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Objective: To search a novel function of erythroid progenitor cells circulating as the major nucleated cell population in umbilical cord blood (CB) cells. Materials and Methods: Human CB–derived CD36+ erythroid progenitors were subjected to cDNA microarray. Gene expression and biological property of CB-erythroid progenitors and adult peripheral blood (PB)-erythroid progenitors were compared by using real-time polymerase chain reaction (PCR) and serum-free culture system with erythropoietin (EPO). Results: The microarray revealed 124-fold higher levels of insulin-like growth factor-II (IGF-II) gene expression in CB-CD36+ erythroid progenitors than in stimulated lymphocytes of adult PB. Real-time PCR verified that IGF-II mRNA levels were highest in CB-CD36+ erythroid progenitors compared to other CB- or adult PB-fractionated cells. When CB-CD36+ erythroid progenitors were cultured with EPO in serum-free medium, anti-IGF-II-antibody (Ab) reduced the number of erythroid colonies. When CB- and adult PB-derived erythroid colony-forming cells (ECFCs) were cultured with interleukin-3, stem cell factor, and EPO, mRNA levels per cells of IGF-II peaked on day 12, but those of type 1 and type 2 receptors did not increase with ECFCs maturation. The maturation rate by IGF-II was higher in CB-ECFCs than in adult PB-ECFCs. The majority of CB-ECFCs expressed IGF-II protein. Anti–IGF-II-Ab, but not anti–IGF-I-Ab, reduced the number of CB-ECFCs in liquid culture with EPO. Anti–IGF-II-Ab accelerated apoptosis of ECFCs, assessed by dimethylthiazole tetrazolium bromide, bromodeoxyuridine, and flow cytometric analyses. ECFCs failed to attain full maturity in the presence of anti–IGF-II-Ab. Conclusions: These results suggest that IGF-II is produced by erythroid progenitors themselves, and has a crucial role in fetal erythropoiesis by modulating apoptosis and maturation in an autocrine fashion. [Copyright &y& Elsevier]

Suehiro Y, Muta K, Nakashima M, Abe Y, Shiratsuchi M, Shiokawa S, Ikuyama S, Yoshikawa Y, Watanabe T, Nishimura J. A novel mechanism in suppression of erythropoiesis during inflammation: a crucial role of RCAS1.Eur J Haematol 2005: 74: 365–373.© Blackwell Munksgaard 2005.A novel human tumor-associated antigen, receptor-binding cancer antigen expressed on SiSo cells (RCAS1), induces apoptosis in normal human erythroid progenitor cells, which express putative RCAS1 receptors. In the present study, we investigated a possible role of RCAS1 produced by human peripheral blood monocytes (CD14-positive cells) and monocyte-derived macrophages. RCAS1 was immunohistochemically detected in monocytes as well as macrophages. When macrophages were stimulated with lipopolysaccharide (LPS), the expression of RCAS1 was remarkably enhanced. An increased production of RCAS1 mRNA was observed in LPS-stimulated macrophages by quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) analysis. Soluble RCAS1 molecules were only detected in the culture supernatants obtained from LPS-stimulated macrophages. Moreover, LPS-stimulated macrophages induced cell death of erythroid progenitor cells through RCAS1 production. These results suggest that macrophages may negatively regulate erythropoiesis at least in part through the production of RCAS1 molecules, and this may contribute to the pathogenesis of the anemia seen in patients with inflammatory disorders. [ABSTRACT FROM AUTHOR]

Objective. Hematopoiesis is regulated by proliferation, differentiation, and death. p16INK4a has been reported to regulate apoptosis and differentiation of diverse cells, as well as arresting the cell cycle at G1 phase. The aim of this study is to explore the properties of p16 in apoptosis and differentiation of erythroid cells.Methods. We transfected the INK4a gene to K562 cells, which defect the INK4a gene, and compared the effect of enforced expression of p16INK4a with that of various additives, topoisomerase I inhibitor (SN 38), interferon-α, phosphatidyl-inositol-3 kinase inhibitor (LY294002), and serum deprivation, which arrest cell cycle at different phases. We also investigated the role of p16INK4a in normal day-6 human erythroid colony-forming cells by transfecting the INK4a gene.Results. p16INK4a induced cell cycle arrest at the G0/G1 phase, and promoted erythroid differentiation in viable K562 cells, but induced apoptosis in K562 cells with incomplete differentiation. The apoptosis induced by p16 was accompanied with downregulation of bcl-x and nuclear NF-κB. These findings were not observed in K562 cells treated with various additives. p16INK4a decreased the cell viability and promoted apoptosis in day-9 ECFC.Conclusion. We propose that p16INK4a plays a role in maintaining homeostasis during erythroid differentiation, and that the mechanisms for this effect are not confined to those inducing cell cycle arrest. [Copyright &y& Elsevier]

