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Biomedical subjects

R D Christensen

Publications and source records attributed to R D Christensen.

At least 145 records · Page 8Linked to original sources
PubMed1988

Stimulation of neutrophil production in CSF-1-responsive clones.

The hematopoietic growth factor CSF-1 has been considered relatively lineage specific for the production of macrophages, whereas GM-CSF elicits a predominance of neutrophils. It is likely that in vivo, individual clones are stimulated by the two CSFs, although the effect of dual stimulation on progenitors and their progeny has not been completely explored. We found that in cultures initiated with low concentrations of CSF-1 or GM-CSF, alone or in combination, production of macrophages predominated. Maximally stimulatory concentrations of CSF-1 elicited a predominance of macrophages, whereas maximal GM-CSF elicited many more neutrophil/macrophage colonies and pure neutrophil colonies. A combination of maximal CSF-1 and GM-CSF elicited the same differentiation as GM-CSF alone. Delayed addition of GM-CSF to cultures initiated with CSF-1 elicited colonies indistinguishable from GM-CSF alone, suggesting that neutrophil production had been switched on by GM-CSF. In mapping studies, colonies initiated by CSF-1 increased or switched on neutrophil production when GM-CSF was added as a second stimulus. These studies show that individual clones are responsive to both CSFs, and that the differentiating influence of GM-CSF predominates over that of CSF-1. In cultures to which only CSF-1 was added, a population of progenitors was sustained that produced neutrophils only after a GM-CSF stimulus. Thus, CSF-1 may participate in maintaining a reserve of progenitors for neutrophils during periods of increased neutrophil demand.

Animals↗
PubMed1987

Exercise-induced changes in the blood concentration of leukocyte populations in teenage athletes.

Neutrophilia following exercise is well described in adults and children. However, the effects of exercise on less concentrated leukocyte populations, such as circulating colony forming unit-granulocyte macrophage (CFU-GM), CFU-granulocyte, erythrocyte, megakaryocyte, macrophage (CFU-GEMM), and the various lymphocyte subsets, is not clear. To obtain this information, members of a high school track team were asked to run flights of stairs at their most rapid pace for 10 min. Prior to and 5 min following the exercise, blood concentrations of various leukocyte populations were measured. As expected, the circulating neutrophil concentration increased following exercise (26% increase). However, the largest postexercise increases were in eosinophils (139% increase) and lymphocytes (67% increase). The increase in blood lymphocytes was primarily due to an increase in total T-cells (52% increase) and T-suppressor cells (49% increase), with no significant elevation in T-helper cell or B-cell populations. The exercise did not induce an increase in the immature/total neutrophil ratio or in the number of circulating CFU-GM or CFU-GEMM.

Adolescent↗
PubMed1987

The effect of administration of immunoglobulin to newborn rats with Escherichia coli sepsis and meningitis.

Newborn rats 24-36 h old were injected transthoracically with various doses of Escherichia coli K1. Eighty-six of 92 rats which received 10(4) colony-forming units/g body weight were dead within 48 h. Two h after injection, E. coli were recovered from the blood of six of six rats and from the cerebrospinal fluid of two of six. Sixteen h after injection, E. coli were recovered from all blood (7/7) and spinal fluid (11/11) specimens cultured. Animals inoculated with 10(4) E. coli/g exhibited neutropenia and depletion of the neutrophil storage pool. In other studies, newborn rats inoculated with E. coli were injected intraperitoneally with various doses of human serum immunoglobulin, modified for intravenous use (MISG). One hundred percent (25/25) injected with 1500 mg/kg lived. In contrast to infected animals injected with albumin (controls), MISG recipients did not develop neutropenia nor did they deplete their neutrophil reserves. The effects of treating infected animals with MISG, antibiotics, or a combination of antibiotics plus MISG were compared. When administered within 2 h after the E. coli, all treatments resulted in survival rates of over 75%. However, when delayed for 6 h, 63% (17/27) of antibiotic recipients, 50% (12/24) of MISG recipients, and 91% (30/33) of those receiving both treatments lived (p less than 0.01 versus antibiotics or MISG).

Albumins↗
PubMed1987

Kinetic evaluation of the pool sizes and proliferative response of neutrophils in bacterially challenged aging mice.

