132 results on '"Lipschitz DA"'
Search Results
2. Effect of age on second messenger generation in neutrophils
- Author
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Lipschitz, DA, primary, Udupa, KB, additional, Indelicato, SR, additional, and Das, M, additional
- Published
- 1991
- Full Text
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3. Protein-energy undernutrition and the risk of mortality within 1 y of hospital discharge in a select population of geriatric rehabilitation patients
- Author
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Sullivan, DH, primary, Walls, RC, additional, and Lipschitz, DA, additional
- Published
- 1991
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4. Impact of nutrition status on morbidity and mortality in a select population of geriatric rehabilitation patients
- Author
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Sullivan, DH, primary, Patch, GA, additional, Walls, RC, additional, and Lipschitz, DA, additional
- Published
- 1990
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5. Nutrition and health in the elderly.
- Author
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Lipschitz DA
- Published
- 1991
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6. Role of colony-stimulating factor in myelopoiesis in murine long-term bone marrow cultures
- Author
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Lipschitz, DA, Udupa, KB, Taylor, JM, Shadduck, RK, and Waheed, A
- Abstract
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.
- Published
- 1987
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7. Effect of age on hematopoiesis in man
- Author
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Lipschitz, DA, Udupa, KB, Milton, KY, and Thompson, CO
- Abstract
We have shown previously that the cause of anemia in healthy elderly subjects can usually not be identified. In this study, hematopoiesis was examined in 18 healthy elderly subjects with unexplained anemia and in 15 young and 15 healthy elderly individuals without anemia. No reduction in circulating testosterone was noted, making decreased androgen levels as a cause for the anemia unlikely. The 2,3 diphospho- glycerate (2,3DPG) levels in the anemic subjects were significantly higher than their corresponding controls, suggesting that the anemia was pathologic, as no increase would be expected if the low hemoglobin was a physiologic adjustment to age. The anemia was associated with a reduction in marrow normoblast and CFU-E number, but no decrease in BFU- E levels was seen. This suggests that the mechanism of the anemia is a decrease in stem cell proliferation. This could be caused by a reduction in circulating erythropoietin or a defect in end organ response. A second possibility is that a basic cellular abnormality exists. The presence of an overall reduction in hematopoiesis in anemic elderly (decreased peripheral blood counts, reduced marrow myeloid precursors, and CFU-C levels) makes this especially likely. The abnormality may be caused by a mechanism unrelated to the aging process. The fact that nonanemic elderly also have reductions in hematopoiesis suggests that age contributes to the defect.
- Published
- 1984
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8. The effect of high ascorbic acid supplementation on body iron stores
- Author
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Cook, JD, Watson, SS, Simpson, KM, Lipschitz, DA, and Skikne, BS
- Abstract
The level of assimilation of dietary iron is believed to have an important influence on iron status. To examine the effect of enhancing the availability of dietary iron on iron balance, 17 adult volunteer subjects were given 2 g of ascorbic acid daily with meals for 16 weeks. Serum ferritin levels before and after the study averaged 46 and 43 micrograms/L, respectively, indicating a negligible effect on iron stores. When vitamin C supplementation was continued for an additional 20 months in five iron-replete and four iron-deficient subjects, serum ferritin determinations again failed to indicate any significant effect of the vitamin C on iron reserves. These findings were not explained by intestinal adaptation to the enhancing effect of the vitamin, because radioisotopic measurements of nonheme iron absorption showed no reduction in the enhancing effect of 1 g of ascorbic acid after four months of megadoses of vitamin C. It is concluded that altering the availability of nonheme dietary iron has little effect on iron status when the diet contains substantial amounts of meat.
- Published
- 1984
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- View/download PDF
9. Evidence that microenvironmental factors account for the age-related decline in neutrophil function
- Author
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Lipschitz, DA, Udupa, KB, and Boxer, LA
- Abstract
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.
- Published
- 1987
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10. The role of calcium in the age-related decline of neutrophil function
- Author
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Lipschitz, DA, Udupa, KB, and Boxer, LA
- Abstract
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.
- Published
- 1988
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11. Endotoxin-induced suppression of erythropoiesis: the role of erythropoietin and a heme synthesis stimulating factor
- Author
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Udupa, KB and Lipschitz, DA
- Abstract
The regulation of erythropoiesis is primarily controlled by erythropoietin (Ep). Recently, however, other factors that both stimulate and inhibit erythropoiesis have been reported. Using an in vitro liquid culture of bone marrow cells, a factor in normal mouse serum was demonstrated that markedly stimulated heme synthesis by marrow erythroid cells. In this study, the role of this heme synthesis stimulating factor (HSF) and Ep in the erythropoietic suppression caused by endotoxin administration to mice was examined. Although HSF levels did not alter appreciably after endotoxin injection, marrow erythroid cells from these animals became unresponsive to the factor. This could be reversed if Ep was added to the culture in vitro or if the hormone was injected into the mice 18 hr prior to harvesting the marrow. This marrow erythroid cell response is identical to that seen in animals in whom Ep levels are markedly reduced, such as that found in exhypoxic polycythemia, and suggest a decrease in the hormone following endotoxin administration. Additional studies demonstrated that when Ep was injected into mice 6 hr after endotoxin administration, an increase in femoral erythroid colony-forming units (CFU-E), proerythroblast number, and 59 Fe incorporation into femoral marrow cells could be demonstrated. These findings, together with the marrow erythroid cell response to the hormone, suggest that the mechanism for suppression of erythropoiesis after endotoxin injection is a reduction in the level of circulating Ep.
- Published
- 1982
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12. The clinical significance of ferritinuria
- Author
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Lipschitz, DA, Allegre, A, and Cook, JD
- Abstract
Urinary ferritin levels were measured by a “2-site” immunoradiometric assay in normal volunteers and in patients with various hematologic disorders. The mean urinary ferritin concentration in normal subjects averaged 2.2 microgram/liter, only 3% of the serum ferritin level. Elevated urinary ferritin levels averaging 45 microgram/liter were observed in patients with hematologic malignancies, but there was a proportional increase in serum ferritin so that the urinary level still averaged only 7% of the serum value. The highest urinary ferritin values (mean 170 microgram/liter) were associated with chronic hemolytic anemia, and in these patients, urinary ferritin rose disproportionately in relation to the serum, averaging 82% of it. This higher urinary level apparently reflects increased ferritin in renal tubular cells due to glomerular filtration of unbound hemoglobin, a mechanism that is supported by a highly significant correlation between urinary ferritin and serum haptoglobin levels. In normal subjects and in patients with malignancy, the source of urinary ferritin appears different, since a highly significant correlation was observed between urinary ferritin and reticuloendothelial iron stores as measured by serum ferritin or total iron-binding capacity. In this setting, the most likely source of urinary ferritin is the iron contained in renal tubular cells, which is apparently in equilibrium with body iron stores.
- Published
- 1980
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13. The effect of age and sex on the routinely used measurements to assess the nutritional status of hospitalized patients
- Author
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Mitchell, CO, primary and Lipschitz, DA, additional
- Published
- 1982
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14. Detection of protein-calorie malnutrition in the elderly
- Author
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Mitchell, CO, primary and Lipschitz, DA, additional
- Published
- 1982
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15. The Arkansas aging initiative: an innovative approach for addressing the health of older rural Arkansans.
