bluuebunny/crossref_metadata_2025 huggingface dataset:
Biology of the hemopoietic microenvironment
Authors: Mayani Hector , Guilbert Larry J. , Janowska‐Wieczorek Anna
Published: July 2010

Abstract: In adult mammals, hemopoiesis takes place primarily in the bone marrow. The steady‐state production of blood cells depends to a large extent on the interaction between hemopoietic stem/progenitor cells (HPC) and the different components of the microenvironment present in the medullary cavity. During the last three decades, in vivo and in vitro studies have allowed significant advances in understanding of the biology of such a hemopoietic microenvironment. Although not evident in histological sections, it is well known that the hemopoietic microenvironment is a highly organized structure that regulates the location and physiology of HPC. The hemopoietic microenvironment is composed of stromal cells (fibroblasts, macrophages, endothelial cells, adipocytes), accessory cells (T lymphocytes, monocytes), and their products (extracellular matrix and cytokines). Microenvironmental cells can regulate hemopoiesis by interacting directly (cell‐to‐cell contact) with HPC and/or by secreting regulatory molecules that influence, in a positive or negative manner, HPC growth. Recent in vitro studies suggest that functional abnormalities of the hemopoietic microenvironment may be implicated in the manifestation of certain hematological disorders such as aplastic anemia, and acute and chronic myelogenous leukemia. Thus, the characterization of the structure and function of the human hemopoietic microenvironment may have relevance in understanding and treating different hematological disorders.
Therapeutic effect of heme arginate in myelodysplastic syndromes
Authors: Timonen T. T. T. , Kauma H.
Published: July 2010

Abstract: In order to investigate, whether heme would induce a response in myelodysplastic syndromes (MDS), 14 symptomatic patients (4 RA, 3 RARS and 7 RAEB) were treated with infusions of heme arginate 3 mg/kg body weight on 4 consecutive days, mostly for six cycles at 2‐week intervals. Three of 14 patients (21%) showed an improvement in anemia (97–152, 79–120 and 92–114 g/l) within a few weeks, and 1 showed a milder increase in hemoglobin level (102–118 g/l). Of the 2 responders with marked thrombocytopenia, 1 showed an improvement in the platelet count (7–37 × 109/l) and her regular need for red cell and platelet transfusions ceased. Some regression in bone marrow (BM) cytology was seen in all 3 responders. One of the responders is still in remission 41 months after cessation of the treatment, while in the other 2 the response lasted for 26 and 5 months. Four patients progressed during the treatment: 1 RA to RAEB, 1 RAEB to RAEBt and 2 RAEB, both with very complex chromosomal abnormalities at the beginning of the therapy, to acute erythroleukemia (AML‐M6). Pretreatment δ‐aminolevulinic acid synthase and heme synthase activities were generally low. Five patients had mild thrombophlebitis, but not after the infusion procedure was changed. No other side‐effects common to growth factors occurred. In conclusion, it is likely that heme arginate has a therapeutic effect on some MDS patients, obviously by stimulating erythropoiesis. The response may be long‐lasting.
TNF‐specific deactivation of granulocytes in vivo: A possible mechanism of self‐protection
Authors: Schleiffenbaum Boris , Olgiati Licia , Fehr Jorg
Published: July 2010

Abstract: Granulocytes (PMN) have recently been shown to be specifically deactivated towards tumor necrosis factor (TNF) by preexposure to TNF itself and to other stimuli such as endotoxin and complement C5a in vitro. When TNF (200 μg/m2) was infused to a male volunteer, we found ex vivo an almost complete TNF‐specific deactivation of PMN adhesion (57 ± 3* vs 6 ± 2%**), of exocytosis of secondary granules (37 ± 1* vs 7 ± 1%**) and of the respiratory burst as measured by hexose monophosphate shunt activation (74 ± 1* vs 12 ± 3** nM/107 PMN/45 min). Furthermore, up‐ and down‐regulation, respectively, of the PMN surface adhesion molecules Mac‐1 and LAM‐1 became TNF‐resistant. Similar to the results obtained in vitro, deactivation correlated with a decrease in the number of cellular TNF receptors. In PMN of 4 patients exposed to activated complement during hemodialysis, a state of TNF‐specific cross‐deactivation could also be demonstrated.
Serum transferrin receptor in the megaloblastic anemia of cobalamin deficiency
Authors: Carmel Ralph , Skikne Barry S.
Published: July 2010

Abstract: In order to further study the relation between transferrin receptor and erythropoiesis we examined serum receptor levels in megaloblastic anemia, which is the classic example of ineffective erythropoiesis. We studied 33 patients with unequivocal cobalamin deficiency, only 22 of whom were anemic. High serum transferrin receptor levels were found in 12 patients, all of whom were anemic and had high lactate dehydrogenase (LDH) levels; in contrast, only 10 of the 21 patients with normal receptor levels were anemic. Receptor correlated most strongly with LDH (r = 0.573, p<0.001) and, inversely, with hemoglobin values (r= ‐0.560, p<0.001); it also correlated with ferritin and total bilirubin levels, but not with cobalamin, MCV or erythropoietin. No association was found with the hemolytic component of megaloblastic anemia, represented indirectly by haptoglobin levels. Changes induced by cobalamin therapy were also examined in 13 patients. Transferrin receptors rose in all 6 patients who initially had high levels and in 2 of 3 patients who had borderline levels, but not in the 4 patients with initially normal levels. The receptor levels began to rise within 1–3 days, peaked at about 2 weeks and returned to normal at about the 5th wk. The findings indicate that serum transferrin receptor levels reflect the severity of the megaloblastic anemia. The elevated receptor levels rise further with cobalamin therapy, however, as effective erythropoiesis replaces ineffective erythropoiesis, and these persist until the increased erythropoiesis returns to normal.
Differential effects of granulocyte‐ and granulocyte‐macrophage colony‐stimulating factors (G‐ and GM‐CSF) on neutrophil adhesion in vitro and in vivo
Authors: Yong Kwee L. , Linch David C.
Published: July 2010

