losartan-potassium and Hyperplasia

The Friend spleen focus-forming virus has been a valuable tool for understanding the molecular events involved in the multiple stages of leukaemia. As summarized in Figure 3, the primary effect of SFFV, which occurs within days, is to cause a polyclonal proliferation of erythroid precursor cells that can proliferate in the absence of their normal regulator erythropoietin. This is the direct result of the unique envelope glycoprotein encoded by SFFV, which is transported to the cell surface and apparently interacts with the EpoR or another component of the multimeric EpoR complex, resulting in the constitutive activation of the Epo signal transduction pathway. Within this proliferating population of erythroid cells is a rare cell that has undergone several genetic changes due to the integration of the viral genome in specific sites in the mouse DNA. This leads to the activation of a gene encoding the PU.1 transcription factor, whose high expression in erythroid cells may be the cause of the block in differentiation that is characteristic of SFFV-transformed erythroid cells. SFFV integration can also lead to the inactivation of the p53 tumour supressor gene, giving these cells a growth advantage in the mouse. The disease induced by SFFV in mice is very similar to polycythaemia vera in humans (Golde et al, 1981). The major clinical feature of polycythaemia vera is the continuous expansion of the number of mature red blood cells in the presence of low serum Epo levels. Also, BFU-E and CFU-E from these patients can form in the absence of Epo like the analogous cells from SFFV-infected mice (Casadevall et al, 1982). It is possible that haematopoietic cells from individuals suffering from this disease express a protein similar to the envelope glycoprotein of SFFV that can interact with the EpoR and lead to its constitutive activation. Alternatively, these patients may contain a mutant EpoR gene that is constitutively activated like the mutant EpoR described earlier. As we understand more fully how the SFFV envelope protein constitutively activates te EpoR complex, we can begin to design therapies to counteract its action that can then be applied to treating patients with polycythaemia vera or other human diseases associated with uncontrolled erythropoiesis.

Topics: Animals; Cell Transformation, Neoplastic; Cell Transformation, Viral; Defective Viruses; DNA-Binding Proteins; Erythroid Precursor Cells; Erythropoiesis; Erythropoietin; Friend murine leukemia virus; Genes, env; Genome, Viral; Helper Viruses; Hyperplasia; Leukemia, Erythroblastic, Acute; Leukemia, Experimental; Mice; Mutagenesis, Insertional; Receptors, Erythropoietin; Retroviridae Infections; Retroviridae Proteins, Oncogenic; Signal Transduction; Spleen Focus-Forming Viruses; Tumor Virus Infections; Viral Envelope Proteins; Virus Replication

Erythropoietin (EPO) enhances re-endothelialization and anti-apoptotic action. Larger clinical studies to examine the effects of high-dose EPO are in progress in patients with acute myocardial infarction (AMI).. The aim of this multi-center pilot study was to investigate the effect of `low-dose EPO' (6,000 IU during percutaneous coronary intervention (PCI), 24 h and 48 h) in 35 patients with a first ST-elevated AMI undergoing PCI who was randomly assigned to EPO or placebo (saline) treatment. Neointimal volume, cardiac function and infarct size were examined in the acute phase and 6 months later (ClinicalTrials.gov identifier: NCT00423020). No significant regression in in-stent neointimal volume was observed, whereas left ventricular (LV) ejection fraction was significantly improved (49.2% to 55.7%, P=0.003) and LV end-systolic volume was decreased in the EPO group (47.7 ml to 39.0 ml, P=0.036). LV end-diastolic volume tended to be reduced from 90.2% to 84.5% (P=0.159), whereas in the control group it was inversely increased (91.7% to 93.7%, P=0.385). Infarction sizes were significantly reduced by 38.5% (P=0.003) but not in the control group (23.7%, P=0.051). Hemoglobin, peak creatine kinase values, and CD34(+)/CD133(+)/CD45(dim) endothelial progenitors showed no significant changes. No adverse events were observed during study periods.. This is a first study demonstrating that short-term `low-dose' EPO to PCI-treated AMI patients did not prevent neointimal hyperplasia but rather improved cardiac function and infarct size without any clinical adverse effects.

Topics: Aged; Angioplasty, Balloon, Coronary; Biomarkers; Cardiovascular Agents; Chi-Square Distribution; Coronary Angiography; Coronary Restenosis; Creatine Kinase; Endothelial Cells; Erythropoietin; Female; Hemoglobins; Humans; Hyperplasia; Japan; Male; Middle Aged; Myocardial Infarction; Myocardium; Pilot Projects; Placebo Effect; Prospective Studies; Recombinant Proteins; Stem Cells; Stroke Volume; Time Factors; Treatment Outcome; Ultrasonography, Interventional; Ventricular Function, Left; Ventricular Remodeling

Hematopoietic evaluation of the patients after Hematopoietic stem cell transplantation (HSCT) is very important. Erythroblast macrophage protein (Emp) is a key protein with function in normal differentiation of erythroid cells and macrophages. Emp expression correlates with erythroblastic island formation, a process widely believed to be associated with hematopoiesis in bone marrow. We aimed to investigate the hematopoietic function of bone marrow from 46 HSCT patients and 16 inpatients with severe anemia applied to the treatment of EPO by measuring Emp expression level.. Emp mRNA and protein expression levels in mononuclear cells of bone marrow and peripheral blood samples were detected by RT-PCR and Western blotting method respectively.. While hematopoiesis occurs in bone marrow, Emp expression level was elevated and more erythroblastic islands were found , and Emp is upregulated in bone marrow in response to erythropoietin (EPO) treatment.. Emp expression correlates with erythroblastic island formation and has an important function for bone marrow hematopoiesis. Emp could be a potential biomarker for hematopoietic evaluation of HSCT patients.

