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Biomedical subjects

M Hallman

Publications and source records attributed to M Hallman.

At least 19 recordsLinked to original sources
PubMed1992

Inositol supplementation in premature infants with respiratory distress syndrome.

BACKGROUND: Inositol influences cellular function and organ maturation. Feeding premature infants inositol-rich breast milk increases their serum inositol concentrations. Whether inositol supplementation benefits infants receiving fluids for parenteral nutrition, which are inositol-free, is not known. METHODS: We carried out a placebo-controlled, randomized, double-blind trial to determine the effects of administering inositol (80 mg per kilogram of body weight per day) during the first five days of life to 221 infants with respiratory distress syndrome who were receiving parenteral nutrition (gestational age, 24 to 32 weeks; birth weight, less than 2000 g). All the infants were treated with mechanical ventilation and some with surfactant as well. The primary end point was survival at 28 days without bronchopulmonary dysplasia. RESULTS: The 114 patients given inositol had significantly lower mean requirements for inspiratory oxygen (P less than 0.01) and mean airway pressure (P less than 0.05) from the 12th through the 144th hour of life than did the 107 infants given placebo. Eighty-one infants given inositol and 51 given placebo survived without bronchopulmonary dysplasia (71 vs. 55 percent; P = 0.005). In the 65 infants given surfactant, however, inositol had no effect on the degree of respiratory failure. Thirteen infants given inositol and 21 given placebo had retinopathy of prematurity (13 vs. 26 percent; P = 0.022); none of the infants given inositol had stage 4 disease, whereas 7 of those given placebo did (0 vs. 9 percent; P = 0.012). Among the infants given placebo, those who had poor outcomes (death, bronchopulmonary dysplasia, or stage 4 retinopathy of prematurity) had lower serum inositol concentrations during days 2 through 7 than those who had good outcomes (P less than 0.01). CONCLUSIONS: The administration of inositol to premature infants with respiratory distress syndrome who are receiving parenteral nutrition during the first week of life is associated with increased survival without bronchopulmonary dysplasia and with a decreased incidence of retinopathy of prematurity.

Bronchopulmonary Dysplasia↗
PubMed1992

Free radical activity during development of insulin-dependent diabetes mellitus in the rat.

Free radical-induced lipid peroxidation was quantified by measuring expired pentane from diabetic prone BB Wistar rats of 45-90 d of age. Insulin-dependent diabetes mellitus was manifest at the age of 71 +/- 8 d. Expired pentane increased from 2.1 +/- 0.7 to 5.0 +/- 3.0 pmol/100g/min (p less than 0.01) at manifestation of the disease and remained high throughout the test period. In healthy age-matched control rats it persisted low. In rats made diabetic with streptozotocin, expired pentane remained low. The changes in expired pentane suggest that the development of endogenous insulin-dependent diabetes mellitus in BB rats is associated with increased free radical activity. This is not due to hyperglycemia or ketosis per se, and reflects a fundamental difference in the free radical activity between the spontaneously diabetic BB rats and the disease produced by streptozotocin. Development of spontaneous insulin-dependent diabetes in BB rats is associated with increased free radical activity that persists after the manifestation of the disease.

Animals↗
PubMed1992

Transforming growth factor-beta opposes the stimulatory effects of interleukin-1 and tumor necrosis factor on amnion cell prostaglandin E2 production: implication for preterm labor.

