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Biomedical subjects

A Najman

Publications and source records attributed to A Najman.

At least 55 records · Page 3Linked to original sources
PubMed1993

Characterization and functional analysis of adult human bone marrow cell subsets in relation to B-lymphoid development.

To study the frontiers between pluripotent stem cells and committed progenitors and to further define the B-cell pathway in adult bone marrow (BM), CD34+ subpopulations and CD34- B-lineage cells were analyzed by multiparameter flow cytometry, studied by light and electron microscopy, and in short-term and long-term cultures (LTC). While the total CD34+ cells represent 4.9% +/- 0.8 of BM mononuclear cells within the lymphoid-blast window, 73.8 +/- 3.5%, 14.4 +/- 1.8% and 8.8 +/- 2.9% of them were CD34+ CD10- CD19-, CD34+ CD10+ CD19+, and CD34+ CD10+ CD19-, respectively. CD34+ CD10+ CD19+ cells represent a smal homogeneous TdT4 c micro-blast population. Although expressing CD38 and high level of HLA-DR antigens, like myeloid committed progenitors, they did not generate LTC, myeloid, and T lymphoid colonies suggesting that the CD34+ CD10+ CD19+ population represents exclusively B lymphoid committed progenitors. By contrast, all myeloid progenitors and LTC-initiating cells were found in the CD34+ CD10- CD19- cell fraction. This fraction appeared more heterogeneous and contained CD38- HLA-DRlow small cells, larger blasts, and promonocyte-like cells exhibiting small peroxidase-positive granules. Interestingly, CD10 was also present on CD34+ CD19- cells. This population mainly coexpressed CD33 and gave rise to macrophagic colonies.

Adult↗
PubMed1993

[Inflammatory hyposideremic anemia].

Inflammatory low iron is the second cause, after true iron deficiency, of acquired anaemia. It is mainly due to insufficient erythropoiesis resulting from inhibition of the erythroid progenitor and to disturbances in the synthesis and action of erythropoietin. These changes seem to be dependent on factors, such as TNF-alpha, interleukin-1 and interferon-gamma, which are released in inflammatory processes. Alterations in iron metabolism seem to be secondary, but also partly provoked by the same inhibitory agents. All these anaemias share a common character, i.e. lowering of serum iron level without increase of transferrin level, while plasma ferritin level is within normal limits. In addition to symptomatic therapy by red cell transfusions, numerous trials have shown that recombinant erythropoietin is effective in the treatment of the anaemia that accompanies cancers, chronic inflammatory and rheumatic diseases and of the anaemia provoked by HIV infection.

Anemia, Hypochromic↗
PubMed1993

Unstable alpha-chain hemoglobin variants with factitious beta-thalassemia biosynthetic ratio: Hb Questembert (alpha 131[H14]Ser-->Pro) and Hb Caen (alpha 132[H15]Val-->Gly).

Hb Questembert [alpha 131(H14)Ser-->Pro] was found in several members of a French family suffering from congenital Heinz body anemia. The unstable hemoglobin was expressed in the peripheral red blood cells at a very low level. Globin biosynthetic studies revealed a high specific activity of the abnormal chain and an alpha-/beta-labeling ratio similar to that of beta-thalassemia trait. Hb Caen [alpha 132(H15) Val-->Gly] is another unstable variant with the same globin biosynthesis abnormality. In both cases the structural modification is localized at the end of the H helix, a region encoded by the third exon. The mechanism for the unbalanced globin synthesis is not yet clear. It may be related 1) to a defect in chain assembly, 2) to an increased rate of degradation of the variant chain followed by the release of unlabeled beta-chains from the abnormal hemoglobin, thus leading to an apparent suppression of beta-chain synthesis, or 3) to a modified stability of the abnormal alpha-globin mRNA.

Adult↗
PubMed1993

The tetrapeptide AcSerAspLysPro (Seraspenide), a hematopoietic inhibitor, may reduce the in vitro toxicity of 3'-azido-3'-deoxythymidine to human hematopoietic progenitors.

