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Results for “bone marrow cellularity”

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PubMed1994

Acute promyelocytic leukemia is a distinct subset of acute myelocytic leukemia with unique clinicopathologic characteristics including longer duration of relapse free survival: experience in 13 cases.

Acute promyelocytic leukemia(APL) is a subtype of acute myelocytic leukemia(AML) associated with unique features such as the presence of atypical promyelocytes and bleeding tendency due to disseminated intravascular coagulation(DIC). In a retrospective study, we analyzed 96 cases of AML seen at our hospital between June, 1989 and December 1993. Thirteen cases of APL(14%) were identified and their clinicopathologic characteristics were analyzed. The 86 cases of other types of AML served as controls. The distinct clinicopathologic features of APL as contrasted to other types of AML included younger age of patients, shorter duration of symptom before diagnosis, higher level of albumin at presentation, and a higher proportion of patients having coagulation abnormalities (75 vs. 25%). Bone marrow cellularity was higher in APL when compared to other types of AML (100 vs. 90%, P = 0.013). Of 13 patients with APL, 4 died of bleeding/sepsis between days 2 to 4 after admission. Seven of 9 patients who received induction therapy achieved complete remission(CR). CR rate in APL was similar to other types of AML (78 vs. 64%, P = 0.743). Five of seven patients who achieved CR remain in continuous CR at 9+ to 42+ months. CR duration is significantly longer in APL when compared to other types of AML (P = 0.029). In conclusion, this study showed that APL is a distinct entity among subtypes of AML with clinically significant bleeding tendency and rapidly fatal course if untreated. With appropriate antileukemic therapy, CR can be achieved in the majority of patients and the patients show a longer duration of CR when compared to other types of AML.

Acute Disease↗

PubMed1994

Immunotoxicity of mono-nitrotoluenes in female B6C3F1 mice: I. Para-nitrotoluene.

para-Nitrotoluene (p-nitrotoluene) is used primarily as an intermediate in the production of various dyes, explosives, pharmaceuticals, and in the production of rubber and agricultural products. Previous investigations indicated that p-nitrotoluene was mutagenic in the Ames Test and that other mono-substituted nitrotoluenes bound covalently to hepatic macromolecules. The objective of these studies was to evaluate the potential immunotoxicity of p-nitrotoluene in mice exposed by the oral route. Mice exposed to p-nitrotoluene (200-600 mg/kg) daily for 14 days showed modest dose-dependent increases in liver and spleen weights. The livers of mice exposed subchronically to 400 and 600 mg/kg showed a mild to moderate swelling of the hepatocytes adjacent to the central veins; this swelling appeared to be reversible and there was no evidence of necrosis. The proportion of monocytes in blood was decreased in mice treated with p-nitrotoluene or toluene. Serum chemistries, bone marrow cellularity and the number of CFU-M and CFU-GM were unaffected. Immunologic investigations showed p-nitrotoluene suppressed the IgM response to sRBC and the DHR response to KLH. There was a 24% decrease in the percentage of CD4+ T lymphocytes in the spleen. There was no dose-dependent alteration of peritoneal macrophage numbers or differential count, unstimulated natural killer cell activity, response to B cell mitogen LPS, C3 activity or interferon levels. Exposure of mice to p-nitrotoluene decreased resistance to Listeria monocytogenes but not to Streptococcus pneumoniae, Plasmodium yoelii or the B16F10 melanoma, and increased resistance to the PYB6 tumor. These studies indicated that the immune system is an important target for toxicity of p-nitrotoluene. The decreased host resistance to L. monocytogenes can be attributed to the decrease in T lymphocytes and to a decreased delayed hypersensitivity response to KLH.

Administration, Oral↗

PubMed2001

The effects of SCF/G-CSF prestimulation on radiation sensitivity and engraftment in nonmyeloablated murine hosts.