OBJECTIVE: In preterm labor increased concentrations of interleukin-1 and tumor necrosis factor are present in amniotic fluid. These cytokines may promote labor by stimulating the production of prostaglandins by intrauterine tissues. In many biologic processes, transforming growth factor-beta modifies the actions of cytokines. We studied the effect of transforming growth factor-beta on the cytokine-induced prostaglandin E2 production by amnion cells. STUDY DESIGN: Human amnion cells in monolayer culture were treated with interleukin-1, tumor necrosis factor, or vehicle in the presence or absence of transforming growth factor-beta. The prostaglandin E2 production was measured. RESULTS: Transforming growth factor-beta decreased the interleukin-1- or tumor necrosis factor-induced prostaglandin E2 production by 70% to 80% and the basal prostaglandin E2 synthesis by 27%. The synergistic stimulation of prostaglandin E2 production by the combination of interleukin-1 with tumor necrosis factor was inhibited by 80% in cells treated with transforming growth factor-beta. Transforming growth factor-beta 1, -beta 2, and -beta 1,2 were equipotent. CONCLUSION: Transforming growth factor-beta suppresses the cytokine-induced prostaglandin E2 production by amnion cells and may be an important factor in maintaining pregnancy in the face of labor-promoting cytokines.

Amnion↗
PubMed1992

Premature rupture of the membranes: effect of penicillin prophylaxis and long-term outcome of the children.

To assess the value of prophylaxis with penicillin in women with premature rupture of membranes (PROM) and the long-term outcome of children born after prolonged PROM, we studied 221 women with this condition. Penicillin (5 mu twice, 6 hours apart) was given intravenously to 50 women and placebo to 51 women, whereas 76 comparable patients were treated without penicillin or placebo. The time interval between PROM and delivery ranged from 14 hours to 56 days. Chorioamnionitis occurred more frequently (p less than 0.05) among patients with placebo (14%) than among those treated with penicillin (2%). One puerperal endometritis appeared in the placebo group compared with none in the penicillin group. One newborn (1.7%) born to a mother with placebo prophylaxis developed septicemia, compared with none in the penicillin group. The outcomes of pregnancies complicated with PROM treated without penicillin or placebo were comparable with those in the placebo group. In addition, we compared somatic and psychomotor development of 159 children born to mothers with prolonged PROM (more than 12 hours; mean, 5.6 days; range, 14 to 1344 hours) with those of 43 children born at similar gestational age within 5 hours after PROM. No pulmonary sequelae could be linked to the long time period between PROM and delivery, but infants born soon after PROM more often (p less than 0.05) had cerebral palsy (8 of 43, 18.6%) than did infants born after prolonged PROM (7 of 159; 4.4%). We conclude that, in cases with PROM, penicillin prophylaxis decreases maternal and neonatal infectious morbidity and that the long interval between PROM and delivery does not impair the long-term outcome for these children.

Adult↗
PubMed1991

The effects of indomethacin and a beta-sympathomimetic agent on the fetal ductus arteriosus during treatment of premature labor: a randomized double-blind study.

To study the effect of maternal indomethacin or nylidrine hydrochloride treatment on the fetus ductus arteriosus and the pulmonary artery, 27 women with threatened preterm labor between 24 and 34 weeks' gestation were studied by echocardiography. Fourteen women were treated with indomethacin and 13 with nylidrin. Both systolic and diastolic velocities in the ductus increased after administration of indomethacin indicating constriction in nine fetuses, and exceeded the corresponding velocities in the fetuses of the nylidrin group (p = 0.001). However, there were no changes in pulmonary artery flow velocities (p greater than 0.5). In the indomethacin group, there was a significant linear positive relationship between the gestational age and the change in ductal flow velocity. Three of the nine patients with ductal constriction also had tricuspid regurgitation. These findings indicate that indomethacin, not nylidrin, causes transient constriction of the ductus arteriosus and the constrictive response increases with the gestational age. We recommend echocardiographic surveillance of fetal hemodynamics when prostaglandin synthesis inhibitors are used in the treatment of spontaneous preterm labor.

Blood Flow Velocity↗
PubMed1991

Synergistic stimulation of amnion cell prostaglandin E2 synthesis by interleukin-1, tumor necrosis factor and products from activated human granulocytes.

