Follow-up study of the early, randomised paracetamol trial to preterm infants, found no adverse reactions at the two-years corrected age.

AIM: We examined the long-term outcomes and safety of early intravenous paracetamol for ductus arteriosus closure at a corrected age of two years. METHODS: This was a follow-up of the 2013-2014 randomised, double-blind Preterm Infant's Paracetamol Study at Oulu University Hospital, Finland, which recruited 48 very preterm infants within 24 hours of birth. They received intravenous paracetamol or a placebo for four days. In 2015-2017, we followed up 44 infants (92%) at two years of corrected age. This included clinical and neurodevelopmental assessments and a parental medical history questionnaire. RESULTS: The 44 infants (55% boys) were born at 235 -316 weeks of gestation. No differences in the cardiac parameters, including blood pressures and ultrasound scan results, were found. Neurodevelopmental stages, as quantified by the Griffiths test, were similar. No signs of autism were reported. Asthma medication was more common in the control group, but the difference was not significant. Atopy scores, numbers of infections and the use of public health services were similar between the two groups. CONCLUSION: No long-term adverse reactions of early intravenous paracetamol were detected two years later. Larger trials are needed on the safety and efficacy of paracetamol prophylaxis for early ductal closure in very preterm infants.

Intravenous paracetamol was associated with closure of the ductus arteriosus in extremely premature infants.

AIM: Symptomatic patent ductus arteriosus may lead to serious complications in extremely preterm and extremely low birthweight infants and is often resistant to medication. We evaluated early intravenous paracetamol for pain prevention during respiratory therapy, in an attempt to understand the ductal treatment of such infants. METHODS: Our cohort were 295 extremely preterm or extremely low birthweight infants, born at less than 28 weeks or 1000 g, respectively, who were treated in the neonatal intensive care unit of Oulu University Hospital from 2002 to 2015, before and after intravenous paracetamol was introduced in June 2009. Ductal closure dates, paracetamol medication details, morbidities and mortality data were evaluated. RESULTS: Intravenous paracetamol was given to 128 infants, starting at a median of 4.4 hours age (range: 0-169 hours), with a mean total dosage of 212 mg/kg (range: 7.5-1175 mg/kg). We also included 167 controls who were mainly treated before we used intravenous paracetamol. Ibuprofen (p < 0.001) and ligation (p = 0.002) were lower in the paracetamol group than controls. No adverse effects were detected. Paracetamol was not associated with other morbidities. CONCLUSION: We found that early use of intravenous paracetamol decreased the incidence of ductal therapies in extremely premature or extremely low birthweight infants.

The reliability of the disabled children's quality-of-life questionnaire in Swedish children with diabetes.

AIM: To determine the reliability of the disabled children's quality-of-life measure (DISABKIDS) chronic generic questionnaire and diabetes module in children. The questionnaire is being evaluated for repeated routine health-related quality-of-life (HrQoL) assessment and in association with the Swedish national paediatric diabetes registry (Swediabkids), which is a tool for regular clinical use. METHODS: Children and parents completed the questionnaire during a routine visit to the diabetes clinic. In total, 120 families completed the test and retest. Split-half reliability correlation and intraclass correlation (ICC) coefficients were calculated. Bland & Altman plots were calculated on the generic HRQoL domain. RESULTS: Both child and parent versions showed good internal consistency. Test-retest ICC coefficients for the generic HrQoL module were 0.913 for the children and 0.820 for the parent version. All generic domains independently showed good reliability. The diabetes module had a score of 0.855 for children and 0.823 for parents. Split-half correlation for generic and diabetes modules was 0.930 and 0.848 for children, 0.953 and 0.903 for parents. Bland and Altman plots showed substantial agreement between the two administrations for both children and parents. CONCLUSION: The DISABKIDS questionnaire is a reliable instrument for the repeated measurements of HrQoL in children with diabetes.

Intramembraneous bone tissue responses to calcium sulfate: an experimental study in the rabbit maxilla.