- Author
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Beverly CJ, McAtee RE, Chernoff R, Davis GV, Jones SK, and Lipschitz DA
- Subjects
- Arkansas, Diffusion of Innovation, Humans, Organizational Case Studies, Poverty, Cooperative Behavior, Geriatrics organization & administration, Health Services Accessibility organization & administration, Rural Health
- Abstract
The Donald W. Reynolds Institute on Aging at the University of Arkansas for Medical Sciences in Little Rock is addressing one of the most pressing policy issues facing the United States: how to care for the burgeoning number of older adults. In 2001, the Institute created the Arkansas Aging Initiative, which established seven satellite centers on aging across the state using $1.3 to $2 million dollars annually from the state's portion of the Master Tobacco Settlement. These centers on aging assist the state's population of older adults, many of whom reside in rural areas, live in poverty, and suffer from poor health. The centers provide multiple avenues of education for the community, health care providers, families, and caregivers. The Arkansas Aging Initiative, in partnership with local hospitals, also makes geriatric primary and specialty care more accessible through senior health clinics established across rural Arkansas. In 2005, older adults made more than 36,000 visits to these clinics. All sites have attracted at least one physician who holds a Certificate of Added Qualifications in geriatrics and one advanced practice nurse. Other team members include geriatric medical social workers, pharmacists, nutritionists, and neuropsychologists. This initiative also addresses other policy issues, including engaging communities in building partnerships and programs crucial to maximizing their limited resources and identifying opportunities to change reimbursement mechanisms for care provided to the growing number of older adults. We believe this type of program has the potential to create a novel paradigm for nationwide implementation.
- Published
- 2007
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16. Aging activates adipogenic and suppresses osteogenic programs in mesenchymal marrow stroma/stem cells: the role of PPAR-gamma2 transcription factor and TGF-beta/BMP signaling pathways.
- Author
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Moerman EJ, Teng K, Lipschitz DA, and Lecka-Czernik B
- Subjects
- Adipocytes cytology, Animals, Bone Morphogenetic Proteins genetics, Bone Morphogenetic Proteins physiology, Cell Differentiation physiology, Mice, Mice, Inbred C57BL, RNA, Messenger genetics, Signal Transduction genetics, Signal Transduction physiology, Stromal Cells physiology, Transforming Growth Factor beta genetics, Adipocytes physiology, Cellular Senescence physiology, Mesenchymal Stem Cells physiology, Osteogenesis physiology, PPAR gamma physiology, Transforming Growth Factor beta physiology
- Abstract
Osteoblasts and adipocytes originate from a common progenitor, which arises from bone marrow mesenchymal stroma/stem cells (mMSC). Aging causes a decrease in the number of bone-forming osteoblasts and an increase in the number of marrow adipocytes. Here, we demonstrate that, during aging, the status of mMSC changes with respect to both their intrinsic differentiation potential and production of signaling molecules, which contributes to the formation of a specific marrow microenvironment necessary for maintenance of bone homeostasis. Aging causes a decrease in the commitment of mMSC to the osteoblast lineage and an increase in the commitment to the adipocyte lineage. This is reflected by changes in the expression of phenotype-specific gene markers. The expression of osteoblast-specific transcription factors, Runx2 and Dlx5, and osteoblast markers, collagen and osteocalcin, is decreased in aged mMSC. Conversely, the expression of adipocyte-specific transcription factor PPAR-gamma2, shown previously to regulate osteoblast development and bone formation negatively and to regulate marrow adipocyte differentiation positively, is increased, as is a gene marker of adipocyte phenotype, fatty acid binding protein aP2. Furthermore, production of an endogenous PPAR-gamma activator(s) that stimulates adipocyte differentiation and production of autocrine/paracrine factor(s) that suppresses the osteoblastic phenotype are also increased. In addition, expression of different components of TGF-beta and BMP2/4 signaling pathways is altered, suggesting that activities of these two cytokines essential for bone homeostasis change with aging.
- Published
- 2004
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17. Financial effect of a hospital outpatient senior clinic on an academic medical center.
- Author
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Dang S, Baker G, and Lipschitz DA
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- Aged, Hospital Charges, Humans, Medicare, Referral and Consultation economics, Retrospective Studies, United States, Ambulatory Care Facilities economics, Fee-for-Service Plans economics, Health Services for the Aged economics, Hospitalization economics, Hospitals, University economics
- Abstract
Objectives: To estimate the billed charges generated for the university hospital (UH) by patients seen in a UH outpatient senior clinic over a 6-month period. To estimate the average billed charges per geriatric patient generated for the UH over the same 6-month period., Design: Retrospective analysis., Setting: Hospital-based outpatient senior clinic at a university medical center., Participants: Outpatients aged 65 and older., Measurements: The total inpatient, outpatient, and professional fee charges generated for the UH by the senior health center (SHC) patients were estimated for a 6-month period, with the use of billing data from the professional and hospital billing systems. To estimate the multiplier effect and average charges per SHC patient per year, our analysis focused on professional charges generated directly in the SHC and professional fees and hospital charges generated by secondary referral (inpatient and outpatient)., Results: One thousand nine hundred ninety-eight patients were seen in the SHC during the 6-month period. For every $1 billed in professional charges in the SHC, $17 was billed elsewhere in the hospital system. Geriatric medicine professional charges generated by the 1,998 SHC patients over the 6-month period totaled $546,691. The 6-month charges by the rest of the hospital system for the same 1,998 patients included hospital inpatient charges of $4,684,195 for all departments; hospital outpatient charges (ancillary plus technical, including facility fees for the SHC) of $3,027,212; and professional fees of $1,606,287 for other departments, thereby producing a multiplier factor of 17. The average overall charges per geriatric patient per 6 months totaled $4,937, which included hospital inpatient, hospital outpatient, and professional fees. The UH generated an average of $3,860 in hospital charges per SHC patient per 6 months. The average hospital charges generated per established SHC patient per 6 months were $2,936. The average hospital charges for a new SHC patient were $7,187 per 6 months. The average professional charges were $1,078 per patient per 6 months., Conclusions: This study provides a reasonable estimate of the substantial multiplier, or "flow-through," effect of a senior clinic on its parent medical center. Although senior clinics may be a cost center when viewed in isolation, these clinics are actually revenue generators when viewed from the perspective of the entire health system.
- Published
- 2002
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18. Activation of an adipogenic program in adult myoblasts with age.
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Taylor-Jones JM, McGehee RE, Rando TA, Lecka-Czernik B, Lipschitz DA, and Peterson CA
- Subjects
- Adipocytes metabolism, Animals, Biomarkers, CCAAT-Enhancer-Binding Protein-alpha genetics, Carrier Proteins, Cell Differentiation, Cells, Cultured, Fatty Acid-Binding Protein 7, Fatty Acid-Binding Proteins, Lipoprotein Lipase genetics, Mice, Mice, Inbred DBA, Muscle, Skeletal metabolism, Proto-Oncogene Proteins genetics, Receptors, Cytoplasmic and Nuclear genetics, Transcription Factors genetics, Triglycerides metabolism, Wnt Proteins, Adipocytes cytology, Muscle, Skeletal cytology, Neoplasm Proteins, Nerve Tissue Proteins
- Abstract
Myoblasts isolated from mouse hindlimb skeletal muscle demonstrated increased adipogenic potential as a function of age. Whereas myoblasts from 8-month-old adult mice did not significantly accumulate terminal markers of adipogenesis regardless of culture conditions, myoblasts from 23-month-old mice accumulated fat and expressed genes characteristic of differentiated adipocytes, such as the fatty acid binding protein aP2. This change in differentiation potential was associated with a change in the abundance of the mRNA encoding the transcription factor C/EBPalpha, and in the relative abundance of PPARgamma2 to PPARgamma1 mRNAs. Furthermore, PPARgamma activity appeared to be regulated at the level of phosphorylation, being more highly phosphorylated in myoblasts isolated from younger animals. Although adipogenic gene expression in myoblasts from aged animals was activated, presumably in response to PPARgamma and C/EBPalpha, unexpectedly, myogenic gene expression was not effectively repressed. The Wnt signaling pathway may also alter differentiation potential in muscle with age. Wnt-10b mRNA was more abundantly expressed in muscle tissue and cultured myoblasts from adult compared with aged mice, resulting in stabilization of cytosolic beta-catenin, that may potentially contribute to inhibition of adipogenic gene expression in adult myoblasts. The changes reported here, together with those reported in bone marrow stroma with age, suggest that a default program may be activated in mesenchymal cells with increasing age resulting in a more adipogenic-like phenotype. Whether this change in differentiation potential contributes to the increased adiposity in muscle with age remains to be determined.