Clinical observations during infection suggest that in aged patients, the kinetic or proliferative responses of neutrophils to infection may be deranged. To test this hypothesis, the neutrophil responses of 6-month-old and 30-month-old mice were compared. After intrapulmonary injection of Escherichia coli, young mice exhibited neutrophilia and diminution of the neutrophil storage pool (NSP) by a mean of 6.4 x 10(6) neutrophils/two femurs. This was accompanied by an increase in the pool of CFU-GM from a control value of 1.1 x 10(5) cells/two femurs (range 0.7 to 1.4) to 1.5 x 10(5) (1.1 to 1.9) (P less than .05) and the thymidine suicide (relative proliferative rate) of CFU-GM rose from 27% (19 to 42) to 51% (31 to 61) (P less than .05). Furthermore, the CFU-GM of infected young mice displayed enhanced differentiation to the neutrophil series. In contrast, old mice exhibited a greater mean diminution of the NSP: 12.8 x 10(6) neutrophils. Also, old mice experienced a reduction in CFU-GM from 2.3 x 10(5) (1.0 to 3.9) (controls) to 1.3 x 10(5) (1.2 to 1.5)/two femurs (P less than .05), a reduction in the proliferation of CFU-GM and reduced differentiation of CFU-GM to neutrophils. These experiments establish that the neutrophil response of infected old mice is disordered, with exaggerated depletion of the NSP and lack of stimulus-driven granulocytopoiesis as reflected by a paradoxical reduction in the number and proliferative rate of precursors. This defect may be compounded by decreased differentiation of precursors to neutrophils.

Aging↗
PubMed1987

Intravenous immunoglobulin for prophylaxis or treatment of bacterial infection in neonates.

The high rate of bacterial infection in premature neonates has been correlated with low levels of opsonic antibody. Infants born at term who develop a bacterial infection generally have very low levels of antibody toward the organisms with which they are infected. In order to provide adequate levels of antibacterial antibody to neonates, several strategies have been devised and tested. In this report, studies on animal investigations and clinical trials are reviewed.

Bacterial Infections↗
PubMed1986

Granulocyte-macrophage progenitor cells in term and preterm neonates.

In groups of adults, and term and preterm neonates, we determined: the blood concentration, the proliferative rate, and the variety of progeny of committed granulocyte-macrophage progenitor cells (CFU-GM). In five of eight term neonates and in all premature infants, a potentially significant limitation of neutrophil production was detected. Unlike the slowly proliferating CFU-GM present in the blood of healthy adult subjects (7% thymidine suicide, range 0% to 32%), the circulating CFU-GM in the premature subjects were proliferating at a near maximal rate (55%, range 40% to 75%, P less than 0.001). Because CFU-GM proliferation is nearly maximal in the baseline, noninfected state, neonates may have restricted ability to increase neutrophil production from CFU-GM during times of increased neutrophil need, such as during bacterial infection. Such inability may predispose neonates to exhaustion of the neutrophil supply during bacterial infection.

Adult↗
PubMed1985

Neutrophil myeloperoxidase concentration: changes with development and during bacterial infection.

In experimental animals, the quantity of myeloperoxidase (MPO) in a volume of whole blood, and the neutrophil concentration in that same volume, were determined and the results expressed as units of MPO (10(-7))/neutrophil. Two situations are reported in which the concentration of MPO/neutrophil was found to change; during the growth and development of animals and during bacterial infection. Premature and newborn rats had only 25% of the MPO/neutrophil found in adults. One to three wk olds had 50% of the adult enzyme concentration. During fatal bacterial infection, MPO/neutrophil fell rapidly, often to undetectable levels, but during sublethal infections, following a 24-h lag period in adults and a 48-h lag in neonates, the concentration increased to twice normal.

Age Factors↗
PubMed1984

Putative methods for prevention and treatment of neonatal septicemia.

The high mortality rate observed in newborn infants who contract bacterial sepsis within the first day of life has prompted investigators to seek new methods for the prevention and treatment of this disorder. Among the putative measures recommended for prevention are: administration of antimicrobials to all infants at the time of delivery, identification and treatment of pregnant women colonized with those bacteria known to be major neonatal pathogens and immunization of women to major neonatal pathogens. Three other measures, targeted at diminishing the mortality and morbidity in those in whom preventive measures fail, include: granulocyte transfusion, exchange transfusion and administration of antibody.

Animals↗
PubMed1984

Exchange transfusion as an alternative to granulocyte concentrate administration in neonates with bacterial sepsis and profound neutropenia.

