130 days gestation appears to affect the mesenchymal portion of the lung and accelerate alveolarization but not to accelerate surfactant maturation.
Prostaglandin treatment of infants with cyanotic congenital heart disease G. William Henry,* Roger A. Hurwitz, Donald A. Girod, M.D., Randall L, Caidwell, M.D., and Harold King, M.D., Indianapolis, Ind. Neonates with severe obstruction to pulmonary blood flow may depend on persistence of a patent ductus arteriosus for the maintenance of adequate systemic oxygenation. Since February, 1977, 19 such infants have received a prostaglandin E (PGE 0 infusion in an attempt to preserve ductal patency. The PGE~, administered by scalp vein, was begun at age 24 hours to 9 days, and duration varied from 5 hours to intermittently over 13 days.
Table III
Prior to PGE1 Initial post-PGE1 Maximum post-PGE1
Mean Pa,,~ (mm Hg)
Range (mm Hg)
25 52 63
14-32 31-125 31-125
Dosages ranged from 0.025 to 0.3 /~g/kg/minute. All 19 infants had a marked rise in arterial Po._, (Pa%) (Table llI). The difference between Pa% prior to PGEI and during the PGE, was highly significant (P < 0.001). No other cardiovascular side effects such as systemic hypotension or arrhythmias were noted. Systemic side effects included mild pyrexia in 5, seizures in 2 (both were febrile; one had hypomagnesemia and sever~ hypocalcemia), and occasional flushing. There were no deaths prior to or during the 26 surgical procedures. Ten infants have survived for 3 to 19 months. This study indicates that PGE1, administered by peripheral vein, is effective in maintaining duetal patency in neonates with severe right ventricular outflow obstruction.
Hepatic cholestasis associated with parentera! nutrition in infancy: Incidence and clinical utility of liver function tests Richard Inwood,* Rita Vileisis,* and Carl E. Hunt, Chicago, Ill. Parenteral nutrition (PN) is extensively used in critically ill neonates and infants. Hepatic dysfunction with cholestasis is a now well-recognized complication whose etiology and management are still controversial. Total and direct bilirubin (TB and DB), serum glutamic oxalacetic and glutamic pyruvic transaminases (SGOT and SGPT), and alkaline phosphatase (ALP) were measured weekly to better define the incidence and proper management of infants undergoing PN in the Neonatal 1CU at Children's Memorial Hospital. All infants received Aminosyn, glucose, and Intralipid, according to our standard protocol. During a 9-month period, 8 of the 42 infants who received PN developed hepatic cholestasis as defined by a DB _> 2.0 mg/dl. No infant on PN for < 14 days developed cholestasis, whereas 35% (8/23) on prolonged PN (~> 14 days) developed cholestasis. Cholestatic (Ch) infants had significantly shorter gestations and lower birth weights (P < 0.05) than noncholestatic (NCh) infants on prolonged PN. The duration of exposure to PN was similar for Ch and NCh infants on prolonged PN. SGOT and SGPT did not rise preceding the onset of cholestasis. Although ALP values became significantly higher in Ch infants versus NCh infants at one week prior to onset of cholestasis, there was no significant difference in ALP values at time of onset. Thus, there is no apparent benefit to measuring SGOT, SGPT, and ALP prior to onset of cholestasis. The etiology of PN-associated cholestasis has not yet been clarified. Nevertheless, in all patients the abnormal fiver function values progressively returned to normal after PN was discontinued.
Do neonatal androgen levels affect antibody productiJn? Jean F. Kenny and Pamela C. Pangburn,* Pittsburgh, Pa., and Sioux Falls, S. D. The reasons that male infants are more susceptible to infections in early infancy, particularly with gram-negative bacteria, remain obscure. Although data suggest that postpubertal levels of estrogen (E) in females may enchance immunity, levels of E in male and female infants are low and insignificantly different. Recent data, however, show marked sex differences in serum concentrations (C) of testosterone (T) in infancy, with levels in males of 0 to 3 months ranging from 350 to 2,000 pg/ml, and those in females of the same age from 50 to 100 pg/ml. To determine what effects these C of T might have on numbers of anti-bacterial antibody-producing cells (APC), spleen cell suspensions from outbred male Swiss mice, injected with 3 x 10~' heat-killed Escherichia coli 3 days before, were incubated in vitro with C of T ranging from 5 to 5,000 pg/ml. After 24 hours, numbers of anti-E.coli APC as determined in an agar-gel were compared for T-treated and untreated (U) portions of the same suspension. At 50 pg/ml, 21 of 27 (77%) of the T-treated suspensions had increased numbers of APC over the U
Volume 96 Number 1
(P = 0.003). The mean number of 1,280 APC/spleen for T-treated was 45% greater than that of the U. By contrast, at 500 pg/ml and above, APC were significantly reduced; at 500 pg/ml 27 of 36 suspensions had fewer APC than U (P = 0.002). T-treated suspensions averaged 42% fewer. Comparable studies show that at C of estradiol (E0 of 500 to 5,000 pg/ml and of progesterone (P) of 500 pg to 50 ng/ml, increases in APC occur, but at C of 50 ng/ml and 500 ng/ml of these hormones respectively, APC are reduced. Thus, T, E~, and P enhance at lower C and suppress numbers of APC at higher C. On a molar basis, T is the most potent hormone, with its effects at the lowest C. Findings suggest that serum levels o f T in male infants may suppress, whereas those in female infants may enhance, the proliferation and/or differentiation of antibacterial APC.