OBJECTIVE: Previous studies have shown improved engraftment in a murine model when granulocyte colony-stimulating factor (G-CSF) and stem cell factor (SCF) were administered for 5 days prior to irradiation, with significant levels of engraftment in the growth factor-preconditioned group even at very low radiation doses. We sought to explore the mechanisms behind this effect. METHODS: The radiation sensitivity of mice with or without 5 days of prestimulation with G-CSF (200 microg/kg/d) and SCF (50 microg/kg/d) was compared. To further evaluate whether growth factor prestimulation enhances engraftment by mobilization of hematopoietic progenitors into peripheral blood, thus creating less endogenous competition within the marrow compartment, female mice were pretreated with 5 days of G-CSF/SCF or control diluent. Engraftment of 40 x 10(6) peripheral blood stem cells (PBSCs) harvested from G-CSF/SCF-mobilized male mice was compared in the two recipient groups. RESULTS: There was no difference in survival between the pretreated and control mice at the radiation doses tested. Additionally, there was no significant difference in the recovery of blood counts, bone marrow cellularity, colony-forming unit (CFU) content, or stem cell numbers assessed 4 months later in a competitive repopulation model. Engraftment levels of male cells did not differ between G-CSF/SCF-pretreated and control recipients, and could be detected in 30% of recipients at 20-24 weeks (4/12 in each group) at overall levels of 0.1-1%. CONCLUSIONS: The enhanced engraftment in cytokine pretreated recipients is unlikely to be due to increased endogenous stem-cell killing or to the creation of endogenous marrow "space" by egress of endogenous stem cells after cytokine prestimulation.

Animals↗

PubMed1999

Technetium-99m sulfur colloid scanning and correlative magnetic resonance imaging in patients with hairy cell leukemia and hypocellular bone marrow biopsies after 2-chlorodeoxyadenosine.

It has been observed that some patients in complete remission (CR) after 2-chlorodeoxyadenosine (2-CdA) for hairy cell leukemia (HCL) have hypocellular bone marrow biopsies despite normal peripheral blood cell counts. This discrepancy between bone marrow cellularity and peripheral blood cell counts suggests the possibility of abnormal sites of hematopoiesis. To determine sites of hematopoiesis, 11 radionuclide scans using technetium-99m (99mTc) sulfur colloid were performed in eight patients. Although no single, pattern was observed on the 99mTc sulfur colloid scans, two of the eight patients, both with virtually aplastic marrows, had multiple areas of increased uptake in the distal appendicular skeleton, suggesting abnormal sites of hematopoiesis. The same two patients had magnetic resonance imaging (MRI), which confirmed the abnormal sites of hematopoiesis.

Adult↗

PubMed1990

Effects of granulocyte colony-stimulating factor on hematopoietic injury induced by anticancer drugs in mice.

The in vivo effects of the subcutaneous administration of the granulocyte colony-stimulating factor (G-CSF) on chemotherapy-induced hematopoietic injury were evaluated in BALB/c mice. Mice treated with chemotherapeutic drugs were injected once a day for up to 12 days with 2 micrograms of recombinant human G-CSF, and following this, bone marrow cellularity, spleen weight, and peripheral blood cell counts were measured 24 h after cessation of the G-CSF treatment. Treatment of normal mice had minimal effect on the elevation of the white blood cell (WBC) count or on the hosts' resistance to K. pneumoniae infection. Spleen weight was significantly higher in normal mice treated with G-CSF, and the platelet counts were slightly lower. In mice treated with cyclophosphamide (150 mg/kg), G-CSF treatment caused an elevation of WBC and an enhancement of antibacterial resistance. Variable amounts of an accelerated recovery of neutrophils by G-CSF treatment was also observed in nimustine hydrochloride (50 mg/kg)-, mitomycin c (MMC) (8 mg/kg)-, or vindesine sulfate (VDS) (4 mg/kg)-treated mice. A significant decrease in PLT counts was observed in MMC- or VDS-treated hosts given G-CSF. These results indicate that administration of G-CSF may facilitate hematopoietic recovery in chemotherapy-treated cancer patients and that it may help them to increase their resistance to life-threatening infection. Conversely, treatment with G-CSF and chemotherapeutic drugs may cause a more severe thrombocytopenia than is observed with only chemotherapy treatment.

Animals↗

PubMed1982

Reduction of hematopoietic stem cells and adaptive increase in cell cycle rate in rickets.