A high rate of mortality is observed in the subset of neonates with early-onset bacterial sepsis who develop profound neutropenia and depletion of the marrow neutrophil reserve. Several studies suggest that transfusion of apheresis-collected adult neutrophils into such subjects can be beneficial, yet inherent delays in preparation of neutrophil concentrates can limit their clinical utility. In six neonates with sepsis and profound neutropenia, we performed double-volume exchange transfusions using freshly drawn donor blood and determined that a net gain of 0.3-0.7 X 10(9) neutrophils/kg body weight had occurred. The blood neutrophil count of the patients increased from 220 to 1,660/mm3 before the transfusion to 1,650-5,140/mm3 immediately afterward. We next attempted to further increase the number of neutrophils delivered by exchange transfusion by subjecting blood donors to 2 min of physical exercise in order to induce neutrophilia. After such exercise, 30% (range 18-55%) more neutrophils were harvested. The metabolic burst activity and in vitro migration of neutrophils after exercise did not differ from paired preexercise values.

Adult↗
PubMed1984

Pre- and postnatal development of granulocytic stem cells in the rat.

Bacterial sepsis is a relatively common problem in the neonatal period, particularly among prematurely delivered infants. The newborn rat has been widely used as a model for sepsis neonatorum, and in that model incomplete development of the neutrophil system has been postulated to be an important factor predisposing neonates to death from bacterial infection. In this study, that hypothesis was further tested by assessing neutrophil development in rats of various pre- and postnatal ages. Using standard soft agar colony techniques for detecting granulocyte-macrophage progenitor cells [CFU(c)], the number of CFU(c)/g of body weight was seen to increase from 0.5 + 0.1 X 10(3) at 19-20 days gestation to 10.5 +/- 0.2 X 10(3) at 4 weeks. The anatomic location of CFU(c) changed from totally hepatic at 16 days gestation to almost totally myeloid at 4 weeks. Lastly, the proportion of mature, stored neutrophils/CFU(c) decreased from 2440 +/- 40 at 19-20 days gestation to 430 +/- 75 at 4 weeks.

Animals↗
PubMed1984

Treatment of experimental group B streptococcal infection with hybridoma antibody.

Previous studies have shown a reduction in mortality rate from 90% to zero when neonatal rats, inoculated with group B streptococci (GBS) were injected with type-specific IgM antibody. However, in those studies, the antibody was administered simultaneously with the bacteria and at the same site, unlike the situation which would exist if antibody was used clinically to treat established infection. In the present experiments, we administered antibody intraperitoneally at various intervals following intrathoracic inoculation of GBS. When antibody was administered immediately after, or up to 2 h following bacterial inoculation, all animals survived. When antibody administration was delayed for 4, 5, or 6 h, survival rates of 92, 60, and 29% were observed. When antibody administration was delayed for more than 6 h, no survival occurred. Failure of antibody to protect animals from death coincided temporally with profound depletion of the neutrophil storage pool. In other experiments, depletion of the neutrophil storage pool was produced by a separate, noninfectious mechanism (subcutaneous implantation of sterile polyvinyl sponge discs) after which animals were inoculated with GBS. Antibody did not provide protection from death in animals with neutrophil storage pool depletion.

Animals↗
PubMed1983

Granulocytic stem cell (CFUc) proliferation in experimental group B streptococcal sepsis.

Adult rats infected with group B streptococci (GBS) develop neutrophilia and display a marked increase in granulocytic stem cells (CFUc). In contrast, infected neonatal rats develop a profound neutropenia and their CFUc do not increase. In order to better understand this phenomenon, we assessed the CFUc proliferative rate in control and infected adult and neonatal rats using the technique of [3H]-thymidine suicide. Beginning only 3 h after GBS inoculation, adult rats increased CFUc proliferative activity, as illustrated by an increase in thymidine suicide, from 38 +/- 2% cell kill in control animals to 70 +/- 2% when infected (mean + S.E., P less than 0.001). In contrast, the CFUc thymidine suicide rate did not increase in infected neonates. It was noted, however, that the baseline CFUc thymidine suicide rate in uninfected neonatal rats exceeded the rate in uninfected adult rats by 2-3-fold. The CFUc thymidine suicide rate was therefore determined in uninfected premature (74 +/- 1%), newborn (70 +/- 2%), 1-wk-old (70 +/- 1%), 6-wk-old (32 +/- 1%) and 6-month-old (37 +/- 3%) rats. These findings suggest that the proliferative rate of granulocytic stem cells is already maximal or near maximal in noninfected neonatal animals. In contrast to adults, the neonates' granulocyte production from stem cells can not significantly increase, even if bacterial infection is present.

