Evidence for downregulation of erythropoietin receptor in bone marrow erythroid cells of patients with chronic idiopathic neutropenia.

Objective: The aim of this study is to probe the mechanisms underlying anemia in patients with chronic idiopathic neutropenia (CIN) by evaluating parameters of bone marrow (BM) erythropoiesis.

Patients And Methods: Ten CIN patients fulfilling the criteria of anemia of chronic disease, 27 nonanemic CIN patients, and 30 healthy volunteers were enrolled in the study. Reserves and survival characteristics of BM erythroid cells were evaluated using flow cytometry and clonogenic assays.

Changes in maternal plasma levels of VEGF, bFGF, TGF-beta1, ET-1 and sKL during uncomplicated pregnancy, hypertensive pregnancy and gestational diabetes.

Background: Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), transforming growth factor-beta1 (TGF-beta1), endothelin-1 (ET-1) and soluble c-kit ligand (sKL) are cytokines involved in embryogenesis.

Materials And Methods: Maternal plasma cytokines were measured with ELISA during the three trimesters of gestation and on the day of delivery in 93 pregnant women and 18 age-matched non-pregnant control women.

Results: The VEGF and bFGF levels increased during the first trimester and declined thereafter, but they remained above the controls' values until delivery.

Helicobacter pylori infection is probably the cause of chronic idiopathic neutropenia (CIN)-associated splenomegaly.

Splenic volume and Helicobacter pylori (H. pylori) infection were evaluated in 67 patients with chronic idiopathic neutropenia (CIN) and 39 healthy individuals. Using ultrasound, splenomegaly was found in 61.

Normal bone marrow hematopoietic stem cell reserves and normal stromal cell function support the use of autologous stem cell transplantation in patients with multiple sclerosis.

Bone marrow (BM) stem cell reserves and function and stromal cell hematopoiesis supporting capacity were evaluated in 15 patients with multiple sclerosis (MS) and 61 normal controls using flow cytometry, clonogenic assays, long-term BM cultures (LTBMCs) and enzyme-linked immunosorbent assays. MS patients displayed normal CD34+ cell numbers but a low frequency of colony-forming cells (CFCs) in both BM mononuclear and purified CD34+ cell fractions, compared to controls. Patients had increased proportions of activated BM CD3+/HLA-DR+ and CD3+/CD38+ T cells that correlated inversely with CFC numbers.

High prevalence of Helicobacter pylori infection and monoclonal gammopathy of undetermined significance in patients with chronic idiopathic neutropenia.

The prevalence of Helicobacter pylori infection was evaluated in 120 patients with chronic idiopathic neutropenia (CIN), 8 patients with monoclonal gammopathy of undetermined significance (MGUS) associated with CIN, and 74 age- and sex-matched normal volunteers, all derived from the same geographical area. The purpose of the study was to investigate the possible causal relationships of H. pylori infection with the development of MGUS in CIN patients.

Acute myeloid/NK precursor cell leukemia with trisomy 4 and a novel point mutation in the extracellular domain of the G-CSF receptor in a patient with chronic idiopathic neutropenia.

Chronic idiopathic neutropenia (CIN) has been well recognized as a granulocytic disorder not associated with increased risk to malignant transformation. Four cases, however, of acute myeloid leukemia have been recently reported in patients with CIN. In the current paper, we report on a CIN patient who developed acute myeloid/natural killer (NK) precursor cell leukemia 11 years after diagnosis and 4 months after initiation of treatment with recombinant human granulocyte colony-stimulating factor (rhG-CSF).

The role of apoptosis in the pathophysiology of chronic neutropenias associated with bone marrow failure.

Chronic neutropenia syndromes associated with bone marrow (BM) failure comprise distinct congenital and acquired hematologic disorders with varying degree of neutropenia due to decreased or ineffective BM neutrophil production. Recent evidence suggests that defective granulocytopoiesis in these neutropenia states is a consequence of accelerated apoptotic cell death of BM myeloid progenitor cells and/or their differentiated progeny. Inherited or spontaneously appearing mutations in the ELA2 gene encoding for neutrophil elastase have been implicated in the accelerated apoptotic process of the BM myeloid cells in patients with cyclic and severe congenital neutropenia.

Impaired granulocytopoiesis in patients with chronic idiopathic neutropenia is associated with increased apoptosis of bone marrow myeloid progenitor cells.