- Published
- 2002
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19. Assay of intracellular hydrogen peroxide generation in activated individual neutrophils by flow cytometry.
- Author
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Ito Y and Lipschitz DA
- Subjects
- Cell Separation methods, Flow Cytometry methods, Granulocytes cytology, Humans, Indicators and Reagents, Kinetics, Neutrophils physiology, Hydrogen Peroxide blood, Neutrophil Activation physiology, Neutrophils cytology
- Published
- 2002
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20. Inhibition of Osf2/Cbfa1 expression and terminal osteoblast differentiation by PPARgamma2.
- Author
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Lecka-Czernik B, Gubrij I, Moerman EJ, Kajkenova O, Lipschitz DA, Manolagas SC, and Jilka RL
- Subjects
- Adipocytes drug effects, Adipocytes metabolism, Animals, Bone Marrow metabolism, Cell Differentiation, Cell Line, Core Binding Factor Alpha 1 Subunit, Gene Expression, Lipoprotein Lipase metabolism, Mice, Osteoblasts drug effects, Phenotype, Rosiglitazone, Thiazoles pharmacology, Transfection, Neoplasm Proteins, Osteoblasts metabolism, Receptors, Cytoplasmic and Nuclear physiology, Thiazolidinediones, Transcription Factors metabolism, Transcription Factors physiology
- Abstract
Cells of the bone marrow stroma can reversibly convert among different phenotypes. Based on this and on evidence for a reciprocal relationship between osteoblastogenesis and adipogenesis, we have isolated several murine bone marrow-derived clonal cell lines with phenotypic characteristics of osteoblasts or adipocytes, or both. Consistent with a state of plasticity, cell lines with a mixed phenotype synthesized osteoblast markers like type I collagen, alkaline phosphatase, osteocalcin, as well as the adipocyte marker lipoprotein lipase, under basal conditions. In the presence of ascorbic acid and beta-glycerophosphate-agents that promote osteoblast differentiation-they formed a mineralized matrix. In the presence of isobutylmethylxanthine, hydrocortisone, and indomethacin-agents that promote adipocyte differentiation-they accumulated fat droplets, but failed to express adipsin and aP2, markers of terminally differentiated adipocytes. Furthermore, they were converted back to matrix mineralizing cells when the adipogenic stimuli were replaced with the osteoblastogenic ones. A prototypic cell line with mixed phenotype (UAMS-33) expressed Osf2/Cbfa1-a transcription factor required for osteoblast differentiation, but not PPARgamma2-a transcription factor required for terminal adipocyte differentiation. Stable transfection with a PPARgamma2 expression construct and activation with the thiazolidinedione BRL49653 stimulated aP2 and adipsin synthesis and fat accumulation, and simultaneously suppressed Osf2/Cbfa1, alpha1(I) procollagen, and osteocalcin synthesis. Moreover, it rendered the cells incapable of forming a mineralized matrix. These results strongly suggest that PPARgamma2 negatively regulates stromal cell plasticity by suppressing Osf2/Cbfa1 and osteoblast-like biosynthetic activity, while promoting terminal differentiation to adipocytes., (Copyright 1999 Wiley-Liss, Inc.)
- Published
- 1999
21. Impaired glutathione peroxidase activity accounts for the age-related accumulation of hydrogen peroxide in activated human neutrophils.
- Author
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Ito Y, Kajkenova O, Feuers RJ, Udupa KB, Desai VG, Epstein J, Hart RW, and Lipschitz DA
- Subjects
- Adult, Aged, Female, Flow Cytometry, Humans, Kinetics, Male, N-Formylmethionine Leucyl-Phenylalanine pharmacology, Neutrophil Activation drug effects, Neutrophils drug effects, Selenium blood, Superoxide Dismutase blood, Aging blood, Glutathione Peroxidase blood, Hydrogen Peroxide blood, Neutrophil Activation physiology, Neutrophils physiology
- Abstract
Background: As assessed by flow cytometry, the increase in hydrogen peroxide in individual neutrophils from old volunteers was significantly greater than in neutrophils from young volunteers. To explain the discrepancy in previous reports that showed reduced superoxide generation with age and our finding, we measured the kinetics of antioxidative enzymes., Methods: Neutrophils were obtained from young (ages 21-34) and old (ages over 65) volunteers. The increase in hydrogen peroxide following stimulation with formyl peptide in individual neutrophils was assessed by flow cytometry by using dihydrorhodamine 123. The enzyme kinetics was determined from the best fit curve using Michaelis-Menten equations., Results: Aging was associated with a significant reduction in the Vmax for glutathione peroxidase. The decreased activity was not due to selenium deficiency as the serum and neutrophil concentrations were identical with age. Following activation, a significant increase in the Km was noted in neutrophils from young but not from old volunteers., Conclusions: These results account for the increased intracellular accumulation of hydrogen peroxide as a function of age in stimulated neutrophils. These results provide evidence in humans of an age-related impairment in antioxidative defense mechanisms that support the free radical theory of aging.
- Published
- 1998
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22. Upregulation of functional ryanodine receptors during in vitro aging of human diploid fibroblasts.
- Author
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Huang MS, Adebanjo O, Moonga BS, Goldstein S, Lai FA, Lipschitz DA, and Zaidi M
- Subjects
- Adenosine Diphosphate Ribose analogs & derivatives, Adenosine Diphosphate Ribose pharmacology, Antibodies immunology, Antibodies metabolism, Caffeine pharmacology, Calcium metabolism, Cyclic ADP-Ribose, Fibroblasts, Fluorescent Antibody Technique, Humans, Microscopy, Fluorescence, Cellular Senescence physiology, Ryanodine Receptor Calcium Release Channel metabolism, Up-Regulation physiology
- Abstract
We demonstrate for the first time that cellular aging in vitro is accompanied by a dramatic elevation in the levels of ryanodine receptor-bearing Ca2+ channels. These channels normally reside within microsomal membranes and gate Ca2+ release from intracellular stores. We therefore measured cytosolic Ca2+ levels in 'young' (30 mean population doublings, MPDs) and 'senescent' (53 to 58 MPDs) human diploid fibroblasts (HDFs). Application of the known ryanodine receptor modulators, caffeine or cyclic adenosine diphosphate-ribose (cADPr), triggered cytosolic Ca2+ signals in both young and senescent cells. The signal magnitude however was significantly greater in senescent compared with young HDFs. In parallel, incubation with a highly specific anti-ryanodine receptor antiserum resulted in specific immunofluorescence only in senescent HDFs. We envisage that elevated levels of functional ryanodine receptors may underlie the defective Ca2+ handling and cellular degeneration that occurs with aging., (Copyright 1998 Academic Press.)
- Published
- 1998
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23. Effects of myelotoxic agents on cytokine production in murine long-term bone marrow cultures.
