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Biomedical subjects

R Hoffman

Publications and source records attributed to R Hoffman.

At least 235 records · Page 13Linked to original sources
PubMed1991

Correlation of plasma methotrexate concentration with human chorionic gonadotropin and therapeutic response to low-dose methotrexate-citrovorum factor in low-medium-risk gestational trophoblastic tumors.

Seventeen patients with low- or medium-risk gestational trophoblastic tumors (GTT) and one patient with a placental-site trophoblastic tumor were treated according to an 8-day schedule of low-dose methotrexate (LDMTX) alternating with citrovorum factor (CF). Plasma concentrations of methotrexate (MTX) were correlated with serum human chorionic gonadotropin (hCG) levels and clinical response. After an intramuscular dose of 50 mg, plasma MTX levels rose rapidly, reached a peak concentration of 5.8 x 10(-6) M/liter at 1 hour and persisted above 10(-6) M/liter normally considered inhibitory for DNA synthesis, for approximately 7 1/2 hours. Rapid plasma clearance followed with plasma levels reaching 5-7 x 10(-8) M/liter at the time of CF administration. At 48 hours, plasma MTX levels continued to exceed 10(-8) M/liter--the break point for the appearance of clinical toxicity due to MTX. In six of sixteen, or 38%, an initial rise in hCG levels was observed. Five of the seventeen patients, or 29%, and the one patient with PSTT developed MTX resistance. The administered dose (approximately 30 mg/M2) and plasma pharmacokinetics did not differ significantly between the tumors that responded and became resistant to MTX. The authors conclude that MTX resistance in GTT occurs as a result of impaired cell membrane uptake, gene amplification of dihydrofolate reductase, or both.

Chorionic Gonadotropin↗
PubMed1991

Pregnancy-associated aplastic anemia--report of 3 cases.

3 patients with pregnancy-associated aplastic anemia are reported. Management throughout most of the pregnancy consisted of supportive care. In 2 patients an improvement in blood counts occurred after delivery and, in 1 of these, the pancytopenia recurred during a subsequent pregnancy. In 1 case no improvement occurred after delivery and the patient ultimately required an allogeneic bone marrow transplantation. The outcome of these 3 cases demonstrates that pregnancy-associated aplastic anemia can be managed successfully. The improvement that often occurs after delivery suggests a pathogenetic role for pregnancy in the development of this disease.

Adult↗
PubMed1991

Medication-taking by the frail elderly in two ethnic groups.

A complex and dangerous area of medical intervention with the elderly population is drug therapy. Although drugs have contributed to the well-being of many older persons, some elderly individuals are at risk due to polypharmacy and age-related factors. The purpose of this preliminary study was to investigate the medication-taking behaviors of two ethnic groups of noninstitutionalized frail elderly individuals. The findings indicate that these individuals may be at risk for harm due to their medication-taking practices. Healthcare professionals must evaluate drug use by the elderly and be aware of the risks of drug misuse by this vulnerable group.

Aged↗
PubMed1991

Megaloblastic hematopoiesis in vitro. Interaction of anti-folate receptor antibodies with hematopoietic progenitor cells leads to a proliferative response independent of megaloblastic changes.

We tested the hypothesis that anti-placental folate receptor (PFR) antiserum-mediated effects on hematopoietic progenitor cells in vitro of increased cell proliferation and megaloblastic morphology were independent responses. We determined that (a) purified IgG from anti-PFR antiserum reacted with purified apo- and holo-PFR and specifically immunoprecipitated a single (44-kD) iodinated moiety on cell surfaces of low density mononuclear cells (LDMNC); (b) when retained in culture during in vitro hematopoiesis, anti-PFR IgG (in contrast to PFR-neutralized anti-PFR IgG and nonimmune IgG) consistently led to increased cloning efficiency of colony forming unit-erythroid (CFU-E), burst forming unit-E (BFU-E), CFU-granulocyte macrophage (CFU-GM), and CFU-GEM megakaryocyte (CFU-GEMM), and objectively defined megaloblastic changes in orthochromatic normoblasts from CFU-E- and BFU-E-derived colonies; (c) when anti-PFR antiserum was removed after initial (less than 1 h) incubation with LDMNC, a cell proliferation response was induced, but megaloblastic changes were not evident. (d) Conversely, delay at 4 degrees C for 24 h before long-term plating with antiserum resulted in megaloblastosis without increased cell proliferation; (e) however, 500-fold molar excess extracellular folate concentrations completely abrogated the expected anti-PFR antiserum-induced megaloblastic changes, without altering cell proliferative responses. Thus, although cell proliferative and megaloblastic changes are induced after short-term and prolonged interaction of antibody with folate receptors on hematopoietic progenitors, respectively, they are independent effects.