The BCR-ABL fusion gene is important for the leukemogenesis of chronic myeloid leukemia (CML). A relationship between types of BCR-ABL transcripts in CML and clinical features has been proposed. We present here a patient with CML who carried an aberrant BCR-ABL transcript with an intronic sequence insert. A 26-year-old woman was diagnosed as having Philadelphia chromosome (Ph) positive CML. Reverse transcription polymerase chain reaction detected an atypically large BCR-ABL mRNA transcript. Sequencing revealed a 589bp insertion consisting of a 5' portion of BCR intron b2 and a 3' portion of ABL intron 1b between BCR exon b2 and ABL exon a2. Although the typical b2a2 transcript was undetectable initially, it appeared after intensive chemotherapy. The aberrant transcript presumably arose as a result of a lack of splicing, and chemotherapy might modify the disease course by selecting the subpopulation of the CML clone expressing typical BCR-ABL mRNA dominantly. [ABSTRACT FROM AUTHOR]

The aim of the present study was to confirm the histopathological features of aggressive B-cell lymphoma in Papua New Guinea (PNG)—an EBV endemic region. The immunophenotypic features and expression of EBV-encoded proteins and RNA in B-cell lymphomas were analyzed in 21 PNG children, and compared to the corresponding features of 17 Japanese children with Burkitt lymphoma (BL). Histological diagnosis of the lymphomas from the PNG children was BL in nine patients; atypical Burkitt/Burkitt-like variant of BL (BLL) in three; diffuse large B-cell lymphoma (DLBCL) in four; and B-lymphoblastic lymphoma (B-LBL) in five. The lymphomas from the PNG children had a high positive rate on EBV-RNA in situ hybridization (EBV-ISH; 66.7%). With regard to the histological typing, 10 of 12 patients (83%) with BL/BLL, one of four (25%) with DLBCL, and three of five (60%) with B-LBL were positive for EBV-ISH. The findings of EBV-positive B-LBL were surprising because it is commonly considered that lymphoblastic lymphoma is not associated with EBV. EBV positivity was not detected in the 12 Japanese patients who were available for the EBV-ISH evaluation. It is concluded that it is possible that a proportion of DLBCL and B-LBL besides BL/BLL are associated with EBV in endemic region. [ABSTRACT FROM AUTHOR]

Recent reports have demonstrated that erythroid progenitor cells contain and secrete various angiogenic cytokines. Here, the impact of erythroid colony-forming cell (ECFC) implantation on therapeutic angiogenesis was investigated in murine models of hindlimb ischemia. During the in vitro differentiation, vascular endothelial growth factor (VEGF) secretion by ECFCs was observed from day 3 (burst- forming unit erythroid cells) to day 10 (erythroblasts). ECFCs from day 5 to day 7 (colony-forming unit erythroid cells) showed the highest VEGF productivity, and day 6 ECFCs were used for the experiments. ECFCs contained larger amounts of VEGF and fibroblast growth factor-2 (FGF-2) than peripheral blood mononuclear cells (PBMNCs). In tubule formation assays with human umbilical vein endothelial cells, ECFCs stimulated 1.5-fold' more capillary growth than PBMNCs, and this effect was suppressed by antibodies against VEGF and FGF-2. Using an immunodeficient hindlimb ischemia model and laser-Doppler imaging, we evaluated the limb salvage rate and blood perfusion after intramuscular implantation of ECFCs. ECFC implantation increased both the salvage rate (38% vs. 0%, P < 0.05) and the blood perfusion (82.8% vs. 65.6%, P < 0.01). In addition, ECFCs implantation also significantly increased capillaries with recruitment of vascular smooth muscle cells and the capillary density was 1.6-fold higher than in the control group. Continuous production of human VEGF from ECFCs in the skeletal muscle was confirmed at least 7 days after the implantation. Implantation of ECFCs promoted angiogenesis in ischemic limbs by supplying anglogenic cytokines (VEGF and FGF-2), suggesting a possible novel strategy for therapeutic angiogenesis. [ABSTRACT FROM AUTHOR]