Abstract: A direct comparison of granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) and granulocyte colony‐stimulating factor (G‐CSF) effects on neutrophil adhesiveness has been carried out. In vitro, GM‐CSF and G‐CSF upregulate neutrophil CD11b to a similar degree (to 227 ± 69%, and 232 ± 70% of control cells, respectively, p< 0.0005), but GM‐CSF is more effective in downregulating neutrophil leucocyte adhesion molecule‐1 (LAM‐1), reducing levels to 33 ± 4% (p< 0.0005), while G‐CSF causes a fall to only 65 ± 17% (p<0.005) of control. The concentration of GM‐CSF needed to achieve maximal activity is at least one log less than that of G‐CSF. In vivo, both GM‐CSF and G‐CSF upregulate neutrophil CD11b (to 296 ± 45% and 370 ± 150%, respectively of baseline), but surface levels of LAM‐1 on circulating cells are unchanged. GM‐CSF increased neutrophil adhesion to cultured human endothelium in vitro (from 9.3 ± 0.7% to 15.4 ± 1.3%, p<0.0005, n = 10), while G‐CSF was without effect. In vivo, both GM‐CSF and G‐CSF produce a transient leucopenia, but recovery of peripheral counts occurs much earlier (by 60 minutes) with G‐CSF, than with GM‐CSF (only 50% of cells have demarginated at 120 min). GM‐CSF appears to be greater proadhesive agonist for neutrophils than G‐CSF.
Red cell and plasma ferritin in a group of normal fetuses at different ages of gestation
Authors: Carpani Giovanni , Marini Fabrizio , Ghisoni Luciano , Buscaglia Mauro , Sinigaglia Elisabetta , Moroni Gianalessandro
Published: July 2010

Abstract: Plasma and cell ferritin were determined in 47 normal fetuses at different gestational ages in order to evaluate fetal iron status. Plasma ferritin shows an increase during pregnancy (17.7 μg/l — mean geometrical value of fetuses between 18 and 20 weeks; 56.8 μg/l mean geometrical value of fetuses between 32 and 35 wk) and significantly correlates to hemoglobin and number of red blood cells. Red cell ferritin, too, increases throughout pregnancy (from 92.7 ag/cell to 265 ag/cell) and shows a better correlation to hemoglobin and number of red blood cells. Experimental evidence has been provided showing that the placenta takes up ferritin and is important in iron storage and transport (even against a concentration gradient). Our data support this theory and suggest a situation of positive balance between iron uptake and utilization during intrauterine life.
Expression and function of β‐adrenergic receptors in human hematopoietic cell lines
Authors: Maki T. , Andersson L. C. , Kontula K. K.
Published: July 2010

Abstract:We investigated the expression and functional characteristics of β‐adrenoceptors in a panel of 10 phenotypically different human hematopoietic cell lines. A binding assay with [125I]iodocyanopindolol as the ligand revealed that cell lines of myelomonocytic or histiocytic derivation (HL‐60, ML‐2, RC‐2A, U‐937) expressed high numbers of β‐adrenoceptors. An intermediate density of receptors was found in a non‐T, non‐B cell leukemia line (Nall‐1), whereas T‐cell (JM, CCRF‐CEM), B‐cell (Raji) or erythroleukemic cell lines (K‐562, HEL) displayed minimal or undetectable binding of the radioligand. Isoprenaline‐stimulated cAMP production by the cells correlated to their extent of β‐adrenoceptor expression. Southern blot hybridization analysis of genomic DNA from the cell lines with a32P‐labelled β2‐adrenoceptor cDNA probe revealed no evidence for major rearrangement or amplification of the receptor gene. Incubation with isoprenalinein vitrosuppressed the proliferation of the receptor‐rich RC‐2A cells but did not affect the growth rate of the receptor‐deficient K‐562 cells. Treatment with propranolol slightly enhanced the proliferation of the RC‐2A cells but did not markedly alter the growth rate of two other cell lines, regardless of their β‐adrenoceptor status. These findings indicate a regulatory influence by the sympathoadrenergic system on selected cells of the myelomonocytic lineage.
Detection of the prethrombotic state due to procoagulant imbalance
Authors: Mannucci P. M. , Giangrande P. L. F. , Bonomi A. Bianchi
Published: July 2010

Abstract: We have reviewed the laboratory methods used to diagnose the prethrombotic state, defined as a procoagulant imbalance between the production and inhibition of enzyme activity in the coagulation pathway short of fibrin deposition. One diagnostic approach is that of measuring the plasma levels of activation peptides which are released from the zymogens of the coagulation cascade when they are activated. Another approach is that of measuring the plasma levels of complexes formed in plasma when enzymes of the coagulation cascade are neutralized by their naturally‐occuring inhibitors such as thrombin‐antithrombin complex. The clinical usefulness of these methods still needs to be defined with prospective studies.
Bolus therapy with mitoxantrone and vincristine in combination with high‐dose prednisone (NOP‐bolus) in resistant multiple myeloma
Authors: Wislsff Finn , Gimsing Peter , Hedenus Michael , Hippe Erik , Palva Ilmari , Talstad Ingebrigt , Turesson Ingemar
Published: July 2010