Topics: Adolescent; Adult; Bone Marrow; Cell Adhesion Molecules; Cell Shape; Cytoskeletal Proteins; Erythroblasts; Erythropoietin; Female; Gene Expression Regulation; Hematopoietic Stem Cell Transplantation; Humans; Hyperplasia; Immunosuppression Therapy; Male; Young Adult

1. Recombinant human erythropoietin (rHuEPO) has been used for the management of renal anaemia. Recent studies suggest pleiotropic properties of rHuEPO in various tissues. The aim of the present study was to investigate the vasoprotective effects of rHuEPO in renal failure rats. 2. Rats subjected to 5/6 and 17/18 nephrectomy (5/6Nx and 17/18Nx rats, respectively) were treated with rHuEPO (75 U/kg, s.c.) three times a week for 2 weeks. 3. Administration of rHuEPO to 5/6Nx or 17/18Nx rats had no effect on systolic blood pressure or decreased haematocrit. However, rHuEPO treatment normalized proteinuria and creatinine clearance in 5/6Nx, but not in 17/18Nx, rats. 4. Vasodilation in response to acetylcholine in aortic rings was impaired in 5/6Nx and 17/18Nx rats and improved by rHuEPO in both groups. Immunohistochemical analysis revealed that macrophage infiltration into adventitial areas and the expression of osteopontin were enhanced in aortas from 5/6Nx and 17/18Nx rats, but that rHuEPO suppressed these effects. In addition, rHuEPO attenuated medial hyperplasia and NADPH oxidase-derived superoxide production in 5/6Nx and 17/18Nx rats. 5. Activation of the Akt signalling pathway was evident in rHuEPO-treated rats as the increased expression of phosphorylated Akt and glycogen synthase kinase-3β. Treatment with rHuEPO restored the expression of phosphorylated endothelial nitric oxide synthase in the aorta and urinary excretion of NO(x) in nephrectomized rats. 6. These results suggest that a low dose of rHuEPO results in the normalization of endothelial function, vascular inflammation and oxidative stress in rats with renal ablation beyond haematopoiesis. In addition, these vasoprotective effects are observed even in a state of deteriorating renal dysfunction.

Topics: Acetylcholine; Animals; Aorta, Thoracic; Blood Pressure; Creatinine; Erythropoietin; Glycogen Synthase Kinase 3; Glycogen Synthase Kinase 3 beta; Hematocrit; Hematopoiesis; Humans; Hyperplasia; Macrophages; Male; NADPH Oxidases; Nephrectomy; Nitric Oxide; Nitric Oxide Synthase Type III; Nitroprusside; Osteopontin; Oxidative Stress; Proteinuria; Proto-Oncogene Proteins c-akt; Rats; Rats, Wistar; Recombinant Proteins; Superoxides; Vasculitis; Vasodilation

Erythropoietin (EPO) directly stimulates the proliferation of vascular smooth muscle cells, and this is believed to be one of the mechanisms of vascular access failure of hemodialysis patients. However, precise mechanisms of the EPO-induced proliferation of vascular smooth muscle cells are not certain. HMG-CoA reductase inhibitors (statins) are primarily used to reduce cholesterol levels, but also exert other effects, including reno-protective effects. We evaluated the effect of several statins with various hydrophilicities on the EPO-induced proliferation of primary cultured rat vascular smooth muscle cells (VSMCs) in vitro. EPO significantly and concentration-dependently increased DNA synthesis as assessed by [³H]thymidine incorporation, cell proliferation as assessed by WST-1 assay, and activation of the p44/42MAPK pathway. Therapeutic doses of statins (pravastatin, simvastatin, atorvastatin and fluvastatin) in patients with hypercholesterolemia almost completely suppressed all of the EPO-induced effects in a concentration-dependent manner. Co-addition of mevalonic acid almost completely reversed the effects of statins. Statin alone did not affect the basal proliferation capacity of the cells. The effects were almost similar among the statins. We concluded that statins inhibited EPO-induced proliferation in rat VSMCs at least partly through their inhibition of HMG-CoA reductase activity. In the future, statins might prove useful for the treatment of EPO-induced hyperplasia of vascular access. Because the statins all showed comparable effects irrespective of their hydrophilicities, these effects might be a class effect.

Topics: Animals; Cell Culture Techniques; Cell Proliferation; Epoetin Alfa; Erythropoietin; Hydrophobic and Hydrophilic Interactions; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Hyperplasia; Male; MAP Kinase Signaling System; Mevalonic Acid; Muscle, Smooth, Vascular; Osmolar Concentration; Protective Agents; Rats; Rats, Sprague-Dawley; Recombinant Proteins

Topics: Angioplasty, Balloon, Coronary; Cardiovascular Agents; Coronary Restenosis; Endothelial Cells; Erythropoietin; Humans; Hyperplasia; Myocardial Infarction; Myocardium; Recombinant Proteins; Stroke Volume; Time Factors; Treatment Outcome; Ventricular Function, Left; Ventricular Remodeling

