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Biomedical subjects

C M Baum

Publications and source records attributed to C M Baum.

At least 19 recordsLinked to original sources
PubMed2000

Myelopoietin, an engineered chimeric IL-3 and G-CSF receptor agonist, stimulates multilineage hematopoietic recovery in a nonhuman primate model of radiation-induced myelosuppression.

Myelopoietins (MPOs) constitute a family of engineered, chimeric molecules that bind and activate the IL-3 and G-CSF receptors on hematopoietic cells. This study investigated the in vivo hematopoietic response of rhesus monkeys administered MPO after radiation-induced myelosuppression. Animals were total body irradiated (TBI) in 2 series, with biologically equivalent doses consisting of either a 700 cGy dose of Cobalt-60 ((60)Co) gamma-radiation or 600 cGy, 250 kVp x-irradiation. First series: On day 1 after 700 cGy irradiation, cohorts of animals were subcutaneously (SC) administered MPO at 200 microg/kg/d (n = 4), or 50 microg/kg/d (n = 2), twice daily, or human serum albumin (HSA) (n = 10). Second series: The 600 cGy x-irradiated cohorts of animals were administered either MPO at 200 microg/kg/d, in a daily schedule (n = 4) or 0.1% autologous serum (AS), daily, SC (n = 11) for 23 days. MPO regardless of administration schedule (twice a day or every day) significantly reduced the mean durations of neutropenia (absolute neutrophil count [ANC] < 500/microL) and thrombocytopenia (platelet < 20,000/microL) versus respective control-treated cohorts. Mean neutrophil and platelet nadirs were significantly improved and time to recovery for neutrophils (ANC to < 500/microL) and platelets (PLT < 20,000/microL) were significantly enhanced in the MPO-treated cohorts versus controls. Red cell recovery was further improved relative to control-treated cohorts that received whole blood transfusions. Significant increases in bone marrow-derived clonogenic activity was observed by day 14 after TBI in MPO-treated cohorts versus respective time-matched controls. Thus, MPO, administered daily was as effective as a twice daily schedule for multilineage recovery in nonhuman primates after high-dose, radiation-induced myelosuppression.

Animals↗
PubMed2000

Effective ex vivo generation of granulopoietic postprogenitor cells from mobilized peripheral blood CD34(+) cells.

OBJECTIVE: Neutropenia following high-dose chemotherapy and peripheral blood progenitor cell (PBPC) transplantation might be abrogated by an additional transplantation of ex vivo generated granulopoietic postprogenitor cells (GPPC). Therefore, the ex vivo expansion of CD34(+) PBPC was systematically studied aiming for optimum GPPC production. MATERIALS AND METHODS: CD34(+) PBPC were cultured in serum-free medium comparing different (n = 32) combinations of stem cell factor (S), interleukin 1 (1), interleukin 3 (IL-3) (3), interleukin-6 (6), erythropoietin (E), granulocyte colony-stimulating factor (G), granulate-macrophage colony-stimulating factor (GM), daniplestim (D, a novel IL-3 receptor agonist), and Flt3 ligand (FL) under various culture conditions. Ex vivo generated cells were assessed by flow cytometry, morphology, and progenitor cell assays. RESULTS: Addition of G +/- GM but not GM alone to cultures stimulated with S163E effectively induced the generation of GPPC. GPPC production was maximum after 12 to 14 days. Best expansion rates were observed when cells were cultured at 1.5x10(4)/mL in 21% O(2). Modifications of culture conditions were either less or equally effective (i.e., modification of starting cell concentrations, low oxygen, addition of serum albumin or autologous plasma, repetitive feeding). Comparison of different cytokine combinations revealed that the optimum GPPC expansion cocktail consisted of S6GD+FL (day 12: 130-fold cellular expansion, 32% myeloblasts/promyelocytes, 49.4% myelocytes/metamyelocytes, 12.4% bands/segmented), which furthermore expanded CD34(+) cells (3.4-fold) and clonogenic progenitors (13.4-fold). CONCLUSION: Using the S6DG+FL expansion cocktail, GPPC could be effectively produced ex vivo starting from positively selected CD34 PBPC, possibly enabling amelioration or even abrogation of posttransplant neutropenia.