We examined the interactions between supernatant from FMLP-activated human granulocytes, recombinant interleukin-1 (IL-1) and recombinant tumor necrosis factor (TNF) in the stimulation of prostaglandin E2 (PGE2) production by human amnion cells. Amnion cells from elective term cesarian sections were cultured in monolayer culture. Human granulocytes were activated with FMLP and centrifuged to obtained cell-free supernatant. Amnion cells were treated with granulocyte supernatant, IL-1 alpha, IL-1 beta, TNF-alpha, TNF-beta, or different combinations of these. Each of the stimulators alone enhanced the PGE2 production 5- to 27-fold. Granulocyte supernatant was synergistic with each of the cytokines. The combinations of IL-1 alpha or IL-1 beta with either TNF-alpha or TNF-beta caused a synergistic stimulation of amnion cell PGE2 production as well, whereas the combinations of IL-1 alpha with IL-1 beta or of TNF-alpha with TNF-beta were not synergistic. Furthermore, granulocyte supernatant was synergistic with the combination of IL-1 and TNF, resulting in a more than 150-fold stimulation of PGE2 production. Indomethacin completely suppressed these effects. We propose that granulocyte products acting together with IL-1 and TNF enhance PGE2 synthesis during inflammation, and serve as signals for the initiation of preterm labor in the setting of intra-amniotic infection.

Amnion↗
PubMed1991

A product of activated human granulocytes stimulates prostaglandin E2 synthesis in human amnion cells.

Cell-free supernatant from formylmethionyl-leucyl-phenylalanine (fMLP)-activated granulocytes causes a time- and concentration-dependent stimulation of prostaglandin E2 (PGE2) production in amnion cells. PGE2 concentration in the culture medium after 36 h treatment with granulocyte supernatant (from 40 x 10(6) granulocytes/ml of amnion cell medium), 1.49 +/- 0.71 pg/ng DNA (n = 13), was significantly higher (p = 0.0015) than in control cells (0.33 +/- 0.23 pg/ng DNA, n = 13). Indomethacin abolished this stimulation. Granulocyte supernatant and human epidermal growth factor (hEGF) had an additive effect on amnion cell PGE2 production. Catalase, superoxide dismutase (SOD), protease inhibitors or the platelet-activating factor (PAF) antagonist L-659,989 had no effect. Actinomycin D, cycloheximide and mepacrine reduced the PGE2 production. The phospholipase A2 activity present in granulocyte supernatants was resistant to heating, whereas heating decreased their PGE2-stimulating activity by 92%. Exogenous phospholipase A2 had no effect on PGE2 synthesis. The granulocyte product could be precipitated with ammonium sulphate. On gel filtration of supernatant, two peaks of PGE2-synthesis stimulating activity were obtained (molecular weights 12,000 and 60,000). This data serve to explain the association of chorioamnionitis with preterm labor: activated granulocytes release a protein(s) that induces prostaglandin production in amnion cells, and thus promote labor.

Amnion↗
PubMed1991

Randomized, placebo-controlled trial of human surfactant given at birth versus rescue administration in very low birth weight infants with lung immaturity.