Percutaneous vascular interventions lead inevitably to a destruction of the endothelial lining at the site of injury. There are conflicting data on the therapeutic benefit of hematopoietic growth factors aiming at mobilisation of circulating endothelial cells to accelerate the reendothelialisation process. Aim of our study was to evaluate the impact of a maximised 7 day-combination therapy with G-CSF plus EPO on the healing process following balloon injury of the rat carotid artery.. Osmotic pumps to systemically deliver G-CSF and EPO at saturating doses during the first seven days post injury were implanted into the peritoneal cavity of splenectomised male Sprague-Dawley rats. Cytokine treatment resulted in significantly elevated numbers of white blood cells, hematocrit levels, circulating hematopoietic stem cells, and-temporarily-circulating endothelial precursors. Functional reendothelialisation as assessed by Evan's blue staining on day 14 post injury was not affected by the cytokine treatment. The neointimal response was analysed on day 7 and 28 post injury, and was significantly higher at the day 7 timepoint (Cytokines: I/M-ratio 1.10+/-0.09 vs. Saline: 0.36+/-0.06). Cytokine treated rats also displayed higher rates of thrombotic occlusion (Cytokines: 25-33% vs. Saline: 0%). Serum levels of PAI-1, TGFbeta1, and PDGF-BB were not elevated in the cytokine treated rats. The proliferative rates both in the injured vessel wall and the surrounding adventitia as assessed by BrdU incorporation were significantly higher in the cytokine treated animals. The number of CD45(pos) hematopoietic cells was significantly higher in the adventitia of the cytokine treated rats. Vasa vasorum were not found to be significantly different. The increased neointimal response was not due to expression of G-CSF- or EPO-receptors on VSMCs within the vessel wall or myofibroblasts in the adventitia.. The systemic administration of G-CSF plus EPO during the first week after balloon-injury impairs the vascular healing process by increasing the neointimal response and the risk for thrombotic occlusion.

Topics: Animals; Becaplermin; Carotid Artery Injuries; Catheterization; Disease Models, Animal; Drug Therapy, Combination; Endothelial Cells; Erythropoietin; Granulocyte Colony-Stimulating Factor; Hematopoietic Stem Cell Mobilization; Hyperplasia; Immunohistochemistry; Leukocyte Common Antigens; Male; Plasminogen Activator Inhibitor 1; Platelet-Derived Growth Factor; Proto-Oncogene Proteins c-sis; Rats; Rats, Sprague-Dawley; Thrombosis; Transforming Growth Factor beta1; Tunica Intima; Wound Healing

The JAK2(V617F) mutation was found in most patients with myeloproliferative disorders (MPDs), including polycythemia vera, essential thrombocythemia, and primary myelofibrosis. We have generated transgenic mice expressing the mutated enzyme in the hematopoietic system driven by a vav gene promoter. The mice are viable and fertile. One line of the transgenic mice, which expressed a lower level of JAK2(V617F), showed moderate elevations of blood cell counts, whereas another line with a higher level of JAK2(V617F) expression displayed marked increases in blood counts and developed phenotypes that closely resembled human essential thrombocythemia and polycythemia vera. The latter line of mice also developed primary myelofibrosis-like symptoms as they aged. The transgenic mice showed erythroid, megakaryocytic, and granulocytic hyperplasia in the bone marrow and spleen, displayed splenomegaly, and had reduced levels of plasma erythropoietin and thrombopoietin. They possessed an increased number of hematopoietic progenitor cells in peripheral blood, spleen, and bone marrow, and these cells formed autonomous colonies in the absence of growth factors and cytokines. The data show that JAK2(V617F) can cause MPDs in mice. Our study thus provides a mouse model to study the pathologic role of JAK2(V617F) and to develop treatment for MPDs.

Topics: Animals; Erythropoietin; Hematopoietic Stem Cells; Hyperplasia; Janus Kinase 2; Mice; Mice, Transgenic; Mutation, Missense; Myeloproliferative Disorders; Phenotype; Thrombopoietin; Transgenes

A therapeutic strategy that would mitigate the events leading to hyperplasia and facilitate re-endothelialization of an injured artery after balloon angioplasty could be effective for a long-term patency of the artery. It is hypothesized that erythropoietin (EPO), which has both anti-inflammatory and antiapoptotic properties, will prevent hyperplasia, and its ability to proliferate and mobilize endothelial progenitor cells will re-endothelialize the injured artery. To test this hypothesis, EPO (5000 IU/kg) in solution was injected intraperitoneally 6 hours before vascular injury and then on every alternate day for a week or as a single dose (5000 IU/kg) in a sustained release gel formulation 1 week before the vascular injury. Morphometric analysis revealed nearly continuous re-endothelialization of the injured artery in EPO solution-treated animals (90% vs less than 20% in saline control); however, the treatment also caused excessive neointima formation (intima/media ratio, 2.10 +/- 0.09 vs 1.60 +/- 0.02 saline control, n = 5, P < .001). The EPO gel also induced similar excessive neointima formation. Immunohistochemical analysis of the injured arteries from the animals treated with EPO solution demonstrated a significant angiogenic response in adventitia and media, thus explaining the formation of excessive neointima. Although the results are in contrast to expectation, they explain a greater degree of stenosis seen in hemodialysis access fistulas in patients who are on EPO therapy for anemic condition. The results also caution the use of EPO, particularly in patients who are at a risk of vascular injury or are suffering from an atherosclerotic condition.