- Author
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Hauser SP, Allewelt MC, and Lipschitz DA
- Subjects
- Animals, Bone Marrow Cells metabolism, Cell Culture Techniques, Female, Gene Expression, Interleukin-6 genetics, Macrophage Colony-Stimulating Factor genetics, Mice, Mice, Inbred C57BL, RNA, Messenger, Time Factors, Bone Marrow Cells drug effects, Ceftazidime pharmacology, Growth Inhibitors pharmacology, Interleukin-6 biosynthesis, Macrophage Colony-Stimulating Factor biosynthesis, Methotrexate pharmacology
- Abstract
In long-term bone marrow cultures we studied the effect of the addition of the myelotoxic agents methotrexate (MTX) and ceftazidime (CEF) on the kinetics of cytokine production in the supernatant (SN) and on mRNA expression in the adherent stromal layer. In response to a medium change, a prompt and significant increase in colony-stimulating activity (CSA) and interleukin 6 (IL-6) concentrations in the SN occurred, peaking 12 h later. Two macrophage colony-stimulating factors (M-CSF) mRNA of 23 kb and 4 kb were identified. In response to the medium change, the 4.0-kb transcript increased significantly six h later. The 2.3-kb transcript expression was stronger than the 4-kb mRNA but did not cycle with medium change. At medium change, IL-6 mRNA was only minimally expressed; then a prompt increase occurred, which peaked six h later. The addition of 500 mg/ml (=915 microM) CEF to the culture caused a dose-dependent suppression of CSA and IL-6 supernatant concentrations and IL-6 and M-CSF mRNA expression. By contrast, 1 microM MTX had minimal effect on cytokine concentrations in the SN following medium change. mRNA expression was, however, suppressed. These results provide insights into the possible mechanisms whereby cytokines lead to increased myeloid cell proliferation following medium change. We also demonstrate that two myelotoxic agents have different effects on cytokine production. This information could be of value in developing rational approaches to the therapeutic use of cytokines in drug-induced neutropenia.
- Published
- 1998
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24. Cellular and molecular biomarkers indicate precocious in vitro senescence in fibroblasts from SAMP6 mice. Evidence supporting a murine model of premature senescence and osteopenia.
- Author
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Lecka-Czernik B, Moerman EJ, Shmookler Reis RJ, and Lipschitz DA
- Subjects
- Animals, Biomarkers, Cells, Cultured, Cellular Senescence, Gene Expression, Mice, Mice, Inbred C57BL, Aging, Premature etiology, Bone Diseases, Metabolic etiology, Disease Models, Animal
- Abstract
A variety of short-lived mouse strains (SAMP strains) and control strains of less abbreviated life span (SAMR strains) have been proposed as murine models of accelerated senescence. Each SAMP strain, in addition to displaying "progeroid" traits of accelerated aging, exhibits a singular age-related pathology. The application of this animal model to the study of normal aging processes has been and remains controversial. Therefore, we have undertaken a study of dermal fibroblasts derived from the short-lived SAMP6 strain, which shows early-onset and progressive osteopenia. We have investigated cellular and molecular characteristics that are associated with in vitro aging of normal human fibroblasts, and which are exacerbated in fibroblasts from patients with Werner syndrome, a human model of premature senescence. We found that SAMP6 dermal fibroblasts, relative to SAMR1 and C57BL/6 controls, exhibit characteristics of premature or accelerated cellular senescence with regard to in vitro life span, initial growth rate, and patterns of gene expression.
- Published
- 1997
- Full Text
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25. Increased adipogenesis and myelopoiesis in the bone marrow of SAMP6, a murine model of defective osteoblastogenesis and low turnover osteopenia.
- Author
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Kajkenova O, Lecka-Czernik B, Gubrij I, Hauser SP, Takahashi K, Parfitt AM, Jilka RL, Manolagas SC, and Lipschitz DA
- Subjects
- Adipocytes pathology, Aging genetics, Animals, Bone Density genetics, Bone Development genetics, Bone Diseases, Metabolic metabolism, Bone Diseases, Metabolic pathology, Bone Marrow Cells metabolism, Cell Differentiation genetics, Cells, Cultured, Colony-Forming Units Assay, Disease Models, Animal, Interleukin-6 metabolism, Mice, Osteoblasts metabolism, Osteoblasts pathology, Stem Cells metabolism, Stem Cells pathology, Bone Diseases, Metabolic genetics, Bone Marrow Cells pathology, Leukopoiesis genetics
- Abstract
Bone formation and hematopoiesis are anatomically juxtaposed and share common regulatory mechanisms. However, little is known about the interrelationship between these two processes. We have previously shown that the senescence accelerated mouse-P6 (SAMP6) exhibits decreased osteoblastogenesis in the bone marrow that is temporally linked with a low rate of bone formation and decreased bone mineral density. Here we report that in contrast to decreased osteoblastogenesis, ex vivo bone marrow cultures from SAMP6 mice exhibited an increase in the number of colony-forming unit adipocytes, as well as an increase in the number of fully differentiated marrow adipocytes, compared with SAMR1 (nonosteopenic) controls. Further, long-term bone marrow cultures from SAMP6 produced an adherent stromal layer more rapidly, generated significantly more myeloid progenitors and produced more IL-6 and colony-stimulating activity. Consistent with this, the number of myeloid cells in freshly isolated marrow from SAMP6 mice was increased, as was the number of granulocytes in peripheral blood. The evidence that SAMP6 mice exhibit decreased osteoblastogenesis, and increased adipogenesis and myelopoiesis, strongly suggests that a switch in the differentiation program of multipotential mesenchymal progenitors may underlie the abnormal phenotype manifested in the skeleton and other tissues of these animals. Moreover, these observations support the contention for the existence of a reciprocal relationship between osteoblastogenesis and adipogenesis that may explain the association of decreased bone formation and the resulting osteopenia with the increased adiposity of the marrow seen with advancing age in animals and humans.
- Published
- 1997
- Full Text
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26. The pivotal role of interleukin 6 in formation and function of hematopoietically active murine long-term bone marrow cultures.
- Author
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Hauser SP, Kajkenova O, and Lipschitz DA
- Subjects
- Animals, Antibodies, Monoclonal pharmacology, Bone Marrow drug effects, Cells, Cultured, Colony-Stimulating Factors metabolism, Culture Media, Female, Horses, Interleukin-6 immunology, Kinetics, Mice, Mice, Inbred C57BL, Recombinant Proteins pharmacology, Stromal Cells physiology, Time Factors, Bone Marrow metabolism, Bone Marrow Cells, Interleukin-6 metabolism, Interleukin-6 physiology
- Abstract
The multifunctional cytokine interleukin 6 (IL-6) is involved in the regulation of inflammatory and immune responses, and influences many bone and bone marrow functions. In this report we show high concentrations of IL-6 in the supernatant of murine long-term bone marrow cultures (LTBMC). The concentration increases following medium change peaking 12 h later. IL-6 plays a critical role in the generation and maintenance of myelopoiesis in LTBMC. The addition of monoclonal anti-IL-6 antibody to culture significantly suppresses myeloid cell production. IL-6 is also necessary for stromal layer development and the initiation of myelopoiesis in LTBMC. Horse sera (HS) containing low concentrations of IL-6 did not support LTBMC stromal layer development or myeloid cell production, whereas those with high concentrations did. LTBMC initially set up with horse serum containing high IL-6 concentration produced higher concentrations of colony-stimulating activity and IL-6 at the fifth week after culture initiation than those with low concentrations. The ability of a deficient serum to support myelopoiesis could be improved by the addition of recombinant IL-6 to culture. Similarly, the addition of an anti-IL-6 antibody to culture impaired the ability of a HS to initiate and support myelopoiesis in LTBMC. These results suggest that IL-6 is one of the factors that play an essential role in the formation and function of hematopoietically active LTBMC.