OBJECTIVES: The purpose of this study was to histologically examine the responses of intramembraneous bone to calcium sulfate (CaS) and evaluate the resorption and replacement process. MATERIAL AND METHODS: Fourteen rabbits were used in this study. Defect healing without any filling material was compared with CaS. Five millimetres wide and 4 mm deep defects were drilled with a trephine bur on both sides of the edentulous space between the incisors and the molars. Test vs. control sites were randomly selected and thereby compared in each animal. The animals were killed after 2, 4 and 8 weeks for histological examination. RESULTS: After 2 weeks, the specimens showed a great extent of degradation of CaS. No signs of the material could be seen after 4 and 8 weeks. There were no statistically significant differences in bone regeneration between the test and control sites within the 8 weeks group in this study. However, there was tendency of more blood vessels in the test sites after 4 weeks of healing. CONCLUSION: The present study showed that CaS does not interfere with intramembraneous bone healing. In this animal model, the CaS exhibited resorption/degradation early in the healing process while seemingly stimulating angiogenesis. However, there was no significant increase in bone regeneration in the sites treated with CaS during an 8 week period of healing and observation time, as compared with a control defect.

Health and the use of health care services in 5-year-old very-low-birth-weight infants.

AIM: We aimed to study the effect of prematurity, time of birth and level of birth hospital on morbidity and the use of health care services at age 5. METHODS: This national study included all very-low-birth-weight infants (VLBWI, <32 gestational weeks or birth weight < or =1500 g) born in Finnish level II or III hospitals in 2001-2002 (n = 918), and full-term controls (n = 381). Parental questionnaires and register data were used to compare morbidity, and the use of health care services between VLBWI and full-term controls, and within VLBWI according to the time of birth and birth hospital level. RESULTS: Cerebral palsy, retinopathy of prematurity, other ophthalmic problems, respiratory infections, asthma or chronic lung disease, and inguinal hernia were overrepresented in VLBWI compared with the controls. VLBWI had more outpatient and inpatient days than the controls. The time of birth and birth hospital level were not associated with the use of services or with prematurity-related morbidity. CONCLUSION: Although morbidity and the use of health care services were increased in the surviving VLBWI, the average use of services was relatively small at age 5. In surviving VLBWI, the time of birth and the birth hospital level did not affect morbidity or the use of services.

Association of population mixing and acute lymphocytic leukemia in children and young adults.

BACKGROUND: The association of population mixing (PM1) with childhood acute lymphocytic leukemia (ALL2) has been reproduced in multiple studies. However, the mechanism underlying this association is unknown. METHODS: Ecological study of incidence of pediatric ALL among 253 counties in the State of Texas (USA) using surrogates of genetic and environmental PM. ALL incidence data were obtained from Texas Cancer Registry and county population statistics from the US Census Bureau. Poisson regression was used to compare ALL incidence and PM. RESULTS: There is substantial and variable genetic and environmental PM among counties in Texas. Indicators of genetic PM including proportion of multiracial households, ratio of Hispanics to non-Hispanics, and ratio of foreign to native-born residents were all significantly associated with a higher incidence of ALL (IRR3 1.81 (95CI 1.05-3.13), 1.67 (95CI 1.16-2.37), and 1.59 (95CI 1.03-2.48), respectively). Surrogates of environmental PM namely population density and persons per household were not associated with incidence of ALL; IRRs 1.29 (95CI 0.4-4.15) and 1.47 (95CI 0.89-2.43). CONCLUSIONS: These findings are consistent with prior patterns and magnitudes of PM association with ALL. Our findings suggest that the implicated mechanism of leukemogenesis in PM may be genetically transmitted rather than environmental.

Bruton's tyrosine kinase together with PI 3-kinase are part of Toll-like receptor 2 multiprotein complex and mediate LTA induced Toll-like receptor 2 responses in macrophages.

Lipoteichoic acid (LTA) of Gram-positive bacteria initiates innate immune responses via Toll-like receptor-2 (TLR2), resulting in the activation of intracellular signaling and production of inflammatory cytokines in macrophages. Although Bruton's tyrosine kinase (Btk) is biologically important molecule implicated in immune regulation and recently in TLR signaling its importance for LTA-TLR2 mediated responses has not been evaluated. In this study, we detected Btk in the LTA signaling complex with TLR2 and PI 3-kinase (PI3K). The constitutive interaction of these proteins was mediated via PI3K Src homology (SH3) -domain. Both Btk and PI3K were activated by LTA stimulation and the LTA induced cytokine expression was differentially modulated by these kinases. LTA induced the activation of nuclear factor kappaB (NFkappaB), however, only Btk inhibition affected the LTA induced Ser536 phosphorylation and DNA-binding of NFkappaB. In conclusion, our results demonstrate that Btk and PI3K occupy important roles in TLR2-induced activation of macrophages, resulting in selective regulation of cytokines.