Abstract: Microsatellite instability (MSI) in haematopoietic malignancies has been controversial. Particularly in non-Hodgkin lymphoma, the data published to date lack unity. Using a unique fluorescent technique, we found MSI in eight (14%) tumours in a panel of 59 carefully selected non-Hodgkin lymphoma patients. Our fluorescent technique also reveals two qualitatively distinct modes of MSI, i.e. Type A and Type B. Based on our previous studies using DNA mismatch repair (MMR) gene-knock out animals, we have concluded that Type A MSI is a direct consequence of defective MMR. MSI observed in non-Hodgkin lymphomas was uniformly Type A, which implies that MMR deficiency occurs in this malignancy. Intriguingly, in non-Hodgkin lymphoma patients treated by CHOP/VEPA-based therapies, response to chemotherapy was significantly worse in those with microsatellite-unstable tumours (p =0.027). As a consequence, the patient outcomes at 1 year after treatment were significantly less favourable in this population (p =0.046), although the survival difference was not statistically confirmed in a longer term. These findings suggest that in some non-Hodgkin lymphomas MMR deficiency may lead to drug resistance in tumour cells and, consequently, to poor patient outcomes. In non-Hodgkin lymphoma, MSI may be a potential biomarker that predicts the tumour response against chemotherapy. [Copyright &y& Elsevier]

Abstract: RNA interference (RNAi), a process by which target messenger RNA (mRNA) is cleaved by small interfering complementary RNA (siRNA), is widely used for investigations of regulation of gene expression in various cells. In this study, siRNA complementary to 5′ region of exon II of α-globin mRNA was examined for its role in erythroid colony forming cells (ECFCs) isolated from normal peripheral blood donor. On day 6 of cell culture, 1×106 ECFCs were transfected with lipofectamine-containing α-globin specific siRNA. After 48h of transfection, α-globin specific siRNA produced significantly reduction of α-globin mRNA level in a dose-dependent manner, but it did not affect the level of β-globin mRNA. Significantly, decreased numbers of hemoglobinized erythroid cells relative to the control were observed supporting the inhibitory effect of this α-globin mRNA specific siRNA. [Copyright &y& Elsevier]

Abstract: To clarify the roles of microRNAs (miRNAs) in erythropoiesis, the expression of miR-155, miR-221, miR-223, and miR-451 were analyzed during the differentiation of purified normal human erythroid progenitors in a liquid culture system. Cells increased almost 500-fold in a number, and differentiated to benzidine-positive mature erythroblasts. Analyses of miRNA expression using the quantitative real-time polymerase chain reaction showed that the expression level of miR-155 decreased about 200-fold, and that the expression of miR-451 increased about 270-fold during 12 days of cultures. A moderate down-regulation of miR-221 and miR-223 was observed. MiR-451 was expressed in red blood cells about 104-fold more than in granulocytes, obtained from normal human peripheral blood. These observations suggest that miR-155 and miR-451 are key molecules for normal erythroid differentiation, and that quantitative assays of the two miRNAs may be a relevant method for analyzing pathological erythropoiesis. [Copyright &y& Elsevier]

Epithelioid hemangioendothelioma (EHE) is a rare tumor originating from the vascular endothelium; it has an intermediate malignant potential. EHEs affect all age groups and mostly originate from the soft tissues of the extremities, lungs, and liver. Spinal EHEs, especially those occurring in the bone marrow region, are extremely rare. We report a case of EHE with massive involvement of the liver, vertebrae, and cranial bones that caused severe myelofibrosis (MF) in a 67-yr-old-male patient. Hyaluronan deposits were diffusely observed in the tumor tissue biopsies obtained from both the liver and bone marrow. Furthermore, the serum hyaluronan level increased markedly along with rapid progression of the disease. To the best of our knowledge, this is the first report of MF occurring in an EHE; hyaluronan may have played an important role in the pathogenesis of fibrosis in this case. [ABSTRACT FROM AUTHOR]

