A novel cause of error in capnographic confirmation of intubation in the neonatal intensive care unit.
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Breath Tests↗
Biomedical subjects
W M Maniscalco
Publications and source records attributed to W M Maniscalco.
Transforming growth factor-beta induces a chondroitin sulfate/dermatan sulfate proteoglycan in alveolar type II cells.
Alveolar type II cells can synthesize extracellular matrix (ECM) components in vitro, including proteoglycans. Transforming growth factor-beta (TGF-beta) profoundly influences ECM production and is found in areas of lung fibrosis. To determine whether type II cell proteoglycan synthesis is regulated by TGF-beta, we cultured adult rabbit type II cells with TGF-beta 1 and analyzed the synthesis of proteoglycans secreted into the culture medium. TGF-beta 1 increased 35SO4 incorporation into glycosaminoglycans of secreted proteoglycans 2.5-fold. Analysis of the intact proteoglycans revealed that TGF-beta 1 induced accumulation of a chondroitin sulfate/dermatan sulfate proteoglycan with molecular mass between 70 and 100 kDa and a core protein of 36 kDa. There were no effects on several other core proteins. Type II cells cultured with TGF-beta 1 and beta-D-xyloside, an acceptor for glycosaminoglycan polymerization, had increased glycosaminoglycan synthesis independent of the availability of core proteins. These data indicate that type II cell proteoglycan synthesis, at the levels of both core protein and glycosaminoglycans, is regulated by TGF-beta 1. We speculate that the induced 70- to 100 kDa proteoglycan is decorin, an ECM proteoglycan involved in collagen fibrillogenesis and TGF-beta binding.
Animals↗
Transforming growth factor-beta 1 modulates type II cell fibronectin and surfactant protein C expression.
Extracellular matrix (ECM) deposition by alveolar type II cells is important for repair of a damaged alveolar epithelium. Transforming growth factor-beta (TGF-beta) is abundant in injured lung and has profound effects on ECM production and cell differentiation. We determined the effects of TGF-beta 1 on type II cell expression of fibronectin and surfactant protein C (SP-C) in vitro. TGF-beta 1 increased the proportion of type II cells with detectable mRNA for fibronectin from 9 to 68%, as demonstrated by in situ hybridization, and increased the fibronectin mRNA levels 10-fold. TGF-beta 1-treated cultures had increased immunostaining for fibronectin and increased secretion of metabolically labeled fibronectin. A decreased proportion of type II cells treated with TGF-beta 1 had detectable mRNA for SP-C, and the abundance of this message per cell decreased to 25% of control values. No effects of TGF-beta 1 were noted on the proportion of cells that contained lamellar bodies, which was 87% in both groups. These data indicate that TGF-beta 1 regulates type II cell fibronectin protein an mRNA levels. In addition, the decreased abundance of SP-C mRNA suggests that TGF-beta 1 may also modulate type II cell differentiation in lung injury.
Animals↗
Use of natural surfactants to prevent and treat respiratory distress syndrome.
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Adrenal Cortex Hormones↗
Neonatal Trichosporon beigelii infection: report of a cluster of cases in a neonatal intensive care unit.
Trichosporon beigelii, a ubiquitous yeast found in soil, causes superficial dermatologic infections in normal hosts and rare cases of disseminated disease among immunocompromised patients. Neonatal cases are exceptionally rare. We report a cluster of cases of T. beigelii infections in a tertiary care hospital in Rochester, NY, during May to July, 1991. Three cases occurred in very low birth weight premature infants (23 to 25 weeks of gestation), two of whom died. The organism was isolated from urine alone in one case, skin and blood in one case and blood, tracheal aspirate and central venous catheter tip in one case. In a fourth, full term infant with respiratory distress syndrome T. beigelii was grown only from a femoral central venous catheter tip with no clinical evidence of infection. An epidemiologic investigation was performed and the mode of transmission in this outbreak was not identified, although cross-infection was suspected in the initial two cases. Our isolates were inhibited but not killed by usually achievable concentrations of amphotericin B. T. beigelii may cause outbreaks of serious infection in neonatal intensive care units, especially among premature infants.
Antifungal Agents↗
Alveolar type II cells synthesize hydrophobic cell-associated proteoglycans with multiple core proteins.