Topics: Animals; Carotid Arteries; Carotid Artery Injuries; Cell Movement; Cell Proliferation; Delayed-Action Preparations; Disease Models, Animal; Endothelial Cells; Endothelium, Vascular; Erythropoietin; Gels; Hyperplasia; Immunohistochemistry; Injections, Intraperitoneal; Neovascularization, Pathologic; Rats; Rats, Sprague-Dawley; Stem Cells; Tunica Intima

Effects of erythropoietin on parathyroid cell function has not been studied before.. We aimed to demonstrate whether erythropoietin receptor present in parathyroid cells.. The specimens of normal parathyroid gland, parathyroid adenoma and hyperplasia were retrieved from our pathology archives. The sections were stained immunohistochemically. Quantitative gene expression study was performed for erythropoietin and erythropoietin receptor.. Erythropoietin receptors were detected by immunohistochemical staining and by its gene expression. Its density was higher in normal parathyroid, followed by parathyroid adenoma and hyperplasia.. Erythropoietin receptor is present in normal parathyroid, parathyroid adenoma, and hyperplasia.

Topics: Adenoma; Erythropoietin; Gene Expression Regulation; Humans; Hyperplasia; Parathyroid Glands; Parathyroid Neoplasms; Receptors, Erythropoietin

We investigated whether the mobilization of endothelial progenitor cells (EPCs) by exogenous erythropoietin (Epo) promotes the repair of injured endothelium. Recombinant human Epo was injected (1000 IU/kg for the initial 3 days) after wire injury of the femoral artery of mice. Neointimal formation was inhibited by Epo to 48% of the control (P<0.05) in an NO-dependent manner. Epo induced a 1.4-fold increase in reendothelialized area of day 14 denuded vessels, 55% of which was derived from bone marrow (BM) cells. Epo increased the circulating Sca-1(+)/Flk-1(+) EPCs (2.0-fold, P<0.05) with endothelial properties NO dependently. BM replacement by GFP- or beta-galactosidase-overexpressing cells showed that Epo stimulated both differentiation of BM-derived EPCs and proliferation of resident ECs. BM-derived ECs increased 2.2- to 2.7-fold (P<0.05) in the Epo-induced neoendothelium, where the expression of Epo receptor was upregulated. Epo induced Akt/eNOS phosphorylation and NO synthesis on EPCs and exerted an antiapoptotic action on wire-injured arteries. In conclusion, Epo treatment inhibits the neointimal hyperplasia after arterial injury in an NO-dependent manner by acting on the injured vessels and mobilizing EPCs to the neo-endothelium.

Topics: Animals; Apoptosis; Bone Marrow Cells; Bone Marrow Transplantation; Cell Movement; Cells, Cultured; Endothelium, Vascular; Enzyme Activation; Erythropoietin; Femoral Artery; Humans; Hyperplasia; Male; Mice; Mice, Inbred C57BL; Nitric Oxide; Nitric Oxide Synthase Type III; Proto-Oncogene Proteins c-akt; Receptors, Erythropoietin; Recombinant Proteins; Tunica Intima; Wound Healing; Wounds and Injuries

Chronic eosinophilic leukemia (CEL) is a rare myeloproliferative disease in which autonomous, clonal proliferation of eosinophilic precursors results in persistent increase of eosinophils in the blood and bone marrow. A case of CEL spontaneous oscillation of white blood cell (WBC) count is presented. The cycle of WBC variation comprised about 60 days. Similar cyclic variations were noted in his platelet count, hemoglobin level and bone marrow cellularity, as well as in the spleen size, which was directly correlated with the WBC count. The numbers of bone marrow erythroid colony-forming units (CFU-E), granulocyte-macrophage colony-forming units (CFU-GM) and the serum level of colony-stimulating factors (CSFs) were also regularly changed during the oscillation of WBC. Bone marrow hyperplasia was accompanied with the increase in peripheral WBC count, suggesting that the variation of cell production caused the cyclic oscillation.

Topics: Bone Marrow; Chronic Disease; Erythropoietin; Hemoglobins; Humans; Hypereosinophilic Syndrome; Hyperplasia; Interleukin-1; Interleukin-2; Interleukin-6; Leukocyte Count; Leukocytosis; Male; Middle Aged; Periodicity; Platelet Count; Thrombocytosis; Tumor Necrosis Factor-alpha; Tumor Stem Cell Assay

Tumoral calcinosis is a rare form of soft tissue calcifications, initially described as an idiopathic condition, which could occur in uremic patients. Despite its distinct clinical and morphologic presentations, the underlying pathogenesis is unknown. We present a dialysis patient who developed tumoral calcinosis over the right shoulder after receiving a misplaced injection of human recombinant erythropoietin probably into the periarticular tissue. This case serves as an example highlighting the importance of periarticular inflammatory reaction in precipitating the development of the lesion in predisposed patients.