The close but complex physiological interactions between osteogenesis and hematopoiesis during differentiation, development, and function are unclear. As vitamin D has a major role in bone metabolism and function, we have investigated the effects of vitamin D deficiency on bone marrow cellular kinetics. Using rats in vitamin D-deficient status in utero as well as in postfetal life, we have investigated changes in hematopoiesis. Total cellularity, colony-forming unit (CFU) content, and the cycled rate were determined from the axial compartment of the femoral marrow. A marked reduction in the CFU content and a corresponding increase in the cycle fraction began at 30 days of age and stabilized by 45 days of age at 4.2 +/- 0.4 CFUs per 1 X 10(5) nucleated cells in the vitamin D-deficient animals as compared with 9.4 +/- 1.6 in the control group. During the same period of time the CFU generation time decreased from 61 +/- 5 h in the normal animals to 24 +/- 6 h in the vitamin D-deficient animals. Administration of either 1,25-dihydroxyvitamin D [1,25-(OH)2D3] or 24,25-(OH)2D3 at 45 days of age on a daily basis for 7-14 days failed to correct the defect although the serum calcium and phosphate were corrected. The data indicate that factors influencing the development of bones may affect bone marrow cells as well. Vitamin D metabolites may be needed for normal development and function of marrow-colony-forming cells in utero.

Acclimatization↗

PubMed1994

Immunotoxicity of mono-nitrotoluenes in female B6C3F1 mice: II. Meta-nitrotoluene.

The nitrotoluenes are chemicals used in dyes, agricultural products, pharmaceuticals and explosives. In the present studies, the toxicology and immunotoxicity of meta-nitrotoluene (m-nitrotoluene) were evaluated. Mice, exposed to m-nitrotoluene at dose levels of 200, 400 and 600 mg/kg/body weight for 2 weeks by gastric gavage, gained body weight over the treatment period to a slightly greater extent than the control groups. Of the selected organs weighed, the liver and kidney of mice exposed to m-nitrotoluene were increased in weight while the thymus weight was decreased. The liver of mice exposed to m-nitrotoluene, but not ortho-nitrotoluene, showed slight to moderate swelling of the hepatocytes adjacent to the central veins. The hepatocyte swelling appeared to be reversible and there was no evidence of necrosis. The hematology and serum chemistries examined were unaffected by m-nitrotoluene exposure although there were modest decreases in the percentage of polymorphonuclear leukocytes and eosinophils in differential blood counts. Bone marrow cellularity and the number of CFU/M and CFU/GM were unaffected by m-nitrotoluene exposure. m-Nitrotoluene suppressed the IgM response to sRBC and the DHR response to KLH. There was a slight (8%) decrease in the percentage of B lymphocytes in the spleen. The response to the T cell mitogens was suppressed by as much as 39%. Fc-mediated adherence and phagocytosis of chicken erythrocytes and NK cell activity were increased dose dependently in mice exposed to m-nitrotoluene. Several immune parameters were unaffected by exposure to m-nitrotoluene, including the IgG response to sRBC, responses to the B cell mitogen LPS and to allogeneic cells, and serum interferon levels. Resistance to Streptococcus pneumoniae and Plasmodium yoelii were unaffected also. Resistance to the tumor model PYB6 was increased. Exposure of mice to m-nitrotoluene decreased resistance to Listeria monocytogenes. The decreased resistance to L. monocytogenes may be related to an effect on T cells, evidenced by a decrease in T cell numbers and in the DHR.

Administration, Oral↗

PubMed1984

Flow cytometric analysis of deoxyribonucleic acid (DNA) content in adult leukemia.

Flow cytometric analysis of the bone marrow cellular DNA content was performed in 40 adult patients with acute leukemia. Twenty-eight had AML (29 previously untreated and 9 relapse) and 12 ALL (8 previously untreated and 4 relapse). For the whole series, the mean G1/0-phase compartment was 82 +/- 1.3%, the mean S-phase compartment 14 +/- 1%, and the mean G2 +M-phase compartment 4 +/- 0.7%. The percentage of cells in the S-phase had a positive correlation with the LDH level, but not with other parameters. Patients at relapse had significantly lower percentages of cells in the S-phase in AML and significantly higher in ALL. The changes of the S-phase size of the same patients at the first and relapse phases varied. Patients who obtained complete remission had significantly higher percent S phase than patients who did not. This difference was more significant in ALL. Percent cytoreduction had no correlation with the remission rate or S-phase size. Therefore, we analyzed changes of cells in the S-phase of patients with untreated AML during chemotherapy. The reduction rate of cells in the S-phase of patients who obtained complete remission was significantly higher than that of patients who did not.