Animals↗
PubMed1991

Tiazofurin down-regulates expression of c-Ki-ras oncogene in a leukemic patient.

The increased activity in cancer cells of inosine 5'-monophosphate dehydrogenase (IMP DH, EC 1.1.1.205), the rate-limiting enzyme of de novo GTP biosynthesis, was suggested as a sensitive target for chemotherapy. Tiazofurin (NSC 286193), through its conversion to the active metabolite, thiazole-4-carboxamide adenine dinucleotide (TAD), is a strong inhibitor of IMP DH. In our clinical trial, tiazofurin caused return to the chronic phase in patients with chronic granulocytic leukemia in blast crisis (Tricot, G.; Jayaram, H.N.; Weber, G.; Hoffman, R. Tiazofurin: Biological effects and clinical uses. Int. J. Cell Cloning 8:161-170; 1990). In K562 human leukemic cells, tiazofurin down-regulated the expression of c-Ki-ras and c-myc oncogenes, which was followed by induced differentiation. We now report down-regulation by tiazofurin of the c-Ki-ras oncogene in a patient with chronic granulocytic leukemia in blast crisis. A single tiazofurin infusion (2,200 mg/m2) on days one and two decreased IMP dehydrogenase activity (the apparent t1/2 was 30 min), GTP concentration (the apparent t1/2 was 6 hr), and expression of ras (the apparent t1/2 was 8 hr) and c-myc (the apparent t1/2 was 38.5 hr) oncogenes in the leukemic cells. No further tiazofurin was given, because on days three and four the chemotherapeutic impact became evident in a tumor-lysis syndrome and the blast cells were cleared from the periphery by day five. The decrease in IMP DH activity, GTP concentration, and expression of c-Ki-ras oncogene were early markers of the successful chemotherapeutic impact of tiazofurin in a patient with chronic granulocytic leukemia in blast crisis.

Adenine Nucleotides↗
PubMed1991

Human CD34+ HLA-DR- bone marrow cells contain progenitor cells capable of self-renewal, multilineage differentiation, and long-term in vitro hematopoiesis.

Human bone marrow cells expressing CD34 but not HLA-DR were isolated by immunofluorescence flow cytometric cell sorting. These cells contained a hematopoietic cell (CFU-B1) capable of producing, in an in vitro semisolid culture system, blast-cell-containing colonies, which possessed the capacity for self-renewal and commitment to multipotential differentiation. In addition, CD34+ HLA-DR- marrow cells contained primitive megakaryocyte progenitor cells, the burst-forming unit-megakaryocyte (BFU-MK). A subset of CD34+ HLA-DR- marrow cells lacking the expression of CD15 and CD71 was obtained by flow cytometric cell sorting and was capable of sustaining in vitro hematopoiesis in suspension culture for up to 8 weeks in the absence of a preestablished adherent marrow cell layer. The combination of IL-3 + IL-1 alpha and IL-3 + IL-6 sustained proliferation of these cells for 8 weeks, induced maximal cellular expansion, and increased the numbers of assayable progenitor cells. These studies demonstrate that human CD34+ HLA-DR- marrow cells and their subsets contain primitive multipotential hematopoietic cells capable of self-renewal and of differentiation into multiple hematopoietic lineages.

Antigens, CD↗
PubMed1991

Standards of care for hospice patients with pressure ulcers.

Pressure ulcers are a major concern of hospice nurses. A recent survey of hospice agencies in an area of the southwest indicated a lack of specific standards of care for patients with pressure ulcers and no systematic method to identify patients at risk. Standards of care were subsequently developed to identify patients at risk and to manage pressure ulcers of hospice patients.

