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Biomedical subjects

D A Lipschitz

Publications and source records attributed to D A Lipschitz.

At least 55 records · Page 3Linked to original sources
PubMed1989

The pattern of myeloid suppression and recovery after the addition of methotrexate to murine long-term bone marrow culture.

Treating long-term bone marrow culture with 10(-7)-10(-5) M methotrexate caused a 95% reduction in myelopoiesis as assessed by supernatant cell count and granulocyte/macrophage colony forming unit number. The suppression was irreversible with 10(-5) M methotrexate. Complete recovery of myeloid cell production occurred four and five weeks after cultures were treated with either 10(-7) M or 10(-6) M methotrexate, respectively. The suppression of myelopoiesis was completely prevented if 10(-3) M leucovorin was added to culture within 6 h of 10(-6) M methotrexate. The addition to culture of lung conditioned medium containing high concentrations of granulocyte/macrophage colony-stimulating factor shortened the time of myelopoietic suppression by one week. The addition of WEHI-3B medium containing both interleukin 3 and GM-CSF shortened the suppression by two weeks. This in vitro model provides unique opportunities to examine mechanisms involved in the myelopoietic and chemotherapy-induced suppression. A close analysis of approaches to modify the recovery process will also be possible.

Animals↗
PubMed1989

An approach to assessing the reliability of anthropometrics in elderly patients.

Although anthropometrics have traditionally been utilized in the assessment of protein-energy malnutrition, little is known of the reliability of these measurements in elderly patient populations. In this study, the reliability of an anthropometric measurement protocol, designed for ease in measurement of both independent and functionally debilitated elderly patients, is evaluated. An analysis of variance technique was used to calculate the test-retest variance for each of three observers. Although the experience of the three observers was equivalent, the precision of their measurements varied considerably. After repeat practice sessions, improved measurement reliability was demonstrated. For all the observers, the test-retest variance was found to be proportional to the size of the measurement and to be influenced by the accuracy in which the site for each measurement was located. Based on this study, we conclude that when using anthropometrics it is important to know the reliability of each observers' measurements. Because of the correlation between the test-retest variance and the measurement value, we suggest that the variance be expressed as a percentile. A method for transforming the variances is presented.

Aged↗
PubMed1988

Proerythroblast stimulating activity: its purification from mouse serum and its effect on mouse erythroid cell proliferation in vitro.

A factor in mouse serum which stimulates proerythroblast proliferation in in vitro culture (proerythroblast stimulating activity-PSA) was purified by green A dye ligand and high performance liquid chromatography (HPLC). As judged by HPLC, PSA obtained after these two steps appeared to be a homogenous protein of Mr 100,000. It increased the proliferation of proerythroblasts when added alone to a liquid culture of bone marrow which was treated with anti-RBC antibody to remove haemoglobin containing erythroid cells. PSA functioned synergistically with erythropoietin (Ep) so that when added to culture together proliferation was 10-fold higher than when added to culture alone. PSA also increased CFU-E number but only when added together with Ep. Dose-response studies indicated that PSA increased CFU-E number when Ep remained constant and vice versa. PSA addition to culture could be delayed by as much as 12 h without any decrease in the number of CFU-E colonies that developed. When PSA was added to BFU-E cultures at the time of culture initiation no increase in BFU-E was seen. If, however, PSA was added 5 d after culture initiation BFU-E colonies were significantly increased. These results demonstrate that there is a factor (PSA) which can be purified from mouse serum which is not Ep. Its major site of action appears to be the more mature erythroid precursors that have the capacity to divide.

Animals↗
PubMed1988

The role of calcium in the age-related decline of neutrophil function.

Upon activation by formyl-methionyl-leucyl-phenylalanine (FMLP), either in the presence of absence of cytochalasin B, neutrophils from old subjects generated significantly less superoxide than did neutrophils from the young. This reduction in activity was associated with a significant decrease in the basal cytosolic calcium concentration and a diminished flux of calcium to the cytosol after activation. At all concentrations of FMLP tested, cytosolic calcium remained significantly lower in neutrophils from the old as compared with the young, whereas permeability to extracellular calcium and efflux of calcium from the cell were also significantly diminished. Pretreatment of the cell with the ionophore ionomycin elevated the cytosolic calcium concentration and significantly improved function in old neutrophils. These findings demonstrate that aging results in alterations in neutrophil calcium homeostasis that may play a role in the age-related decline in neutrophil function.