Topics: Administration, Oral; Adult; Bursa, Synovial; Calcinosis; Calcium; Calcium Carbonate; Dialysis Solutions; Erythropoietin; Female; Glomerulonephritis, IGA; Humans; Hypercalcemia; Hyperplasia; Injections, Intramuscular; Kidney Failure, Chronic; Leukocytosis; Parathyroid Hormone; Patient Compliance; Peritoneal Dialysis, Continuous Ambulatory; Radiography; Recombinant Proteins; Shoulder Joint

Objectives were to develop new means to isolate useful numbers of primary progenitor cells and to quantitatively assay the stepwise maturation of erythroblasts.. Approaches involved dosing mice with thiamphenicol (TAP) to yield staged cohorts of pro-erythroid cells; optimizing conditions for their EPO-dependent in vitro growth and survival; developing assays for CFU-E maturation; analyzing stage-specific transcript expression; and expressing a heterologous, erythroid-specific tag (EE372) in transgenic mice.. Per TAP-treated mouse, 3 x 10(7) highly EPO-responsive erythroid progenitor cells were generated that represented up to 30% of total splenocytes and showed strict dependence on EPO for survival, growth, and immediate response gene expression. In this developing cohort, a tightly programmed sequence of gene expression was observed, and maximal expression of c-kit, EPO receptor, and beta-globin transcripts occurred at 72, 96, and 120 hours post-TAP withdrawal, respectively. Also, the newly discovered erythroid-specific dual-specificity kinase, DYRK3, was revealed to be expressed at a late CFU-E stage. In vitro, these progenitor cells matured stepwise from high FALS Ter119- cells (24-hour culture) to high FALS Ter119+ cells (24-36 hours) to low FALS Ter119+ maturing erythroblasts (40-48 hours) and sharp differences in their morphologies were observed. Finally, a MACS-based procedure for the purification of erythroid progenitor cells from TAP-treated EE372 transgenic mice also was developed.. A comprehensive new system for isolating large numbers of primary murine erythroid progenitor cells and quantitatively monitoring their development is established that should serve well in investigations of endogenous and pharmacological regulators of red blood cell development.

Topics: Animals; Biomarkers; Cattle; Cell Differentiation; Cell Separation; Culture Media; Culture Media, Serum-Free; DNA-Binding Proteins; Dyrk Kinases; Erythroid Precursor Cells; Erythroid-Specific DNA-Binding Factors; Erythropoiesis; Erythropoietin; Fetal Blood; Flow Cytometry; Globins; Hyperplasia; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Transgenic; Protein Serine-Threonine Kinases; Protein-Tyrosine Kinases; Proto-Oncogene Proteins c-kit; Receptor Protein-Tyrosine Kinases; Receptors, Cell Surface; Receptors, Erythropoietin; Spleen; Thiamphenicol; Transcription Factors; Transcription, Genetic

We report the case of a 41-year-old black man with acquired immunodeficiency syndrome who developed a severe chronic anemia due to parvovirus infection. Bone marrow biopsy revealed erythroid aplasia. The infectious nature of the anemia was not recognized, and the patient was treated with erythropoietin. The patient's reticulocyte response was inadequate, however, and he remained anemic. A second bone marrow biopsy showed erythroid hyperplasia and prominent intranuclear parvovirus inclusions within erythroid progenitors. Erythropoietin was discontinued and was followed by a course of intravenous immunoglobulin, which resulted in rapid correction of anemia. To our knowledge, this is the first reported case of fulminant human parvovirus infection exacerbated by erythropoietin administration and documented by sequential bone marrow histologic examination. This case illustrates the critical importance of considering parvovirus in the etiology of chronic anemia with erythroid aplasia in immunocompromised patients.

Topics: Adult; AIDS-Related Opportunistic Infections; Anemia, Aplastic; Antibodies, Viral; Erythrocytes; Erythropoietin; Fatal Outcome; Humans; Hyperplasia; Immunoglobulins, Intravenous; Male; Parvoviridae Infections; Parvovirus B19, Human; Recombinant Proteins; Virus Activation

A 71-year-old man presented with epigastralgia and tarry stool. Laboratory examination showed anemia (Hb 7.1 g/dl) due to hemorrhagic gastric ulcer and positive Coombs' test without features of hemolysis. Initial bone marrow smears disclosed normal granulocytes and megakaryocytes, but only erythroid hyperplasia with multinuclearity and megaloblastosis was identified. Cytogenetic studies revealed normal karyotype. Congenital dyserythropoietic anemia (CDA) type II was initially suspected. Serologically, however, acid hemolysis and anti-I * i tests were negative as were the results of another Coombs' test. The second bone marrow aspiration disclosed a marked decrease in multinucleated erythroblasts together with an increase in those that had internuclear chromatin bridges. Electron microscopy of bone marrow specimens demonstrated morphological features of CDA types I and II, thus yielding a final diagnosis of elderly dyserythropoietic anemia, which is similar to both CDA types. It was suggested that the reactive secretion of erythropoietin due to bleeding played a role in these pathologic changes.

Topics: Aged; Anemia, Dyserythropoietic, Congenital; Bone Marrow Cells; Erythroblasts; Erythropoietin; Humans; Hyperplasia; Male; Peptic Ulcer Hemorrhage; Stomach Ulcer

Previously, flow cytometric determination of peroxidase activity, cell size, and reactivity to lymphocyte antibodies were used to produce bone marrow differentials in untreated rats. In the present study, abnormal hematologic profiles were induced with erythropoietin (EPO), recombinant murine stem cell factor (rm-SCF), granulocyte-macrophage stimulating factor (GM-CSF), and cyclophosphamide (CP). Manual and flow cytometric data showed comparable levels of erythroid and myeloid hyperplasia in EPO- and rm-SCF/GM-CSF-treated animals, respectively. In CP-treated animals, flow cytometric data revealed significant decreases in cellularity at concentrations of CP > or = 5 mg/kg. In contrast, 20 mg/kg CP were necessary to induce microscopically apparent hypoplasia in histologic bone sections, showing that the automated methodology was a more sensitive indicator of bone marrow hypocellularity than was the more conventional manual method. Megakaryocyte counts were consistently higher by flow cytometer than by manual counts performed on cytocentrifuge preparations made from the same cell suspensions but were similar to megakaryocyte counts performed on histologic sections of femur, indicating that the automated methodology produced a more accurate reflection of true megakaryocyte numbers. Induction of hematologic abnormalities in the present study showed that manual bone marrow differentials can be replaced with the more efficient and reliable flow cytometric method in most preclinical toxicology studies.