Adjuvants, Immunologic↗
PubMed2000

Effective ex vivo generation of megakaryocytic cells from mobilized peripheral blood CD34(+) cells with stem cell factor and promegapoietin.

OBJECTIVE: The additional transplantation of ex vivo-generated megakaryocytic cells might enable the clinician to ameliorate or abrogate high-dose chemotherapy-induced thrombocytopenia. Therefore, the ex vivo expansion of CD34(+) PBPC was systematically studied aiming for an optimum production of megakaryocytic cells. MATERIALS AND METHODS: CD34(+) PBPC were cultured in serum-free medium comparing different (n = 23) combinations of stem cell factor (SCF) (S), IL-1beta (1), IL-3 (3), IL-6 (6), erythropoietin (EPO) (E), thrombopoietin (TPO) (T) and promegapoietin (PMP, a novel chimeric IL-3/TPO receptor agonist). Ex vivo-generated cells were assessed by flow cytometry, morphology, and progenitor cell assays. RESULTS: Addition of TPO to cultures stimulated with S163E, a potent progenitor cell expansion cocktail previously described by our group, effectively induced the generation of CD61(+) cells (day 12: 31.4 +/- 7.9%). The addition of PMP tended to be more effective than TPO +/- IL-3. Whereas EPO was not required to maximize TPO- or PMP-induced megakaryocytic cell production, the use of IL-6 and IL-1beta augmented cellular expansion as well as CD61(+) cell production rates in the majority of cytokine combinations studied. Thus, the most effective CD61(+) cell expansion cocktail consisted of S163 + PMP which resulted in 65.9 +/- 3.0% CD61(+) at day 12 and an overall production of 40.7 +/- 4.5 CD61(+) cells per seeded CD34(+) PBPC. However, the basic 2-factor combination S + PMP also allowed for an effective CD61(+) cell production (day 12 CD61(+) cell production: 15.1 +/- 1.6). Moreover, maximum amplification of CFU-Meg was observed after 7 days using this two-factor cocktail (12.9 +/- 2.6-fold). The majority of CD61(+) cells generated in TPO- or PMP-based medium were low-ploidy 4N and 8N cells, and ex vivo-generated CD61(+), CD41(+), and CD42b(+) cells were mainly double positive for FACS-measured intracellular von Willebrand Factor (vWF) (76.7 +/- 3.3%, 58.8 +/- 4.4%, and 82.7 +/- 2.5%, respectively). CONCLUSIONS: Taken together, this study demonstrates that megakaryocytic cells can be effectively produced ex vivo with as little as two-factors (SCF + PMP), an approach that might be favorably employed in a clinical expansion trial aiming to ameliorate high-dose chemotherapy-induced thrombocytopenia.

Cell Differentiation↗
PubMed2000

Clinical-scale production of granulocyte progenitor and post-progenitor cells using daniplestim, leridistim, Progenipoietin, Promegapoietin and autologous plasma.

BACKGROUND: Supplementation of PBPC autografts with ex vivo expanded PBMC may significantly reduce or eliminate the period of neutropenia associated with high-dose chemotherapy. METHODS: Unmanipulated growth-factor mobilized PBMC were expanded in media containing daniplestim, leridistim, Promegapoietin, and Progenipoietin (DLPP) and 2% autologous plasma at 4 x 10(5) PBMC/mL, first in 25 cm(2) T-flasks, with sampling on Days 7, 10, 13 and 15, and then in 1264 cm(2) Nunclon Cell Factories, with sampling on Days 7 and 13. RESULTS: In T25-flasks, maximal CFU-GM expansion ([38.2 +/- 9.5]-fold) occurred on Day 10, whereas maximal total cell expansion ([6.7 +/- 1.1]-fold) occurred on Day 15. Production of CD15(+)CD11b(-) and CD15(+)CD11b(+) granulocytic post-progenitors (3.0 +/- 0.4 x 10(6) and 3.7 +/- 0.9 x 10(6), respectively) was also maximal at Day 15. Compared with the previously studied combination of Flt3L, PIXY321, G-CSF, GM-CSF and Epo, the DLPP cocktail performed similarly, with the exception of yielding larger GM colonies at Day 10 and fewer granulocyte post-progenitors on Day 15. In Cell Factories, CFU-GM were expanded (31.6 +/- 14.5)-fold, while total nonadherent cells were expanded (2.6 +/- 0.5)-fold. The two stack Cell Factory cultures seeded with 1.0 x 10(8) unselected PBMC produced approximately 3.3 x 10(6) CFU-GM and 1.3 x 10(8) myeloid post-progenitors. DISCUSSION: Whereas expansion of cell numbers, CFU-GM and granulocytic post-progenitors in Cell Factories mirrored that achieved in T25-flasks, future preclinical studies with the DLPP cytokine combination may be performed in small volumes, with subsequent translation to the larger volume Cell Factories. Sufficient expansion can be achieved using the DLPP cytokine combination in the Cell Factories to provide the numbers of progenitors required for clinical trials.

