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R D Christensen

Publications and source records attributed to R D Christensen.

At least 91 records · Page 5Linked to original sources
PubMed1993

Diminished transcription of interleukin-8 by monocytes from preterm neonates.

Developmental delays, which impair antibacterial host defense, are present in the neutrophil system of human preterm neonates. We hypothesized that diminished production of interleukin-8 (IL-8), a neutrophil chemotactic peptide, might in part be responsible for these defects. To test this, monocytes from the blood of preterm neonates, term neonates, and adults were isolated immunologically by "negative panning" and subsequently stimulated with interleukin-1 alpha (IL-1 alpha), tumor necrosis factor alpha (TNF-alpha), or lipopolysaccharide (LPS), after which IL-8 levels in the supernatants were measured by ELISA. Total cellular RNA was extracted and IL-8 mRNA was assessed by Northern blotting and by competitive polymerase chain reaction (PCR) analyses. After stimulation with IL-1 alpha, IL-8 accumulation was lowest in supernatants of monocytes from preterm neonates, intermediate in supernatants of monocytes from term neonates and greatest from monocytes of adults. Similarly, when stimulated with TNF-alpha or LPS, monocytes from preterm neonates produced less IL-8 than cells from term neonates and adults. These differences in IL-8 concentrations paralleled differences in IL-8 mRNA expression.

Adult↗
PubMed1993

A randomized, double-blind, placebo-controlled trial of recombinant erythropoietin in treatment of the anemia of bronchopulmonary dysplasia.

Because anemia in patients with bronchopulmonary dysplasia is characterized by inappropriately low serum concentrations of erythropoietin but increased in vitro sensitivity of erythroid progenitors to erythropoietin, we speculated that administration of human recombinant erythropoietin would correct this anemia. Fifteen infants with the anemia of bronchopulmonary dysplasia were randomly assigned to receive erythropoietin or placebo subcutaneously for 10 days. Changes in reticulocyte count, hematocrit, blood lactate concentration, neutrophil count, platelet count, heart rate, oxygen requirement, weight gain, and number of transfusions were assessed. In the 10 erythropoietin recipients (99 +/- 12 days of age), hematocrit values increased from 0.325 +/- 0.006 to 0.381 +/- 0.013 (mean +/- SEM; p < 0.005) and reticulocyte counts from 122 +/- 20 to 446 +/- 48 x 10(3)/microliters (p < 0.005); lactate values remained unchanged. In the five placebo recipients (91 +/- 12 days of age), hematocrits and reticulocyte counts remained unchanged, and lactate values increased from 0.73 +/- 0.14 to 1.34 +/- 0.25 mumol/gm (p < 0.05). During the 30 days after the treatment period, one erythropoietin recipient and four placebo recipients were given transfusions. Other measured variables remained unchanged in both groups. We conclude that erythropoietin is effective in treatment of the anemia of bronchopulmonary dysplasia.

Anemia↗
PubMed1993

Single-dose pharmacokinetics of recombinant human erythropoietin in preterm infants after intravenous and subcutaneous administration.

Pharmacokinetics of recombinant human erythropoietin (rHuEPO) were studied in a group of very low birth weight infants after both intravenous and subcutaneous administration. The volume of distribution was larger and the clearance more rapid than those reported in adults. The maximum concentration of erythropoietin after subcutaneous doses of rHuEPO was variable, but bioavailability was high (42%) compared with values reported in adults. These observations could be useful in optimizing treatment of the anemia of prematurity with rHuEPO.

Anemia, Neonatal↗
PubMed1993

The failure of newborn mice infected with Escherichia coli to accelerate neutrophil production correlates with their failure to increase transcripts for granulocyte colony-stimulating factor and interleukin-6.