Topics: Animals; Bone Marrow Cells; Bone Marrow Examination; Cell Count; Cyclophosphamide; Erythropoietin; Female; Flow Cytometry; Granulocyte-Macrophage Colony-Stimulating Factor; Hematologic Diseases; Hyperplasia; Male; Rats; Rats, Wistar; Stem Cell Factor

Systemic disorders, often immune in nature, can sometimes be associated with the presence of thymic pathology. Thymic enlargement due to lymphoid hyperplasia or thymoma is a common occurrence in patients with myasthenia gravis. In patients with pure red cell aplasia, at least 10% to 15% of patients are found to have thymoma, usually of spindle cell or medullary type. Pure red cell aplasia with demonstrable thymic enlargement due to lymphoid follicular hyperplasia is distinctly unusual, and has not been previously reported. The authors report such a case developing in a patient with end-stage renal failure maintained on hemodialysis and erythropoietin therapy. Because the red cell aplasia resolved after thymectomy, the disease process was considered etiologically related to the reactive lymphoid hyperplasia.

Topics: Adult; Drug Resistance; Erythropoietin; Female; Humans; Hyperplasia; Kidney Failure, Chronic; Red-Cell Aplasia, Pure; Thymoma; Thymus Gland

Topics: Adrenal Medulla; Adrenalectomy; Adult; Erythropoietin; Hematocrit; Humans; Hyperplasia; Male; Nephrectomy

To understand the etiology of bone modulation and hypercalcemia observed in granulocytosis of a tumor-bearing animal model and to gain insight into the implication of sustained hematopoietic stimulation on the bone tissue, in vivo responses of normal mouse hematopoietic and bone tissues to long-term injections of recombinant human and murine granulocyte colony-stimulating factor (G-CSF), murine granulocyte-macrophage CSF (GM-CSF), and human erythropoietin were quantitatively analyzed. Osteoclast activation was estimated by the osteoclast-endosteal ratio, determined by morphometric analyses of femoral sections. Medullary and bone areas were measured on transverse ground bone sections of the tibia. Recombinant murine G-CSF provoked marked granulocytosis associated with significant increases in the number of marrow granulocytes and their progenitors, and caused expansion of granulopoietic marrow into fatty marrow. The bone of G-CSF-treated mice showed a significant increase in endosteal osteoclast numbers with medullary area enlargement and a reduction in the bone thickness; indicative of endosteal bone resorption. Although GM-CSF had little effect on granulopoiesis, it caused peritoneal macrophages to increase and induced similar bone changes as those observed in G-CSF treatment. Enhanced erythropoiesis stimulated by erythropoietin was also associated with evidence of endosteal bone resorption. Bone changes induced by these growth factors were not associated with hypercalcemia. These animal studies document association of bone modulation in sustained stimulation of hematopoiesis, and implicate important physiologic effects of hematopoietic growth factors on skeletal tissue in vivo.

Topics: Animals; Blood Cell Count; Bone Development; Bone Marrow; Erythropoietin; Female; Granulocyte Colony-Stimulating Factor; Granulocyte-Macrophage Colony-Stimulating Factor; Granulocytes; Hematopoiesis; Hematopoietic Stem Cells; Hyperplasia; Injections, Subcutaneous; Mice; Neutrophils; Osteoclasts; Recombinant Proteins

While investigating the cause of mild polycythemia in a young man, a testicular seminoma was discovered with unusual and tumor-dependent features: an absolute polycythemia with high plasma erythropoietin (EPO) levels, an overproduction of estradiol and testosterone, and a dramatic Leydig cell hyperplasia surrounding the tumor tissue. The authors attempted to gain insight into the relationship between this testicular tumor and the hormonal overproduction, i.e., of EPO, estradiol, and testosterone. Their results favored the conclusion that the high EPO levels and the polycythemia were an indirect effect secondary to the steroid overproduction rather than a direct EPO-producing activity. Moreover, the steroid overproduction by the testis could be caused by a paracrine mechanism through human chorionic gonadotropin activity on the Leydig cells.

Topics: Adult; Chorionic Gonadotropin; Dysgerminoma; Erythropoietin; Estradiol; Humans; Hyperplasia; Leydig Cells; Male; Polycythemia; Steroids; Testicular Neoplasms; Testosterone