- Published
- 1997
- Full Text
- View/download PDF
27. Murine marrow stromal response to myelotoxic agents in vitro.
- Author
-
Hauser SP, Udupa KB, and Lipschitz DA
- Subjects
- Animals, Bone Marrow Transplantation, Cell Count, Cell Division, Cells, Cultured, Colony-Forming Units Assay, Fibroblasts drug effects, Hematopoietic Stem Cells drug effects, Mice, Mice, Inbred C57BL, Antimetabolites, Antineoplastic pharmacology, Bone Marrow Cells, Ceftazidime pharmacology, Hematopoietic Stem Cells cytology, Methotrexate pharmacology
- Abstract
Previous studies have shown that the haemopoietically active murine long-term bone marrow culture (LTBMC) is a useful model for studying drug-induced suppression and recovery of myelopoiesis. We studied the effects on stromal morphology and stromal progenitors, assessed as colony forming unit-fibroblasts (CFU-F), of the addition of either the antimetabolite methotrexate (MTX) or the betalactam ceftazidime (CEF) to LTBMC. The examination of 500 micrograms/ml CEF-treated cultures revealed a stroma that appeared empty, with modest reduction in total stromal counts, and significant decreases in fat-containing and endothelial cells. In contrast, treatment with 1 microM MTX for 1 week initially caused minimal morphologic stromal changes, thereafter total stromal cell count as well as fibroblastoid, endothelial, fat containing and macrophage cells significantly increased. Haemopoiesis and the stroma recovered. Both CEF and MTX reversibly suppressed stromal progenitor cells in LTBMC. When added directly to CFU-F cultures, the concentrations resulting in a 50% colony growth inhibition were 214 micrograms/ml for CEF and 375 nM for MTX. These results suggest that CEF, but not MTX, has direct toxic effects on the stroma of established LTBMC. Stromal cell increase following MTX treatment probably indicates a stromal response that may contribute to haemopoietic cell recovery.
- Published
- 1996
- Full Text
- View/download PDF
28. Excess formation of lysophosphatidic acid with age inhibits myristic acid-induced superoxide anion generation in intact human neutrophils.
- Author
-
Ito Y, Ponnappan U, and Lipschitz DA
- Subjects
- Adult, Aged, Arachidonic Acid metabolism, Calcium pharmacology, Humans, Ionomycin pharmacology, Myristic Acid, Neutrophils drug effects, Phosphatidic Acids metabolism, Phospholipases A metabolism, Phospholipases A2, Aging metabolism, Lysophospholipids metabolism, Myristic Acids pharmacology, Neutrophils metabolism, Superoxides metabolism
- Abstract
A superoxide anion generation rate upon exposure to myristate of 1.93 +/- 0.34 nmol/min/10(6) cells in neutrophils from elderly human donors was significantly less than a value of 3.02 +/- 0.48 nmol/min/10(6) neutrophils from young donors. Myristate activation resulted in equal increases of AA in both the young and the old indicating no effect of aging on the PLA2 pathway to response. By contrast, the PLD-induced generation of PA was significantly higher in the old than in the young. In addition, myristate induced a significant age-related enhancement in LPA generation, in the old but not in the young. The mass of LPA generated following activation was 3.5 nmol/ 2.5 x 10(7) cells/ml in the young while in the old it averaged 7.0 nmol/2.5 x 10(7) cells/ml. The inhibitory effects of LPA may explain the age-related impaired ability to generate superoxide anion following activation by myristate.
- Published
- 1996
- Full Text
- View/download PDF
29. Evidence suggesting a stimulatory role for interleukin-10 in erythropoiesis in vitro.
- Author
-
Wang CQ, Udupa KB, and Lipschitz DA
- Subjects
- Animals, Cells, Cultured, Dose-Response Relationship, Drug, Drug Synergism, Erythroid Precursor Cells cytology, Erythroid Precursor Cells drug effects, Female, Macrophages drug effects, Macrophages physiology, Mice, Mice, Inbred C57BL, Erythropoiesis drug effects, Erythropoietin pharmacology, Interleukin-10 pharmacology
- Abstract
Interleukin-10 (IL-10) has been shown to exert anti-inflammatory effects by suppressing macrophage proliferation and inhibiting cytokine production. In this study we show that in the presence of erythropoietin (EPO), the addition of IL-10 results in a significant dose-dependent increase in both Burst Forming Unit-Erythroid (BFU-E) and Colony Forming Unit-Erythroid (CFU-E) colony growth in both serum-containing and serum-free murine cultures in vitro. IL-10 acts at the later stages of erythroid cell proliferation and differentiation as the increase in colony number was greater in CFU-E than in BFU-E, and was similar when IL-10 was added to BFU-E cultures at the time of culture initiation as when its addition to culture was delayed for 7 days. Furthermore, no increase in BFU-E colony number was noted when IL-10, added at the time of culture initiation, was neutralized by the addition to culture of a monoclonal anti-IL-10 antibody up to 7 days later. The increases in BFU-E by IL-10 addition were not the result of prolongation of BFU-E colony lifespan, which was not significantly different in IL-10 treated and control cultures, respectively. Rather IL-10 stimulated the proliferation of erythroid clusters that were now large enough to be recognized as colonies. IL-10-induced stimulation of erythropoiesis appeared to be independent of its inhibitory effects on macrophage function, as stimulation of erythroid colony growth was similar in macrophage-containing and depleted cultures. Studies to determine if the IL-10 effect was direct or indirect yielded equivocal results. A limiting dilution assay suggested a direct effect. However, a log/log dose response curve with IL-10 did not pass through the origin suggesting an indirect effect. These studies indicate that IL-10 acts synergistically with EPO to significantly increase stimulation of erythroid differentiation and proliferation in vitro and may be involved in the regulation of normal erythropoiesis in vivo.
- Published
- 1996
- Full Text
- View/download PDF
30. Effect of age on the fatty acid composition of phospholipids in human lymphocytes.
- Author
-
Ponnappan U, Holley DH, and Lipschitz DA
- Subjects
- Adult, Aged, Humans, Lymphocyte Activation, Aging metabolism, Fatty Acids analysis, Lymphocytes chemistry, Phospholipids analysis
- Abstract
We have examined the fatty acid composition of phospholipids of unstimulated and PHA-stimulated T cells from young and old donors. Our results demonstrate that aging is accompanied by decreases in the saturated fatty acids, myristic acid, and palmitic acid, and a concomitant increase in the unsaturated arachidonic acid. Following activation with PHA for 24 h, age-associated differences in fatty acids could no longer be detected. In contrast to the lymphocyte, aging did not affect the fatty acid composition of either serum or neutrophil phospholipids. Exposure of lymphocytes from old donors to myristic acid complexed medium increased the levels of myristate in the phospholipids to levels similar to that seen in lymphocytes from young donors. We conclude from these studies that aging is accompanied by an alteration in the fatty acid profiles of phospholipids, and that incubation in myristic acid complexed medium modulates these profiles. These alterations are unique to lymphocytes and may contribute to the age-related declines in lymphocyte function.