Age Factors↗
PubMed1983

The effect of hybridoma antibody administration upon neutrophil kinetics during experimental type III group B streptococcal sepsis.

Groups of newborn rats were transthoracically inoculated with 1 X 10(6) type III group B streptococci/g body wt, either alone or in combination with 1.5 microgram/g body wt of type-specific antibody derived from hybridoma cell lines. Ninety-four percent of the animals who received bacteria alone died. In contrast, none of those treated with antibody died (P less than 0.005). Kinetic studies suggested that antibody may have offered protection, In part, by facilitating the neutrophil response. Animals who received only bacteria exhibited a marked neutropenia (20 +/- 18/mm3, mean +/- S.E.M.) whereas infected animals treated with antibody did not (3800 +/- 30/mm3, P less than 0.001). Furthermore, within 2 h of inoculation, antibody-treated animals mobilized and stored neutrophils, whereas significant neutrophil mobilization did not occur in the animals which received bacteria alone until 6 h. In the animals receiving bacteria alone, exhaustion of the neutrophil supply quickly occurred (remaining storage neutrophils at 6 h, 0.2 +/- 0.1 X 10(6) cells). In contrast, animals, which received antibody, maintained an adequate supply of stored neutrophils (7.0 +/- 0.4 X 10(6) P less than 0.001). The migration of neutrophils to the site of inoculation was measured by assaying the lungs' content of myeloperoxidase, a marker enzyme for granulocytes. The right and left lungs of animals not receiving antibody accumulated the same quantity of neutrophils, with peak pulmonary neutrophil accumulation occurring 6 h after the infection. In antibody recipients, however, the inoculated lung accumulated significantly more neutrophils than the opposite lung and peak pulmonary neutrophil accumulation occurred at 2 rather than 6 h.

Animals↗
PubMed1983

The neutrophil response to polyvinyl sponge implantation.

Neutrophil release and migration in mice were studied over a 24-hr period after the sc implantation of a single polyvinyl sponge. The release of neutrophils from the marrow was evaluated by directly counting the residual neutrophils in the femoral marrow of animals with sponges. Sponge and tissue neutrophil content was determined by extraction and assay of myeloperoxidase (MPO), a marker enzyme for neutrophils. A maximum depletion of 48% of the mature neutrophils in the marrow was observed 5 hr after sponge implantation, in keeping with significant release of neutrophils for migration to the sponge. The released cells were not found in the circulating granulocyte pool, since neutropenia was noted. The accumulation of neutrophils in the sponge increased throughout the 24-hr period, whereas in the tissue adjacent to the sponge maximum accumulation of neutrophils occurred within 7 hr. In fact, neutrophils migrated to at least three sites--the sponge, the skin overlying the sponge, and the skin in which an incision had been made to insert the sponge. The sponge content of neutrophils represented 0.3-33% of the neutrophils migrating to the combined lesion (sponge and skin sites). Therefore, if the neutrophil response to foreign body implantation is to be measured in its entirety, it is necessary to quantify not only the neutrophils within the foreign body but also those in the tissues surrounding it. These studies describe an animal model for neutrophil release and migration to tissues following a standard stimulus. It is proposed that this model may be useful in exploring the factors which influence the release and migration of neutrophils in vivo.

Animals↗
PubMed1982

Review: deficiencies in the neutrophil system of newborn infants, and the use of leukocyte transfusions in the treatment of neonatal sepsis.

Bacterial sepsis is a major cause of morbidity and mortality in the neonatal period. Deficiencies in neutrophil chemotaxis, phagocytosis, and bacterial killing have all been proposed as factors possibly responsible for this problem. In addition, the neutrophil storage pool, or all segmented neutrophils, band neutrophils, and metamyelocytes/kg body weight stored within the marrow, appears to be very small in neonates compared to that in adults, and when an infection develops in a neonate, neutrophil production from stem cells may be limited. In this paper we review the evidence for these neonatal neutrophil deficiencies and examine the animal and clinical studies which have tested leukocyte transfusion as a possible adjunctive therapeutic modality for sepsis neonatorum.

Adult↗