A randomized, placebo-controlled trial of human surfactant given intratracheally at birth (prophylactic) versus rescue administration after the onset of severe respiratory distress syndrome (RDS) was conducted among preterm infants born at 24 to 29 weeks of gestation. Singleton fetuses were randomly assigned to receive (1) placebo (air), (2) prophylactic surfactant treatment, or (3) rescue surfactant treatment; infants of multiple births received either (1) prophylactic or (2) rescue treatment. Of 282 potentially eligible fetuses, 246 infants received treatments at birth and 200 infants had RDS. Outcomes are presented both as an intention-to-treat analysis (including infants who met exclusion criteria at or after birth) and as a full treatment protocol analysis for those infants with RDS and likely to benefit from surfactant. Preterm infants (mean 1.0 kg birth weight, 27 to 28 weeks of gestational age) randomly assigned to receive prophylactic treatment received surfactant soon after birth; those assigned to receive rescue surfactant had instillation at a mean age of 220 minutes if the lecithin-sphingomyelin ratio was less than or equal to 2.0 and no phosphatidylglycerol was detected in either amniotic fluid or initial airway aspirate, oxygen requirements were a fraction of inspired oxygen of greater than 0.5, and mean airway pressure was greater than or equal to 7 cm H2O from 2 to 12 hours after birth. Up to four treatment doses (or air) were permitted within 48 hours; approximately 60% of surfactant-treated infants required two or more doses. Surfactant-treated infants had significantly less pulmonary interstitial emphysema than placebo-treated infants (p = 0.02), but there were no other significant differences in mortality rates or morbidity. Indexes of oxygenation and ventilation were improved in surfactant recipients during the first 24 hours. An intention-to-treat analysis found no significant differences between infants given placebo and surfactant-treated infants or between prophylactic- and rescue-treated infants; an improved total mortality rate (p = 0.002) was found among surfactant-treated infants in Helsinki but not in San Diego. Among infants with RDS, the total mortality rate was significantly improved (p = 0.004) with surfactant treatment but not the proportion alive and without bronchopulmonary dysplasia at 28 days (p = 0.052), or the proportion alive and without bronchopulmonary dysplasia at 38 weeks of postconceptional age (p = 0.18) to adjust for differences in prematurity. Deaths caused by RDS or bronchopulmonary dysplasia were significantly reduced among surfactant recipients (p = 0.0001). Neither among singletons nor among multiple-birth infants was there a selective advantage to prophylactic versus rescue treatment.(ABSTRACT TRUNCATED AT 400 WORDS)

Bronchopulmonary Dysplasia↗
PubMed1991

Immunogenicity of surfactant. I. Human alveolar surfactant.

The immunogenicity of lung surfactant derived from amniotic fluid has been well established. We have set out to examine the antigenic similarity of human surfactant to non-human alveolar surfactants currently being used therapeutically in clinical trials with neonatal respiratory distress syndrome. To this end, we raised a series of eight monoclonal antibodies in rats directed to human surfactant (H1 to H8). All antibodies bound human surfactant as measured by ELISA. Four of these monoclonal antibodies bound surfactant components by Western blot analysis: all bound a 9-10-kD species. In addition, one antibody (H2) bound a protein of 16 kD, one (H8) a 6-kD protein, and one (H6) a 30-kD protein. When mixed with surfactant, three antibodies, H4, H7 and H8, profoundly altered surfactant activity in vitro in the pulsating bubble surfactometer. Three other antibodies, H1, H2, and H5 moderately inhibited surfactant's surface activity. We also examined the cross-reactivity of these monoclonal antibodies with bovine (CLSE) and porcine (Curosurf) surfactants. By Western blot analysis, only H6 bound these heterologous surfactants. Other antibodies did so by ELISA. However, functional assays indicated that antibodies H7, H8 and H4 all greatly inhibited CLSE surface activity in vitro. Five antibodies (H1-H4 and H8) inhibited Curosurf function. Thus, human surfactant species, especially low molecular weight species, are highly antigenic. Antibodies to alveolar surfactants may inhibit surfactant function in vitro. As indicated by Western blot and cross-inhibition data, human lower molecular weight surfactants share epitopes with proteins from therapeutically important porcine and bovine surfactants. The potential importance of these findings to treatment of neonatal respiratory distress syndrome with heterologous surfactants is discussed.

Amniotic Fluid↗
PubMed1991

Immunogenicity of surfactant. II. Porcine and bovine surfactants.