Abstract:In a phase II study, 58 patients with resistant multiple myeloma (MM) were treated with a combination chemotherapy (NOP‐bolus regimen) consisting of mitoxantrone (16 mg/m2for the first 25 patients and 12 mg/m2for the subsequent 33), vincristine (2 mg), both as bolus injections on day 1 and prednisone (250 mg/d on d 1–4 and 17–20). In patients > 70 years of age, the mitoxantrone dose was reduced to 12 mg/m2or 8 mg/m2, respectively. The treatment was repeated every 4 weeks. A response (>50% reduction in M component) was obtained in 26% of the patients and a minor response (clinical improvement but <50% reduction in M component) in another 21%. Median response duration was 27 wk and median survival for all patients was 25 wk. There were no differences in response rate or duration between patients receiving the high or low mitoxantrone dose, but patients in the low‐dose group had fewer serious infections.
Long‐term survival in acute lymphoblastic leukaemia in adults
Authors:   Finnish Leukaemia Group
Published: July 2010

Abstract: Between November 1983 and January 1987, 51 consecutive previously untreated adults below 65 years of age were treated for acute lymphoblastic leukaemia with LI or L2 morphology. Induction regimen for the first 15 patients consisted of 4 weekly doses of doxorubicin and vincristine, and of asparaginase and prednisolone. Two more doses of doxorubicin and vincristine were given for refractory disease. Next 36 patients received in addition cyclophosphamide on day 1. Consolidation comprised 17 rotating cycles of three regimens. Three intensification cycles were given, and maintenance treatment lasted until 3 years, or relapse. Median follow‐up time for living patients is 62 months. 82% of the patients achieved remission. Median relapse‐free survival (RFS) was 13 months, and 17% of the patients are in remission at 54 + to 80 + months. Age over 25 yr, a low white blood cell (WBC) count, and a low blast cell count were associated with a longer RFS. Median survival was 24 months, and 33% of the patients lived for 4 yr. Adverse prognostic factors were: age ≤25 of >45 yr, a high WBC count, and a high blast cell count. The results support the policy of concentrating more effort on the initial chemotherapy.
Biochemical characterization of size‐separated human red blood cells
Authors: Vaysse Jenny , Gattegno Liliane , Pilardeau Paul
Published: July 2010

Abstract: Human red blood cells (RBC) are heterogeneous with respect to their size; the physiological significance of this heterogeneity has not yet been fully elucidated. To further investigate this problem, some characteristics of human RBC fractionated according to their mean corpuscular volume (MCV) by counterflow centrifugation were determined. Larger RBC are more prone to hypotonic lysis. The membrane protein content per cell increases with the MCV, but no obvious difference in the distribution of the major proteins can be demonstrated. The lipid content per cell also rises with the RBC size, while the percentages of the main lipid components do not significantly vary. However, the variations of sialic acid content per RBC according to MCV are more important than those of protein or lipid; thus, the sialic acid‐to‐protein ratio gradually increases with the MCV. This indicates that, in spite of the lack of major changes in the membrane composition, some qualitative differences exist between large and small cells.
Overexpression of multidrug resistance‐associated p170‐glycoprotein in acute non‐lymphocytic leukemia
Authors: Michieli Mariagrazia , Damiani Daniela , Geromin Antonella , Michelutti Angela , Fanin Renato , Raspadorl Donatella , Russo Domenico , Visani Giuseppe , Dinota Angelo , Pileri Stefano , Tsuruo Takashi , Grandi Maria , Baccaranl Mlchele , Tura Sante
Published: July 2010

Abstract: Resistance to several cytotoxic agents, including anthracyclines, vinca alkaloids and epipodophylline derivatives (multidrug resistance, or MDR) can develop in tumor cells by overexpression of a 170‐kd glycoprotein (p170) which is an essential component of a membrane transport system leading to increased drug efflux and decreased intracellular drug concentration. By means of a p170‐directed monoclonal antibody (MRK‐16) and immunocytochemistry (alkaline phosphatase anti‐alkaline phosphatase technique), we investigated the expression of p170 in marrow blast cells of 59 cases (38 at diagnosis and 21 in relapse) of acute‐non‐lymphocytic leukemia (ANLL). The proportion of strongly MDR‐positive cells was higher in relapse that at diagnosis (median 15.5% vs 1.5%). Out of 31 patients who were evaluable for the results of first remission induction, failure of first‐line treatment (including Daunorubicin, standard‐dose and high‐dose Arabinosyl Cytosine, and sometimes also Mitoxantrone) occurred in 8/22 MDR‐positive cases and in 1/9 MDR‐negative ones (p = 0.21). Failure of first‐line treatment was always associated with a progressive increase of p170 expression. Total failures (no remission plus early relapse) were more frequent (p = 0.001) among MDR‐positive cases (16/22) than among the others (2/9). These data show that MDR is very frequent in ANLL also at diagnosis and suggest that MDR can contribute to early failure of standard treatment.
A prospective randomized comparison of single‐agent interferon (IFN)‐alpha with the combination of IFN‐alpha and low‐dose IFN‐gamma in chronic myelogenous leukaemia
Authors: KIoke O. , Wandl U. , Opalka B. , Moritz T. , Nagel‐Hiemke M. , Franz T. , Becher R. , Hirche H. , Seeber S. , Niederle N.
Published: July 2010