Cell Culture Techniques↗
PubMed2000

Mobilization of peripheral-blood stem cells by concurrent administration of daniplestim and granulocyte colony-stimulating factor in patients with breast cancer or lymphoma.

PURPOSE: To evaluate the safety and hematopoietic activity of daniplestim administered concurrently with granulocyte colony-stimulating factor (G-CSF) for peripheral-blood stem-cell (PBSC) mobilization. PATIENTS AND METHODS: In the initial dose-escalation phase, 25 patients with adenocarcinoma of the breast (AB; 13 patients) or lymphoma (12 patients) were given daniplestim at doses ranging from 0.1 to 3.75 microgram/kg/d plus G-CSF 10 microgram/kg/d. In the randomized phase, 52 patients with AB (27 patients) or lymphoma (25 patients) were randomized within disease categories to the daniplestim dose chosen in the dose-escalation phase plus G-CSF 10 microgram/kg/d (D+G) or placebo plus G-CSF 10 microgram/kg/d (P+G) for up to 7 days. RESULTS: A daniplestim dose of 2. 5 microg/kg/d was chosen for further study because it was hematopoietically active and had an acceptable side-effect profile. In the randomized phase, in patients with AB, D+G was associated with a higher probability (P =.0696) of collecting >/= 2.5 x 10(6) CD34(+) cells/kg and significantly higher circulating CD34(+) cell counts (P =.0498) on days 6 through 9 after the initiation of dosing. The target level was more likely to be reached with additional leukaphereses in the patients given D+G. Patients given P+G did not benefit from additional leukaphereses beyond the first procedure. The type of mobilization did show a trend toward a shorter duration of neutropenia in the D+G group. The adverse events with D+G consisted largely of mild to moderate flu-like symptoms, including headache and fever, and occurred more frequently than with P+G. CONCLUSION: Daniplestim administered at 2.5 microgram/kg/d is tolerable and active when combined with G-CSF, and the combination may prove more effective than G-CSF alone in promoting the collection of adequate numbers of CD34(+) cells for PBSC infusion in patients with AB.

Adenocarcinoma↗
PubMed1999

Home-based multidisciplinary diagnosis and treatment of inner-city elders with dementia.

The Memory and Aging Project Satellite (MAPS) of the Washington University Alzheimer's Disease Research Center was developed to meet the medical, social, and housing needs of minority and medically underserved elders with cognitive impairments. MAPS is located in the offices of the St. Louis Area Agency on Aging (AAA). This program provides multidisciplinary outreach, as well as home-based diagnosis, treatment, and case management. It differs from most other satellite programs in that it seeks to provide service to individuals who do not voluntarily seek help for dementia. Cognitively impaired clients had numerous, unmanaged medical conditions and social problems. Few clients were adequately served by health and social service systems. Despite recent contact, only 10% of clients received a formal diagnosis of dementia from a physician. Treatment was hampered by the absence or limitations of caregivers. Despite the complexities of these cases, the MAPS staff have been generally successful in addressing client problems.

Aged↗
PubMed1997

Occupational therapy practice: focusing on occupational performance.