The gap between behavioral risk status and willingness to change behavior among healthcare professionals.

AIMS:: This study explored behavioral health risk factors among healthcare professionals and investigated the at-risk persons' satisfaction with their health habits and ongoing change attempts. METHODS:: The study was based on a cross-sectional web-based survey directed at the nurses and physicians ( N = 1233) in Finnish healthcare. Obesity, low physical activity, smoking, and risky alcohol drinking were used as behavioral health risk factors. RESULTS:: In all, 70% of the participants had at least one behavioral risk factor, and a significant number of at-risk persons were satisfied with their health habits and had no ongoing change process. Good self-rated health and good self-rated work ability were significantly associated with whether a participant had a behavioral health risk factor. CONCLUSION:: Overall, unhealthy behaviors and a lack of ongoing change attempts were commonly observed among healthcare professionals. Work in healthcare is demanding, and healthy lifestyles can support coping. Thus, healthy lifestyle programs should also be targeted to healthcare professionals.

A systematic review and meta-analysis of long-term studies (five or more years) assessing maxillary sinus floor augmentation.

The objective was to test the hypothesis of no difference in long-term (≥5 years) implant treatment outcomes after maxillary sinus floor augmentation (MSFA) with autogenous bone graft compared to a mixture of autogenous bone graft and bone substitutes or bone substitutes alone. A MEDLINE (PubMed), Embase, and Cochrane Library search in combination with a hand-search of relevant journals was conducted. Human studies published in English between January 1, 1990 and October 1, 2016 were included. Nine studies fulfilled the inclusion criteria. The survival of suprastructures has never been compared within the same study. The 5-year implant survival after MSFA with autogenous bone graft was 97%, compared to 95% for Bio-Oss; the reduction in vertical height of the augmented sinus was equivalent with the two treatment modalities. Non-comparative studies demonstrated high survival rates for suprastructures and implants regardless of the grafting material used. Meta-analysis revealed an overall estimated patient-based implant survival of 95% (confidence interval 0.92-0.96). High implant stability quotient values, high patient satisfaction, and limited peri-implant marginal bone loss were revealed in non-comparative studies. No long-term randomized controlled trial comparing the different treatment modalities was identified. Hence, the conclusions drawn from the results of this systematic review should be interpreted with caution.

Intraamniotic interleukin-1 accelerates surfactant protein synthesis in fetal rabbits and improves lung stability after premature birth.

Intraamniotic infection is associated with increased IL-1 activity in amniotic fluid, increased incidence of preterm labor, and with decreased incidence of respiratory distress syndrome in infants born prematurely. We hypothesized that an elevated IL-1 in amniotic fluid promotes fetal lung maturation. On day 23 or 25 of gestation (term 31 d), either IL-1alpha (150 or 1,500 ng per fetus) or its antagonist IL-1 receptor antagonist (IL-1ra, 20 microg) was injected to the amniotic fluid sacs in one uterine horn, whereas the contralateral amniotic sacs were injected with vehicle. Within 40 h, IL-1alpha caused a dose-dependent increase in surfactant protein-A (SP-A) and SP-B mRNAs (maximally, fivefold), without affecting lung growth or increasing inflammatory cells in the lung. Both genders, and upper and lower lung lobes were similarly affected. IL-1ra did not modify SP-A, -B, or -C mRNA. IL-1 increased the intensity of staining of alveolar type II cells for SP-B, and the concentrations of SP-B, -A, and disaturated phosphatidylcholine in bronchoalveolar lavage. The dynamic lung compliance and the postventilatory expansion of lungs were increased two- to fourfold after IL-1alpha treatment. In fetal lung explants, IL-1alpha increased the expression of SP-A mRNA. IL-1 in amniotic fluid in preterm labor may promote lung maturation and thus be part of a host-defense mechanism that prepares the fetus for extrauterine life.

Analysis of labeling and clearance of lung surfactant phospholipids in rabbit. Evidence of bidirectional surfactant flux between lamellar bodies and alveolar lavage.