Erythropoietin (EPO) stimulates erythroid growth by enhancing the proliferation, maturation and survival of late-stage erythroid progenitor cells. However, the entire process of EPO stimulation remains undetermined. To further clarify the intracellular mechanisms by which EPO affects the growth of erythroid progenitor cells, we analyzed proteins obtained from purified human erythroid colony-forming cells (ECFCs) cultured with or without EPO, and one of the proteins apparently related with EPO stimuli was identified as mortalin (mthsp70/PBP74/Grp75/mot-2), which is a member of the heat shock protein 70 family of chaperones. The amount of mortalin mRNA in ECFCs increased in an EPO dose-dependent manner, and ECFC growth was dependent on the amount of mortalin. Furthermore, expression of mortalin in ECFCs was suppressed by a phosphatidylinositol 3-kinase inhibitor. Finally, we analyzed gene expression patterns in ECFCs cultured with or without EPO after treatment with mortalin small interfering RNA (siRNA) using a DNA microarray. When ECFCs treated with mortalin siRNA were cultured with EPO, the expression of several genes overlapped with the profile seen in control ECFCs cultured without EPO. Our data suggest that mortalin is involved in the mediation of EPO signaling and plays an important role in stimulating the growth of erythroid progenitor cells. [ABSTRACT FROM AUTHOR]

Notch signaling plays an important role in cell fate decisions in developmental systems. To clarify its role in committed hematopoietic progenitor cells, we investigated the effects of Notch signaling in erythroid colony forming cells (ECFCs) generated from peripheral blood. ECFCs express Notch receptors, Notch1 and Notch2, and Notch ligands Delta1, Delta4, and Jagged1. When we assayed the effects of Notch ligands on erythroid maturation by flow cytometry, we found that immobilized Delta1 and immobilized Delta4 in particular inhibited maturation, whereas Jagged1 had no effect. In addition, Delta4 inhibited proliferation without reducing cell viability. Increases in expression levels of the Notch target gene hairy enhancer of split (HES) -1 were evident by real-time PCR after stimulation with immobilized Delta4. The effect of soluble Delta4 on expression of HES-1 was less pronounced than that seen with the immobilized form, indicating that all surface-bound ligands are important for effective signal transduction. When ECFCs were cultured in the presence of soluble Delta4 at a low cell concentration, erythroid maturation was slightly inhibited, but at a high concentration, maturation was promoted via competition of soluble Delta4 with endogenous ligands. These results indicate a pivotal role of Notch signaling in regulating erythroid maturation and proliferation, and further suggest that cell–cell interactions modulate growth of erythroid progenitor cells via Notch system. [ABSTRACT FROM AUTHOR]

Due to genetic heterogeneity of β-thalassemia (β-thal) patients, several efforts have been undertaken to determine the efficacy of hydroxyurea treatment. The aim of this work is to determine the responder and nonresponder for hydroxyurea treatment in β-thal intermedia based on γ-globin mRNA and fetal hemoglobin (HbF) induction in human erythroid progenitor cells purified from a patient’s peripheral blood. Eighteen β-thal/hemoglobin E patients [13 βE/codon41/42(-TCTT), 4 βE/codon17, and 1 βE/IVS-654], requiring blood transfusion occasionally, with Hb levels of 5.20–8.50 g/dl were studied. The relative levels of γ-globin mRNA was measured by real-time reverse-transcription polymerase chain reaction and HbF by high-performance liquid chromatography. The results indicated that erythroid progenitor cells treated with 30 μmol/l hydroxyurea for 96 h preferentially enhanced Gγ-and Aγ-globin mRNA. The mean values of Gγ-globin mRNA fold induction were higher than Aγ-globin mRNA (12±4 vs 4±0.30), the Pearson’s correlation of Gγ-and Aγ-globin mRNA was r=0.80. Induction of Gγ/Aγ globin mRNA is up to ninefold. A 30% increase in the proportion of HbF out of the total Hb was found in cultures derived from four patients, 20–30% in cultures from nine patients, and less than 20% in cultures from five patients. In cultures from only two patients, increase in the proportion of HbF was less than 3%, and Gγ/Aγ globin mRNA is less than 0.50. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) is refractory to conventional chemotherapy. To achieve a sustained complete remission, we performed planned non-myeloablative allogeneic stem cell transplantation (NST) after autologous hematopoietic stem cell transplantation (HSCT) in a patient with stage III MM. Autologous HSCT was performed using high-dose melphalan after conventional chemotherapy, followed by NST from an HLA-identical sibling using low-dose total body irradiation (200&ThickSpace;cGy) for conditioning. Cyclosporine and mycophenolate mofetil were used for graft-vs-host disease (GVHD) prophylaxis. Acute GVHD was transiently seen in the skin and intestine, while, in addition, mild chronic GVHD was seen in the oral mucosa and skin. Complete donor chimerism was achieved and the disappearance of tumor-derived monoclonal B cells was confirmed based on an analysis of immunoglobulin light chain messenger signals on day 156 when chronic GVHD occurred. The clinical course in this case strongly suggested the existence of a graft-vs-myeloma effect. [ABSTRACT FROM AUTHOR]