Abstract: In patients with previously untreated chronic myelogenous leukaemia (CML) the efficacy of single‐agent interferon (IFN)‐alpha at an initial dose of 4 times 106 U/m2 (arm A) was compared with the combined administration of the identical dose IFN‐alpha plus a total dose of 50 μg IFN‐gamma (arm B). 51 patients entered this study between April 1987 and October 1989; the analysis was performed in March 1991 and was focused on response rates and toxicity. 54% of patients on arm A and 56% of arm B patients attained haematologic remission. 29% of patients on arm A and 24% of arm B patients had partial haematologic remission. A decrease in Philadelphia chromosome (Ph)‐positive metaphases of more than 10% was only seen in patients who had achieved complete haematologic normalization. In 21% of patients on arm A and 20% of arm B patients, the percentage of Ph‐positive cells declined to less than 35%. Toxicity was different between the two study groups with more pronounced hepatotoxicity observed in patients treated with IFN‐alpha alone. Among the patients receiving both IFNs, alpha and gamma, there were 2 fatal infectious complications. This serious toxicity in conjunction with lack of a clinically meaningful difference between the two treatment schedules has led us to terminate the study. In conclusion, the addition of low‐dose IFN‐gamma failed to improve the efficacy of IFN‐alpha in this study.
Immune responses and serum levels of cytokines in adult T‐cell leukemia patients and human T‐cell leukemia virus type‐I carriers
Authors: Nakasone Tadashi , Araki Koichi , Masuda Masato , Oshiro Kazuiku , Arakaki Hitoshi , Shimoji Tadao , Shinzato Osamu , Mimura Goro
Published: July 2010

Abstract: To find predictive parameters for development and progression of adult T‐cell leukemia (ATL) in human T‐cell leukemia virus type‐I (HTLV‐I) carriers, we investigated cellular immune responses such as mitogenic responses and natural killer activity of the peripheral blood mononuclear cells (PBMC). And serum or plasma levels of cytokines, including tumor‐necrosis factor‐α (TNF‐α), interferon‐γ (IFN‐γ) and immunosuppressive acidic protein (IAP), were also measured in patients with ATL, healthy HTLV‐I carriers and healthy HTLV‐I non‐carriers as controls. Results are as follows:

(1) increased spontaneous proliferation and decreased mitogenic responses of PBMC already existed in HTLV‐I carriers;

(2) IAP was significantly higher in patients with acute/lymphoma type ATL than in those with chronic/smoldering type, HTLV‐I carriers and HTLV‐I non‐carriers. These results suggest that spontaneous proliferation or mitogenic responses and IAP may be useful parameters for the development and progression of ATL from the carriers.

Since HTLV‐I carriers already have various grades of immunosuppression, we should seriously try to prevent further HTLV‐I transmission.
High‐dose mitoxantrone and etoposide conditioning in autologous bone marrow transplantation for relapsed Hodgkin's disease
Authors: Lim S.H. , Baglin T.P. , Flavell D. J. , Flavell S. U. , Wimperis J. Z. , Marcus R. E.
Published: July 2010

Abstract: We administered high‐dose mitoxantrone in combination with etoposide to 6 patients with relapsed Hodgkin's disease as the conditioning regimen for autologous bone marrow transplantation. This regimen was well tolerated and no significant cardiotoxicity was observed. Responses of the Hodgkin's disease to this therapy were favourable but short‐lived. Serial measurements of the serum levels of mitoxantrone suggested an open 3‐compartment model of drug distribution. The rapid early phase of drug distribution was followed by an intermediate phase and a slow terminal drug‐elimination phase. However, mitoxantrone was still detected in the serum of all patients 7 days after the last dose of mitoxantrone and on the day of bone marrow re‐infusion. The clinical significance of such findings is unclear but they may suggest a need for the use of other anthracycline‐related cytotoxic agents for the conditioning in autologous bone marrow transplantation.
Origin of mutation in sporadic cases of haemophilia‐B
Authors: Kling Stefan , Ljung Rolf , Sjorin Elsy , Montandon Jane , Green Peter , Giannelli Francesco , Nilsson Inga Marie
Published: July 2010

Abstract: Of the 45 haemophilia‐B patients registered at the haemophilia centre in Malmo, Sweden, 24 are the sole members of their families to be affected, and in 13 of these 24 cases, ascendant relatives are available for study. Detection of the gene defect showed the mutation to be de novo in the proband in 3 of these 13 cases, and inherited from a carrier mother in the remaining 10 cases. All 10 carrier mothers were shown to have de novo mutations, as the patients' grandfathers were phenotypically and/or haematologically normal, and the grandmothers were non‐carriers. Seven restriction fragment length polymorphisms (RFLPs) of the factor IX gene were used to determine whether the de izovo mutations of the 10 carrier mothers were of paternal or maternal origin. In 6/10 cases, the RFLP patterns were informative, and indicated the mutation to be of paternal origin.
A novel deletion of FVIII gene associated with variable levels of FVIII inhibitor*
Authors: Figueiredo Mauro Silverio , Bernardi Francesco , Zago Marco Antonio
Published: July 2010

Abstract: We describe a novel gross deletion of the factor VIII gene in 5 related patients with severe hemophilia A. The deletion extends from intron 15 to at least 8.5 kb beyond the 3′ end of the gene (at least 95 kb of extension), and is associated with variable levels of FVIII inhibitor in 4 of the patients. The carrier detection in the family was based on the abnormal restriction pattern of the partially deleted gene.
Demonstration of Ph1‐negative host haemopoietic progenitor cells in an allogeneic marrow transdant recbient with chronic myelocytic leikaernia;sing polymerase chain reaction
Authors: Chuhjo Tatsuya , Nakao Shinji , Ohtaguro Mamiko , Nakatsumi Tomoko , Niki Takeo , Tsuchiya Haruo , Shiobara Shintaro , Mori Takao , Matsuda Tamotsu
Published: July 2010