- Published
- 1996
- Full Text
- View/download PDF
31. Approaches to the nutritional support of the older patient.
- Author
-
Lipschitz DA
- Subjects
- Aged, Humans, Nutrition Disorders diagnosis, Nutrition Disorders diet therapy, Obesity prevention & control, Protein-Energy Malnutrition prevention & control, Weight Loss, Nutrition Disorders prevention & control, Nutritional Support methods
- Abstract
Malnutrition is a common problem in older persons, and in the presence of disease, is accompanied by increased morbidity and mortality. This article provides a rational approach to the nutritional care of the common nutritional problems that occur in the elderly. These problems include obesity, a condition that occurs with some prevalence in older persons, weight loss and being significantly underweight, and hypoalbuminemic malnutrition. An approach to the nutritional management of patients with pressure ulcers is also discussed.
- Published
- 1995
32. Effect of age on marrow macrophage number and function.
- Author
-
Wang CQ, Udupa KB, Xiao H, and Lipschitz DA
- Subjects
- Animals, Antibodies, Monoclonal, Cell Count, Colony-Forming Units Assay, Cytokines metabolism, Female, Flow Cytometry, In Vitro Techniques, Macrophage Activation, Macrophage-1 Antigen metabolism, Macrophages immunology, Mice, Mice, Inbred C57BL, Aging pathology, Aging physiology, Bone Marrow Cells, Macrophages cytology, Macrophages physiology
- Abstract
Employing flow cytometry and a monoclonal antibody against the murine macrophage antigen, Mac-1, we found a significant increase in the number of marrow macrophages in aged mice. This was reflected as significant increase with age in the number of alpha-naphthyl acetate esterase positive cells, as well as in colony forming unit-macrophage (CFU-M) progenitor cells. Macrophages from the marrow of old mice generated significantly less tumor necrosis factor alpha (TNF alpha) than did macrophages from young mice, either spontaneously or when activated by granulocyte-macrophage colony stimulating factor (GM-CSF). Furthermore, conditioned medium (CM) derived from either marrow or peritoneal macrophages of old mice caused less suppression of burst forming unit-erythroid (BFU-E) colony growth than did CM obtained from young mice. Aging, therefore, is associated with an increase in the number of marrow macrophages that have an impaired ability to generate or release cytokines. The increase in macrophage number may reflect a compensation for their reduced function. Altered macrophage number and function may contribute to the age-related decline in hematopoietic reserve capacity.
- Published
- 1995
- Full Text
- View/download PDF
33. Appropriate and effective use of the NSI checklist and screens. An update on caring for the elderly by preventing malnutrition.
- Author
-
Barrocas A, Bistrian BR, Blackburn GL, Chernoff R, Lipschitz DA, Cohen D, Dwyer J, Rosenberg IH, Ham RJ, and Keller GC
- Subjects
- Aged, Humans, Dietary Services methods, Nutrition Assessment, Nutrition Disorders prevention & control
- Published
- 1995
- Full Text
- View/download PDF
34. Treatment of acute myelogenous leukemia in patients over 50 years of age with V-TAD: a Southwest Oncology Group study.
- Author
-
Bigelow CL, Kopecky K, Files JC, Head D, Lipschitz DA, Grever M, and Appelbaum FR
- Subjects
- Age Factors, Aged, Aged, 80 and over, Antineoplastic Combined Chemotherapy Protocols adverse effects, Cytarabine administration & dosage, Cytarabine adverse effects, Daunorubicin administration & dosage, Daunorubicin adverse effects, Etoposide administration & dosage, Etoposide adverse effects, Female, Humans, Leukemia, Myeloid, Acute mortality, Male, Middle Aged, Survival Analysis, Thioguanine administration & dosage, Thioguanine adverse effects, United States, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myeloid, Acute drug therapy
- Abstract
Acute myelogenous leukemia (AML) in the elderly continues to have a poor prognosis and new treatment approaches are needed. This Phase II trial was undertaken to evaluate the complete remission rate and toxicity of a chemotherapeutic regimen including etoposide and 6-thioguanine, combined with reduced doses of cytosine arabinoside and daunorubicin (V-TAD) in individuals greater than 50 years of age with AML. Thirty-five patients, ranging in age from 51 to 80 years (median, 66 years), were registered onto the study. Twenty-nine patients were entered at the first dose level (daunomycin 20 mg/m2 days 1 and 2, ara-C 75 mg/m2 days 1-5, 6-thioguanine 75 mg/m2 every 12 hr days 1-5, and etoposide 50 mg/m2 days 1, 2, and 3) and six patients underwent therapy at the second dose level (ara-C 75 mg/m2 days 1-7 with the remainder of the regimen unchanged). After achieving a complete remission, patients underwent two to three consolidation cycles of chemotherapy. Thirty-one patients were evaluable for response. Thirteen patients (ten of twenty-five at the first dose level and three of six at the second dose level) achieved a complete remission (42%). Median remission duration was 6 months (range 1-21 months). The current regimen, while tolerated, did not result in improved survival compared with prior treatment regimens because of a high incidence of resistant and recurrent leukemia.
- Published
- 1995
- Full Text
- View/download PDF
35. Morphological characterization of stromal cell types in hematopoietically active long-term murine bone marrow cultures.
- Author
-
Hauser SP, Waldron JA, Upuda KB, and Lipschitz DA
- Subjects
- Animals, Cells, Cultured, Mice, Mice, Inbred C57BL, Time Factors, Bone Marrow Cells, Hematopoiesis, Stromal Cells cytology
- Abstract
Accurate histological evaluation of stromal morphology is very difficult in cultures incubated in plastic flasks. Employing glass flasketts, we were able to characterize the morphology and immunocytochemistry of four marrow stromal cell types in a functionally intact microenvironment of murine long-term bone marrow cultures (LTBMCs). Fibroblastoid cells stained positively for collagen Type I and III, negatively for von Willebrand factor (vWf), the mouse macrophage F4/80 antigen, and the Bandeiraea simplicifolia lectin I isolectin B4 (BSL I-B4). Endothelial cells stained positively for vWf antigen and lectin BSL I-B4 but negatively for collagen Types I and III and for F4/80 antigen. Fat-containing cells had a dense, ovaloid, indented nucleus and fat-containing vacuoles. Macrophages were strongly positive for the F4/80 antigen and stained weakly with BSL I-B4. Between the fourth and ninth weeks after culture initiation, fibroblastoid and endothelial cells remained constant, between 21 +/- 2% and 24 +/- 2% and between 3 +/- 0.3% and 4 +/- 0.4%, respectively, of the total stromal cell population. By contrast, the percentage of fat-containing cells decreased significantly from 26 +/- 3% at Week 4 to 17 +/- 2% at Week 9, and macrophages increased significantly from 49 +/- 1% at Week 4 to 57 +/- 1% at Week 9. This characterization of the stromal cell types in functionally intact LTBMCs should assist in the study of the complex interactions among the marrow stroma, cytokine production, and hematopoiesis.
- Published
- 1995
- Full Text
- View/download PDF
36. Age-related declines in hematopoietic reserve capacity.
- Author
-
Lipschitz DA
- Subjects
- Adult, Aged, Antineoplastic Agents adverse effects, Humans, Middle Aged, Neoplasms physiopathology, Neutropenia chemically induced, Aging physiology, Hematopoiesis physiology, Neoplasms drug therapy
- Published
- 1995
37. Interferon-gamma exerts its negative regulatory effect primarily on the earliest stages of murine erythroid progenitor cell development.