Turnover and clearance of lung surfactant phospholipids were studied with particular reference to myoinositol-induced perturbation in the acidic phospholipids. Administration of myoinositol decreased [(3)H]palmitate and [(32)P]phosphate incorporation into phosphatidylglycerol by 80-90% in whole lung, and by 94-99% in lamellar bodies and in alveolar lavage. The increased incorporation of radioactive isotopes into phosphatidylinositol following myoinositol, was inverse to the decrease in phosphatidyl-glycerol incorporation. Myoinositol treatment affected neither content nor labeling of phosphatidylcholine or disaturated phosphatidylcholine as studied within 50 h of administration. Phosphatidylglycerol was pulse labeled by intravenous [(32)P]phosphate and [(3)H]palmitate, followed by myoinositol. The biological half-lives of phosphatidylglycerol in the microsomal fraction, lamellar bodies, and alveolar lavage were 1.6, 4.6, 5.4 h (with (3)H), and 2.8, 6.5, 7.0 h (with (32)P), respectively.(32)P-labeled lung surfactant tracer was applied to the airways in saline suspension and the clearance of phospholipid radioactivity was measured in alveolar lavage, alveolar macrophages, lamellar bodies and lung homogenates. The clearance rates of phosphatidylcholine, disaturated phosphatidylcholine, phosphatidylglycerol, and phosphatidylinositol as studied in whole lung over 6 h were 3.4-5.8% h. Only a small amount of phospholipid radioactivity was recovered in the alveolar macrophage fraction (including bis-[monoacylglycerol]phosphate). Phospholipid radioactivity in alveolar lavage fell to 40-70% of the maximum during the 1st h, and to 5-18% over the next 6 h. During 2 h after the application of phospholipids, the radioactivity in the lamellar body fraction increased, and the specific radioactivities approached those in alveolar lavage. The association of phosphatidylglycerol with lamellar bodies was unaffected by myoinositol. Phosphatidylinositol entered more slowly than did phosphatidylglycerol from microsomes to the alveolar lavage fraction, and from alveolar lavage to lamellar bodies. These differences may be of importance regarding the poor performance of phosphatidylinositol-containing surfactant at birth. Further investigations are needed to clarify the possible role for the postulated bidirectional surfactant flux between the lamellar body and alveolar lavage fractions in maintaining the activity of surfactant.

Evidence of lung surfactant abnormality in respiratory failure. Study of bronchoalveolar lavage phospholipids, surface activity, phospholipase activity, and plasma myoinositol.

Autopsy findings suggest that lung surfactant is damaged in the adult respiratory distress syndrome. In the present study 225 bronchoalveolar lavage specimens (78 from 36 patients, 1-78 yr old with respiratory failure, 135 from another 128 patients with other respiratory disease, and 12 from healthy controls) were assayed for the lung profile [lecithin/sphingomyelin (L/S) ratio, saturated lecithin, phosphatidylinositol, and phosphatidylglycerol]. Bronchoalveolar lavage fluid was further analyzed for phospholipids and for phosphatidic acid phosphohydrolase, phospholipase A2, and phosphatidylinositol phosphodiesterase activities. A lipid-protein complex was isolated and analyzed for surface activity, and plasma was measured for myoinositol. There were only small differences seen in the recovery of total phospholipid between respiratory failure patients and normal controls. However, in respiratory failure, phospholipids in bronchoalveolar lavage were qualitatively different from those recovered either from normal controls or from patients with other lung disease: the LO/S ratio, phosphatidylglycerol, and disaturated lecithin were low, whereas sphingomyelin and phosphatidylserine were prominent. These abnormalities were present early in respiratory failure and tended to normalize during recovery. Low L/S ratio (less than 2), and low phosphatidylglycerol (1% or less of glycerophospholipids) in bronchoalveolar lavage was always associated with respiratory failure. Abnormal lavage phospholipids were not due to plasma contamination. The phospholipase studies revealed little evidence of increased catabolism of phospholipids. In respiratory failure, the lipid-protein complexes from lung lavage were not surface active, whereas that from healthy controls had surface properties similar to lung surfactant. Phospholipids from patients with respiratory failure were similar to those from respiratory distress syndrome in the newborn. However, the latter condition is characterized by fast recovery of surfactant deficiency and by high plasma myoinositol that suppresses the synthesis of surfactant phosphatidylglycerol and increases phosphatidylinositol (Pediatr. Res. 1981. 15: 720). On the other hand, in adult respiratory distress syndrome, the abnormality in surfactant phospholipids may last for weeks and in most cases is associated with low phosphatidylinositol, low phosphatidylglycerol, and low plasma myoinositol.