Type II alveolar epithelial cells interact with the extracellular matrix via cell surface receptors for matrix ligands. Cell surface proteoglycans, which are hydrophobic due to their membrane insertion domains, are one of several classes of molecules that may be receptors for matrix ligands. To analyze the hydrophobic proteoglycans synthesized by adult alveolar type II cells, we labeled these cells with 35SO4 and [3H]leucine in short-term primary cultures. Cell-associated hydrophobic proteoglycans and culture medium-derived proteoglycans were purified and characterized. Both the hydrophobic proteoglycans and medium-derived proteoglycans, which were not hydrophobic, had mainly heparan sulfate glycosaminoglycans. Analysis of core proteins of the hydrophobic proteoglycans showed three proteins, 47, 65, and 90 kDa. The 47- and 65-kDa core proteins were substituted only with heparan sulfate chains. The 90-kDa core protein was seen only after digestion with both heparitinase and chondroitin ABC lyase, suggesting it was a hybrid having both heparan sulfate and chondroitin-dermatan sulfate chains. These findings were confirmed by iodination of the core proteins. The hydrophobic cell-associated proteoglycans inserted into artificial liposomes, whereas the medium-derived molecules did not. These data document heterogeneity in core protein and glycosaminoglycan chains among hydrophobic proteoglycans synthesized in vitro by adult alveolar type II cells. These molecules may have diverse functions in regulating type II cell interaction with the extracellular matrix.
Absorption↗
Prevention of neonatal group B streptococcal infections: advances in maternal vaccine development.
OBJECTIVE: We describe the current state of prevention of neonatal group B streptococcal infections and present recent advances toward the development of a maternal vaccine for prevention of this disease. DATA SOURCES: We used a MEDLINE search of the Index Medicus from 1976-1992 for articles regarding group B streptococcus classification and immunology. Group B streptococcus was also cross-referenced with bacterial antigens, antibodies, and vaccines. Relevant textbooks were reviewed. METHODS OF STUDY SELECTION: Fifty-seven articles were selected as providing important background and new findings pertinent to this topic. DATA EXTRACTION AND SYNTHESIS: The literature supports prophylactic use of intrapartum antibiotics in mothers who are known carriers of group B streptococcus but highlights the need for more sensitive rapid screening techniques to identify this high-risk population. The promise of intravenous immunoglobulin for neonatal prophylaxis has not been borne out, although hyperimmune and monoclonal preparations offer renewed hope for prophylaxis and adjuvant therapy. Native bacterial polysaccharides, conjugated oligosaccharides and polysaccharides, and C proteins have been investigated as antigens for candidate vaccines. Antibodies elicited in human and animal studies provide protection against bacterial strains possessing these determinants. The theoretical existence of a "universal antigen" is significant because polysaccharide and C protein formulations are required to be polyvalent. CONCLUSIONS: The development of a vaccine for prevention of neonatal group B streptococcal sepsis is an attainable goal. Further study of the immunogenic properties of bacterial-cell-wall polysaccharides and their conjugates, C proteins, and the potential universal antigen is required.
Bacterial Vaccines↗
A comparison of surfactant as immediate prophylaxis and as rescue therapy in newborns of less than 30 weeks' gestation.
BACKGROUND: Exogenous pulmonary surfactants are administered into the trachea either to prevent respiratory distress syndrome in premature infants or to treat it. In a randomized, multicenter trial, we compared the results of surfactant therapy initiated as prophylaxis with the results of rescue therapy with surfactant. METHODS: Before birth, 479 infants with an estimated gestational age of less than 30 weeks were randomly assigned to receive surfactant as prophylaxis (n = 235) or rescue therapy (n = 244). The infants in the prophylaxis group received a 90-mg intratracheal dose of an exogenous calf-lung surfactant extract at the time of delivery, whereas the infants in the rescue-therapy group received 90 mg of the surfactant several hours after delivery if the fractional inspiratory oxygen concentration was at least 0.40 or if the mean airway pressure was at least 0.686 kPa (7 cm of water), or both. Infants in both groups received additional doses of surfactant at intervals of 12 to 24 hours if these criteria were met. RESULTS: The proportion of infants surviving until discharge to their homes was significantly higher in the prophylaxis group than in the rescue-therapy group (88 vs. 80 percent, P = 0.028). This difference was due primarily to the longer survival of very premature infants (less than or equal to 26 weeks' gestation) in the prophylaxis group than in the rescue-therapy group (75 vs. 54 percent, P = 0.006). According to proportional-hazards regression analysis, the distribution of survival times was better for all infants in the prophylaxis group (P = 0.007) and for the subgroup of infants in the prophylaxis group who were delivered at 26 weeks' gestation or earlier (P = 0.0048). Infants in the prophylaxis group who were delivered at 26 weeks' gestation or earlier had a lower incidence of pneumothorax than similar infants in the rescue-therapy group (7 vs. 18 percent, P = 0.03). CONCLUSIONS: We found a significant advantage to the administration of the initial dose of surfactant as prophylaxis rather than as rescue therapy in very premature infants.