3'-azido-3'-deoxythymidine (AZT), the main antiviral drug used in AIDS treatment, is known to induce anemia and neutropenia. These effects have been attributed to its toxicity to hematopoietic progenitors. In this report, we present a new approach to reduce AZT hematotoxicity by using an inhibitory factor of the hematopoietic stem cells, the tetrapeptide AcSerAspLysPro (AcSDKP, Seraspenide), which has been shown to increase the survival of mice subjected to high doses of chemotherapy and to block reversibly the cycling of human granulocyte-macrophage colony forming unit (CFU-GM) and burst forming unit erythroid (BFU-E) progenitors. Normal bone marrow mononuclear cells (BMMNC) from 14 subjects were incubated with or without AcSDKP (10(-10) M) for 20 h and with or without AZT (100 microM) for another 2 h. After washing, cells were plated in methylcellulose in the presence of interleukin 3 (IL-3), granulocyte-macrophage colony stimulating factor (GM-CSF) and erythropoietin (EPO). Under these conditions, the preincubation of cells with AcSDKP reduced significantly the toxicity of AZT to both BFU-E and CFU-GM at least in 3 out of 8 and 4 out of 10 cases, respectively. A careful statistical analysis of these observations indicates that AcSDKP may be an efficient factor in preserving progenitors against AZT-induced hematopoietic toxicity.

Amino Acid Sequence↗
PubMed1993

Autologous bone marrow transplantation with marrow purged by mafosfamide in seven patients with myelodysplastic syndromes in transformation (AML-MDS): a pilot study.

Seven patients with acute myeloblastic leukemia (AML) occurring on myelodysplastic syndromes (MDS) were consolidated while in complete remission (CR) by autologous bone marrow transplantation (ABMT) with a marrow purged in vitro by mafosfamide. The median age of population was 44 years (range 39-55). MDS FAB diagnosis was established before progression to AML in five patients: refractory anaemia with excess of blast (RAEB) in three patients, RAEB in transformation (RAEB-t) in one patient, and chronic myelomonocytic leukemia (CMML) in one patient. In the remaining two patients, the diagnosis of MDS (as a secondary malignancy in one) was made retrospectively at time of overt AML. Three out the seven patients had karyotypic abnormalities. The median interval between the obtention of CR and ABMT was 7 months (range 6-18). One patient died from transplant related toxicity. Engraftment occurred at a median of 41 days (range 27-60), for white blood cells (> 10(9)/l) and 120 days (range 60-180) for platelets (> 50 x 10(9)/l). Four patients relapsed at 2.5, 6.8, and 25 months post-ABMT. Two patients are alive and well at 10 and 28 months, respectively. ABMT with marrow purged by mafosfamide is feasible in patients with AML following MDS with a prospect of cure. However, further studies are needed to assess the real value of this approach.

Adult↗
PubMed1993

Long-term effects of recombinant human erythropoietin on bone marrow progenitor cells.

Eleven uraemic patients were treated with recombinant human erythropoietin (rHuEpo). Seven haemodialysis patients and four peritoneal dialysis patients received a starting dose of 80 IU/kg i.v. and 40 IU/kg s.c. respectively, thrice weekly. The number of burst-forming-unit erythroid (BFU-E), colony-forming-unit erythroid (CFU-E), granulocyte-monocyte (CFU-GM) and megakaryocyte (CFU-Mk) were assayed 2 weeks before (D0), and 1 (M1) and 6 months (M6) after the initiation of rHuEpo treatment by means of a commonly applied in-vitro clonal assay. All the patients showed the same haematopoietic response. A significant increase of CFU-E and CFU-Mk could be observed within 1 month of treatment. At this time, no significant modification was observed in BFU-E and CFU-GM number. At the 6th month the increase of CFU-E was maintained, whereas a significant fall of BFU-E, CFU-GM and CFU-Mk was observed. These results suggest that in-vivo effects of rHuEpo are not restricted to the erythroid lineage but that erythropoietin might also act as a co-factor of megakaryopoiesis. In the long term erythropoietin might induce erythroid differentiation in multipotent progenitor cells at the expense of the non-erythroid progenitors.