Use of human surfactant low molecular weight apoproteins in the reconstitution of surfactant biologic activity.

Two low molecular weight (LMW) apoproteins were isolated from human pulmonary surfactant. SDS polyacrylamide gel analysis showed one protein (SP 18) to have an apparent molecular weight of 18,000 when unreduced and 9,000 D after reduction. The second protein (SP 9) migrated at approximately 9,000 D in the presence or absence of reducing agents. Both proteins contain a high number of hydrophobic amino acids. The NH2-terminal sequence of SP 18 was determined to be: NH2-phe-pro-ile-pro-leu-pro-tyr-. A cDNA clone isolated from a human adult lung cDNA library contained a long open reading frame encoding at an internal position the human SP 18 amino-terminal sequence. Mixtures of phospholipids (PL) and SP 9 and SP 18 were assessed for their capacity to reduce surface tensions on a pulsating bubble surfactometer. The addition of 1% apoprotein resulted in a reduction of surface tension after 15 s from 42.9 dyn/cm for PL alone to 16.7 and 6.3 dyn/cm for preparations containing SP 9 and SP 18, respectively. In vivo assessment of reconstituted surfactant activity was performed in fetal rabbits. Reconstituted surfactant consisting of PL + 0.5% SP 18 instilled intratracheally at delivery resulted in a marked increase in lung compliance, while the incorporation of 0.5% SP 9 yielded a moderate increase. These data show the ability to produce biologically active surfactant by the addition of isolated LMW apoproteins to defined PL.

Elastase and alpha 1-proteinase inhibitor activity in tracheal aspirates during respiratory distress syndrome. Role of inflammation in the pathogenesis of bronchopulmonary dysplasia.

Pulmonary effluent samples were obtained from 26 preterm or term infants throughout the period of endotracheal intubation. Infants with respiratory distress syndrome, infants with this disorder developing bronchopulmonary dysplasia, and intubated infants without lung disease were compared daily in terms of lung effluent cellularity, albumin, elastase activity, alpha 1-proteinase content and activity, and elastase inhibitory capacity. The elastase activity was determined to be neutrophilic in origin. Polyacrylamide gel electrophoresis of pulmonary effluents from two infants with respiratory distress syndrome and exposed to FiO2 greater than or equal to 0.6 up to 6 d revealed cleavage of alpha 1-proteinase inhibitor to a 47,000-mol weight fragment suggestive of oxidation. Pulmonary effluent neutrophils, macrophages, and elastase activity were increased by day 3 of life in infants with respiratory distress syndrome eventually developing bronchopulmonary dysplasia. Elastase inhibitory capacity and alpha 1-proteinase inhibitor activity were reduced in infants developing chronic lung disease. Bronchopulmonary dysplasia developed in infants with enhanced inflammatory response, but with less or inhibited antiprotease activity.

Lateral ridge augmentation with Bio-Oss alone or Bio-Oss mixed with particulate autogenous bone graft: a systematic review.

The objective of this systematic review was to test the hypothesis of no difference in implant treatment outcomes when using Bio-Oss alone or Bio-Oss mixed with particulate autogenous bone grafts for lateral ridge augmentation. A search of the MEDLINE, Cochrane Library, and Embase databases in combination with a hand-search of relevant journals was conducted. Human studies published in English from 1 January 1990 to 1 May 2016 were included. The search provided 337 titles and six studies fulfilled the inclusion criteria. Considerable variation prevented a meta-analysis from being performed. The two treatment modalities have never been compared within the same study. Non-comparative studies demonstrated a 3-year implant survival of 96% with 50% Bio-Oss mixed with 50% autogenous bone graft. Moreover, Bio-Oss alone or Bio-Oss mixed with autogenous bone graft seems to increase the amount of newly formed bone as well as the width of the alveolar process. Within the limitations of this systematic review, lateral ridge augmentation with Bio-Oss alone or in combination with autogenous bone graft seems to induce newly formed bone and increase the width of the alveolar process, with high short-term implant survival. However, long-term studies comparing the two treatment modalities are needed before final conclusions can be drawn.