Objective: The aim of this study was to reveal the role of peroxisome proliferator-activated receptor γ (PPARγ) in erythropoiesis. Methods: The effects of PPARγ ligands on cellular proliferation and differentiation were investigated in erythroid colony-forming cells (ECFCs) purified from human peripheral blood. Results: RT-PCR analysis revealed that PPARγ mRNA is expressed in ECFCs. Synthetic PPARγ ligands, troglitazone or pioglitazone, suppressed cellular proliferation without inducing apoptosis and delayed maturation of ECFCs, as determined by flow cytometry. The delay in erythroid maturation by troglitazone was confirmed by the down-regulation of γ-globin, β-globin and GATA-1 mRNA, and the maintenance of GATA-2 mRNA. Conclusions: Our results suggest that PPARγ modulates the differentiation process of erythroid progenitor cells, and plays a crucial role in regulating the balance of hematopoiesis. [Copyright &y& Elsevier]

NS-398, a selective inhibitor of cyclooxygenase 2 (COX-2), has been reported to inhibit growth and induce apoptosis in several cancer cell lines that overexpress COX-2. However it has not been extensively studied in multiple myeloma (MM). Here, we studied the effects of COX-2 inhibitors on MM cell lines and primary myeloma patient cells. We investigated the effects of NS-398 on proliferation and apoptosis in three myeloma cell lines (PCM6, U266 and RPMI8226) and isolated CD138-positive cells from MM patients. Furthermore, the combined effects of NS-398 plus dexamethasone (Dex) or thalidomide (Thal) were investigated. All myeloma cell lines express COX-2. NS-398 inhibited growth and induced apoptosis in PCM6, RPMI8226 and CD138-positive MM cells in a time- and dose-dependent manner. At low concentrations (10 μM), NS-398 primarily induced growth arrest without affecting cell viability, but at higher concentrations (over 25 μM), apoptosis was induced. During the process of apoptosis, the number of Fas-positive cells increased. Downstream signals of Fas, such as caspase 8, 3 and 9, were also activated. On the other hand, protein levels of the Bcl-2 family did not change, although mitochondrial transmembrane potential (Δψm) was decreased. Combined incubation with Dex or Thal enhanced NS-398-induced growth inhibition and apoptosis in RPMI8226 cells. The combined effect of Dex was more potent than that of Thal. Our findings suggests that COX-2 plays an important role in regulation of apoptosis in myeloma cells, and COX-2 inhibitors might serve as an effective tool for future chemoprevention and/or treatment of myeloma. [ABSTRACT FROM AUTHOR]

This is the first case report of gastric mucosal-associated lymphoid tissue lymphoma with adult T cell leukemia/lymphoma (ATLL) cell infiltration. A 43-yr-old Japanese woman who was seropositive for antihuman T cell leukemia virus-I antibody complained of epigastric pain in April, 1996. Endoscopy showed gastric ulcers in the antrum. Biopsy specimens showed Helicobacter pylori infection. Her symptoms were relieved by treatment with ranitidine. In March, 1998, she complained of epigastric pain and abdominal fullness. Smears of peripheral blood revealed atypical lymphocytes with nuclear irregularity, consistent with ATLL cells. She was diagnosed to have ATLL. Endoscopy revealed multiple gastric ulcers in the antrum and the angle. Biopsy specimens demonstrated small centrocyte-like cells forming lymphoepithelial lesions, with infiltrations of large atypical lymphoid cells of ATLL. On immunohistochemical staining, the small centrocyte-like cells were positive for B cell markers (L26, CD20), whereas the large atypical lymphoid cells were positive for T cell marker (UCHL-1, CD45RO). Her findings were attributed to gastric mucosal-associated lymphoid tissue lymphoma with gastric involvement with ATLL. [Copyright &y& Elsevier]