Abstract: In an attempt to characterize host‐derived haemopoietic cells in mixed haemopoietic chimeras, we studied bone marrow cells from male patients with chronic myelocytic leukaemia (CML) transplanted with marrow grafts from female donors. Amplification of a Y chromosome‐specific sequence (YDNA) in DNA from marrow mononuclear cells using polymerase chain reaction (PCR) revealed persistence of host cells in 2 of 3 patients studied. On the other hand, persistence of Phl‐positive cells was unable to be demonstrated in the marrow cells from these patients using reverse transcription PCR (RT‐PCR) for detecting bcr‐abl chimeric messenger RNA. RT‐PCR sensitivity for detecting minimal Phl‐positive cells in a background of Ph1‐negative cells proved better than that of the PCR for detecting male cells among female cells. When bone marrow progenitor cells from one of the documented mixed chimeras were analyzed after an in vitro colony assay using PCR, 2 of 12 erythroid burst‐forming units (BFU‐E) proved to be YDNA‐positive, i.e., of host origin, whereas none of them was shown to be Ph1‐positive, although 12 BFU‐E analyzed in the marrow cells obtained pretransplant from the same patient were all YDNA‐ and Phl‐positive. These findings indicate that, in some marrow transplant recipients with CML, a small number of host‐derived normal haemopoietic progenitor cells may persist following lethal chemoradiotherapy and allogeneic bone marrow transplantation despite the fact that Phl‐positive clones can be eradicated.
Erythropoietin levels in cobalamin deficiency: Comparison of anemic and non‐anemic, subtly deficient patients
Authors: Carmel Ralph , MacPhee Robert D.
Published: July 2010

Abstract: The major stimulus for eythropoietin secretion is the circulating hemoglobin level, but other poorly understood factors appear to influence the erythropoietin level as well. Therefore, the effect of cobalamin deficiency was studied in patients who were not anemic, even though many of them had macrocytosis or metabolic deficiency of the bone marrow cells. All 15 cobalamin‐deficient patients without anemia had normal erythropoietin levels, including the 4 patients with macrocytosis and 3 in whom metabolic cobalamin deficiency of the marrow cells was documented with the deoxyuridine suppression test. Moreover, among 21 cobalamin‐deficient patients with anemia, the 4 least anemic patients also had normal erythropoietin levels. The other 17 anemic patients had elevated erythropoietin levels. Erythropoietin levels correlated with the severity of the anemia (r = 0.423, p<0.05). However, wide individual variations were observed; 4 patients with hemoglobin levels of 37–43 g/l had erythropoietin levels ranging from 69 to 3300 units/l, for example. These observations support the hypothesis that the hemoglobin level is the major, but not the sole factor that determines erythropoietin levels. As long as it does not produce anemia, however, cobalamin deficiency does not raise erythropoietin levels even when it induces metabolic deficiency of the bone marrow and macrocytosis.
Dysplastic peripheral blood polymorphs link acute myeloblastic leukaemia in elderly to the mvelodvsdastic Syndromes
Authors: Hast Robert , Widell Susanne
Published: July 2010

Abstract: We studied dysplastic features in peripheral blood polymorphs from 80 patients with acute leukaemia. Thirty‐seven patients with de novo acute myeloblastic leukaemia (AML) were compared to 26 patients with AML that had developed after a myelodysplastic phase (MDS‐AML), and 17 cases of acute lymphoblastic leukaemia (ALL). Cytoplasmic hypogranulation in neutrophils, measured as a score value (G‐score; normal range: 255–300), and the percentage of pelgeroid polymorphs (ppp; normal range: 0–5%) were studied retrospectively by reviewing the diagnostic peripheral blood smears. The mean G‐score was decreased in MDS‐AML (178 ± 67.9), and in de novo AML (212 f 65.l), but not in ALL (275 ± 24.3). When de now AML patients were divided by age, the elderly (> 60 yr) had significantly (p = 0.0001) lower mean G‐score than the younger (<45 yr) ones; 156 ± 64.8 v 243 ± 41.4. This age‐related difference became accentuated when only patients with extreme hypogranulation (G‐score < 150) were studied. Elderly de now AML patients also had significantly (p = 0.0057) higher mean ppp. By studying the degree of polymorph dysplasia in the peripheral blood, it seems possible to identify a subset of dysplastic elderly AML patients, who might have passed a (preleukaemic) MDS phase unnoticed.
Epidemiology of thrombocytopenia in HIV inlection
Authors: Sloand Elaine M. , Klein Harvey G. , Banks Steven M. , Vareldzis Basil , Merritt Sheila , Pierce Phillip
Published: July 2010

Abstract: Thrombocytopenia is a known complication of human immunodeficiency virus Type‐I (HIV‐1) infection, and more data need to be collected on its frequency, severity, and clinical sequelae. We determined the frequency of thrombocytopenia and its relationship to other HIV infection characteristics from a review of records of 1004 HIV‐infected patients attending two outpatient clinics in Washington, D.C. The self‐reported sources of HIV‐1 exposure were male homosexual activity (68j, bisexual activity (10%), heterosexual activity (6%), and intravenous drug use (15%). Fifty‐nine percent of the individuals were white, 37% were black and 94% were male. Fifteen percent had AIDS. Thrombocytopenia occurred more frequently in subjects with AIDS (21.2%) than in HIV‐infected individuals who did not fit clinical criteria for AIDS (9.2%) (p<0.001). Patients with few CD4‐positive cells and an advanced stage of disease were more likely to have low platelet counts: 30% with an absolute CD4 cell count lower than 200/mm3vs 8 % with CD4 counts between 200 and 500 (p<0.00001), and 18.5yo with Stage IV disease compared to 7.6% in Stage I1 (p< 0.001) had platelet counts less than 150000/mm3. Thrombocytopenia was more frequent in white males and older subjects. Although subjects infected by heterosexual exposure had a lower frequency of thrombocytopenia, intravenous drug users and homosexual men exhibited similar frequencies of thrombocytopenia. Of all subjects with platelet counts less than 50000/mm3, 40% reported bleeding and 1 died of an intracranial hemorrhage. Thrombocytopenia occurs frequently in HIV‐infected people, primarily in those with AIDS, low CD4 cell numbers, and advanced stages of diseases
PML/RAR‐α rearrangement in acute promyelocytic leukaemias apparently lacking the t(15;17) translocation
Authors: Coco Francesco Lo , Diverio Daniela , D'Adamo Francesca , Avvisati Giuseppe , Alimena Giuliana , Nanni Mauro , Alcalay Myriam , Pandolfi Pier Paolo , Pelicci Pier Giuseppe
Published: July 2010