Changes in the health system require occupational therapy practitioners to focus their concerns on the long-term health needs of people and to help them develop healthy behaviors not only to improve their health, but also to minimize the health care costs associated with dysfunction. Occupational therapy practitioners must initiate efforts in the community to integrate a range of services that promote, protect, and improve the health of the public. This article shares the experiences of Canadian occupational therapy practitioners, who were challenged by their government nearly 15 years ago to establish a system that demonstrates effectiveness by improving the health of occupational therapy clients. By focusing on occupational performance, occupational therapy practitioners assist clients in becoming actively engaged in their life activities. This requires client-centered and family-centered practice and services that span from the agency or institution to the community. Occupational therapy practitioners must work collaboratively with persons in the client's environment (e.g., family members, teachers, independent living specialists, employers, neighbors, friends) to assist the client in obtaining skills and to make modifications to remove barriers that create a social disadvantage. A focus on occupational performance requires occupational therapy personnel to reframe how we think about occupational therapy to a sociomedical context and to take an active role in building healthy communities.

Canada↗
PubMed1996

Combination therapy for radiation-induced bone marrow aplasia in nonhuman primates using synthokine SC-55494 and recombinant human granulocyte colony-stimulating factor.

Combination cytokine therapy continues to be evaluated in an effort to stimulate multilineage hematopoietic reconstitution after bone marrow myelosuppression. This study evaluated the efficacy of combination therapy with the synthetic interleukin-3 receptor agonist, Synthokine-SC55494, and recombinant methionyl human granulocyte colony-stimulating factor (rhG-CSF) on platelet and neutrophil recovery in nonhuman primates exposed to total body 700 cGy 60Co gamma radiation. After irradiation on day (d) 0, cohorts of animals subcutaneously received single-agent protocols of either human serum albumin (HSA; every day [QD], 15 micrograms/kg/d, n = 10), Synthokine (twice daily [BID], 100, micrograms/kg/d, n = 15), rhG-CSF (QD, 10 micrograms/kg/d, n = 5), or a combination of Synthokine and rhG-CSF (BID, 100 and 10 micrograms/kg/d, respectively, n = 5) for 23 days beginning on d1. Complete blood counts were monitored for 60 days postirradiation and the durations of neutropenia (absolute neutrophil count < 500/microL) and thrombocytopenia (platelet count < 20,000/microL) were assessed. Animals were provided clinical support in the form of antibiotics, fresh irradiated whole blood, and fluids. All cytokine protocols significantly (P < .05) reduced the duration thrombocytopenia versus the HSA-treated animals. Only the combination protocol of Synthokine + rhG-CSF and rhG-CSF alone significantly shortened the period neutropenia (P < .05). The combined Synthokine/rhG-CSF protocol significantly improved platelet nadir versus Synthokine alone and HSA controls and neutrophil nadir versus rhG-CSF alone and HSA controls. All cytokine protocols decreased the time to recovery to preirradiation neutrophil and platelet values. The Synthokine/rhG-CSF protocol also reduced the transfusion requirements per treatment group to 0 among 5 animals as compared with 2 among 5 animals for Synthokine alone, 8 among 5 animals for rhG-CSF, and 17 among 10 animals for HSA. These data showed that the combination of Synthokine, SC-55494, and rhG-CSF further decreased the cytopenic periods and nadirs for both platelets and neutrophils relative to Synthokine and rhG-CSF monotherapy and suggest that this combination therapy would be effective against both neutropenia and thrombocytopenia consequent to drug- or radiation- induced myelosuppression.

Anemia, Aplastic↗
PubMed1995

CD34+ progenitor cells from asymptomatic patients are not a major reservoir for human immunodeficiency virus-1.