Randomized trial of early erythropoietin supplementation after preterm birth: Iron metabolism and outcome.

BACKGROUND: Excess of iron and oxidant injury shortly after birth may be associated with neonatal morbidities in preterm infants. AIMS: The aim was to determine whether administration of erythropoietin without iron supplementation decreases iron load and morbidity. STUDY DESIGN AND SUBJECTS: In a randomized trial, we administered erythropoietin (EPO 250IU/kg daily during the first 6days of life) or placebo to 39 preterm infants (BW 700-1500g, GA≤30.0weeks). OUTCOME MEASURES: The iron status, postnatal morbidities and follow-up at the age of two years were investigated. RESULTS: In all, 21 EPO- and 18 placebo-treated infants were recruited. A requirement of red blood cell transfusions during first 28days was similar between the study groups. EPO treatment decreased total serum iron concentration (p=0.035). EPO supplementation had no significant effect on serum transferrin receptors or reactive non-protein-bound iron. There were no differences in neonatal morbidity or in survival without major neurological abnormality at two years of age. CONCLUSIONS: A 6-day course of EPO decreased the iron load in preterm infants. There was no change in reactive, non-protein bound iron plasma levels and no influence on the outcomes during early childhood. Whether the neurocognitive effects of early EPO treatment can be detectable later in childhood remained to be verified.

Effect of extracellular myo-inositol on surfactant phospholipid synthesis in the fetal rabbit lung.

In the present investigation, myo-inositol was elevated in fetal serum by dietary manipulation. The myo-inositol-containing diet doubled the already high fetal serum myo-inositol between fetal days 26 and 28 but had no detectable effects on the lung. However, myo-inositol decreased betamethasone-induced (0.2 mg/kg, days 26.3 and 27.3, to the doe) inhibition in lung growth and potentiated the hormone-induced increase in alveolar space saturated phosphatidylcholine. This effect could not be explained by alteration of glucocorticoid-stimulated enzyme activity (phosphatidate cytidylyltransferase, phosphatidic acid phosphohydrolase, choline phosphate cytidylyltransferase) in the lung. Lung explants from 26-day-old fetuses were grown in a serum-free medium for 4 days. myo-Inositol (1.5 mM) had only a small effect on the phospholipid incorporation. Dexamethasone and thyroxine increased the incorporation of the precursors into surfactant phosphatidylglycerol and saturated phosphatidylcholine. myo-Inositol, in the presence of the hormones, switched the acidic surfactant phospholipid from phosphatidylglycerol to phosphatidylinositol and further increased the incorporation of surfactant-associated saturated phosphatidylcholine. myo-Inositol-excess preferentially increased the incorporation of NADPH (derived from glucose) and acetate into the fatty acid moiety of surfactant phosphatidylcholine. It is proposed that the high extracellular myo-inositol in immature fetuses provides an environment that promotes both the hormone-stimulated differentiation and the growth.

Phosphatidylglycerol in lung surfactant. II. Subcellular distribution and mechanism of biosynthesis in vitro.

Lamellar inclusion bodies, apparent precursors for alveolar surfactant lining, have remarkably similar phospholipid composition to surfactant from alveolar lavage, but distinctly different from other fractions studied: mitochondria, microsomal fraction containing endoplasmic reticulum membranes, plasma membranes and nuclei. Surfactant contained (as % of total phospholipid phosphate): 75.5-77.0% lecithin, 11.0-11.2% phosphatidylglycerol, 4.2-4.6% phosphatidylethanolamine, 3.0-3.2% phosphatidylinositol, 1.5-1.7% bis-(monoacylglycerol) phosphate, 1.2-1.9% phosphatidylserine, and 0.7-1.5% sphingomyelin. Fatty acids of phosphatidylglycerol from lamellar bodies were similar to those from microsomes but different from those in mitochondria. Lung homogenate in continuous sucrose density gradient displayed two major activity peaks of phosphatidylglycerol synthesis: the heavier from mitochondria; the lighter from endoplasmic reticulum. Studies on mechanism of phosphatidylglycerol synthesis in vitro revealed (in these two fractions) CDP-diglyceride and sn-glycerol phosphate precursors to phosphatidylglycerol phosphate, that hydrolysed to phosphatidylglycerol. In microsomes disaturated CDP-diglycerides were 1.6-1.9 times more active substrates than in mitochondria, whereas CDP-diglycerides from egg lecithin were almost equally active. In contrast to lung mitochondria no cardiolipin synthesis was detected in microsomes. The highest specific activities for phosphatidate cytidyltransferase, CDP-diglyceride-inositol phosphatidyltransferase, choline phosphotransferase, and phosphatidylethanolamine methyltransferase were all found in microsomes. The present in vitro studies and additional evidence (M. Hallman and L. Gluck, (1975) Fed. Proc. 34, 274) support the hypothesis that de novo synthesis of surfactant lecithin phosphatidylinositol and phosphatidylglycerol takes place in the endoplasmic reticulum of alveolar cells.