Protein-containing surfactants of human and animal origin are being used increasingly to treat neonatal and adult respiratory distress syndromes. This trend led us to examine the antigenicity of two important preparations of animal surfactant, cow lung surfactant extract (CLSE) and a porcine surfactant preparation, Curosurf. We describe here 15 monoclonal antibodies against Curosurf and four against CLSE. Antibodies were studied by Western blot analysis to determine their ability to recognize protein components of their respective surfactant preparations. They were also tested for their ability to inactivate surfactant in vitro, assayed using the pulsating bubble surfactometer. Several antibodies directed against CLSE or Curosurf functionally inactivate the surfactant to which they were raised. We determined the degree of immunologic cross-reactivity between antibodies directed to CLSE and Curosurf against the other surfactant and also against human surfactant, both by Western blot and by examining functional inactivation in vitro. Antibodies to these animal surfactants that are commonly used therapeutically may inactivate the specific animal surfactant to which they were raised, as well as human and other surfactants. Generally, when antibodies inactivate surfactant from more than one animal species, they inactivate heterologous surfactants comparably to the extent to which they inactivate the surfactant to which they are directed. Immune complexes between anti-surfactant antibodies and surfactant have been described in the course of neonatal respiratory distress syndrome. The potential pathophysiological importance of anti-surfactant antibodies may therefore lie in their ability to inactivate administered surfactant, other similar surfactants and endogenous surfactant. In so doing, these antibodies may potentiate surfactant deficiency or pulmonary injury initiated by other stimuli.

Animals↗
PubMed1991

Lung surfactant in respiratory distress syndrome.

Severe respiratory failure is always associated with a defect in the surfactant system. Surfactant substitution in newborn infants with respiratory distress syndrome (RDS) has gained worldwide acceptance. In the present study, we have evaluated whether surfactant diagnostics are of use in choosing recipients of exogenous surfactant. In addition, we studied whether factors apparently unrelated to surfactant influence the degree of respiratory failure and surfactant responsiveness. In small preterm infants, the surfactant indices in amniotic fluid (L/S ratio and phosphatidylglycerol), within 3 days of birth, predicted the risk of RDS with a sensitivity of 90-100%, and a specificity of 50-85%. The surfactant indices, measured in BAL, predicted the risk of ARDS (which became evident 1 to 7 days later) with a sensitivity of 50-60% and a specificity of 59-65%. In small preterm infants with RDS, the amount of fluids given during the first day correlated positively with the degree of respiratory failure and negatively with the degree of surfactant responsiveness. According to an experimental study, in hydrostatic lung edema, exogenous surfactant is diluted by edema fluid and becomes sensitive to inhibitors of surfactant function. Beside dosage, quality, and time of administration, the management of patients largely dictates the responsiveness to exogenous surfactant.

Humans↗
PubMed1991

Perinatal development of inositol synthesis and catabolism in rabbit kidney.

Inositol influences growth and perinatal development. To investigate the causes of the decrease in serum inositol levels during perinatal development, the rate-limiting enzyme activities in the catabolism and synthesis of inositol, inositol oxygenase and glucose-6-phosphate:L-inositol-1-phosphate cyclase (cyclase) were measured. The specific activity of inositol oxygenase (uniquely present in the kidney) increased 18-fold between the 25th fetal and the 17th neonatal days, and, at the same time, the specific activity of cyclase decreased by 50%. Between cortex and medulla, there were striking differences in the distribution of inositol oxygenase, when compared to the distribution of both cyclase and free inositol. Inositol supplementation during pregnancy increased serum inositol both in the doe and the fetuses, and tended to increase the inositol concentration in organs with relatively low cyclase activity and low free inositol (liver, lung). An acute oral inositol load and/or glucocorticoid intramuscularly is administered to the pregnant doe did not alter either maternal or fetal inositol oxygenase activities. It is proposed that the tissue contents of inositol are in part regulated by the rate of the endogenous synthesis. The development of inositol oxygenase activity may influence serum inositol concentrations during the perinatal period, in addition to the diet.

Aging↗
PubMed1991

Surfactant protein A, phosphatidylcholine, and surfactant inhibitors in epithelial lining fluid. Correlation with surface activity, severity of respiratory distress syndrome, and outcome in small premature infants.