- Author
-
Wang CQ, Udupa KB, and Lipschitz DA
- Subjects
- Animals, Antibodies analysis, Antibodies immunology, Antibodies pharmacology, Cell Differentiation drug effects, Cell Differentiation physiology, Cell Division drug effects, Cell Division physiology, Cells, Cultured, Dose-Response Relationship, Drug, Drug Synergism, Erythroid Precursor Cells drug effects, Erythroid Precursor Cells physiology, Female, Granulocyte-Macrophage Colony-Stimulating Factor immunology, Granulocyte-Macrophage Colony-Stimulating Factor pharmacology, Granulocyte-Macrophage Colony-Stimulating Factor physiology, Interleukin-1 immunology, Interleukin-1 pharmacology, Interleukin-1 physiology, Mice, Mice, Inbred C57BL, Tumor Necrosis Factor-alpha immunology, Tumor Necrosis Factor-alpha pharmacology, Tumor Necrosis Factor-alpha physiology, Erythroid Precursor Cells cytology, Interferon-gamma pharmacology
- Abstract
Interferon-gamma (INF-gamma) has been shown to suppress erythropoiesis and perhaps to contribute to the anemia of chronic disease. In this study we demonstrated that the concentration of INF gamma required to suppress murine burst forming unit-erythroid (BFU-E) growth was significantly less than that required to suppress colony forming unit-erythroid (CFU-E) growth. INF gamma acted at the most primitive step in erythroid progenitor cell differentiation and proliferation, as inhibition was maximal when added at the time of BFU-E culture initiation. Inhibition was progressively less if INF gamma addition was delayed after culture initiation. The effects of INF gamma on BFU-E did not require the presence of interleukin-1 alpha (IL-1 alpha), tumor necrosis factor-alpha (TNF alpha), or granulocyte macrophage colony stimulating factor (GM-CSF), as its effects were not neutralized by monoclonal antibodies against IL-1 alpha, TNF alpha, or GM-CSF. This applied whether INF gamma was added to culture with individual antibodies or with a combination of all three antibodies. INF gamma was not required for IL-1 alpha- or TNF alpha-induced suppression of BFU-E, as their effects were not neutralized by a monoclonal anti-INF gamma antibody. In contrast, GM-CSF-induced suppression of BFU-E was negated by the simultaneous addition of anti-INF gamma. We have previously shown that the addition of TNF alpha does not suppress BFU-E growth in cultures from marrow depleted of macrophages. Suppression did occur, however, if a small concentration of INF gamma that does not inhibit and increasing concentration of TNF alpha were added to culture, suggesting a synergistic effect between INF-gamma and TNF alpha. These observations suggest that INF gamma is a potent direct inhibitor of erythroid colony growth in vitro. It exerts its negative regulatory effect primarily on the earliest stages of erythroid progenitor cell differentiation and proliferation, as much higher doses are required to suppress late erythroid cell development. INF gamma is also involved in GM-CSF-induced inhibition of BFU-E colony growth.
- Published
- 1995
- Full Text
- View/download PDF
38. Effects of ceftazidime, a betalactam antibiotic, on murine haemopoiesis in vitro.
- Author
-
Hauser SP, Udupa KB, and Lipschitz DA
- Subjects
- Animals, Bone Marrow Cells, Ceftazidime antagonists & inhibitors, Cell Division drug effects, Cells, Cultured, Colony-Forming Units Assay, Dose-Response Relationship, Drug, Erythroid Precursor Cells drug effects, Female, Guinea Pigs, Hematopoietic Stem Cells cytology, In Vitro Techniques, Mice, Mice, Inbred C57BL, Time Factors, Tretinoin pharmacology, Ceftazidime pharmacology, Hematopoiesis drug effects, Hematopoietic Stem Cells drug effects
- Abstract
Agranulocytosis has been reported in 5-15% of patients treated with high-dose betalactam antibiotics (BLA). We investigated the toxic effect of ceftazidime (CEF) as a representative of these antibiotics on colony-forming unit-granulocyte/macrophage (CFU-GM), on burst-forming unit-erythroid (BFU-E) colony growth and on myelopoiesis in murine long-term bone marrow culture (mLTBMC). The CEF concentration resulting in a 50% inhibition of growth was 146 micrograms/ml (267 microM) for CFU-GM, 132 micrograms/ml (241 microM) for BFU-E and 180 micrograms/ml (329 microM) for myeloid cell production in the supernatant of mLTBMC. Following addition of CEF to mLTBMC, CFU-GM remained low for 1 week and total myeloid cell production remained low for 2 weeks after removal of CEF from culture. Thereafter the values returned to control levels. The myeloid differential counts in the supernatant and adherent layers demonstrated a 'maturation arrest', which could be overcome by simultaneously adding all-trans retinoic acid to culture. These results demonstrate that CEF has reversible inhibitory effects on myelopoiesis and highlight the utility of in vitro haemopoietic assays as models to examine drug-induced haemopoietic dyscrasias.
- Published
- 1994
- Full Text
- View/download PDF
39. Evidence suggesting a negative regulatory role for macrophages in murine erythropoiesis in vivo.
- Author
-
Wang CQ, Udupa KB, Xiao H, and Lipschitz DA
- Subjects
- Animals, Bone Marrow Cells, Female, Hypoxia, Interleukin-1 metabolism, Mice, Mice, Inbred C57BL, Tumor Necrosis Factor-alpha metabolism, Erythropoiesis, Macrophages physiology
- Abstract
Increasing the rate of erythropoiesis in C57BL/6 mice, either by hypoxia or by the injection of recombinant erythropoietin (Epo), resulted in significant reductions in marrow macrophage number, as assessed by flow cytometry employing the monoclonal antibody against the macrophage antigen Mac-1 and by histologic determination of reductions in the number of marrow esterase-positive cells. This decline was paralleled by decreases in marrow colony-forming unit-macrophage (CFU-M) and colony-forming unit-granulocyte/macrophage (CFU-GM) number. The intramedullary concentration of the cytokines interleukin-1 alpha (IL-1 alpha) and tumor necrosis factor-alpha (TNF-alpha), which are produced by macrophages, was also reduced. Cessation of erythropoiesis was associated with increases in macrophage number, CFU-M and CFU-GM colony number, and IL-1 alpha concentrations. Increased erythropoiesis resulted in reductions in number of burst-forming unit-erythroid (BFU-E) colonies, which were less sensitive to suppression by macrophages as evidence by less increase in colony number when macrophages were removed from the marrow before in vitro BFU-E culture. BFU-E colony number was suppressed less when IL-1 alpha and TNF-alpha were added to cultures obtained from animals with stimulated erythropoiesis. Compared to controls, BFU-E number and suppression by macrophages increased significantly when erythropoiesis was reduced. These observations provide compelling evidence for a regulatory role for macrophages in normal erythropoiesis in vivo, presumably acting as a negative balance to the stimulatory effects of Epo.
- Published
- 1994
40. Screening for nutritional status in the elderly.
- Author
-
Lipschitz DA
- Subjects
- Aged, Female, Humans, Male, Middle Aged, Nutritional Status, Protein-Energy Malnutrition diagnosis, Thinness diagnosis, Weight Loss, Geriatric Assessment, Nutrition Assessment, Nutrition Disorders diagnosis
- Abstract
A comprehensive assessment of nutritional status is a critically important component of any patient evaluation. Based upon clinical information, anthropometric data, and a small number of laboratory investigations, an accurate appraisal of nutritional status should be possible and an appropriate intervention plan can be developed. The actual approach depends on the particular problem discovered. These are discussed in detail elsewhere in this issue.