Interleukin-1 binding and prostaglandin E2 synthesis by amnion cells in culture: regulation by tumor necrosis factor-alpha, transforming growth factor-beta, and interleukin-1 receptor antagonist.

Proinflammatory cytokines may promote preterm labor in the setting of intrauterine infection. Tumor necrosis factor (TNF) and interleukin-1 (IL-1) synergistically stimulate the production of prostaglandin E2 (PGE2) by amnion cells. Transforming growth factor-beta (TGF-beta) inhibits the cytokine-stimulated PGE2 production. In the present study, we investigated the binding of IL-1 beta on human amnion cells in culture. Untreated amnion cells possessed 540 +/- 60 IL-1 receptors per cell, with a dissociation constant of 1.4 +/- 0.4 nM. Cells treated with TGF-beta 1 (10 ng/ml) had 570 +/- 110 receptors per cell. TNF-alpha (50 ng/ml) increased the number of IL-1 receptors to 2930 +/- 590. TGF-beta 1 inhibited the receptor upregulation by TNF-alpha. Cells treated with TGF-beta 1 and TNF-alpha expressed 1140 +/- 590 receptors per cell. The binding affinity was not changed by the cytokines. IL-1 receptor antagonist (IL-1ra) inhibited the stimulation of amnion cell PGE2 production by IL-1 beta, but not by TNF-alpha. Amnion cells secreted large amounts of IL-1ra (1.1 +/- 0.3 ng/10(5) cells). Treatment of the cells with TGF-beta 1 or TNF-alpha did not affect the release of IL-1ra. We conclude that IL-1 receptor expression is an important step in the regulation of the effects of cytokines on amnion cell PGE2 production.

The effect of betamethasone and fetal sex on the synthesis and maturation of lung surfactant phospholipids in rabbits.

In the present study we investigated the maturation of the surfactant phospholipids and the role of fetal sex on the effect of betamethasone in male and female rabbit fetuses. Betamethasone was administered to the doe (0.2 mg/kg intramuscularly) 42 and 18 h prior to killing. The fetuses were studied at 27 and 28 days from conception. Results from the alveolar lavage show that male fetuses tended to have a lower disaturated phosphatidylcholine/sphingomyelin ratio and lower levels of phosphatidylinositol. Phosphatidylglycerol was detected in trace amounts. This was apparently due to the high extracellular levels of myo-inositol inhibiting the synthesis of surfactant phosphatidylglycerol while increasing the synthesis of surfactant phosphatidylinositol. Betamethasone increased the recovery of disaturated phosphatidylcholine and phosphatidylinositol from the lung lavage in both sexes. As studied in lung slices in vitro, the betamethasone treatment decreased the incorporation of glucose into phospholipids, including into the fatty acid moiety of disaturated phosphatidylcholine, although it had no significant effect on the incorporation of glucose into the glycerol moiety of disaturated phosphatidylcholine. However, the addition of palmitate increased the incorporation of glucose into the glycerol moiety of disaturated phosphatidylcholine. The betamethasone treatment did not increase the incorporation of [1-14C]pyruvate into disaturated phosphatidylcholine. Following betamethasone administration, the availability of fatty acids may become rate-limiting for the synthesis of surfactant phospholipids. Betamethasone increased the activities of phosphatidic acid phosphohydrolase and phosphatidate cytidyltransferase in a fraction of microsomal membranes. The present evidence suggests that the glucocorticoid-induced lung maturation and the maturation of the normal lung are associated with an increase in the activity of the enzymes which are involved in metabolizing phosphatidic acid to neutral and acidic surfactant secretion of the male fetus was not explained by possible sex-related differences in the biosynthesis of the phospholipids.