We quantified circulating and storage neutrophils, their precursors and progenitors, and mRNA for some of the cytokines involved in granulocytopoiesis, in newborn and adult mice following intrapulmonary inoculation of Escherichia coli. Four hours following inoculation of adult and newborn mice with a quantity of organisms 2 logs below the LD100, all animals were neutropenic. After 24 h, adults had recovered from the neutropenia but neonates had not (p < 0.001). Accelerated neutrophil production was evident in the infected adults, and correlated with the appearance of granulocyte colony-stimulating factor (G-CSF) transcripts in the liver, spleen, and lung, and interleukin-6 (IL-6) transcripts in the spleen and lung. An increase in neutrophil production was not observed in the neonates, and none of their organs tested had transcripts for either G-CSF or IL-6, but they did have transcripts for cytokines not involved in granulocytopoiesis; macrophage colony-stimulating factor and its receptor (c-fms). We speculate that the failure to increase neutrophil production in infected neonatal mice is the result of failure to increase production of relevant cytokines.

Animals↗
PubMed1992

Effect of interleukin-11 on cycling status and clonogenic maturation of fetal and adult hematopoietic progenitors.

A recently cloned human cytokine, interleukin-11 (IL-11), has functional similarities to IL-6. We tested the hypothesis that the hematopoietic actions of IL-11 in vitro also resemble those of IL-6. The effect of IL-11 on the cell cycle status of fetal and adult hematopoietic progenitors was assessed using serum-free incubations followed by tritiated thymidine suicide studies. Its effect on clonogenic maturation was assessed by including IL-11, either as a single agent or with subplateau or plateau concentrations of other recombinant cytokines, in cultures that contained neutralizing monoclonal antibodies directed against relevant growth factors. Similar to IL-6, IL-11 resulted in accelerated cycling of fetal colony-forming units-mixed (CFU-MIX), CFU-granulocyte macrophage (CFU-GM), and erythroid burst-forming units (BFU-E). This effect was additive to that of submaximal, but not to plateau, concentrations of IL-6. However, no effect of IL-11 was observed on cycling status of adult progenitors. As a single agent, IL-11 failed to support clonal maturation of either fetal or adult progenitors. IL-11 was additive to GM-CSF in supporting clonal maturation of CFU-GM from adult marrow but not from fetal blood. We conclude that the in vitro hematopoietic actions of IL-11 on cell cycle status of hematopoietic progenitors resemble those of IL-6. However, unlike IL-6, IL-11 as a single agent failed to support clonal maturation of fetal CFU-GM, BFU-E, and CFU-MIX.

Adult↗
PubMed1992

Erythropoietin affects the maturation pattern of fetal G-CSF-responsive progenitors.

A transient hyporegenerative neutropenia has been reported in neonates, but not in older children or adults, undergoing treatment with recombinant erythropoietin (epo). Monocytopenia has not been reported. We postulated that epo might selectively reduce the responsiveness of neonatal progenitors to Granulocyte Colony-Stimulating Factor (G-CSF), while not similarly affecting their responsiveness to Macrophage Colony-Stimulating Factor (M-CSF). To test this hypothesis two types of experiments were performed. First, progenitors of adult or fetal origin were pre-incubated with epo (or control), then washed, and their responsiveness to G-CSF and M-CSF evaluated in clonogenic culture assays. Second, clonogenic maturation was initiated using either G-CSF or M-CSF, after which the effect of a late addition of epo to the developing clones was evaluated. Indeed, pre-incubation with epo resulted in production of fewer neutrophils from fetal progenitors grown in G-CSF (P less than 0.001), but it did not reduce the number of macrophages generated from progenitors grown in M-CSF. Adding epo to the already-developing G-CSF-responsive and M-CSF-responsive adult and fetal clones did not alter colony development. Thus, epo appears to have an action on G-CSF-responsive, but not-M-CSF-responsive fetal progenitors, resulting in reduced production of neutrophils. This effect is no longer apparent, however, when progenitors have matured to the 8-cell clone stage.

Adult↗
PubMed1992

Evaluation of the mechanism causing anemia in infants with bronchopulmonary dysplasia.