Abstract: Recent investigations have clarified some of the molecular mechanisms underlying the t(15;17) translocation specific for acute promyelocytic leukaemia (APL). Together with providing new insights into the pathogenesis of the disease, the identification of breakpoints within the RAR‐α and PML loci on chromosomes 17 and 15 has allowed a new relevant diagnostic tool for the recognition of this leukaemic form. We report the molecular characterization of 6 cases of acute myelogenous leukaemia (AML) in which a diagnosis of typical M3 by conventional morphocytochemistry (FAB criteria) was not accompanied by cytogenetic evidence of the specific t(15;17) aberration. DNA rearrangements were documented in all cases at the PML and RAR‐α loci. Moreover, in 4 cases also analysed by Northern blot hybridization, we could detect aberrant RAR‐α transcripts. These findings highlight the specificity of PML/RAR‐α rearrangements in APL, whereas the lack of t(15;17) may be attributed to sub‐microscopic translocations as well as to the presence of non‐neoplastic cells undergoing mitosis in the samples examined for karyotype.
DDAVP‐induced enhancement of platelet retention: Its dependence on platelet‐von Willebrand Factor and the platelet receptor GP IIb/IIIa
Authors: Lethagen S. , Nilsson I. M.
Published: July 2010

Abstract:Although DDAVP has been shown to be haemostatically efficacious in patients with various congenital or acquired platelet disorders, no reasonable explanation has been found for this effect. We have previously shown DDAVP to increase platelet adhesiveness as measured with a platelet retention test. The aim of the present study was to investigate the mechanism of action responsible for the increased platelet retention in response to DDAVP. Patients with vWD type III and type Ia, severe haemophilia and severe thrombasthenia, as well as healthy controls, were included in the study. The effect of different concentrations of vWF in plasma and platelets was explored, as was the effect on platelet function of apyrase and monoclonal antibodies against GP IIb/IIIa and GP Ib. We found the effect of DDAVP on platelet retention to be unaffected by changes in the plasma concentration of vWF. The enhanced platelet retention after DDAVP is apparently dependent on the presence of platelet‐vWF and on a normal function of the GP IIb/IIIa. The effect is not mediated via ADP or thrombin. The platelet‐stimulating effect of DDAVP may be one explanation for the positive haemostatic effect in patients with certain platelet disorders.
Suspected distinct activation pathways of human lymphocytes induced by antilymphocyte globulin and anti‐CD 3 monoclonal antibody result in different secretion of hematopoietic colony‐stimulating activities
Authors: Kawano Yoshifumi , Takaue Yoichi , Takeda Eiji , Hirao Atsushi , Saito Shin‐ichi , Sato Junko , Abe Takanori , Shimizu Takeshi , Gratwohl Alois , Nissen Catherine , Speck Bruno , Kuroda Yasuhiro
Published: July 2010

Abstract: We evaluated the activation sequence of peripheral blood lymphocytes from healthy donors using different mitogens, including antilymphocyte globulin (ALG), antLCD3 monoclonal antibody (OKT3), and phytohemagglutinin (PHA). Blood mononuclear cells stimulated by ALG, OKT3 and PHA incorporated 3H‐thymidine in the same way. When enriched T cells were tested in the presence of interleukin‐lα (0 to 100 Ujml), incorporation of 3H‐thymidine was greater in those cells stimulated by ALG than by PHA. OKT3 did not activate enriched T cells. Thymidine incorporation was reduced to less than 50% of maximum concentrations by the addition of 10‐7 mol/1,25‐dihydroxyvitamin D3 (vit D3) in PHA‐ or OKT3‐activated cells. However, the inhibitory effect of vit D3 was not apparent in ALG‐activated cells. Production of granulocyte‐macrophage colony‐stimulating factor and interleukin‐3 by lymphocytes upon activation was consistently higher when cells were treated with ALG or PHA than with OKT3. Taken together, the data indicate that there appear to be distinct functional mechanisms between ALG‐ and OKT3‐induced lymphocyte activation that lead to characteristic immunohematologic events.
Neutrophil kinetics shortly after initial administration of recombinant human granulocyte colony‐stimulating factor: Neutrophil alkaline phosphatase activitv as an endorrenous marker
Authors: Katoh Masako , Shirai Tatsuo , Shikoshi Ken , Ishii Makoto , Saito Masaki , Kitagawa Seiichi
Published: July 2010

Abstract: Recombinant human granulocyte colony‐stimulating factor (rhG‐CSF) was administered (1.5 pg/kg body weight) subcutaneously once daily for 5 to 9 days to 5 patients with malignant lymphoma. In all patients, initial administration of rhG‐CSF induced a rapid fall in the neutrophil count within 30 minutes, followed by a recovery and an increase in the neutrophil count within 150 min. A rapid fall in the neutrophil count was accompanied by increased expression of neutrophil C3bi‐receptors, and neutrophils left in the circulation had lower activity of neutrophil alkaline phosphatase (NAP) and phagocytosis. A decrease in the NAP scores observed at 30 min reflected a preferential decrease of neutrophils with high NAP activity. A recovery and an increase in the neutrophil count were accompanied by a further decrease of NAP scores, which was caused by a preferential increase of neutrophils with lower NAP activity. The NAP scores of mature neutrophils from peripheral blood were not affected by in vitro treatment of cells with rhG‐CSF for up to 150 min at 37 °C. These findings and the previous observations that neutrophils in the circulating and marginal pools have high NAP activity and neutrophils in the bone marrow pool have low NAP activity taken together suggest that, following initial administration of rhG‐CSF, functionally active neutrophils leave the bloodstream preferentially, which is primarily followed by an influx of neutrophils from the bone marrow, but not by demargination of sequestered neutrophils.
Investigation of how different filters affect some biochemical properties of stored platelet concentrates
Authors: Jaremo P. , Kutti J.
Published: July 2010