Controversy exists as to whether hematopoietic progenitor cells are infected by human immunodeficiency virus-1 (HIV-1) in vivo. Most studies have focused on patients with acquired immunodeficiency syndrome (AIDS)/AIDS-related complex, and little data are available on asymptomatic patients with well preserved CD4+ T-cell counts. To determine if CD34+ hematopoietic progenitor cells are infected early in the course of HIV-1 disease, we evaluated 10 asymptomatic HIV-1 seropositive (HIV-1+) patients. The CD34+ cell fraction was purified by a two-step procedure consisting of both affinity chromatography and fluorescence-activated cell sorting that resulted in a median purity of over 99%. Using conventional and nested polymerase chain reaction (PCR) assays, we evaluated the presence and frequency of HIV-1 proviral DNA. Both bone marrow mononuclear cells and CD34- cells from all 10 patients were strongly positive for the HIV-1 pol and/or gag gene sequences. In contrast, sorted CD34+ cells from only two of 10 patients were positive, and the number of copies of proviral DNA in these samples was estimated to be from 2 to 5 per 250,000 cells. To test the in vitro functional capacity of CD34+ progenitors, these cells were assayed in both methylcellulose and long-term stromal culture. We found no significant reduction in the number of colony-forming unit-erythroid (CFU-E), burst-forming unit-erythroid (BFU-E), or colony-forming unit-granulocyte macrophage (CFU-GM) colonies, or in the frequency of cobblestone area forming cells from limit dilution analysis in HIV-1+ asymptomatic patients. Pooled methylcellulose colonies generated from CD34+ cells were HIV-1- in nine of 10 samples. All progeny from long-term cultures of CD34+ cells were HIV-1-. We conclude that the CD34+ hematopoietic progenitor compartment is not infected in the majority of asymptomatic HIV-1+ patients, and that these cells may represent a suitable target for strategies designed to protect developing CD4+ T cells from infection.

Adult↗
PubMed1995

Potent interleukin 3 receptor agonist with selectively enhanced hematopoietic activity relative to recombinant human interleukin 3.

A systematic evaluation of structure-activity information led to the construction of genetically engineered interleukin 3 (IL-3) receptor agonists (synthokines) with enhanced hematopoietic potency. SC-55494, the most extensively characterized member of this series, exhibits 10- to 20-fold greater biological activity than recombinant human IL-3 (rhIL-3) in human hematopoietic cell proliferation and marrow colony-forming-unit assays. In contrast, SC-55494 is only twice as active as rhIL-3 in priming the synthesis of inflammatory mediators such as leukotriene C4 and triggering the release of histamine from peripheral blood leukocytes. The enhanced hematopoietic activity of SC-55494 correlates with a 60-fold increase in IL-3 alpha-subunit binding affinity and a 20-fold greater affinity for binding to alpha/beta receptor complexes on intact cells relative to rhIL-3. SC-55494 demonstrates a 5- to 10-fold enhanced hematopoietic response relative to its ability to activate the priming and release of inflammatory mediators. Therefore, SC-55494 may ameliorate the myeloablation of cancer therapeutic regimens while minimizing dose-limiting inflammatory side effects.

Amino Acid Sequence↗
PubMed1995

Detecting cumulative trauma disorders in workers performing repetitive tasks.

On-site testing of 157 poultry processors disclosed that 50% had three or more abnormal upper extremity findings out of a total of 22 possibles. The average worker had five to six abnormal findings. Impaired pinch strength, decreased vibration sensitivity in the fingertips, and reports of current numbness were the most prevalent. Of workers with signs, 25% reported no symptoms, whereas only 8% of workers reported symptoms but had no signs. The investigators concluded that this measurement method has utility for assessments of worker populations to determine prevalence of CTDs and, potentially, for preclinical detection of these disorders to permit early intervention, reduce medical costs, and minimize disability. The need for accurate measurement to enhance early detection and prevention is discussed.

Adult↗
PubMed1992

Isolation of a candidate human hematopoietic stem-cell population.

We have identified a rare (0.05-0.1%) subset of human fetal bone marrow cells that contains multipotent hematopoietic precursors. The population of human precursor cells that express Thy-1 and CD34 but no known lineage markers is enriched for clonogenic activity that establishes long-term, multilineage (myelomonocytic and B lymphoid) cultures on mouse marrow stromal lines. Further, the Thy-1+CD34+ subset that takes up little of the fluorescent mitochondrial dye rhodamine 123 contains virtually all the cells that establish long-term cultures. In human fetal thymus transplanted into SCID (severe combined immunodeficiency) mice, Thy-1+CD34+ fetal bone marrow cells differentiate into T lymphocytes. In two of nine cases, allogeneic Thy-1+CD34+ cells could engraft intact human fetal bone marrow grown in SCID mice, resulting in donor-derived myeloid and B cells. By extrapolation, the rare human Thy-1+Lin-CD34+ cell population contains pluripotent hematopoietic progenitors; we propose that it is highly enriched for candidate hematopoietic stem cells.