The purpose of this investigation was to compare the erythropoietic effects of recombinant interleukin 6 (IL-6) and recombinant erythropoietin (EPO) on the marrow and peripheral blood in vivo. IL-6 administered to rats as a single i.v. injection induces a selective erythroid hyperplasia of the marrow's late normoblasts at 12 and 24 h with a return to preinjection numbers of normoblasts at 48 and 72 h. The hyperplasia of late normoblasts in the marrow is accompanied by a left-shifted peripheral reticulocytosis. Daily injection of IL-6 does not induce any effects on the erythroid population of the marrow or circulation beyond those of a single injection. After daily administration of IL-6 for 4 or 7 days, the erythroid differential in the marrow and the peripheral reticulocyte count are equal to negative control values, indicating a rapid tachyphylaxis to the erythropoietic effect of IL-6. In contrast to IL-6, EPO administered as a single i.v. injection induces a panerythroid marrow hyperplasia with sequential peak increases in pronormoblasts and early normoblasts at 24 h, intermediate normoblasts at 24-48 h, and late normoblasts at 72 h. The peripheral reticulocyte count mirrors the development of erythroid precursors in the marrow by demonstrating an increasing left-shifted reticulocytosis between 24 and 72 h. Daily injection of EPO for 7 days induces a striking erythroid hyperplasia and a myeloid hypoplasia in the marrow. In summary, IL-6 in vivo is a differentiation factor that rapidly induces tolerance to its own effect, whereas EPO in vivo affects all stages of erythropoiesis and sustains erythropoiesis indefinitely. IL-6 may be one of the non-EPO factors in pokeweed mitogen spleen cell-conditioned medium that has been reported by previous investigators to enhance erythropoiesis, although many of those factors were thought to act upon an earlier stage of erythropoiesis. IL-6 is unlikely to exert an indirect erythropoietic effect in vivo via the induction of EPO because the sera of IL-6-treated rats did not contain elevated levels of EPO and because the effects of exogenously administered IL-6 and EPO are so different.

Topics: Animals; Blood Cell Count; Bone Marrow Cells; Dose-Response Relationship, Drug; Erythropoiesis; Erythropoietin; Hyperplasia; Injections, Intravenous; Interleukin-6; Male; Rats; Rats, Inbred Lew; Reticulocytes

The metabolic fate of erythropoietin (EPO) remains unknown. Urinary excretion does not appear to play a major role and liver catabolism has been shown to occur only after terminal sugars on the hormone have been removed. However, it has been proposed that EPO is eliminated by consumption in the bone marrow. In order to examine the extent of such consumption we measured the half-life of radioidinated recombinant EPO injected intravenously (IV) to rats with bone marrows suppressed by cyclophosphamide or hypertransfusion and marrows stimulated by phenylhydrazine or bleeding. The mean half-life or erythropoietin in normal rats was 179 +/- 16 min, with similar half-lives found in the other rats regardless of decreased or increased bone marrow activity. The results indicate that it is unlikely that erythroid activity determines EPO life span and catabolism.

Topics: Animals; Bone Marrow; Cyclophosphamide; Erythropoietin; Half-Life; Hemorrhage; Hyperplasia; Injections, Intravenous; Male; Phenylhydrazines; Rats; Rats, Inbred Strains; Recombinant Proteins

Topics: 5-Aminolevulinate Synthetase; Animals; Bone Marrow; Cell Hypoxia; Cells, Cultured; Enzyme Induction; Erythroid Precursor Cells; Erythropoietin; Ferrochelatase; Gene Expression Regulation; Heme; Hemoglobins; Hydroxymethylbilane Synthase; Hyperplasia; Polycythemia; Rats; Stimulation, Chemical; Transaminases

To investigate the cellular events that accompany erythroid hyperplasia, we studied several effects of erythropoietin (Epo) on marrow CFU-E in sickle cell anemia (SCA). We measured CFU-E number, CFU-E growth as a function both of Epo exposure time and of Epo concentration, and suppression of Epo-induced CFU-E formation by anti-Epo antiserum. With 0.5 U Epo/ml, the number of CFU-E was elevated in SCA (1,087 +/- 520) compared to normal (430 +/- 130). CFU-E were formed even when Epo was immediately neutralized by a 1/150 dilution of anti-Epo. After 40 hr of Epo exposure, only 2% of total CFU-E were expressed in normal marrow, whereas 12%-40% of CFU-E were expressed in SCA. Inhibition of CFU-E growth required at least 1/50 dilution of anti-Epo in SCA and a 1/300 dilution in normal marrow. In contrast to normal, a small number (5%-20%) of CFU-E were expressed in the absence of added Epo in SCA, and this pool required a 1/150 dilution of anti-Epo for inhibition. The Epo dose-response curve in SCA revealed a peak in colony formation around 0.1 U Epo/ml and 0.5 U Epo/ml, whereas only one peak at 0.5 U Epo/ml was seen in normals. These data strongly suggest that, in response to the demands of chronic erythroid hyperplasia in SCA, a pool of CFU-E is present characterized by increased in vitro sensitivity to Epo.

Topics: Anemia, Sickle Cell; Animals; Bone Marrow; Colony-Forming Units Assay; Dose-Response Relationship, Drug; Erythropoiesis; Erythropoietin; Hematopoietic Stem Cells; Humans; Hyperplasia; Immune Sera; In Vitro Techniques; Rabbits

A mesenteric mass, histologically characterized as giant lymph node hyperplasia was found in an 18-yr-old man with at least 11 yr of growth retardation and anemia. The anemia was characterized by iron deficiency from selective malabsorption of iron, and by features of the anemia of chronic disorders. In contrast with a previous report, no inhibitor of erythropoietin was found and there was no abnormality of erythropoietin secretion. Resection of the mass was followed by rapid correction of the anemia and catch-up growth. The mass had histologic features of the hyaline vascular and plasma cell types of Castleman's disease with multinucleate giant cells probably of macrophage origin. Immunologic studies of the mass showed that the B lymphocytes were polyclonal and the T lymphocyte helper/suppressor cell ratio was normal, suggesting that giant lymph node hyperplasia is a local inflammatory reaction.