Adolescent↗

PubMed1984

Immunosuppression following 7,12-dimethylbenz[a]anthracene exposure in B6C3F1 mice. I. Effects on humoral immunity and host resistance.

It has previously been demonstrated that the polycyclic aromatic hydrocarbon (PAH), benzo(a)pyrene (B[a]P), suppresses the terminal step in B-cell differentiation, resulting in a decrease in antibody production to T-dependent and B-2 T-independent antigens. The purpose of this study was to ascertain if this effect was common to carcinogenic PAHs or specific for B[a]P. The PAH 7,12-dimethylbenz[a]anthracene (DMBA) was administered to B6C3F1 female mice by ten sc injections of 0.5, 5, or 10 micrograms/g over a 2-week period (i.e., total dose of 5, 50, and 100 micrograms/g). Immune function and host resistance assays were performed 3 to 5 days following the last injection. The 10 micrograms/g dosage resulted in a marked decrease in spleen weights and spleen and bone marrow cellularity, while thymus and body weights were not significantly altered. The ability to generate B-lymphocyte colonies in vitro from spleen precursor cells was also suppressed at the 10 micrograms/g dose. Exposure to DMBA at 5 micrograms/g or greater resulted in a reduction of up to 97% in the number of IgM plaque-forming cells in response to the T-dependent antigen sheep red blood cells (SRBC). The IgG response to SRBC was similarly depressed. The IgM response to the hapten-conjugated T-independent antigens trinitrophenyl-lipopolysaccharide (TNP-LPS) (specific for B-1 cells) and trinitrophenyl (TNP)-Ficoll (specific for B-2 cells) was also depressed (88 and 97%, respectively) at 10 micrograms/g. DMBA exposure resulted in an increased susceptibility to challenge with the PYB6 transplantable sarcoma and the bacterium Listeria monocytogenes, in contrast to B[a]P exposure, which had no effect on host resistance assays. Thus, DMBA, a more potent carcinogen than B[a]P, produces a more extensive B-cell suppression than B[a]P as well as alters host resistance to tumor and bacterial challenge.

9,10-Dimethyl-1,2-benzanthracene↗

PubMed1992

[Evaluation of marrow neutrophilic reserve in normal subjects and aplastic anemia patients].

The widespread use of potent marrow suppressing drugs in malignant diseases has gained increasing importance in the functional assessment of neutrophil system. A peripheral neutrophil count of 500 cells/cumm is considered to be a good indicator of risk of bacterial infection. However, despite extreme neutropenia, infection is rare in chronic benign neutropenia patients. It may be presumed that adequate marrow reserve delivers mature neutrophil during bacterial infection in these patients. Currently available methods such as determination of blood neutrophil concentration, differential counts, estimation of bone marrow cellularity provide a relatively crude estimates of the functional capacity of the neutrophil system. The use of endotoxin, etiocholanolone and steroids have been introduced to determine the marrow neutrophil reserve with greater accuracy. In this study, intravenous hydrocortisone 100 mg was used to evaluate marrow neutrophilic reserve in normal and aplastic anemia subjects. The results showed significant statistical differences (P less than 0.001) between controls and aplastic subjects in 2, 3, 4 and 5th hour groups after steroid injection. The sensitivity and specificity occurring 3 and 4 hours after steroid injection were 78.6% and 100%, respectively. The normal marrow neutrophilic reserve showed more than 1198/cumm of increment neutrophilic counts 4 hours after steroid injection. No complication was found. The present finding suggests that steroid may be useful as an accurate evaluator of marrow neutrophilic reserve.

Adult↗

PubMed1999

Long-lasting decrease of marrow and circulating long-term culture initiating cells after allogeneic bone marrow transplant.