In seven patients with bronchopulmonary dysplasia and anemia, we evaluated the mechanisms causing the anemia. All had a normocytic, normochromic, hyporegenerative anemia (mean hematocrit 26%; range 21% to 30%). The low hematocrit values seemed physiologically significant because mean (+/- SD), heart rates fell after transfusion (162 +/- 7 to 149 +/- 9 beats/min; p less than 0.005), as did blood lactate concentrations (1.2 +/- 0.3 mumol/gm blood before vs 0.5 +/- 0.3 after transfusion; p less than 0.05). Anemia could not be explained by blood withdrawal or deficiency of vitamin E, folate, or iron. No dyserthropoietic or megaloblastic changes were observed. No erythroid regenerative response was seen in the marrow; however, when recombinant erythropoietic growth factors were added to marrow cells in tissue culture, erythroid cell growth in vitro was normal. In contrast to patients with the "anemia of chronic disorders," these patients had a normal or increased number of marrow sideroblasts and increased serum transferrin saturation. Serum concentrations of erythropoietin were low for patients with anemia (range 11.4 to 47.1 mU/ml); yet the in vitro sensitivity of bone marrow erythroid progenitors (colony-forming units--erythroid) to recombinant erythropoietin was increased (p less than 0.001). We conclude that the anemia in these patients was the result of deficient production of erythropoietin, and we speculate that administration of recombinant erythropoietin would correct the anemia.

Anemia↗
PubMed1992

Defective production of interleukin-6 by monocytes: a possible mechanism underlying several host defense deficiencies of neonates.

Several deficiencies in antibacterial defense have been described in neonates. Among those best characterized are delayed maturation of B cells into antibody producing cells, deficient T-cell maturation, and delayed cycling of hematopoietic progenitor cells after an infectious challenge. No unifying theory has been forwarded, however, to explain the concomitance of these three developmental deficiencies. IL-6, a cytokine produced primarily by monocytes and macrophages in response to stimulation by IL-1, is involved in the regulation of these three processes. Thus, we postulated that defective production of IL-6 could be a mechanism underlying these immune deficiencies of neonates. Indeed, we observed that a peak production, cells of five term neonates produced only one half as much IL-6 (14 120 +/- 2590 pg IL-6/10(6) monocytes) as those of five adults (28 940 +/- 1680 pg, p less than 0.001). Peak production was lower still by monocytes of six preterm neonates (7190 +/- 1400 pg, p less than 0.001 versus term). Production of IL-6 protein was inhibited by actinomycin D and the IL-6 mRNA content of monocytes from neonates, as assessed by competitive polymerase chain reaction, was less than that of adult monocytes. We speculate that defective IL-6 transcription might underlie some of the defects in immune regulation observed in neonates.

Adult↗
PubMed1992

Recombinant erythropoietin as treatment for the late hyporegenerative anemia of Rh hemolytic disease.

Infants with Rh hemolytic disease can develop a "late" anemia characterized by low serum concentrations of erythropoietin but erythroid progenitors that remain highly erythropoietin-responsive. Erythropoietin administration was evaluated in two patients as an alternative to transfusion. Reticulocyte counts increased after 5 days of treatment, and hematocrits increased after 10 days. Neither patient received erythrocyte transfusions following erythropoietin therapy.

Anemia, Hemolytic↗
PubMed1991

Administration of erythropoietin to newborn rats results in diminished neutrophil production.