Adult↗
PubMed1988

Long-term bone marrow culture as a model for host toxicity: the effect of methotrexate on hematopoiesis and adherent layer function.

Long-term bone marrow culture was used to examine the hematopoietic toxicity of the chemotherapeutic agent methotrexate. A dose-related suppression in myelopoiesis was seen when cultures were treated with 10(-3), 10(-4), or 10(-5) M methotrexate followed by folinic acid rescue. Differential counts revealed an initial decrease of postmitotic myeloid cells followed by mitotic precursors and myeloid colony-forming units (CFU-C). Myelopoiesis had disappeared by 7-10 days when 10(-3) M methotrexate was studied, by day 21 with 10(-4) M methotrexate, and by day 28 with 10(-5) M methotrexate. Although 10(-3) M methotrexate caused a predictable suppression in myelopoiesis, the effect of 10(-5) M methotrexate was more variable. In some studies this dose caused significant suppression of myelopoiesis, whereas in others less suppression occurred. This provides some evidence for varying host susceptibility to drug. Microenvironmental (adherent layer) cells were also affected by methotrexate. An increase in proliferation of these cells occurred in proportion to the dose of methotrexate added to culture. Methotrexate did not affect the ability of the adherent cells to produce colony-stimulating activity (CSA), but high doses did prevent the layer's ability to support the proliferation of adherent cell-free marrow. These results indicate that long-term bone marrow culture can be used to successfully predict and define chemotherapeutic host toxicity.

Bone Marrow↗
PubMed1988

An evaluation of the role of microenvironmental factors in the limitation of myelopoiesis in murine long-term bone marrow culture.

On a day-to-day or week-to-week basis, generation of colony-stimulating factor (CSF) by the adherent layer was identical in long-term bone marrow cultures initiated from young or old mice. CSF concentration increased as myelopoiesis failed, no decline in the generation of CSF following increased stimulation was seen, and donor age did not affect the responsiveness of myeloid cells to CSF. Following spontaneous failure of myelopoiesis, adherent layers originally initiated from young or old mice were equally able to support hematopoiesis following recharge. Thus no age-related decline in adherent layer function could be detected.

Age Factors↗
PubMed1987

Effect of donor and culture age on the function of neutrophils harvested from long-term bone marrow culture.

Neutrophils harvested from the supernatants of long-term bone marrow cultures that were initiated from young and old mice were tested for their functional activity. Superoxide generation was measured, as was the secretion of the enzymes lysozyme, myeloperoxidase, and glucuronidase, both basally and following stimulation by phorbol myristate acetate. The function of the neutrophils harvested from cultures that were initiated from young mice was identical to that of cells derived from young mouse peritoneal cavities at the time of death. A minimal decline in function in culture-derived cells was seen over the 15-18 weeks of study. For each of the above measurements examined, neutrophils obtained from cultures initiated from old mice gave values significantly lower than those in neutrophils recovered from cultures initiated from young mice. For some parameters (superoxide generation, myeloperoxidase), the rate of decline in function was more rapid for neutrophils from old rather than young mouse cultures. For other measurements the rates of decline were equal. The results indicated adequate neutrophil function in long-term bone marrow culture for extended periods of time. They also demonstrated that the age-related diminution in neutrophil function observed in vivo persisted in in vitro culture.

Aging↗
PubMed1987

Nutrition, aging, and the immunohematopoietic system.

Aging is associated with declines in immune and hematopoietic functions, which bear many similarities to those caused by protein-calorie malnutrition. This review describes the age-related decline in the immunohematopoietic system and discusses the potential modulatory role of nutrition in these changes.

Adult↗
PubMed1987

Cancer, clinical pharmacology, and aging.

The changes in the pharmacology of cancer chemotherapeutic agents related to age remain largely unexplored. Certain physiologic changes are well documented and dictate changes in therapy such as the decrease in CCNU and methotrexate dosage. Other toxicities are also shown to correlate with age, such as bleomycin toxicity. However, in several retrospective studies of combination therapy, arbitrary dose reductions have probably impacted negatively on survival. Further prospective investigation will be required in order to develop more rational approaches to cancer chemotherapy in the elderly. There is an urgent need to systematically examine the impact of age on the pharmacology of antineoplastic agents. Trials and clinical treatments uniquely designed for older cancer patients are essential in order to develop rational approaches to management.

Aged↗
PubMed1987

Role of colony-stimulating factor in myelopoiesis in murine long-term bone marrow cultures.