Although surfactant deficiency at birth is the major cause of respiratory distress syndrome (RDS), there is insufficient data on surfactant and surfactant inhibitors after birth. In the present study, a total of 345 airway specimens (AS) from 61 neonates of gestational age of 24 to 29 wk (54 with RDS) were analyzed for concentrations of phosphatidylcholine (PC), saturated PC (SPC), surfactant protein A (SP-A), nonsedimentable protein, and free amino acids in epithelial lining fluid (ELF). The relationship between surfactant indices, surface activity, and severity of RDS was studied. Treatment with human surfactant containing SP-A increased [PC]ELF and [SPC]ELF to levels found in infants without RDS. In placebo-treated infants similar concentrations were first reached between Days 4 and 7. Surfactant treatment increased the low SP-A/SPC ratio, although this ratio remained lower than that in exogenous surfactant. In RDS, the concentrations of free amino acids in ELF were 6 to 31 times higher than in infants without RDS. The nonsedimentable proteins of AS and cationic amino acids increased the minimum surface tension of SP-A-deficient surfactant from AS. Addition of SP-A improved the surface activity. According to multiple regression analysis, In [PC]ELF (p less than 0.0001), SPC/PC ratio (p less than 0.0001), In SP-A/SPC ratio (p less than 0.0002), and [protein]ELF (p less than 0.01) correlated with alveolar-arterial oxygen pressure gradient. Of the infants weighing less than 1,000 g, those who were going to die or develop bronchopulmonary dysplasia had a strikingly lower SP-A/SPC ratio during the first week (less than 25 ng/nmol) than those surviving without BPD.(ABSTRACT TRUNCATED AT 250 WORDS)

Amino Acids↗
PubMed1991

Generation of free radicals in lipid emulsion used in parenteral nutrition.

Lipid emulsions used in parenteral nutrition are prone to peroxidation that may be an important feature of oxygen-associated tissue damage. Incubation of lipid emulsion [Intralipid (IL)] with H2O2 and FeCl2 increased lipid peroxidation, measurable as increased production of pentane, from 0.39 +/- 0.33 to 0.99 +/- 0.18 microM (p less than 0.0001). Malondialdehyde was increased from 0.010 +/- 0.005 mM to 0.380 +/- 0.025 mM (p less than 0.001). Superoxide dismutase and catalase (each 100 U/mL) or vitamin C (10 mM) inhibited pentane and malondialdehyde production (p less than 0.0001). Incubation of human erythrocytes in the presence of FeCl2 caused 11.0 +/- 3.2% hemolysis (control 0.95 +/- 0.14%). Addition of 0.44% IL increased hemolysis to 66.5 +/- 3.4%, whereas further addition of vitamin E or C significantly inhibited hemolysis to 16.4 +/- 8.1 and 38.9 +/- 7.1%, respectively (p less than 0.0001). IL was administered i.v. to eight preterm infants. It increased 3- to 28-fold (p less than 0.001) the amount of pentane in expired breath. Partly, this increase was due to pentane dissolved in IL as a result of lipid peroxidation during storage. After discontinuing IL infusion, the elimination of pentane was nonexponential, consisting of a rapid and a slow component. According to our results, IL undergoes peroxidation causing free-radical-dependent damage to human cells. We propose that the adverse effects of parenteral IL are partially caused by free oxygen radicals generated by lipid peroxidation.

Fat Emulsions, Intravenous↗
PubMed1991

The use of synthetic peptides in the formation of biophysically and biologically active pulmonary surfactants.

Synthetic pulmonary surfactants consisting of mixtures of phospholipids with synthetic peptides based on the amino acid sequence of human surfactant apoprotein SP-B were prepared. These surfactants were analyzed for their ability to lower surface tension on a pulsating bubble surfactometer and for their capacity to improve lung compliance and increase alveolar expansion in a fetal rabbit model of surfactant deficiency. The data demonstrate that several peptides, ranging from 17 to 45 residues in length, matching the carboxy-terminal sequence of the SP-B protein, when appropriately recombined with the phospholipid dipalmitoylphosphatidylcholine and phosphatidylglycerol (3:1), are capable of producing a synthetic surfactant with biophysical and biologic activity approaching that of human surfactant derived from amniotic fluid.

1,2-Dipalmitoylphosphatidylcholine↗