Very high concentrations of erythropoietin (epo), in clonogenic cultures, result in reduced production of neutrophils, and fetal progenitors are more sensitive to this effect of epo than are those of adults. However, the significance of this observation is unclear because no evidence of reduced neutrophil production has been presented following administration of recombinant epo to human or animal subjects. In the present study we injected newborn rats, beginning on the first day of life, with 20, 200, or 2,000 U epo/kg body weight, and measured serum epo concentrations after 2, 8, 24, or 48 hours. After selecting a dose that resulted in serum concentrations greater than 1,000 mU/mL (a concentration that resulted in down-modulation of neutrophil production from neonatal rat progenitors in vitro) other newborn rats were treated for 3 days with that dose (1,000 U epo/kg) or a vehicle control. Administration of epo resulted in increased hematocrits (P less than .001), reticulocyte counts (P less than .001), normoblasts/femur (P less than .05), and normoblasts/spleen (P less than .001). Recipients of epo also had more erythroid colony-forming units (CFU-E) (P less than .001) and higher CFU-E tritiated thymidine suicide rates (P less than .01) than did controls. However, femurs and spleens of epo recipients contained fewer postmitotic neutrophils (femur, P less than .01; spleen, P less than .01), proliferative neutrophils (femur, P less than .01; spleen, P less than .02), granulocyte-macrophage colony-forming units (CFU-GM) (P less than .005), and lower CFU-GM tritiated thymidine suicide rates (P less than .01). Seven and nine days after twice-daily administration of 2,000 U epo/kg, blood neutrophil concentrations had diminished (P less than .05). Thus, administration of high doses of recombinant epo to newborn rats resulted in diminished neutrophil production accompanying accelerated erythropoiesis.

Animals↗
PubMed1991

Effect of interleukin-9 on clonogenic maturation and cell-cycle status of fetal and adult hematopoietic progenitors.

We assessed the effect of interleukin-9 (IL-9) on clonogenic maturation and cell-cycle status of hematopoietic progenitors of fetal (umbilical cord blood) and adult (bone marrow) origin. As a single agent IL-9 supported, in a concentration-dependent fashion, maturation of burst-forming units-erythroid (BFU-E) of adult and fetal origin. However, only 1/3 the number of adult BFU-E colonies developed, as did in response to granulocyte-macrophage colony-stimulating factor (GM-CSF), and only 1/6 the number developed as did in response to IL-3. In contrast, the effect of IL-9 on fetal BFU-E colonies was equal to that of GM-CSF and IL-3. Synergistic effects of IL-9 with low concentrations (0.1 ng/mL) of GM-CSF and IL-3 were seen on adult BFU-E colony formation, but no effect was apparent at higher concentrations (1.0 ng/mL). In contrast, using fetal cells, synergistic effects of IL-9 with low and high concentrations of GM-CSF and IL-3 were apparent. Addition of IL-9 to plates containing fetal cells plus GM-CSF and IL-3 not only resulted in more BFU-E colonies, but also in more multicentered (greater than or equal to 10 individual centers) colonies, and more cells per colony. IL-9 had a wider spectrum of action on progenitors of fetal origin than on progenitors of adult origin, supporting the generation of fetal multipotent colony-forming unit (CFU)-Mix and CFU-GM colonies. Incubation with IL-9 did not accelerate cycling of adult or fetal BFU-E, CFU-Mix, or CFU-GM to the extent observed after incubation with IL-6. Thus, IL-9 primarily supported maturation of erythroid progenitors of adult origin, and its addition to plates containing GM-CSF and IL-3 (1.0 ng/mL) did not result in maturation of additional clones. In contrast, IL-9 had a wider spectrum of action on fetal progenitors and, when combined with IL-3 and GM-CSF, resulted in clonogenic maturation of progenitors that did not undergo maturation after stimulation with IL-3 and GM-CSF.

Aging↗
PubMed1991

The mechanism responsible for diminished neutrophil production in neonates delivered of women with pregnancy-induced hypertension.