Weekly medium change or midweek feeding of long-term bone marrow cultures (LTMBCs) results in a significant increase in total myeloid cell production. Proliferative myeloid cells peak 48 hours after feeding, and nonproliferative myeloid cells reach maximum levels at 72 hours. This increase in myelopoiesis is invariably preceded by a significant elevation in biologically and immunologically measurable colony-stimulating factor (CSF) in the supernatants of LTBMC. The level peaks 24 hours after medium change, then gradually returns to basal values. The decrease in CSF relates to its consumption by generating myeloid precursors because no fluctuation in the levels occur in cultures without active myelopoiesis. No significant inhibitors or promoters of CSF were detected. When highly purified L cell CSF, CSF in lung-conditioned medium, or CSF concentrated from LTBMC supernatant is added to cultures, an identical increase in myelopoiesis occurs. Anti-CSF antiserum, added to culture at the time of medium change, totally neutralizes supernatant CSF levels but does not affect myelopoiesis. These findings suggest a potential regulatory role for CSF in myelopoiesis in LTBMC. CSF appears to function within the microenvironment through a mechanism involving cell:cell interactions or by causing the production of other substances that stimulate myelopoiesis. Because exogenous CSF stimulates myelopoiesis, it is likely that it too can react either directly or through microenvironmental cells to stimulate primitive myeloid cells to divide.

Animals↗
PubMed1987

Evidence that microenvironmental factors account for the age-related decline in neutrophil function.

We measured the function of neutrophils harvested from the supernatant of long-term marrow cultures in which stromal cell cultures derived from young mice were recharged with hematopoietic cells from old mice and vice versa. The functions measured were superoxide generation and enzyme secretion (lysozyme and glucuronidase), following cell activation by either phorbol myristate acetate (PMA) or Formyl-methionyl-leucyl-phenylalanine (FMLP). In addition we measured cytosolic calcium concentration and its increase following activation by FMLP. In all culture combinations recharge resulted in the recovery of greater than 2 X 10(6) cells/flask (95% neutrophils, 98% viable). Histologic studies of cytoplasmic markers indicated that recovered neutrophils were derived from the stem cell population employed for recharge. For each neutrophil parameter measured, function was markedly improved when old hematopoietic stem cells were recharged onto a young stroma and was significantly diminished when young stem cells were recharged onto an old stroma. This applied to superoxide generation, basal and stimulated enzyme levels, and to basal cytosolic calcium concentration and its increase following activation by FMLP. These results indicate that when old hematopoietic stem cells proliferate in a young microenvironment, neutrophil function returns virtually to normal. Conversely, function diminishes when young stem cells proliferate in an old stroma. These findings demonstrate, for the first time, that neutrophil function is modulated by microenvironmental factors, hormonal, cellular, or matrix, which are decreased in the elderly. That an age-related decline in function is extrinsic to the cell and is reversible has significance for the study of neutrophil function and of cellular aging and has potential therapeutic implications.

Aging↗
PubMed1986

Influence of aging and protein deficiency on neutrophil function.

This study examined the effect of age and protein deficiency on the function of mouse neutrophils. Compared with appropriate controls aging and protein deficiency caused significant reductions in respiratory burst activity, exocytosis, and enzyme release from neutrophils. Individually, neither aging nor protein deficiency caused decreases in the ability of the neutrophil to phagocytose or kill bacteria. When aged animals were fed a protein deficient diet, however, further reductions in neutrophil function occurred that resulted in significant decreases in phagocytosis and bacterial cell kill. These findings indicate that both aging and protein deficiency compromise neutrophil function. When both variables are present the abnormalities become sufficient to affect the neutrophils' most critically important functions. The results emphasize the importance of protein deficiency in the aged and help explain the high prevalence of bacterial infection in malnourished older individuals.

Aging↗
PubMed1986

In vitro culture of proerythroblasts: characterization of proliferative response to erythropoietin and steroids.

This study characterized variables affecting the in vitro liquid culture of proerythroblasts. When bone marrow from mice depleted of haemoglobin containing cells, was cultured in vitro in the presence of human urinary erythropoietin (Ep) a significant degree of erythroid cell proliferation and maturation occurred as measured directly by 3H-thymidine (3H-TdR) incorporation into DNA (autoradiographical measurement). Proliferation increased in direct proportion to the dose of Ep added to the culture. We also demonstrated a highly significant positive correlation between proliferation measured directly by 3H-TdR incorporation into DNA or indirectly by 59Fe incorporation into haem. Ep was a potent stimulator of proerythroblast proliferation. We also examined the role of the androgenic and non-androgenic steroids on in vitro proliferation. All the hormones tested were stimulatory but only in the presence of Ep. The androgenic steroids primarily affected the more mature erythroid precursors whereas the glucocorticoids were more general growth promoters. Their addition in physiologic concentration to liquid culture reduced Ep requirements. Thus when both testosterone and hydrocortisone were added to culture the Ep concentration that produced the same degree of proliferation as a culture containing Ep alone was decreased by 90%. This finding is important as it indicates that in vitro culture conditions can be created that more closely mimic in vivo erythropoiesis where Ep requirements are far less.