Clinical Protocols↗
Uptake of palmitic acid by rabbit alveolar type II cells.
Alveolar type II cells require a source of palmitic acid for synthesis of dipalmitoyl phosphatidylcholine (DPPC), a major constituent of pulmonary surfactant. Previous studies indicated that maximal rates of DPPC synthesis are achieved only if exogenous palmitate is available to the type II cell. Little is known of the mechanisms by which fatty acids enter type II cells. To determine if uptake is mediated by a membrane carrier system, as described in other cell types, we examined the kinetics of palmitate uptake. Using freshly isolated rabbit type II cells, we demonstrated that radiolabeled palmitate uptake was maximal and linear for 45 s; after 1 min the apparent rate of uptake declined. The initial uptake phase was taken as a measure of cellular fatty acid influx because intracellular radiolabeled palmitate remained 80% nonesterified at this time but was 55% esterified by 2 min. Cellular influx of palmitate showed saturation kinetics with increasing concentration of nonalbumin bound palmitate. Michaelis constant was 52.6 nM, and maximum velocity was 152 pmol.10(6) cells-1.min-1. The hypothesis that saturable cellular influx of palmitate is likely linked to the previously identified membrane fatty acid binding protein (MFABP) was supported by Western-blot analysis of rat lung tissue with an antibody to MFABP that demonstrated the presence of this carrier protein in lung tissue. These data suggest that palmitate uptake by type II cells is saturable and may be mediated by a membrane-associated carrier as described in other cell types.
1,2-Dipalmitoylphosphatidylcholine↗
Effects of exogenous fatty acids and inhibition of de novo fatty acid synthesis on disaturated phosphatidylcholine production by fetal lung cells and adult type II cells.
De novo fatty acid synthesis may be an important source of saturated fatty acids for fetal lung disaturated phosphatidylcholine (DSPC) production. To investigate the roles of de novo fatty acid synthesis and exogenous fatty acids, we incubated dispersed fetal lung cells and freshly isolated adult type II cells with exogenous palmitate and oleate and measured DSPC synthesis. Unlike adult type II cells, fetal lung cells did not increase DSPC synthesis when exogenous palmitate was available; adult type II cells increased DSPC synthesis by 70% in the presence of palmitate. Exogenous oleate decreased DSPC synthesis by 48% in fetal cells but not in adult type II cells. Incubation of fetal lung cells with TOFA [2-furancarboxylate, 5-(tetradecyloxy)-sodium], a metabolic inhibitor of fatty acid synthesis, decreased fatty acid synthesis by 65%. There was a simultaneous 56% inhibition of DSPC production, but no effect on protein, DNA, or glyceride-glycerol production, measured by precursor incorporation. The inhibition of DSPC synthesis associated with TOFA was partially prevented by exogenous palmitate but not oleate. Fetal cells prepared from explants that had been cultured in dexamethasone also had TOFA-associated inhibition of DSPC synthesis that was similar to non-dexamethasone-exposed cells. These studies suggest that under baseline conditions of low fatty acid availability, such as in the fetus, de novo fatty acid synthesis in fetal cells, but not in adult type II cells, provides sufficient saturated fatty acids to support maximal DSPC production. Inhibition of de novo fatty acid synthesis resulting in decreased DSPC production in fetal lung cells in conditions of low fatty acid availability suggests that fatty acid synthesis may be central to maintain DSPC synthesis in the fetus.
Aging↗
Decreased cholestasis with enteral instead of intravenous protein in the very low-birth-weight infant.
Thirty to 50% of very low-birth-weight infants have parenteral nutrition-associated cholestasis. To test the hypothesis that the incidence of cholestasis would be decreased if parenteral amino acids were avoided and protein given enterally, infants with a gestational age of less than 30 weeks were randomized to two groups. One group received amino acid-free parenteral nutrition and whey protein enterally with added premature infant formula. The control group received standard parenteral nutrition with amino acids and enteral premature formula. At the end of 3 weeks of parenteral nutrition, infants who had a direct serum bilirubin level of greater than 3 mg/dl were considered to have significant cholestasis. Twenty-nine infants required parenteral nutrition for 3 weeks, 17 in the whey group and 12 in the control group. No instances of significant cholestasis were observed in the whey group (0/17), whereas seven of 12 infants (58%) in the amino acid control group had cholestasis (p less than 0.001).
Amino Acids↗
Surfactant replacement therapy: impact on hospital charges for premature infants with respiratory distress syndrome.