Adult↗
PubMed1993

Multiple chromosome abnormalities in patients with acute leukemia after autologous bone marrow transplantation using total body irradiation and marrow purged with mafosfamide.

Cytogenetic follow-up studies such as those reported after allogeneic bone marrow transplantation are not available in patients submitted to an autologous bone marrow transplantation (ABMT). Of 114 patients with acute leukemia (69 acute myelocytic AML, 43 acute lymphocytic ALL, 2 undifferentiated) who underwent an ABMT in our institution in the period from February 1983 to December 1989, 66 had evaluable cytogenetic data post-transplant. They all received a pretransplant regimen consisting of cyclophosphamide (CY) and total body irradiation (TBI) followed by reinfusion of marrow purged with mafosfamide. Twenty patients showed chromosomal damage at some time; of these, six relapsed early post-ABMT, one died while in persisting remission at 81 months post-ABMT from overwhelming pneumococcal sepsis related to a previous splenectomy, and 13 are still alive and well at 13 to 88 months post-transplant. The bone marrow cytogenetic abnormalities were complex: they included various numbers of clonal aberrations or variations or combination of those; they affected all but the Y chromosome, with a predominance however for chromosomes 1, 3, 6, and 7; they were often transitory and in some instances became modified with time. None of these chromosomal abnormalities was connected with the initial leukemia, even in the 6 patients who relapsed early. In the other 14 patients, these abnormalities have so far had no detectable unfavourable implication. The origin of these abnormalities is unknown: both the pretransplant regimen (CY and/or TBI) and/or marrow purging with mafosfamide can be incriminated. Additional studies in patients autografted with pretransplant regimen not containing TBI and/or with unpurged marrow are necessary to discriminate between these two possibilities.

Antineoplastic Agents↗
PubMed1992

[Efficacy of danazol in autoimmune hemolytic anemia with cold agglutinins. 4 cases].

The treatment of haemolytic anaemia related to primary cold agglutinin disease is often unsatisfactory. Corticosteroids are not useful in most cases and, beside protection against cold, treatment is frequently limited to transfusions. We report the good results obtained with long-term danazol therapy (600 mg per day initially, than 400 mg per day) in 3 cases of chronic cold agglutinin disease and 1 case of idiopathic haemolytic anaemia with cold agglutinin in serum. The only side-effect was a transient increase of transaminase level requiring reduction of a maintenance dose which could be given during 3 to 7 years.

Adult↗
PubMed1992

Tumor necrosis factor alpha in human long-term bone marrow cultures: distinct effects on nonadherent and adherent progenitors.

Although tumor necrosis factor alpha (TNF alpha) exerts a variety of activities on hematopoietic cells, suggesting it may have some potential therapeutic applications, its long-term effects on hematopoiesis are not well defined. Therefore, we took the advantage of long-term bone marrow cultures (LTBMCs) to evaluate the long-term role of TNF alpha on both the microenvironment and the hematopoietic progenitors. LTBMCs were inoculated with 100 U/ml of recombinant human TNF alpha (rhTNF alpha) either at the onset of the cultures (d0) or at day 21 (d21) when the adherent layer (AL) was already established. Then TNF alpha was added at each weekly medium change. The cellularity and the content of progenitors in both the nonadherent layer (NAL) and AL, the formation of the AL, and the presence of various cytokines in the supernatants were examined weekly. The data showed 1) a strong and durable inhibitory effect on total nonadherent cells; 2) a rapid and transient inhibition of NA progenitors, whereas adherent progenitors were lately affected; and 3) microenvironmental changes consisting of the disappearance of adipocytes and the secretion of high levels of interleukin 6. The results suggest that the inhibitory effects of TNF alpha on the NAL are in part counterbalanced by stromal modifications that in turn lead to a faster exhaustion of hematopoiesis.