Hospices↗
PubMed1991

Metabolic and contractile protein expression in developing rat diaphragm muscle.

Progressive changes in myosin isozyme expression and in energy-generating enzyme activities were followed in the diaphragm and, for comparison, in axial and appendicular muscles of rats from 18 d gestation to maturity. Native myosins were characterized by pyrophosphate gel electrophoresis. Myosin heavy-chain (MHC) isozymes were measured with ELISA using monoclonal antibodies and were localized by immunocytochemistry. RNA transcripts for the MHCs were demonstrated on Northern blots and by RNase protection assays. Quantitative activities of malate dehydrogenase (MDH), beta-hydroxyacyl CoA dehydrogenase (beta OAC), 1-phosphofructokinase (PFK), lactate dehydrogenase (LDH), creatine kinase (CK), and adenylokinase (AK) were measured in muscle homogenates and in individual fibers by fluorometric pyridine nucleotide-dependent assays. Compared to limb muscles, expression of neonatal myosin in the diaphragm is precocious. Neonatal MHC mRNA is prominent in the diaphragm at 19 d gestation, and neonatal myosin is the major MHC isoform present at birth. Slow and fast IIa MHCs are also present at birth. Transcripts for IIa MHC are detectable in the diaphragm at 21 d gestation and are upregulated at birth. Comparable signal for IIa MHC mRNA is not found in the gastrocnemius until 10 d postpartum. Adult fast IIb MHC mRNA was detected only as a faint signal at 30-40 d in the diaphragm and then disappeared. Results indicate that a separate phenotype, the IIx type, matures late in diaphragmatic development. The activities of enzymes representing all of the major energy pathways are higher in the fetal diaphragm than in the fetal hindlimb muscles. For example, beta OAC had sixfold higher activity in the diaphragm than in the extensor digitorum longus (EDL) muscle at birth, activity in the diaphragm than in the extensor digitorum longus (EDL) muscle at birth.

Aging↗
PubMed1990

Parvovirus B19-induced perturbation of human megakaryocytopoiesis in vitro.

Parvovirus B19 infection leads to transient aplastic crises in individuals with chronic hemolytic anemias or immunodeficiency states. An additional unexplained sequela of B19 infection is thrombocytopenia. Because B19 is known to have a remarkable tropism for human erythropoietic elements, and is not known to replicate in nonerythroid cells, the etiology of this thrombocytopenia is uncertain. We sought to define the pathobiology of B19-associated thrombocytopenia by examining the role of B19 on in vitro megakaryocytopoiesis. B19 infection of normal human bone marrow cells significantly suppressed megakaryocyte (MK) colony formation compared with mock-infected cells. No such inhibition was observed with a nonpathogenic human parvovirus, the adeno-associated virus 2 (AAV). The B19-MK cell interaction was also studied at the molecular level. Whereas low-density bone marrow cells containing erythroid precursor cells supported B19 DNA replication, no viral DNA replication was observed in B19-infected MK-enriched fractions as determined by the presence of viral DNA replicative intermediates on Southern blots. However, analysis of total cytoplasmic RNA isolated from B19-infected MK fractions showed a low-level expression of the B19 genome as detected by quantitative RNA dot blots as well as by Northern analysis. Furthermore, a frame-shift mutation in a recombinant AAV-B19 hybrid genome segment that encodes the viral nonstructural (NS1) protein significantly reduced the observed inhibition of MK colony formation. These studies indicate tissue-tropism of B19 beyond the erythroid progenitor cell, and lend support to the hypothesis that B19 genome expression may be toxic to cell populations that are nonpermissive for viral DNA replication.

Blotting, Northern↗
PubMed1990

Excessive zinc ingestion. A reversible cause of sideroblastic anemia and bone marrow depression.

Two patients with sideroblastic anemia secondary to zinc-induced copper deficiency absorbed excess zinc secondary to oral ingestion. The source of excess zinc was a zinc supplement in one case; in the other, ingested coins. In each case, the sideroblastic anemia was corrected promptly after removal of the source of excess zinc. These two cases emphasize the importance of recognizing this clinical entity, since the myelodysplastic features are completely reversible.

Adult↗
PubMed1990

Cytokine regulation of the human burst-forming unit-megakaryocyte.