Characteristics of insulin binding to human fetal and rat myocardial membranes James Stevens,* and J.A. Whitsett* (Introduced by R. Tsang), Cincinnati, Ohio The effects o f insulin on tissue metabolism are regulated by its interaction with insulin receptors present in the plasma membranes o f numerous tissues. Previous studies have demonstrated that insulin is involved in the regulation of myocardial metabolism; however, little is known about possible insulin receptors in this tissue, especially in the neonatal period. In the present study insulin receptor activity was characterized in the human neonatal heart obtained at autopsy and compared with those demonstrated in purified membrane fractions of rat myocardium. Membrane fractions were prepared by differential and sucrose gradient centrifugafion from 5 neonatal myocardial samples obtained immediately post mortem. Insulin receptor activity was determined by ~~ binding assessed by Millipore filtration. Binding was linearly related to membrane protein 50 to 500/~g and was dependent on time, l~sI-iodoinsulin concentrations, and temperature. Scatchard analysis of the binding demonstrated by curvilinear plot suggested negative cooperativity in both fetal and adult samples. Marked insulin degradation activity was noted in samples of human heart at 20 ~ and 37 ~ but was much less at 0 ~ Myocardial plasma membranes were purified by sucrose gradient centrifugation and found to be sixfold enriched in adenylate cyclase, 5'nucleotidase and to have specific insulin binding. The human neonatal heart is rich in insulin receptors and contains marked insulin degrading capacity, suggesting an important role for insulin in the developing myocardium.
Oxytocin and natriuresis in adult and newborn dogs L.I. Kleinman, R.O. Banks,* and R. Gorewit,* Cincinnati, OH and Ithaca, N.Y. Why do kidneys of adult animals but not newborns excrete a large sodium (Na) load? Can this be related to a natriuretic factor? Eleven newborn, 9 adult intact, and 18 adult hypophysectomized (HPX) dogs were volume expanded (8 to 10%) with isotonic saline. Prior to saline loading, fractional excretion of Na
Abstracts
15 9
(FENa) for all groups was similar. Following saline, FENa (%) was greater (P < 0.01) for intact adults (5s _+ 0.6) than for HPX adults (1.3 • 0.3) and puppies (2.8 + 0.7). When salineexpanded newborns and HPX adults were given oxytocin (8 to 10 mU/kg/minute) for two hours. FENa rose signficantly (P < 0.01) to 7.5 • 1.1 and 5.9 _+ 0.4, respectively. In salineexpanded HPX dogs, oxytocin produced a marked reduction in fractional free-water clearance but not fractional urine excretion, suggesting inhibition of Na reabsorption in the diluting segment of the Henle loop. Serum oxytocin levels were measured (radioimmunoassay) in 4 intact adult and 4 newborn dogs before and after saline expansion, tn adults prior to saline, serum oxytocin was 14.5 _+ 1.1/LU/ml and rose to 66.7 • 12.1 following saline. In newborns, oxytocin levels prior to saline were always < 10 ~U/ml. In three puppies with poor natriuretic response to saline, serum oxytocin did not change after saline. In one puppy with a marked natriuresis (FENa = 10.5%), serum oxytocin rose to > 100/zU/ml after saline. These results indicate that oxytocin is necessary for a good natriuretic response to saline loading and that the attenuated natriuretic response to saline loading in the newborn is related to lower serum oxytocin levels. Oxytocin appears to inhibit Na reabsorption in the Henle loop. (Supported in part by the American Heart Association.)
Pharmacokinetic analysis of dosedependent conversion of' cortisone to cortisol Win. H. Barr,* Thomas Aeeto, Jr.,* and John Rider* (Introduced by Jean F. Kenny), Buffalo, N. YI, Charlottesville, Va., and Sioux Falls, S. D., To determine the efficiency of conversion as a function of dose, relative amount of the biologically active metabolite of cortisone (E), hydroeortisone (F), available in systemic circulation was determined following the oral administration of 5 and 50 mg of E containing 1 to 6/~c 14c-E. Twenty-six studies were done: 8 well subjects; 7 children with adrenogenital syndrome; 5 with growth hormone deficiency; 2 with Crohn disease. Plasma concentrations of F were determined by liquid scintillation counting following TLC separation using silica gel HG-254 and a solvent system of methylene chloride-ethanol (90-10). Relative fraction of F which reaches the systemic circulation was estimated by using the area under the plasma concentration time curve normalized for differences in the radioactive dose and surface area of the subject (AUC'), AUC' values of F for 50 mg E given intravenously is only slightly greater than when 50 mg E was given orally, but the F to E ratio was much greater by the oral route, indicating a greater preponderance of the E to F conversion pathway during the absorptive phase. Mean normalized AUC values (in units of percent radioactive dose, l/minute) for5 and 50 mg dose were 283.5 (SD • 104.7) and 157.8 (SD _+ 80.6), respectively (P = < 0.001), indicating almost a 50% difference in conversion efficiencies at two doses. CONCLUSION Conversion o f E to F is dose dependent at 5 to 50 mg dosage range, apparently due to saturable enzymes in the gut and liver and/or saturable transcortin binding during the absorptive