The neonatal neutropenia after pregnancy-induced hypertension is a function of diminished neutrophil production. These studies test the hypothesis that this diminution is due to decreased production of neutrophilic growth factors, reduced responsiveness of neutrophil progenitors to these factors, or the presence of an inhibitor. While the concentrations of placentally derived colony-stimulating factors were similar in normotensive and hypertensive gestations, bioassay demonstrated less colony-stimulating activity in placental conditioned media from hypertensive gestations. Evaluation of the responsiveness of progenitors to recombinant factors revealed no differences between those from normotensive and hypertensive gestations. However, neutrophilic colony formation in vitro was significantly inhibited after the addition of conditioned media or sera from hypertensive gestations, whereas the addition of these from normotensive gestations had no inhibitory effect. Thus this common maternal-fetal disorder is associated with an inhibitor of neutrophil production, which is elaborated by the placenta and present in cord blood serum.

Cells, Cultured↗
PubMed1991

Recombinant erythropoietin compared with erythrocyte transfusion in the treatment of anemia of prematurity.

To assess the risks and benefits of erythropoietin versus erythrocyte transfusion in the treatment of the anemia of prematurity, we randomly assigned 19 anemic preterm infants (birth weight 988 +/- 227 gm; gestational age 27.6 +/- 1.2 weeks; age 41 +/- 15 days; all values mean +/- SD) to receive either transfusion or subcutaneously administered erythropoietin (200 units/kg every other day for 10 doses). In the 10 erythropoietin recipients, corrected reticulocyte counts increased from 2% +/- 1% to 7% +/- 2% (p less than 0.001) and hematocrits increased from 27% +/- 2% to 30% +/- 4% (p less than 0.05). In the nine infants who underwent transfusion, reticulocyte counts did not increase, but hematocrits increased from 28% +/- 4% to 41% +/- 2% after initial transfusion (p less than 0.001) and had decreased to 34% +/- 5% by day 20. Signs attributed to anemia (tachycardia, apnea with bradycardia, and poor weight gain) declined in both the erythropoietin recipients and those who underwent transfusion. However, five of nine infants who underwent transfusion had symptoms within 10 to 14 days and were given further transfusions. Marrow aspiration performed after 7 to 10 days of treatment showed that infants receiving erythropoietin had greater percentages of erythropoietic precursors (p less than 0.01), greater concentrations of mature erythroid progenitors (p less than 0.001), and higher cycling rates of erythroid progenitors (p less than 0.001). The percentage of mature stored neutrophils in marrow was lower in the erythropoietin group than in the transfusion group, resulting in an inverse myeloid/erythroid ratio (0.5:1 vs 6.2:1; p less than 0.001). After 20 days, absolute blood neutrophil counts were lower in the erythropoietin recipients (1.8 +/- 0.9 x 10(3) cells/microliters) than in the infants who underwent transfusion (3.9 +/- 1.9 x 10(3) cells/microliters; p less than 0.05). Administration of erythropoietin thus stimulated erythropoiesis and relieved signs attributed to anemia; the significance of the relative neutropenia remains to be determined. We conclude that erythropoietin administration offers promise as an alternative to erythrocyte transfusion in neonates with symptomatic anemia of prematurity.

Anemia, Neonatal↗
PubMed1991

Effect on neutrophil kinetics and serum opsonic capacity of intravenous administration of immune globulin to neonates with clinical signs of early-onset sepsis.

This study was designed to test the hypothesis that administration of immune globulin to human neonates with early-onset bacterial sepsis would (1) facilitate neutrophil egress from the marrow, (2) improve serum opsonic capacity, and (3) facilitate recovery from the infectious illness. Twenty-two newborn infants with clinical signs of early-onset sepsis were given an intravenous infusion of either 750 mg of immune globulin (IVIG) per kilogram of body weight or the same volume of a vehicle control (albumin). All 22 infants survived, but significant hematologic, immunologic, and respiratory differences were observed after the IVIG and not after the control infusion. Eleven of the patients had neutropenia; 24 hours after the infusions, the neutropenia had resolved in all six IVIG recipients but persisted in all five control recipients (p less than 0.001). Ten patients had I/T neutrophil ratios (a measure of immature neutrophils to total neutrophils on the leukocyte differential count) of less than 0.2. One hour after completion of the infusions, all five IVIG recipients had elevated I/T ratios (mean +/- SEM:0.10 +/- 0.05 before vs 0.43 +/- 0.03 after infusion; p less than 0.001), suggesting a prompt release of neutrophils from the marrow neutrophil storage pool into the circulation; no increase in the I/T ratio was observed in the control recipients. Six hours after the IVIG infusions, the ratio of arterial oxygen tension to fraction of inspired oxygen increased; no increase was observed after control infusions. Serum concentrations of IgG, IgG1, IgG2, IgG3, IgG4, and total hemolytic complement and the capacity of serum to support opsonophagocytosis of type II and type III group B streptococci increased markedly in the IVIG recipients but not in the control subjects. We conclude that administration of 750 mg IVIG per kilogram to neonates with clinical signs of early-onset sepsis was associated with immunologic, hematologic, and physiologic improvement.