We investigated bone marrow (BM) and circulating (PB) hematopoietic progenitor cells in 37 normal donors and in 25 patients 1 to 8 years after successful allogeneic bone marrow transplant. At the time of testing, transplanted patients had normal blood counts and bone marrow cellularity. By flow cytometry, BM CD34+ cells were found to be three- to four-fold decreased in transplanted patients compared to normal donors, while the number of PB CD34+ cells was the same as in normal donors. Using a methylcellulose colony assay, primary BM colony-forming cells (CFU-GM) were decreased 2.1-fold, whereas PB CFU-GM were only marginally decreased. In a long-term culture initiating cell (LTC-IC) assay, an eight-fold decrease of early progenitor cells was observed in the marrow of transplanted patients compared to normal donors, and a five-fold decrease was documented in peripheral blood. We found that the BM LTC-IC cell number correlated with concurrently determined BM CD34+ cells and committed progenitor cell number (measured as CFU-GM) and with PB LTC-IC number, but not with PB CFU-GM and CD34+ cells. We conclude that marrow and circulating early stem cell compartments, as measured by the LTC-IC assay, are greatly and permanently depressed following bone marrow transplant. The correlation between BM and PB LTC-IC indicates that the enumeration of circulating LTC-IC can be used as a measure of the stem cell compartment in the bone marrow after transplant. It seems that the deficiency of the most immature progenitor cells persists forever after successful bone marrow transplant; this means that a complete hematopoietic reconstitution can be sustained by a reduced stem cell pool.

Adolescent↗

PubMed2001

Recombinant human granulocyte colony-stimulating factor therapy for patients with neutropenia and/or neutrophil dysfunction secondary to glycogen storage disease type 1b.

The purpose of this study was to evaluate the efficacy and toxicity of recombinant human granulocyte colony-stimulating factor (rhG-CSF) therapy in patients with neutropenia and/or neutrophil dysfunction secondary to glycogen storage disease (GSD) type 1b. Thirteen patients with neutropenia and/or neutrophil dysfunction secondary to GSD type 1b were treated with rhG-CSF. The effects of therapy on neutrophil numbers and in vitro neutrophil function and on bone marrow cellularity and morphology were studied. The clinical status of the patients and the occurrence of adverse events associated with rhG-CSF use were monitored. Use of rhG-CSF therapy was associated with a significant increase in circulating neutrophil numbers (P <. 01) and an improvement in neutrophil function as assessed in vitro. In addition, rhG-CSF therapy produced a significant increase in marrow cellularity and an increase in myeloid:erythroid (M:E) ratio, indicating stimulation of granulopoeisis. No adverse effects on marrow function were noted; in particular, no myelodysplasia or marrow exhaustion was seen. Use of rhG-CSF therapy was associated with objective and subjective improvements in infection-related morbidity. The therapy was well tolerated, although all patients developed splenomegaly, and 5 patients developed mild hypersplenism that did not require any specific treatment. rhG-CSF therapy is efficacious in the management of neutropenia and neutrophil dysfunction associated with GSD type 1b. Patients on this therapy need to be monitored for hypersplenism. Continued follow-up will be necessary to confirm long-term safety; however, no significant short-term toxicity was noted.

Adolescent↗

PubMed1995

Hematopoietic stem cells in the hereditarily anemic Belgrade laboratory (b/b) rat.

The Belgrade (b/b) rat has hereditary hypochromic microcytic anemia as the consequence of intracellular iron deficiency. Studies in the b/b rat have also demonstrated alteration in hematopoiesis at the progenitor cell level. In the present study, investigations were extended to the bone marrow hematopoietic stem cells as determined by measurements of marrow repopulating ability (MRA) and day 8 spleen colony-forming units (CFU-S-8). A reduced number of CFU-S-8 per femur was found, together with a low incidence per 10(5) bone marrow cells and a nondetectable proliferation rate. The proliferation rate did not increase after treating b/b rat bone marrow cells in vitro with a stimulator for CFU-S proliferation, indicating a proliferative block. The treatment of b/b rats with iron enhanced the proliferation rate and partially increased the number of CFU-S-8 in bone marrow. Chronic transfusion of b/b rats with washed RBC from non-anemic animals restored both the number and the proliferative response of bone marrow CFU-S-8. The MRA of b/b rats was reduced, but in proportion to the decrease in the bone marrow cellularity of these animals. MRA (pre-CFU-S) of b/b rats recovered completely after both iron treatment and chronic transfusions, suggesting that changes in the pre-CFU-S pool are secondary rather than directly induced by the genetic defect. These results indicate the importance for stem cell proliferation of normal oxygenation--the arterial oxygen content in b/b rats is six times lower than in (+/+, b/+) rats--which recovered after the iron treatment and was completely restored after chronic transfusions. High-dose iron therapy abrogated the proliferative block of CFU-S-8, but number of CFU-S-8 was not completely recovered in spite of normalized oxygenation, indicating a possible suppressive effect of iron overload on the marrow microenvironment.