Summary. Sequencing of the immunoglobulin (Ig) gene transcripts of the tumour B cells in lymph node (LN) and bone marrow (BM) from a follicular lymphoma (FL) patient associated with multiple myeloma identified two dominant clones. One of the clones, present in both LN and BM, had somatic mutations and extensive clonal diversity. Among the diversified clones, two dominant populations of identical sequences (group I and II) were present. Group II was a descendant population of group I and had nine more somatic mutations. Group I contained µ-, δ-, γ- and α-expressing clones. Group II clones contained mainly µ- and δ-expressing clones. These findings showed that somatic mutation and isotype switching occurred repeatedly in this patient. [ABSTRACT FROM AUTHOR]

Abstract Background: Hepatitis C virus (HCV) and hepatitis B virus (HBV) are not only hepatotropic, but also lymphotropic viruses. Recently, some reports suggested that these viruses may participate in the development of malignant lymphoproliferative disorders. Methods: We investigated the prevalence of HCV or HBV infection in 348 patients with non-Hodgkin's lymphoma (NHL). We also compared these prevalences with those in blood donors as a control group representing the general population in our area (n = 1 513 358). Next, we evaluated the clinical and pathologic characteristics of HCV- or HBV-infected NHL cases. Non-Hodgkin's lymphoma was classified according to the Working Formulation classification. Results: Thirty-seven cases (14.9%) were found to be infected with HCV or HBV; of these, 20 (8.1%) were infected with HCV, and 17 (6.9%) with HBV. In male NHL patients, the rate of HCV infection was significantly higher than in an age- and sex-matched population in the same area (P < 0.001, Mantel– Haenszel test). The rate of HBV infection also tended to be higher in the population (P = 0.0551). In contrast, in female NHL patients, the rate of HCV or HBV infection was not higher than in the general population. In HCV-infected cases, 15 cases (75%) had B-cell NHL and 16 cases (80%) were classified as being in the intermediate grade; B-cell NHL comprised 83% of all NHL cases. In HBV-infected NHL cases, 11 (65%) were of B-cell type and 10 (58%) were classified as being in the intermediate grade. Conclusions: The high prevalence of HCV or HBV infections in our study population provides epidemiologic evidence suggesting that HCV and HBV infections may be involved in the development of a subgroup of NHL in males. Our investigation also revealed that both HCV- and HBV-infected NHL patients showed certain similarities in clinical and pathologic manifestations. [ABSTRACT FROM AUTHOR]

Thiazolidinedione (TZD) is known to be a potent activator of peroxisome proliferator-activated receptor γ (PPARγ), a nuclear receptor that constitutes a heterodimer with retinoid X receptor (RXR). Since a considerable amount of PPARγ is expressed in various hematopoietic cells, the present study was undertaken to examine the effect of TZD in the absence or presence of LG100268, an RXR-selective ligand, on a cultured promyelocytic leukemia cell line, HL60. Treatment with TZD (25–50 μM troglitazone or pioglitazone) markedly suppressed cell proliferation of HL60. A cell cycle analysis revealed that the suppressive effect of troglitazone on HL60 cell proliferations was caused by G0/G1 cell cycle arrest as well as by an apoptotic effect. Treatment with the same concentration of troglitazone also induced the monocytic differentiation of HL60 cells. The apoptotic or the differentiating effect of TZD on HL60 cells was synergistically enhanced by the combined treatment with 1 μM LG100268, while LG100268 alone neither had an apoptotic nor a differentiating effect on HL60 cells. These results suggest that these actions are mediated through the nuclear receptor system constituted by the PPARγ: RXR heterodimer. [ABSTRACT FROM AUTHOR]

Presents a letter which discussed a case of cytotoxic T-cell lymphoma presenting as pancytopenia due to diffuse reticulofribrosis of bone marrow. Pathogenesis of the fibrosis; Role of cytokines relative to fibrosis; Assessment of the plasma concentrations of the platelet-derived growth factor and the transforming growth factor beta.

A letter to the editor entitled "Neutropenia induced in a patient by treatment with ritodrine: in vitro evaluation of myeloid progenitor colony-forming cells," published within the issue is presented.

Examines the apoptosis resistance of mature neutrophils in a case of chronic neutrophilic leukemia. Implication of the absence of Philadelphia chromosome; Usability of granulocyte macrophage colony-stimulating factor; Susceptibility of spontaneous apoptosis.