Bacterial Infections↗
PubMed1991

Production of interleukin-6 by fetal and maternal cells in vivo during intraamniotic infection and in vitro after stimulation with interleukin-1.

Amniotic fluid samples were obtained by transabdominal amniocentesis from 20 women in preterm labor (less than or equal to 34 wk gestation). Concentrations of IL-6 in culture-positive amniotic fluids (mean 8706 pg/mL, range 5100-14,446 pg/mL) were higher than those in culture-negative fluids (mean 1133 pg/mL, range 15-6534 pg/mL, p less than 0.0001) or fluids from healthy term pregnancies (mean 196 pg/mL, range less than or equal to 5-790 pg/mL, p less than 0.001). To assess possible sources of the Il-6 in amniotic fluid, we tested the ability of a variety of fetal and maternal cells to produce IL-6 in vitro after stimulation with IL-1, a cytokine known to stimulate IL-6 production. Very low concentrations of IL-6 were present in supernatants of cells not stimulated with IL-1; however, high concentrations were observed in supernatants of stimulated umbilical venous endothelial cells, decidual cells, and fetal and maternal blood mononuclear cells. To determine whether cells from adults produce IL-6 with kinetics similar to those of neonates, we incubated mononuclear cells obtained from blood of adults and term and preterm neonates with IL-1. After 6 h, IL-6 was detected in supernatants of adult cells and term neonatal cells, but not in supernatants of preterm cells. Concentrations at 18, 24, and 48 h were similar for adult and term cell supernatants, but were lower in supernatants of preterm cells. We also observed considerably more IL-6 mRNA accumulation in circulating mononuclear cells from adults than in those from neonates.

Amniotic Fluid↗
PubMed1991

Recombinant erythropoietin.

Cloning and expression of the human gene encoding erythropoietin has resulted in the availability of recombinant erythropoietin for clinical and laboratory investigation. Results of such investigations are clarifying the mechanisms that regulate production of erythropoietin in health and disease. It seems likely that erythropoietin administration will reduce, if not replace, erythrocyte transfusions for certain pediatric patients. Those with the anemia of end-state renal disease and anemia of prematurity may be most likely to benefit. Clearly, additional well-controlled studies to assess the risks and benefits of erythropoietin administration will be needed prior to widespread usage of erythropoietin for anemic children.

Adolescent↗
PubMed1991

Neutropenia in donor (anemic) twins involved in the twin-twin transfusion syndrome.

Neutropenia is common in neonates with sepsis and in those born to women with pregnancy-induced hypertension. Neutropenia has not previously been described, however, as a result of the twin-twin transfusion syndrome. We observed neutropenia of 4 to 8 days' duration in each of five "donor" (anemic) twins affected with the twin-twin transfusion syndrome. No evidence of infection was observed. Like neutropenia of pregnancy-induced hypertension, no left shift was seen. Neutrophil kinetic studies were performed on one of the neutropenic patients. Assessment of the marginal, storage, proliferative, and progenitor cell pools indicated that neutropenia resulted from diminished neutrophil production.

Anemia↗