The human burst-forming unit-megakaryocyte (BFU-MK) is a primitive megakaryocytic progenitor cell. A marrow cell population enriched for BFU-MK (CD34+ DR-) was obtained by monoclonal antibody labeling and fluorescence-activated cell sorting. CD34+DR- cells were assayed in a serum-depleted, fibrin clot culture system. Recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF), recombinant interleukin-3 (rIL-3), and megakaryocyte colony-stimulating factor (MK-CSF), partially purified from human plasma, were each individually capable of promoting BFU-MK-derived colony formation. Recombinant erythropoietin, rG-CSF, rIL-4, rIL-6, and thrombocytopiesis stimulating factor, partially purified from human embryonic kidney cell conditioned media, had no stimulatory effect on BFU-MK-derived colony formation when added alone or in various combinations with either GM-CSF, IL-3, or MK-CSF, GM-CSF and IL-3, GM-CSF and MK-CSF, but not IL-3 and MK-CSF had additive actions in promoting BFU-MK-derived colony formation, rIL-1 alpha had no influence alone on BFU-MK cloning efficiency, but had a dose-dependent, synergistic effect with IL-3, but not with GM-CSF or MK-CSF. The synergistic relationship between IL-1 alpha and IL-3 was abrogated by addition of an IL-1 alpha neutralizing antibody but not by a GM-CSF neutralizing antiserum, suggesting that IL-1 alpha acts directly on the BFU-MK and not by stimulating marrow auxiliary cells to secondarily release additional cytokines. Information presented here indicates that the regulatory influence, acting on the different stages of megakaryocyte development, are stage-specific and accomplished by multiple cytokines.

Biological Factors↗
PubMed1990

Tiazofurin: biological effects and clinical uses.

Inosine 5'-phosphate dehydrogenase (IMPDH) activity is increased in all cancer cells. It is the rate-limiting enzyme of guanosine triphosphate (GTP) biosynthesis, and therefore, a sensitive target of chemotherapy. Tiazofurin selectively blocks IMPDH activity. Tiazofurin was found to have an antiproliferative effect on tumor cells in vitro and in the murine system. Based on these findings, Phase I trials were started elsewhere in patients with solid tumors, but were discontinued because of toxicity. In leukemic patients, we were able to demonstrate a good correlation between biochemical parameters (i.e., decline in IMPDH activity and GTP concentrations in blast cells) and clinical response. The most consistent responses to therapy were seen in patients with myeloid blast crisis of chronic myeloid leukemia. Severe toxicity was seen in the earlier patients in the study. However, better patient selection, limitation of treatment duration and earlier recognition and treatment of complications have now made it possible to administer tiazofurin without undue toxicity.

Antineoplastic Agents↗
PubMed1990

Life in the allogeneic environment after lung transplantation.

Because infection and rejection are the principal complications of any transplant procedure and because the alveolar macrophage is crucial to the defense of the lung from infection and may play a role in lung allograft rejection, we have begun to assess functions of this cell that are thought to be important in lung defense from infection and in transplant immunity. Antimicrobial functions include chemotaxis, which is a mechanism for recruiting macrophages to sites of inflammation and phagocytosis, and intracellular killing of microorganisms. As an accessory cell, the alveolar macrophage is necessary for an effective immune response to develop against either microorganisms or transplantation antigens. Our results indicate that the chemotactic, phagocytic but not the killing capability of alveolar macrophages from lung recipients is impaired. Alveolar macrophages and blood monocytes from lung recipients are also significantly impaired in their support for mitogen and antigen presentation to lymphocytes. Thus, the generation of an effective immune response to a microorganism may be impaired. Alveolar macrophages from lung recipients, however, function as well as those from normal subjects in stimulating lymphocyte proliferation in response to donor antigens (primed lymphocyte test) or unrelated allogeneic antigens (mixed lymphocyte reaction), while their respective blood monocytes function poorly in this regard. Our conclusions are that the antimicrobial functions of the alveolar macrophages are impaired after lung transplantation and this may be one mechanism to explain the unusual susceptibility of the lung allograft to infection. Those functions related to transplant immunity, however, are preserved and indicate that the alveolar macrophage may play a role in allograft rejection.

Adolescent↗