- Published
- 1994
41. A clinical evaluation of serum ferritin as an index of iron stores. 1974.
- Author
-
Lipschitz DA, Cook JD, and Finch CA
- Subjects
- Anemia blood, Anemia history, Anemia, Hypochromic blood, Anemia, Hypochromic history, Ferritins blood, History, 20th Century, Humans, Iron metabolism, Ferritins history, Iron history
- Published
- 1992
42. Anemia in the elderly patient.
- Author
-
Mansouri A and Lipschitz DA
- Subjects
- Anemia etiology, Anemia therapy, Erythropoiesis physiology, Humans, Aging blood, Anemia physiopathology
- Abstract
Anemia is one of the most common disorders in elderly patients. The pathophysiology of anemia is the same in the young as well as the old. However, the common presence of multiorgan dysfunction or disease in elderly patients can alter the clinical presentation, response to treatment, and prognosis of anemia in this group.
- Published
- 1992
- Full Text
- View/download PDF
43. Myelodysplastic syndromes in the elderly.
- Author
-
Mansouri A and Lipschitz DA
- Subjects
- Aged, Bone Marrow Transplantation, Cause of Death, Clinical Protocols standards, Cytarabine administration & dosage, Cytarabine pharmacology, Cytarabine therapeutic use, Decision Trees, Granulocyte-Macrophage Colony-Stimulating Factor therapeutic use, Humans, Prognosis, Survival Rate, Myelodysplastic Syndromes diagnosis, Myelodysplastic Syndromes epidemiology, Myelodysplastic Syndromes therapy
- Published
- 1992
- Full Text
- View/download PDF
44. Analysis of treatment failure in acute nonlymphocytic leukemia patients over fifty years of age. A Southwest Oncology Group study.
- Author
-
Ryan DH, Kopecky KJ, Head D, Grever MR, Shiaer SM, Lipschitz DA, Hynes HE, Vial RH, Veith RW, and Gumbart CH
- Subjects
- Aged, Bone Marrow Examination, Cytarabine administration & dosage, Daunorubicin administration & dosage, Etoposide administration & dosage, Female, Humans, Male, Middle Aged, Remission Induction, Treatment Outcome, Antineoplastic Combined Chemotherapy Protocols therapeutic use, Leukemia, Myeloid, Acute drug therapy
- Abstract
Fourteen participating centers registered 33 patients on a Southwest Oncology Group Study of adults with acute non-lymphocytic leukemia (ANLL). Induction consisted of cytosine arabinoside 70 mg/m2 days 1-7 by continuous intravenous (i.v.) infusion, VP-16 50 mg/m2 i.v. over 1 hour days 1-3, and daunomycin 30 mg/m2 i.v. bolus days 1-3. Twenty-five patients (median age 69 years) were evaluable for response. Eleven (44%) achieved a remission marrow but only 8 fulfilled both blood and marrow criteria for complete remission. Of the 11 patients with a remission marrow, there were no patients over 70 years of age. Major coexisting disease data were evaluated. Only 5 patients had no major coexisting disease and 4 of those 5 achieved a remission marrow. The study illustrates and underscores the following problems of remission induction in the elderly: (a) increased susceptibility to the stress of the induction period, with 6 patients (24%) dying before treatment day sixteen; (b) disease resistance to antileukemic therapy with persistent ANLL in 6 patients (24%), despite two induction courses; and (c) hematopoietic stem cell sensitivity in the elderly with marrow regeneration failure documented in 2 patients (8%) following induction. Acute nonlymphocytic leukemia in the elderly has a poor prognosis, and novel therapeutic approaches are warranted.
- Published
- 1992
- Full Text
- View/download PDF
45. Nutrition screening initiative: development and implementation of the public awareness checklist and screening tools.
- Author
-
White JV, Dwyer JT, Posner BM, Ham RJ, Lipschitz DA, and Wellman NS
- Subjects
- Aged, Aged, 80 and over, Humans, Nutrition Disorders etiology, Risk Factors, Nutrition Assessment, Nutrition Disorders diagnosis, Nutritional Status
- Published
- 1992
46. An approach to nutrition screening for older Americans.
- Author
-
Lipschitz DA, Ham RJ, and White JV
- Subjects
- Aged, Algorithms, Forms and Records Control, Humans, Methods, Surveys and Questionnaires, Geriatric Assessment, Health Status Indicators, Nutrition Assessment
- Abstract
The Nutrition Screening Initiative suggests an adaptable, tiered approach to screening for poor nutritional status in older Americans. The first level of screening is a checklist to be completed by elderly individuals or their caregivers. This checklist, which will be widely disseminated, describes the warning signs of poor nutritional status. It is anticipated that individuals will approach their physicians on the basis of scores on this checklist. Also included are two screening tests designed to help clinicians more easily detect poor nutritional status, or risk factors for poor nutrition, in their patients. The level I screen is to be completed by a social service or health care professional, or by other trained personnel. The level II screen focuses on additional information to be obtained following referral to a physician or other qualified health care professional.
- Published
- 1992
47. Malnutrition in the elderly.
- Author
-
Lipschitz DA
- Subjects
- Aged, Aged, 80 and over, Female, Humans, Male, Nutrition Assessment, Protein-Energy Malnutrition classification, Protein-Energy Malnutrition etiology, Protein-Energy Malnutrition therapy
- Abstract
Malnutrition is known to be very common in hospitalized and institutionalized elderly. Various studies report an incidence ranging from 33% to 67% of all patients. Recent evidence also suggests that the presence of nutritional deficiencies is associated with increased morbidity, mortality, and greater use of health care resources. The problem is compounded by the lack of resources in most acute care hospitals and nursing homes to obtain an adequate nutritional assessment or to monitor nutritional status over time. This report will present an overview of nutritional problems in the elderly, and provide an approach aimed at identifying patients at high risk of being malnourished in order to develop rational strategies for management. The role of nutritional factors in the development of pressure sores will also be discussed.
- Published
- 1991
48. Phase II evaluation of bisantrene in refractory multiple myeloma. A Southwest Oncology Group study.
- Author
-
Durie BG, Crowley J, Coltman CA Jr, Chapman RA, Balcerzk SP, Bonnet JD, Lipschitz DA, Stephens RL, and Cheson BD
- Subjects
- Aged, Aged, 80 and over, Anthracenes therapeutic use, Drug Evaluation, Female, Humans, Male, Middle Aged, Antibiotics, Antineoplastic therapeutic use, Multiple Myeloma drug therapy, Tumor Stem Cell Assay
- Published
- 1991
- Full Text
- View/download PDF
49. Consensus of the Nutrition Screening Initiative: risk factors and indicators of poor nutritional status in older Americans.
- Author
-
White JV, Ham RJ, Lipschitz DA, Dwyer JT, and Wellman NS
- Subjects
- Activities of Daily Living, Aged, Dietetics, Health Promotion methods, Health Status, Humans, Mass Screening methods, Risk Factors, United States, Geriatric Assessment, Nutritional Status
- Abstract
Dietetics professionals must become even more proactive in taking the lead in the nutritional screening and assessment of older Americans. They can do so by encouraging all health care providers to become familiar with each older American's circumstances and needs. In addition, as individuals and as a professional health care association, we should urge our colleagues and institutions to establish regular longitudinal surveillance and continuity of care in nutrition services delivery. The timely, appropriate, and cost-effective delivery of nutritional screening, assessment, and care will improve the health and well-being of this valued segment of the US population. Dietetics professionals are a vital part of this process.
- Published
- 1991
50. Impact of nutrition on the age-related decline in immune and hematologic function.
- Author
-
Lipschitz DA
- Subjects
- Aged, Anemia etiology, Diet, Humans, Nutrition Disorders physiopathology, Zinc physiology, Aging physiology, Blood Cells physiology, Immune System physiology, Nutritional Physiological Phenomena
- Published
- 1991
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