Bone Marrow↗
PubMed1992

Reversible inhibitory effects and absence of toxicity of the tetrapeptide acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) in human long-term bone marrow culture.

The effects of acetyl-N-Ser-Asp-Lys-Pro (Ac-SDKP) in human long-term bone marrow cultures (LTBMCs) were assessed by measuring the number of progenitors and the development of stromal cells over a 6-week course. In a first set of experiments, AcSDKP was added weekly at each medium change. Under these conditions, no significant effect of the peptide was observed. In contrast, by adding AcSDKP daily at 10(-10) M, the growth of the progenitors of the non-adherent (NA) compartment was inhibited by about 35%. This inhibition was entirely reversible; after stopping the addition of the peptide at the fourth week, the number of progenitors returned to control level within 2 weeks. Conversely, AcSDKP did not significantly change the number of the progenitors present in the adherent layer. In addition, AcSDKP did not affect the formation of the stromal layer nor induce the secretion of cytokines, such as tumor necrosis factor alpha (TNF-alpha), interleukin 1 beta (IL-1 beta), granulocyte colony-stimulating factor (G-CSF), interleukin 3 (IL-3), or interleukin 6 (IL-6). Our results indicate that AcSDKP has inhibitory but reversible effects on NA progenitors and does not induce long-term modifications of the microenvironment, both of particular interest for its clinical application.

Amino Acid Sequence↗
PubMed1992

The tetrapeptide AcSDKP, an inhibitor of the cell-cycle status for normal human hematopoietic progenitors, has no effect on leukemic cells.

The tetrapeptide acetyl-N-Ser-Asp-Lys-Pro (AcSDKP) inhibits the entry into DNA synthesis of murine spleen colony-forming units (CFU-S) and protects these cells during chemotherapy. This synthetic peptide also inhibits the growth of normal human marrow progenitors granulocyte-macrophage colony-forming units (CFU-GM) and erythroid burst-forming units (BFU-E) and decreases their percentage in DNA synthesis at nanomolar concentration. In view of its clinical application as a marrow protector, we have investigated its effects on malignant cells. Studies were carried out on HL-60 cells and on fresh leukemic cells from patients with either chronic myeloid leukemia (CML) or acute myeloid leukemia (AML). Results showed that AcSDKP, whatever the doses used, did not modify the proliferation of both HL-60 cells and AML cells even when enhanced by stimulating factors such as interleukin 3 or granulocyte-macrophage colony-stimulating factor (GM-CSF). In addition, no change in the number and the percentage in S-phase of both HL-60 clonogenic cells and CML progenitors was observed. Our data clearly demonstrate that the tetrapeptide AcSDKP was ineffective on leukemic cells and therefore by acting selectively on normal progenitors represents a potent therapeutical agent for the protection of normal bone marrow progenitors during chemotherapy.

Adult↗
PubMed1991

GM-CSF instead of autologous bone-marrow transplantation after the BEAM regimen.

Five patients with resistant non-Hodgkin lymphoma (NHL) were given granulocyte-macrophage colony-stimulating factor (GM-CSF, 250 micrograms/m2 daily) after the BEAM pretransplant chemotherapy regimen (carmustine 300 mg/m2, etoposide 1.2 g/m2, cytarabine 800 mg/m2, melphalan 140 mg/m2) because persistent lymphoma cell infiltration of the bone marrow precluded autologous bone-marrow transplantation (BMT). In three patients full haemopoietic reconstitution occurred, with similar kinetics to that seen after autologous BMT. The other two patients died without sustained haemopoietic recovery. GM-CSF may replace autologous BMT in highly selected cases of NHL with progressive disease and bone-marrow involvement.

Adolescent↗