Anemia↗

PubMed1992

Mobilization of peripheral blood progenitor cells by chemotherapy and granulocyte-macrophage colony-stimulating factor for hematologic support after high-dose intensification for breast cancer.

High-dose therapy with autologous marrow support results in durable complete remissions in selected patients with relapsed lymphoma and leukemia who cannot be cured with conventional dose therapy. However, substantial morbidity and mortality result from the 3- to 6-week period of marrow aplasia until the reinfused marrow recovers adequate hematopoietic function. Hematopoietic growth factors, particularly used after chemotherapy, can increase the number of peripheral blood progenitor cells (PBPCs) present in systemic circulation. The reinfusion of PBPCs with marrow has recently been reported to reduce the time to recovery of adequate marrow function. This study was designed to determine whether granulocyte-macrophage colony-stimulating factor (GM-CSF)-mobilized PBPCs alone (without marrow) would result in rapid and reliable hematopoietic reconstitution. Sixteen patients with metastatic breast cancer were treated with four cycles of doxorubicin, 5-fluorouracil, and methotrexate (AFM induction). Patients responding after the first two cycles were administered GM-CSF after the third and fourth cycles to recruit PBPCs for collection by two leukapheresis per cycle. These PBPCs were reinfused as the sole source of hematopoietic support after high doses of cyclophosphamide, thiotepa, and carboplatin. No marrow or hematopoietic cytokines were used after progenitor cell reinfusion. Granulocytes greater than or equal to 500/microL was observed on a median of day 14 (range, 8 to 57). Transfusion independence of platelets greater than or equal to 20,000/microL occurred on a median day of 12 (range, 8 to 134). However, three patients required the use of a reserve marrow for slow platelet engraftment. In retrospect, these patients were characterized by poor baseline bone marrow cellularity and poor platelet recovery after AFM induction therapy. When compared with 29 historical control patients who had received the same high-dose intensification chemotherapy using autologous marrow support, time to engraftment, antibiotic days, transfusion requirements, and lengths of hospital stay were all significantly improved for the patients receiving PBPCs. Thus, autologous PBPCs can be efficiently collected during mobilization by chemotherapy and GM-CSF and are an attractive alternative to marrow for hematopoietic support after high-dose therapy. The enhanced speed of recovery may reduce the morbidity, mortality, and cost of high-dose treatment. Furthermore, PBPC support may enhance the effectiveness of high-dose therapy by facilitating multiple courses of therapy.

Adolescent↗

PubMed1993

Residual myelotoxicity of lindane in mice.

Lindane (gamma-1,2,3,4,5,6-hexachlorocyclohexane), a widely used insecticide, may be found at low concentrations in the human diet. Male B6C3F1 mice given lindane daily at doses of 20 and 40 mg/kg body wt by gavage in corn oil for 3 days had suppressed bone marrow cellularity, erythrocyte precursors, granulocyte-macrophage progenitor cells (CFU-GM), and residual progenitor cell damage, which could be demonstrated by two whole-body irradiations (WBI) at 200 rads. Lindane exposure for 10 consecutive days at doses of 0, 10, or 20 mg/kg did not cause clinical abnormality or changes in body weights, but there were dose-dependent decreases in marrow cellularity, in more pluripotent stem cells and in committed CFU-GMs, which returned to control values by 4 weeks. These mice were then subjected to two 100-rad exposures of WBI at 4 and 9 weeks following cessation of lindane treatment. This level of irradiation caused only a transient drop in number of marrow progenitor cells. Control and lindane-exposed mice were examined at 1 and 6 weeks following the last irradiation, which was 10 and 15 weeks following the final lindane exposure. The lindane-exposed mice had lower progenitor cell numbers and slower recovery from the irradiation. These results indicate that lindane has significant myelotoxicity in mice and short-term lindane exposure can induce residual progenitor cell damage that can be demonstrated by subsequent irradiation.

Animals↗

PubMed1997

Hepatitis-associated aplastic anemia.