To probe the pathophysiologic mechanisms underlying neutropenia in patients with chronic idiopathic neutropenia (CIN) with hypoplastic and left-shifted granulocytic series in the bone marrow (BM), we have studied granulocytopoiesis in 32 adults with CIN by evaluating the number and survival characteristics of cells in several stages of granulocyte differentiation using flow cytometry and BM culture assays. We found that patients with CIN displayed a low percentage of CD34(+)/CD33(+) cells, defective granulocyte colony-forming unit (CFU-G) growth potential of BM mononuclear or purified CD34(+) cells, and low CFU-G recovery in long-term BM cultures (LTBMCs), compared with controls (n = 46). A low percentage of CD34(+)/CD33(+) cells in patients was associated with accelerated apoptosis and Fas overexpression within this cell compartment compared with controls.

Two patients with nonimmune chronic idiopathic neutropenia of adults developing acute myeloid leukemia with aberrant phenotype and complex karyotype but no mutations in granulocyte colony-stimulating factor receptor.

It has been suggested that some cases of nonimmune chronic idiopathic neutropenia of adults (NI-CINA) may be considered preleukemic disorders. This paper describes two patients with NI-CINA who developed acute myeloid leukemia (AML) 34 and 64 months, respectively, following NI-CINA diagnosis. Patient 1 presented erythema nodosum and patient 2 polyarthritis of the large joints 9 and 2 months, respectively, before AML.

Anemia of chronic disease is the more frequent type of anemia seen in patients with chronic idiopathic neutropenia of adults.

This study describes the frequency and the type of anemia seen in patients with nonimmune chronic idiopathic neutropenia of adults (NI-CINA). We found that NI-CINA patients had low hemoglobin levels and increased serum concentrations of erythropoietin (EPO), tumor necrosis factor-alpha (TNF-alpha), and interleukin-1beta (IL-1beta). The hemoglobin levels correlated positively with the number of circulating neutrophils and inversely with the levels of EPO and TNF-alpha but not of IL-1beta.

Prevalence of chronic idiopathic neutropenia of adults among an apparently healthy population living on the island of Crete.

The aim of the present study was to investigate the prevalence of chronic idiopathic neutropenia of adults (CINA) among an apparently healthy population born and living on the island of Crete. The study was carried out with 778 subjects, 392 men aged 16-78 years (median 43 years) and 386 women aged 15-79 years (median 40 years). All were employees of the Medical School or the adjacent University hospital and members of their families.

Selective loss of peripheral blood CD45RO+ T lymphocytes correlates with increased levels of serum cytokines and endothelial cell-derived soluble cell adhesion molecules in patients with chronic idiopathic neutropenia of adults.

The present study was designed to investigate the hypothesis that selective loss of peripheral blood CD45RO+ T lymphocytes in patients with chronic idiopathic neutropenia of adults (CINA), previously reported from our laboratory, may be due to enhanced extravasation into the tissues. Serum levels of endothelial cell-derived soluble cell adhesion molecules (sELAM, sICAM and sVCAM), usually used as indicators of endothelial cell activation, were measured in 73 CINA patients and 32 healthy volunteers using a micro-ELISA method. We found that patients had markedly elevated concentrations of all three soluble cell adhesion molecules studied compared to the controls, and serum levels of sELAM, sICAM and, more importantly, sVCAM correlated inversely with the numbers of both CD4+/CD45RO+ and CD8+/CD45RO+ T cell subsets.

Defective natural killer cell activity of peripheral blood lymphocytes correlates with the degree of neutropenia in patients with chronic idiopathic neutropenia of adults.

Natural killer cell activity (Nka) of peripheral blood mononuclear cells (PBMCs) against K562 cell targets was assessed in 66 patients with chronic idiopathic neutropenia of adults (CINA) using the 16-h 51Cr-release assay. It was found that CINA patients exhibited significantly lower Nkr than normal subjects, which strongly correlated with the degree of neutropenia and the numbers of circulating neutrophils. Patients' NKa was increased by recombinant human interleukin-2 (rhIL-2) or recombinant human interferon-alpha (rhIFN-alpha), but the values obtained did not reach the respective NKa values found in normals.

Impaired release of natural killer cytotoxic factor(s) by peripheral blood lymphocytes in patients with chronic LGL-proliferative disease.

Background: Chronic LGL-proliferative disease (LGL-PD) is a clonal expansion of cells with large granular lymphocyte (LGL) morphology. In most cases, proliferating cells express both suppressor/cytolytic T-cell and natural killer (NK) cell surface markers, but other cell phenotypes may be observed. LGL-PD lymphocytes have been found to lack or show very low natural killer cell activity (NKa).