Surfactant replacement therapy for neonatal respiratory distress syndrome has the potential to reduce morbidity and mortality of very premature infants. To investigate whether surfactant replacement therapy will also reduce hospital charges for these infants, we compared the hospital charges incurred by a group of patients treated with surfactant with charges of control patients. Mortality in the surfactant-treated group (8%) was significantly decreased compared with the control patients (29%). Average daily hospital charges in the surfactant-treated patients were 25% less than for the control patients. Most of the savings in daily hospital charges were due to a 52% reduction in daily charges for laboratory, x-ray, respiratory therapy, and other ancillary services. Similarly, ancillary charges for the first full week of hospitalization were significantly reduced by $1,883 for patients who received surfactant therapy. Analysis of the charges for the entire hospitalization revealed that surfactant-treated patients had a significantly smaller proportion of their charges that resulted from ancillary services and an increased proportion due to room charges. The average total hospital charges for the two groups were similar, but the total hospital charges to produce a surviving infant were $18,500 less in the surfactant-treated group than the charges to produce a survivor from the control group. It is likely that, in addition to a reduction in neonatal mortality and morbidity from respiratory distress syndrome, surfactant replacement therapy may also significantly reduce charges for ancillary services for these patients. In this way, surfactant therapy may be cost-effective by improving survival without increasing overall hospital costs.
Economics, Hospital↗
Surfactant replacement therapy at birth: final analysis of a clinical trial and comparisons with similar trials.
A randomized trial of surfactant replacement therapy at birth was conducted at the University of Rochester between June 1983 and November 1985. Thirty-four premature infants, 25 to 29 weeks' gestational age, received a preventilatory dose of a calf lung surfactant extract in saline prepared at the University of Rochester. A control group of 31 infants received a preventilatory dose of saline alone. The major finding of this trial is that a single preventilatory dose of calf lung surfactant extract reduces the severity of the respiratory distress syndrome during the first 24 hours of life. The beneficial effects, however, are not sustained in many infants and diminish after 24 hours of life. The survival rate was 71% in both the control and surfactant-treated groups. There was a lower incidence of pneumothorax in the surfactant-treated group. There were no differences in the incidence of bronchopulmonary dysplasia, patent ductus arteriosus, and intraventricular hemorrhage. No adverse effects of surfactant replacement therapy were identified. Results of this study suggest that multiple postventilatory doses of surfactant will be required for optimal therapy.
Clinical Trials as Topic↗
Percutaneous central venous catheter colonization with Malassezia furfur: incidence and clinical significance.
Malassezia furfur colonization of central venous catheters has been implicated in the pathogenesis of systemic infections with this lipid-dependent yeast. To determine the incidence of catheter colonization in our neonatal intensive care unit (NICU), 25 consecutively removed percutaneous central venous catheters were examined by rinsing the lumen with saline and plating the rinse fluid on Sabouraud dextrose agar overlaid with olive oil. M furfur grew from the lumina of eight catheters (32%). Surveillance skin cultures were performed in the NICU on two occasions to determine the prevalence of skin colonization with M furfur. M furfur was found on the skin of 64% of the infants. In contrast, only 3% (1/33) of healthy, nonhospitalized infants 2 to 8 weeks of age had skin colonized with M furfur. During the 5-month study period, two NICU infants had evidence of systemic infection with M furfur. We conclude that M furfur frequently colonizes both the skin and percutaneous central venous catheters in NICU infants. Further studies are needed to determine the relationship between skin colonization and catheter colonization, and the factors contributing to systemic disease with this organism.
Age Factors↗
Insulin receptors and insulin effects on type II alveolar epithelial cells.
Type II alveolar epithelial cells (pneumocytes) were isolated to purity from adult rabbits and analyzed for the presence of cell surface insulin receptors and for effects of insulin on cells. Assays were performed on cells cultured for 24 h in Eagle's minimum essential medium. Insulin binding to cells in culture approached a steady-state level by 180 min at 15 degrees C and remained constant for at least 1 h. Competition experiments using native insulin, proinsulin and desoctapeptide supported specificity of binding. Scatchard analysis of binding revealed a class of high-affinity receptors with Kd = 1.5 X 10(-10) M and a low-affinity component with Kd = 4 X 10(-9) M. The number of receptors was estimated at 2000-4000/cell. Insulin added to cell cultures of type II pneumocytes in concentrations from 5 X 10(-11) to 5 X 10(-8) M resulted in a dose-related increase in uptake of 2-deoxyglucose by cells. Insulin also stimulated the incorporation of choline and glucose into phosphatidylcholine and disaturated phosphatidylcholine.
Animals↗
Effects of methylmercuric chloride, cycloheximide, and colchicine on the reaggregation of dissociated mouse cerebellar cells.