Animals↗
PubMed1992

Implantation and maintenance of functional human bone marrow in SCID-hu mice.

Human fetal bone fragments implanted in the immunodeficient C.B-17 scid/scid (SCID) mouse were shown to sustain active human hematopoiesis in vivo. Human progenitor cell activity was maintained for as long as 20 weeks after implantation and was associated with multilineage differentiation in the engrafted bone. Thus, the bone implants provided stem cells as well as the microenvironment requisite for their long-term maintenance and multilineage differentiation. Administration of human erythropoietin (Epo) stimulated human erythropoiesis in human bone implants. This animal model may facilitate direct analysis of a wide variety of physiologic and pathologic conditions of human bone marrow (BM) in vivo.

Animals↗
PubMed1992

Monoclonal antibodies specific for novel murine cell surface markers define subpopulations of germinal center cells.

A panel of mAbs has been generated which selectively, but not exclusively, recognizes populations of cells within germinal centers of immunized mice. All four mAbs stain B cell populations as defined by flow cytometry. The mAbs FH9.5 and C3.5 also stain T cell subsets (CD4+ and CD8+, respectively). Following density gradient centrifugation of spleen cells from immunized mice the majority of FH9.5+ and C3.5+ B cells are found in the low density, activated fractions. The cells bearing the epitope(s) recognized by the C6C3 and the A6A2 mAbs are less frequent, and from flow cytometric analysis the cells stained with these mAbs are B cells and myeloid cells. The surface markers defined by the four mAbs are not induced following mitogen stimulation of small resting B cells suggesting that these molecules are not general activation markers. Cell lines from a variety of hematopoietic lineages expressing the four markers have been identified. The cell surface molecule immunoprecipitated by the FH9.5 mAb is a polypeptide of 23-28 kDa. The C3.5 antigen is an 85- to 95-kDa protein. These mAbs will be useful in elucidating the complex events involved in B cell differentiation and maturation which occur within germinal centers.

Animals↗
PubMed1991

Addressing the needs of the cognitively impaired elderly from a family policy perspective.

Management of the cognitively impaired elderly person in the community is presumed to be cost-efficient and the American way. Although this is what should be done, most would agree that paying for the services that make it possible to do so is not currently within the means of the median income of the family ($25,986) or of the female head of household ($15,350) in this country. This paper reviews the changes in the family, current family policies, and practices of our businesses and government and proposes the services that could be used to support both the impaired person and the family in the management of this evolving societal issue. Strategies for development of payment mechanisms for the proposed services are presented.

Aged↗
PubMed1988

Certification: serving the public interest.

The certification program has undergone an exciting change. The AOTA leadership and AOTA members are to be applauded for making this important step. The AOTCB is still a fledgling organization; nonetheless, it has already made great strides in carrying out its mission. The AOTCB will continue to build on the very excellent foundation AOTA has laid for the certification program. The AOTCB welcomes questions, comments, and suggestions concerning the certification program. To contact AOTCB, write to AOTCB, 1383 Piccard Drive, Rockville, MD 20850-4375 or call (301) 948-9626.

Certification↗
PubMed1987

Study of the DBA/2Ha immunodeficiency: X-chromosome mosaicism and in vivo immunoresponses.

DBA/2Ha mice have an X-chromosome-linked immunodeficiency and lack the receptor to a TRF (T cell replacing factor) on a subpopulation of B cells. Their immunodeficiency is considered to resemble that of CBA/N, another X-chromosome-linked immunodeficiency. To facilitate direct comparisons of the two immunodeficiencies and to study the in vivo manifestations of DBA/2Ha immunodeficiency, we measured phenotypes and functions of B cells of DBA/2Ha mice. We found that the expression of sIgM among B cells is normal in DBA/2Ha mice, heterozygous females equally express both affected and normal B cell subpopulations, and DBA/2Ha mice respond well to a TI-2 antigen (TNP-Ficoll) and a polyclonal activator (LPS). Unlike CBA/N, DBA/2Ha mice demonstrate very little in vivo immunodeficiencies.

Animals↗