Topics: Adolescent; Anemia, Hypochromic; Child; Erythropoietin; Humans; Hyperplasia; Intestinal Absorption; Iron; Lymph Nodes; Male; Mesentery

We have described a 51-year-old patient with unresectable mesenteric giant lymph node hyperplasia of the plasma cell type, severe systemic manifestations, and profound anemia. Supression of erythropoiesis may have been related to the presence of a circulating erythropoietic inhibitor produced by the lymphoid tumor. Markedly elevated titers to Epstein-Barr virus capsid antigen suggest that this virus may be important in the etiology of the abnormal lymphoid proliferation. The marked clinical response and decrease in the size of the tumor following irradiation suggests that radiation therapy may be an alternative form of treatment for similar patients with unresectable lesions.

Topics: Anemia; Erythropoietin; Female; Hamartoma; Humans; Hyperplasia; Lymph Nodes; Mesentery; Middle Aged

Adult rats were subjected sequentially to (1) administration of colloidal carbon, zymosan, or gadolinium; (2) subtotal hepatectomy, bilateral nephrectomy, or sham operation; and (3) a 6-hr bout of hypoxia, starting 1 hr or 24 hr after the operation. Control animals received the respective vehicles. The erythropoietin (Ep) activity was assayed in exhypoxic polycythemic mice on the basis of 48-hr per cent RBC(-59) Fe incorporation values. Ep levels in serum of anephric rats primed with either colloidal carbon or zymosan were considerably more elevated than in control animals. This potentiating effect was observed in rats subjected to hypoxia starting either 1 or 24 hr after nephrectomy. On the other hand, gadolinium did not enhance the extrarenal Ep response to hypoxia. It is emphasized that both colloidal carbon and zymosan induced marked hyperplasia of the hepatic and splenic reticuloendothelial system (RES), while gadolinium did not induce this effect. A strict correlation was thus established between potentiation of extrarenal Ep production and hyperplasia of the RES. It is therefore tentatively concluded that the RES is a source of extrarenal Ep. Additionally, since the liver plays a prominent role in extrarenal Ep production, Kupffer cells may represent a major source for Ep in the anephric rat. Finally, it is of interest that both colloidal carbon and zymosan did not potentiate the Ep response to hypoxia in sham-operated or subtotally hepatectomized rats.

Topics: Animals; Carbon; Colloids; Erythropoietin; Female; Gadolinium; Hepatectomy; Hyperplasia; Hypoxia; Liver; Male; Mice; Mononuclear Phagocyte System; Nephrectomy; Organ Size; Rats; Zymosan

An 11-year-old girl presented with a refractory hypochromic microcytic anemia, hypoferremia, normoblastic hyperplastic bone marrow, hypergammaglobulinemia, and growth retardation. Many varied treatments failed to produce any improvement. Ferrokinetic studies revealed rapid plasma clearance and increased plasma iron turnover, but impaired incorporation of 59Fe. Excretion of 57Co after an oral dose indicated an increased iron absorption. A (99M)Tc-sulfur colloid scintigram of the abdomen failed to demonstrate abnormal uptake. A nodal mass showing the plasma-cell variant of angiofollicular hyperplasia was removed from the gastrolienal ligament. Follow-up studies at 3 and 6 months revealed complete correction of the anemia, a 4.8-cm increase in height, and normal serum gamma-globulin levels. Serum obtained before operation inhibited the incorporation of 59Fe that was induced by a standard dose of erthyropoietin in the exhypoxic mouse system, and this inhibition persisted in serum obtained 3 days after surgery but disappeared by 6 days. The data suggest that the hyperplastic angiofollicular lymph node (plasma-cell variant) secreted a substance the inhibited erythropoiesis.

Topics: Anemia, Hypochromic; Body Height; Child; Depression, Chemical; Erythropoiesis; Erythropoietin; gamma-Globulins; Humans; Hyperplasia; Immunoglobulin G; Iron; Lymph Nodes; Male

Topics: Anemia; Anemia, Aplastic; Animals; Blood; Blood Cells; Busulfan; Cell Differentiation; Cell Division; Chromatography, Gel; Erythropoiesis; Erythropoietin; Female; Humans; Hyperplasia; Iron; Iron Isotopes; Mice; Neuraminidase; Phenylhydrazines; Polycythemia; Sheep

Topics: Animals; Bone Marrow; Bone Marrow Cells; Carbon Isotopes; Cell Differentiation; Centrifugation, Density Gradient; Culture Techniques; Erythropoietin; Female; Glycine; Hemoglobins; Hyperplasia; Iron Isotopes; Male; Mice; Polycythemia; Rats; RNA; RNA, Messenger; Time Factors; Valine

Topics: Animals; Blood Cell Count; Bone Marrow Diseases; Bone Marrow Examination; Cobalt; Cobalt Isotopes; Dogs; Erythrocytes; Erythropoiesis; Erythropoietin; Female; Hematocrit; Hemoglobinometry; Hyperplasia; Male; Mice; Nephrectomy; Phenylhydrazines; Reticulocytes

Topics: Animals; Bone Marrow; Bone Marrow Cells; Bone Marrow Examination; Cobalt; Dogs; Erythropoietin; Hyperplasia; In Vitro Techniques; Nephrectomy