High fetal and neonatal brain levels of methyl mercury (MeHg) have been associated with the abnormal migration of neurons within the cerebellar and cerebral cortices. How MeHg interferes with cellular proliferation, migration, and differentiation is poorly understood. In this study, a cell recognition/cohesion assay based on the ability of dissociated neonatal mouse cerebellar cells to reaggregate was used to test whether MeHg exposure could disrupt cell surface recognition. Reaggregation of dissociated cells was monitored by measuring diameters from low-power photomicrographs. Exposure to 4 mg/kg body wt methylmercuric chloride (MeHgCl) 24 hr prior to the isolation of 3 days postnatal cerebellar cells altered the pattern of reaggregate growth. Between 25 and 51 hr in vitro (hiv), the exposed reaggregates grew at a faster rate than controls. Freshly isolated cells exposed in vitro to 0, 0.5, 1.0, and 4.0 microM MeHgCl initially exhibited a dose-related inhibition in reaggregate growth with an IC50 of 1.5 microM at 24 hiv. Following initial inhibition, exposed groups showed a dose-dependent acceleration in reaggregation similar to that found following in vivo exposure. In contrast, in vitro exposure to cycloheximide resulted in only a dose-related inhibition of reaggregation. No acceleration in growth rate was seen. Colchicine exposure produced no initial inhibition but appeared to mimic the long-term effects seen with both in vivo and in vitro MeHgCl exposure. These studies suggest that MeHgCl alters cerebellar cell recognition through a complex mechanism initially involving depressed synthesis of specific proteins followed by alterations in microtubules. Both effects may involve a disruption in the arrangement of specific cell surface recognition molecules.
Animals↗
In vivo and in vitro demonstration of reduced myelin synthesis following early postnatal exposure to ionizing radiation in the rat.
Irradiation of the immature central nervous system has been demonstrated histopathologically to result in a reduction in the quantity of myelin seen at later developmental ages [S. A. Gilmore, J. Neuropathol. Exp. Neurol. 22, 294-301 (1963). J. A. Beal and J. L. Hall, J. Neuropathol. Exp. Neurol. 33, 128-143 (1974)]. The results from our investigation indicate that this reduction in myelin content can be attributed to a decrease in sulfatide synthesis. Rats received whole-brain irradiation with 0, 500, 1500, 2000, or 2500 rad at 4 days postnatal (dpn). All of the rats exposed to 2000 or 2500 rad and 70% of those exposed to 1500 rad died within 6 to 10 days. At 17 dpn, animals received single intraperitoneal injections of [35S]sodium sulfate. Myelin synthesis, as indexed by the incorporation of sulfate into total lipids and glycolipids, was reduced in a dose-related fashion. To demonstrate a direct effect of ionizing radiation on myelinogenesis, brain cell reaggregate cultures derived from fetal rats were exposed at 12 days in vitro (div) to 0, 250, 500, 1000, or 1500 rad. A dose-related reduction in [35S]sulfate incorporation through 21 div was demonstrated. Reaggregates exposed to 250 or 500 rad but not 1000 or 1500 rad resumed normal myelin synthesis by 28 div. These changes occurred in the absence of histopathological changes, changes in protein content, and changes in the rate of protein synthesis.
Animals↗
Dexamethasone increases de novo fatty acid synthesis in fetal rabbit lung explants.
The effects of dexamethasone on pulmonary de novo fatty acid synthesis were investigated in a fetal rabbit lung explant model. Culture of the explants for 2 or 6 days with dexamethasone produced a 48% increase in de novo fatty acid synthesis, measured by 3H2O incorporation, and a 2.5-fold increase in [3H-methyl] choline incorporation into phosphatidylcholine. A dose-response study showed this effect plateaued at dexamethasone concentrations above 10(-9) M. The distribution of the products of de novo fatty acid synthesis was altered by dexamethasone. Treated cultures had a 2.5-fold increase in esterification of the newly synthesized fatty acids to phosphatidylcholine and an increase in the proportion of all newly synthesized fatty acids that were used for phosphatidylcholine synthesis. Dexamethasone treatment significantly increased the total fatty acid content and the phosphatidylcholine fatty acid content of the explants by 27 and 85%, respectively. The newly synthesized fatty acids were esterified almost equally to the 1 and 2 positions of phosphatidylcholine; this distribution was not altered by dexamethasone. These studies demonstrate that fatty acid synthesis and distribution are regulated in the fetal lung, at least in part, by glucocorticoids. In addition, coordinate regulation of fetal lung de novo fatty acid synthesis and surfactant phosphatidylcholine production by glucocorticoids is likely.
Animals↗