Abstract: The aim of the present study was to investigate how four different filters, i.e. Imugard IG500 (Terumo, Japan), Miropore (Miramed, Italy), Pall P1‐100 (Pall, USA) and Sepacell P1‐10A (Asahi, Japan) affect some biochemical properties of platelet concentrates. The work was conducted using 42 pairs of platelet Concentrates. After 2 days of storage, one of the preparations was filtered and the other served as an unfiltered control. Immediately after filtration, determination of the platelet count, desarginated activated complement factor 3 (C3a des arg) and the extracellular and total concentrations of platelet factor 4 (PF4) and lactate dehydrogenase (LDH) were carried out on both these platelet concentrates. After an additional storage period of 3 d, extracellular concentrations of PF4 and LDH were determined on both concentrates. A significant decrease of extracellular PF4 concentration was found immediately after filtration when Pall P1‐100 and Imugard IG500 were used. During the 3‐d storage after filtration, the concentrates filtered with Imugard IG500 and Pall P1‐100 demonstrated significantly higher platelet lysis as compared to the unfiltered controls. It is concluded that the present work demonstrates storage instability after filtration with Imugard IG500 and Pall P1‐100. Therefore, platelet concentrates filtered with these filters would not appear to be suitable for storage.
Modification of human long‐term bone marrow cultures: Establishment of a functional stromal microenvironment devoid of myeloid progenitors
Authors: Moreau Isabelle , Andreoni Christine , Caux Christophe , Saeland Sem , Rigal Dominique
Published: July 2010

Abstract: Differences in the plastic adhesive properties of bone marrow (BM) cells were used to initiate modified stromal layers (MSL) from long‐term cultures by removing non‐adherent cells shortly (4 to 18 hours) after initial seeding. Following this early modification, adherent cells generated a confluent layer after 21 days of culture. Cellular characteristics of volume and spontaneous fluorescence determined by flow cytometry showed that the MSL included 82% fibroblastic stromal cells, 8% macrophages and 10% myelomonocytic cells. Furthermore, clonogenic assays revealed that the MSL were devoid of hematopoietic progenitor cells. MSL were found to sustain long‐term myelopoiesis for at least 7 weeks from exogenously added hematopoietic progenitors isolated from bone marrow (CD34+ cells), thereby demonstrating their functionality. The present experimental model appears of interest for the study of interactions between defined populations of hematopoietic cells and cells of the adherent layer. Of importance, our present modifications of human long‐term bone marrow culture are technically simple and do not involve manipulation of the stromal cells.
Mechanisms of thrombocytopenia in patients with lymphoproliferative diseases
Authors: Kuznetsov A. I. , Ivanov A. L. , Idelson L. I. , Mazurov A. V.
Published: July 2010

Abstract: Different factors are involved in the development of thrombocytopenia in patients with lymphoproliferative disorders. Significant correlation was detected between the number of megakaryocytes in bone marrow and platelet count (r = 0.485, p = 0.002, n = 37) and significant difference between the number of megakaryocyte in patients with normal platelet count (>200000/μl) and patients with marked thrombocytopenia (platelet count < 100000/μl). All patients in the latter group (n = 15) had a relatively low number of megakaryocytes. Low but significant reverse correlation was found between the level of platelet‐associated IgG (PA‐IgG) and platelet count (r = – 0.249, p = 0.024, n = 82) and significant difference between the mean levels of PA‐IgG in the groups of patients with platelet count > 200000/μl and < 100000/μl. PA‐IgG were increased in 46% of patients in the total group and in 65% of patients with platelet count < 100000/μl. The correlation between platelet count and PA‐IgG was about 2 times higher in splenectomized (r= – 0.549, p = 0.005, n = 24) than nonsplenectomized patients. All splenectomized patients with platelet count < 100000/μl (n = 8) had a significant increase in PA‐IgG. Serum antibodies were detected in only 7% of tested patients. This group was characterized by severe thrombocytopenia (in 6 of 10 patients – platelet count <50000/μl) and a high incidence of haemorrhages (in 5 of 10 patients). Thus the depression of platelet production was suggested to be the basic cause of thrombocytopenia in lymphoproliferative disorders. Involvement of immune mechanisms was revealed in a large number of patients and correlated with a deeper and more complicated thrombocytopenia.
Expression of adhesion antigens of human bone marrow megakaryocytes, circulating megakaryocytes and blood platelets
Authors: van Pampus Elisabeth C. M. , Denkers Ingrid A. M. , van Geel Björn J. M. , Huijgens Peter C. , Zevenbergen Adri , Ossenkoppele Gert J. , Langenhuijsen Mart M. A. C.
Published: July 2010