BACKGROUND: Hepatitis-associated aplastic anemia is a variant of aplastic anemia in which aplastic anemia follows an acute attack of hepatitis. The aplastic anemia, however, is often fatal if untreated. To characterize the illness, investigate the role of hepatitis viruses, and assess the response to immunosuppressive treatment, we studied patients with the syndrome who were referred to the National Institutes of Health (NIH). METHODS: Standard hematologic and biochemical tests and measurements of bone marrow cellularity were used to monitor the patients' response to treatment. Serum was assayed for antibodies and antigens related to hepatitis A, B, and C viruses and for the RNA of hepatitis C and GB virus C by the polymerase chain reaction. All patients were treated with antithymocyte globulin and cyclosporine. RESULTS: Ten patients with hepatitis-associated aplastic anemia were referred to the NIH between 1990 and 1996; all had the typical features of this syndrome. There was evidence of activated CD8 T lymphocytes in the blood. Serologic tests for hepatitis A, B, and C viruses were negative; RNA of hepatitis C virus was undetectable in all patients, but RNA of GB virus C was detected in three patients. Seven of the patients responded to intensive immunosuppressive treatment; the three who did not respond all died within one year of treatment, two from complications of stem-cell or marrow transplantation. CONCLUSIONS: The hepatitis of the hepatitis-associated aplastic anemia does not appear to be caused by any of the known hepatitis viruses. We recommend immunosuppressive treatment for patients who do not have an HLA-matched related donor available for bone marrow transplantation. Several features of the syndrome suggest that it is mediated by immunopathologic mechanism.

Adolescent↗

PubMed1991

Effects of recombinant murine granulocyte-macrophage colony-stimulating factor in cyclophosphamide-treated mice.

To evaluate the efficacy of recombinant murine granulocyte-macrophage colony-stimulating factor (rGM-CSF) in attenuating the myelosuppression associated with chemotherapy, the effects of 100 and 300 ng rGM-CSF, administered twice daily by intraperitoneal injection for 6 consecutive days to mice 24 hours after a dose of 200 mg/kg cyclophosphamide, were measured. Six days after the initial injection of rGM-CSF, a significant increase occurred in the absolute myeloid count compared to that of vehicle-treated animals. The difference was most pronounced on day 7, attaining levels of 327% and 428% of the control; these increases slowly declined to that of the control level by day 19. No significant effect was produced by rGM-CSF on the packed red cell volume or on the platelet count. Furthermore, the administration of rGM-CSF did not alter bone marrow cellularity or increase the number of marrow-derived hematopoietic stem cells. In contrast, a significant splenomegaly occurred, starting on day 6 and continuing until day 17. This was characterized by a pronounced increase in splenic-derived granulocyte (CFU-G), granulocyte-macrophage (CFU-GM), macrophage (CFU-M), megakaryocyte (CFU-MK), and erythroid (BFU-E, CFU-E) stem cells. The increases occurred between days 6 and 9 following the initial administration of rGM-CSF. These findings indicated that the administration of rGM-CSF to cyclophosphamide-treated animals causes an absolute increase in circulating myeloid cells and that these increases are derived from the spleen. The use of recombinant hematopoietic growth factors may permit the administration of more intensive chemotherapy through amelioration of chemically induced leukopenia.

Animals↗

PubMed1990

Human megakaryocytes. VII. Analysis of megakaryocytes for nuclear DNA content distribution in whole marrow cell suspensions by flow cytometry.

These studies were designed to quantitate and determine the DNA content distribution of human marrow megakaryocytes using whole bone marrow. Cellular DNA content within megakaryocytic cells was established by measuring propidium iodide staining in marrow cells expressing platelet glycoprotein IIb/IIIa (Gp IIb/IIIa). These studies were based on the development of a method for rapid analysis of whole marrow cell preparations by a dual fluorescent system. DNA values ranging from 2 to 64 C were observed in all samples tested, with 16 C corresponding to the modal ploidy class representing almost one-half of the cells containing Gp IIb/IIIa. The second most frequent ploidy class corresponded to 32 C, followed by 8 C, with 20% and 15%, respectively. Virtually all high-ploidy megakaryocytes (greater than or equal to 8 C) were of low density (less than 1.050 g/cm3), whereas 2 and 4 C megakaryocytes were evenly distributed between less than or equal to 1.050 and greater than 1.050 g/cm3 marrow cells. These studies conclusively establish DNA content distribution of normal human marrow megakaryocytes and provide a basis for the study of states of altered megakaryocytopoiesis.

Bone Marrow Cells↗