Androgens↗
PubMed1986

Effect of age on therapeutic outcome in advanced diffuse histiocytic lymphoma: the Southwest Oncology Group experience.

To study the influence of chronologic age on treatment outcome in patients with advanced, diffuse large-cell (histiocytic) lymphoma (DHL), we reviewed the results of two recent Southwest Oncology Group (SWOG) clinical trials. From 1974 to 1982, members entered 307 eligible patients treated with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) with or without bleomycin, and CHOP with or without immunotherapy using BCG, levamisole, or both. Complete response (CR) rates declined progressively with advancing age: 65% in those under 40, 60% in the 40 to 54 age group, 55% in the 55 to 64 age group, and 37% in those 65 and older (P = .001). Likewise, survival decreased significantly in older patients: medians were 101 +, 52, 34, and 16 months, respectively (P less than .001). Treatment guidelines included an initial dose reduction of 50% for patients aged 65 or older and for younger patients with bone marrow compromise. Despite protocol specifications, 23 of 81 patients aged 65 or older received initial full-dose therapy. When these patients were compared with younger patients on whom full-dose chemotherapy was started, survival curves, but not CR rates, were still significantly different. There were no significant differences in duration of CR or frequency of treatment complications. These data suggest that older age is associated with a worse prognosis in advanced DHL. Moreover, the initial dose reduction for patients aged 65 or older may have contributed to their inferior outcomes.

Adult↗
PubMed1986

Plasma ferritin determination as a diagnostic tool.

Plasma ferritin is a secretory component of intracellular ferritin synthesis. In normal persons its amount reflects the size of iron stores. A decrease to less than 12 mug per liter indicates iron deficiency. Increased iron stores are associated with an increased plasma ferritin level. Various other conditions, however, can increase the plasma ferritin concentration including increased metabolism, inflammation, tissue damage and neoplastic disease. The use of the plasma ferritin determination in diagnosing iron overload depends on excluding these other causes, leaving storage iron as the only explanation for the increased plasma ferritin. It is then necessary to establish the parenchymal nature of the iron overload by showing an elevated transferrin saturation and, if elevated, the more definitive liver biopsy should be done.

Ferritins↗
PubMed1986

Studies on the kinetics of the erythroid colony-forming cell.

The appearance, rate of formation, and morphologic characteristics of the erythroid colony-forming cell (CFU-E) was studied in control, exhypoxic polycythemic, and anemic mice. Polycythemia resulted in a significant reduction in CFU-E number and a lag time of approximately 8 h before colonies were visible in culture. Thereafter, the rate of formation of colonies, as assessed by the slope of the increase in their number, was identical to the control. The slower appearance of CFU-E in polycythemia was corrected by the injection of erythropoietin (Ep) 8 h prior to sacrifice, but an absolute increase in colony number only occurred when Ep was injected 24 h previously. Polycythemia also slowed the rate of colony maturation, so that at later culture times the colonies more frequently contained fewer cells and consisted of basophilic normoblasts. Anemia did not shorten the time of first appearance of colonies, but their rate of maturation was significantly more rapid than the control. These findings are best explained by a redistribution of CFU-E in various phases of the cell cycle when erythropoiesis is manipulated. Unit-gravity sedimentation studies suggested a greater fraction of CFU-E in long G1 or G0 in polycythemia. In addition, the kinetics of CFU-E development were identical to polycythemia in mice in which S and post-S-phase CFU-E were removed by hydroxyurea injection. It is likely that Ep stimulates CFU-E in all phases of the cell cycle. After stimulation by Ep, however, CFU-E in long G1 must move through the cell cycle prior to commencing cell division. This transit time of 8 h, which is unaffected by the Ep concentration in the medium, results in a lag in appearance and maturation of colonies derived from these cells. These results demonstrate that cellular variables are important in CFU-E kinetics in vitro and provide insights into factors affecting the regulation of normal erythropoiesis.

Anemia↗