Abstract: There is evidence that mature megakaryocytes migrate into sinusoids, enter the blood and fragment in the vascular bed. We wondered whether differences in expression of adhesion antigens could be associated with the egress of megakaryocytes from bone marrow into the peripheral blood or the fragmentation into platelets. Megakaryocytes from human marrow were purified by counterflow centrifugal elutriation followed by a glycoprotein Ib‐dependent agglutination procedure. Megakaryocytes from central venous blood and pulmonary arteries were purified by counterflow centrifugal elutriation alone. Adhesion antigens were labelled in an immunohistochemical assay. Both bone marrow megakaryocytes and platelets from healthy volunteers stained >75% positive for CD36, CD41, CD42, Cdw49b (α subunit VLA2), Cdw49e (α subunit VLA5), Cdw49f (α subunit VLA6) and CD62. Circulating megakaryocytes, although >75% positive for CD41, had, unlike platelets and bone marrow megakaryocytes, a reduced and remarkable heterogenous (5–100% positive) labelling with antibodies against Cdw49b, Cdw49e, Cdw49f. These results could be confirmed by comparing the bone marrow megakaryocytes, circulating megakaryocytes and platelets from 7 patients that were recovered and processed at the same time. Morphologically mature, circulating megakaryocytes have, unlike bone marrow megakaryocytes, a heterogenous expression of adhesion antigens, especially of Cdw49b, Cdw49e, and Cdw49f.
Electrokinetic behaviour and surface sialic acid status of blood platelets in essential thrombocythaemia (ET)
Authors: Crook M. , Machin S. , Crawford N.
Published: July 2010

Abstract: We have previously reported, for platelets from patients with idiopathic thrombocytopenic purpura, that there was in increased electrophoretic mobility that was related to their increased sialic acid content. Heterogeneity in the circulating platelet pool of patients with essential thrombocythaemia (platelet counts 600–1000 × 109/l) has also been investigated by preparative continuous flow electrophoresis (CFE). The surface charge‐dependent separation profiles of all the patients' platelets showed marked anodal shifts compared with the profiles of platelets from age‐ and sex‐matched control subjects separated under identical conditions. The increase above normal in the net electronegativity of the patients' platelets could not be accounted for by differences in surface neuraminidase‐labile or total platelet sialic acid content.
Results in hairy‐cell leukemia patients treated with α‐interferon: Predictive prognostic factors
Authors: Zinzani P. L. , Lauria F. , Raspadori D. , Rondelli D. , Benfenati D. , Pileri S. , Sabattini E. , Tura S.
Published: July 2010

Abstract: Fourty‐four evaluable patients with hairy cell leukemia (HCL) were treated with human lymphoblastoid α‐interferon (α‐IFN), at a dose of 3 × 106 Units a day for 12–18 months while 18 of them continued to receive a three times per week schedule at the same dose as maintenance treatment. Eighteen percent of patients achieved complete response, 64% partial response, and 18% minor response with a median duration of 37.5, 22.9 and 3.5 months respectively. Twenty patients (45%), all partial or minor responders, subsequently had progression of the disease. The progression occurred more frequently in patients who presented at diagnosis with a hairy‐cell index value >0.50 than in those who presented with a hairy‐cell index <0.50: 14/26 (54%) versus 2/11 (18%) respectively. In addition, the progression rate was more evident in “non‐maintained” than in “maintained” patients: 16/26 (61.2%) versus 4/18 (22%). Restarting α‐IFN treatment in 16 of the 20 progressed patients proved effective only in 9 of them. From these findings it appears that a low hairy‐cell index at diagnosis correlates favorably with a good hematological response. Furthermore, continuous therapy with α‐IFN seems very useful in reducing the progression of the disease, in particular in patients with a very high hairy‐cell index at diagnosis.
Treatment of myelodysplastic syndromes with human granulocytic‐macrophage colony stimulating factor (GM‐CSF) or GM‐CSF combined with low‐dose cytosine arabinoside
Authors: Economopoulos T. , Papageorgiou E. , Stathakis N. , Asprou N. , Karmas P. , Dervenoulas J. , Bouronikou H. , Chalevelakis G. , Raptis S.
Published: July 2010

Abstract: In a phase II study, 21 patients with MDS (RAEB, RAEBt, CMML and RA and RAS with severe cytopenia) were randomized to be treated with 3 courses of GM‐CSF (3 μg/kg/day s.c.) alone (11 patients) or in combination with AraC (20 mg/m2/d s.c.) (10 patients) for 14‐d periods, interrupted by 14‐d rest periods. Eight patients discontinued the treatment. In the GM‐CSF group a marked increase in WBC and neutrophil counts during each course of treatment administration were seen in most patients. Platelet counts decreased in 14 of 24 courses of treatment in the GM‐CSF plus AraC group but in none of the GM‐CSF group. Although the changes in the circulating blood cells were transient and the counts tended to return to the pretreatment levels during the rest periods, some more durable effects were seen. In 3/6 patients of the GM‐CSF group who completed the designed treatment, both WBC and neutrophils remained elevated above the pretreatment levels throughout the 3‐month period of treatment, while in one of them thrombocytopenia improved considerably. In the GM‐CSF plus AraC group, 4 out of the 7 patients who completed the treatment showed an improvement of neutropenia as well as anaemia. In these 4 patients the BM percentage of blasts was also decreased. In conclusion, the results of this study indicate that GM‐CSF given intermittently improves leukopenia in some patients with MDS. In addition, the administration of GM‐CSF seems to prevent granulocytopenia of concurrent AraC treatment and may be of benefit in the treatment of these diseases.
The effects of HIV on hematopoiesis
Authors: Calenda Valerie , Chermann Jean‐Claude
Published: July 2010

Abstract:  Hematologic abnormalities are commonly associated with infection by the human immunodeficiency virus (HIV) that is the etiologic agent of the acquired immunodeficiency syndrome (AIDS). Bone marrow examinations reveal frequent dysplasia, dyserythropoïesis, lymphocytic infiltration and plasmocytosis. These marrow morphologic characteristics are strongly associated with peripheral blood cytopenia of one or more lineage: anemia, granulocytopenia or thrombocytopenia are frequently described. The pathophysiology of these observed deficiencies is still unclear, although several mechanisms have been postulated as possible explanations for the hematological features of AIDS patients. The hematologic manifestations observed in patients with AIDS or AIDS‐related complex (ARC) and the postulated pathogenetic mechanisms are discussed in this review.