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G Rothstein

Publications and source records attributed to G Rothstein.

At least 19 recordsLinked to original sources
PubMed2000

Hematopoiesis and cytokines. Relevance to cancer and aging.

Impaired hematopoiesis and dysregulated cytokine expression have important implications for cancer in the elderly. In aged people, hematopoiesis is dysregulated and becomes paradoxically down-modulated under periods of increased hematopoietic demand. This down-modulation may explain, at least in part, the increased incidence of anemia in the elderly, although the cause of anemia can usually be identified in these patients and frequently reversed with targeted therapy. An age-associated decrease in the expression of interleukin-2 may contribute to impaired cellular immunity. Additionally, the increased interleukin-6 production frequently found in the elderly may participate in promoting the survival and proliferation of malignant myeloma and in inducing resistance by myeloma cells to therapies that act through apoptosis. Dysregulation of the expression of these and other cytokines may be a mechanism contributing to age-related impairment of the hematopoietic response, the genesis and therapeutic resistance of specific malignancies, and cancer cachexia.

Adolescent↗
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↗
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↗
PubMed1990

Congenital hypoplastic (Diamond-Blackfan) anemia in seven members of one kindred.

Congenital hypoplastic (Diamond-Blackfan) anemia is a rare macrocytic anemia, generally presenting during infancy or childhood. The condition usually occurs sporadically or in a pattern consistent with autosomal recessive inheritance, although autosomal dominant transmission has been proposed in some kindreds. We report the largest known kindred of congenital hypoplastic anemia, with at least 7 affected individuals over 3 generations, and propose that studies of this kindred may be useful for identifying the mechanism by which their genetic abnormality results in congenital hypoplastic anemia. Erythropoietic investigations on relatives show no inhibitors of erythropoiesis in serum, T-lymphocytes, or macrophages. Their erythroid progenitor cells (CFU-E and BFU-E) were generally quantitatively normal, and were capable of rapid proliferation, as judged by cell-cycle shortening. However, their erythroid progenitors displayed a relative insensitivity to recombinant erythropoietin, and produced relatively few normoblasts per erythroid progenitor cell. We propose that these and subsequent studies may be helpful in selecting candidate genes responsible for the molecular defect in this kindred.

Adolescent↗
PubMed1989

Down-modulation of neutrophil production by erythropoietin in human hematopoietic clones.

In clonogenic assays of hematopoietic progenitors, high concentrations (4 U/mL) of erythropoietin (epo) reduced the formation of granulocyte-macrophage (GM) colonies and diminished the number of granulocytes formed per culture plate. Fetal progenitors were more sensitive to these effects of epo than were progenitors from adults, displaying these reductions at greater than or equal to 1 U epo/mL. The mechanism was investigated by growing fetal progenitors stimulated by recombinant GM-CSF, in the absence of epo, and when eight-cell clones first appeared, mapping their location, then adding epo, and assessing its effect on the subsequent differentiation of the clones. In the absence of epo, the clones developed exclusively into GM colonies. However, if developing clones were presented with epo, 85% matured into GM colonies, but 15% became multilineage or normoblast colonies. In addition, developing clones that were presented with epo produced colonies that contained fewer neutrophils. These effects of epo on neutrophil generation were observed with each of three varieties of recombinant epo, and also with purified human epo, but were not observed using epo that had been neutralized with rabbit anti-epo antiserum.

Adult↗
PubMed1989

A randomized trial to develop criteria for administering erythrocyte transfusions to anemic preterm infants 1 to 3 months of age.

A randomized trial of erythrocyte transfusion vs no transfusion was performed in 16 preterm infants 1 to 3 months old with hematocrits of less than or equal to 0.29 L/L. To determine which (if any) such patients definitely benefit from transfusion, an analysis of outcome variables was performed. Factors that prospectively identified patients who would benefit from transfusions included a heart rate of greater than 152 beats per minute (P less than .01), apnea/bradycardia (heart rate less than 90/min) requiring intervention to increase the heart rate (P less than .01), and a blood lactate level above the reference range (P less than .02). Additional investigations were performed to determine the cause of the low hematocrits in the study patients. All had diminished, rather than accelerated, erythropoiesis. However, neither the anemia of chronic disorders nor iron deficiency anemia contributed to the diminished erythropoiesis. In all cases, serum erythropoietin levels were below the predicted range (P less than .001). Thus, at least some preterm infants aged 1 to 3 months with hematocrits less than or equal to 0.29 L/L definitely derive benefit from erythrocyte transfusion. The presence of tachycardia, apnea/bradycardia, or an elevated blood lactate may prospectively identify such patients.

Anemia, Neonatal↗
PubMed1988

Haematopoietic progenitor cells in an infant who developed pancytopenia following an extensive burn.

We observed a 24-month-old infant who developed anaemia, thrombocytopenia and neutropenia while recuperating from an extensive burn. In order to determine the mechanism(s) responsible for the pancytopenia, we quantified marrow-derived haematopoietic progenitor cells, assessed the relative proliferative rate of haematopoietic progenitor cells, and sought the presence of progenitor cell inhibitors. The concentration and relative proliferative rate of pluripotent progenitors (CFU-GEMM) were elevated. No inhibitors of progenitor cells were observed; in fact, the patient's serum contained very high levels of stimulatory activity for CFU-GEMM as well as for granulocyte-macrophage progenitors (CFU-GM). However, the marrow concentration of erythroid progenitors (BFU-E and CFU-E) was diminished. We conclude that the anaemia in this patient was the result of either hypoproduction of differentiated erythroid progenitors or intramyeloid destruction of early erythroid cells. In contrast, the neutropenia was likely to be due to accelerated neutrophil consumption at a rate that exceeded the capacity for increasing neutrophil production.

Anemia↗
PubMed1988

Responsiveness to recombinant human erythropoietin of marrow erythroid progenitors from infants with the "anemia of prematurity".

We used cells from marrow aspirations that had been performed on 10 infants with the "anemia of prematurity" and tested the responsiveness of their erythroid colony-forming units (CFU-E) to recombinant human erythropoietin. For comparison, we also tested marrow-derived CFU-E from five healthy adults, and circulating CFU-E from cord blood of five healthy neonates. CFU-E from the anemic infants had a 50% maximal response at 0.073 +/- 0.024 U erythropoietin per milliliter (mean +/- SD). They were therefore at least as responsive as were CFU-E from adults, which displayed a 50% maximal response at 0.118 +/- 0.076 U/ml, and as were circulating CFU-E of cord blood origin, which had a 50% maximal response at 0.109 +/- 0.047 U/ml. Because CFU-E from infants with the "anemia of prematurity" appeared highly sensitive to erythropoietin in vitro, we propose that its administration to these patients would likely result in a significant increase in erythrocyte production in vivo.

Anemia, Neonatal↗
PubMed1988

Neutrophil-mediated killing, opsonization, and serum-mediated killing of Escherichia coli K1 by neonatal rats.

Neonates are particularly susceptible to infection with Escherichia coli K1. To investigate the mechanisms which lead to this susceptibility, we examined: (a) the bactericidal activity of neutrophils; (b) opsonization, and (c) the bactericidal activity of serum in developing rats. Neutrophils from adult rats killed E. coli K1 more efficiently than did neutrophils from young animals. Opsonization of E. coli by serum of prematurely delivered rats was poor. Serum from prematurely delivered and term rats promoted growth of E. coli K1, while serum from adult rats killed greater than 95% of the organisms within 90 min. However, the mixture of heat-inactivated serum from adult rats plus serum from prematurely delivered rats killed E. coli K1.

Animals↗
PubMed1988

Erythroid colonies derived from fetal blood display different growth patterns from those derived from adult marrow.

Fetal blood may be useful for the study of hematopoietic development in humans. However, the methods used to study blood cell colonies in adults may not be optimal for the study of colonies derived from fetal blood. Using cord blood from six healthy term pregnancies and marrow from six healthy adult volunteers, we compared the chronology of emergence, morphology, and differentiation of progenitor cell colonies from the two sources. In cultures of adult marrow, erythroid colony-forming unit colonies reached maximal concentrations after 8.5 +/- 0.3 days of culture (mean +/- SEM), but erythroid colony-forming unit colonies derived from fetal blood reached maximal concentrations sooner, after 6.5 +/- 0.2 days (p less than 0.01). Single-centered-erythroid burst-forming unit colonies from adult marrow (45 +/- 5/10(5) light-density, "accessory-cell"-depleted cells) reached a peak at 14 days, but from cord blood they were significantly greater at 9 days (200 +/- 15/10(5) cells) than at 14 days. When studying fetal blood erythroid colony-forming unit and "mature-erythroid burst-forming unit," colonies should be enumerated earlier than when studying adult marrow-derived progenitors. Otherwise, the concentrations of these progenitors will be significantly underestimated.

Adult↗
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

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↗
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↗