bluuebunny/crossref_metadata_2025 huggingface dataset:
Association between immune activation, changes of iron metabolism and anaemia in patients with HIV infection
Authors: Fuchs Dietmar , Zangerle Robert , Artner‐Dworzak Erika , Weiss Günter , Fritsch Peter , Tilz Gernot P. , Dierich Manfred P. , Wachter Helmut
Published: July 2010

Abstract:  The pathogenesis of anaemia associated with human immunodeficiency virus infection is still far from being understood. It cannot be explained by direct effects of the virus on the haematopoietic system. Recent data suggest a role for immune activation. In a cross‐sectional study we compared blood cell counts, haemoglobin and erythropoietin levels of 63 HIV‐seropositive individuals with immune activation markers (interferon‐γ, serum and urine neopterin, and β2‐microglobulin) and with parameters or iron metabolism (serum iron, transferrin, free iron binding capacity, ferritin). We found significant correlations between the concentrations of haemoglobin and the immune activation markers and erythropoietin concentrations. Additional significant correlations existed between the parameters of iron metabolism and haemoglobin levels, and ferritin correlated inversely with transferrin. In sum, low haemoglobin levels in patients were associated with enhanced cellular immune activation, as seen by increased interferon‐γ, neopterin and β2‐microglobulin, and with changes of iron metabolism: low haemoglobin was associated with low transferrin and free iron binding capacity and high ferritin levels. Endogenous release of cytokines such as interferon‐γ‐inhibiting crythropoiesis may be one underlying cause of anaemia in these patients.
Initial versus deferred melphalan‐prednisone therapy for asymptomatic multiple myeloma stage I — A randomized study
Authors: Hjorth Martin , Hellquist Louise , Holmberg Erik , Magnusson Bengt , Rödjer Stig , Westin Jan
Published: July 2010

Abstract:  From October 1983 until December 1988, 50 patients with asymptomatic multiple myeloma stage I were included in a prospective randomized multi‐centre study comparing melphalan‐prednisone (MP) therapy started at the time of diagnosis with deferred therapy where MP was started at the time of disease progression. Twenty‐five patients were randomized to each group. The median time from diagnosis to start of therapy in the group with deferred therapy was 12 months. The reasons for starting therapy were increasing M‐protein in 8 cases, symptomatic bone disease in 9 and anaemia in 5. In 2 cases, disease progression was complicated by vertebral fractures necessitating radiotherapy. Two patients in the group in which MP was started at the time of diagnosis developed acute leukaemia. No differences in response rate, response duration or survival were observed between the treatment groups. We conclude that in asymptomatic myeloma deferral of chemotherapy is feasible in well‐informed and well‐controlled patients but conveys no advantage in survival. In clinical practice the benefits of treatment deferral are to some extent outweighed by disease progression before start of treatment.
The role of ABO matching in platelet transfusion
Authors: Heal J. M. , Rowe J. M. , McMican A. , Masel D. , Finke C. , Blumberg N.
Published: July 2010

Abstract:  A prospective controlled trial was performed to determine whether the use of ABO‐identical platelets from the start of treatment might provide higher post‐transfusion platelet increments, reduce the number of platelet transfusions and ultimately delay the onset of refractoriness. Forty newly diagnosed patients with haematological diseases were randomized to receive either pooled ABO‐identical platelets or pooled platelets unmatched for ABO group throughout their course. The corrected platelet count increments (CCI) were calculated for the first 25 transfusions of each patient and non‐immune factors present at the time of each platelet transfusion were documented. The mean CCI for the first 25 transfusions in the ABO‐identical group was significantly higher (6600 ±: 7900 SD) than that achieved with ABO unmatched platelets (5200 ±: 7900; p<0.01). The effect was most marked for the first 10 transfusions for each patient where the CCI was 64% higher in the ABO‐identical group (8200 ±: 7500 vs 5000 ±: 8100; p<0.0002). Patients given ABO‐identical platelets required only about half as many transfusions in the first 30 days (10 versus 17, p<0.05) or during the first admission (11 versus 21 p<0.01) as patients in the ABO‐unmatched group. A smaller percentage of patients in the ABO‐identical group became refractory (36% vs 75% p<0.03). The data suggest that patients requiring long‐term platelet support should be transfused with ABO‐identical platelets.
Radioprotective potential of primitive hematopoietic precursors forming colonies in diffusion chambers in mice
Authors: Niskanen Eero , Sigounas George
Published: July 2010

Abstract:  The purpose of this study was to determine the radioprotective ability of primitive hematopoietic precursors which form colonies in diffusion chambers in mice (CFU‐D). Thirty‐two lethally irradiated female ICR mice were injected with 5 to 7 male ICR mouse bone marrow‐derived CFU‐D colonies each. Fourteen of these mice survived over 30 days and were sacrificed at intervals up to a year. As a control, 20 lethally irradiated female ICR mice received cells from intercolony areas. All of these mice died before day 20. DNA samples obtained from hematopoietic organs and liver from 8 sacrificed mice were analyzed for the presence of CFU‐D colony‐derived cells. Only in 1 ICR mouse was CFU‐D colony origin DNA detected by Southern analysis in all hematopoietic organs: bone marrow, spleen, thymus and lymph nodes. In 6 mice, only selected hematopoietic organs were repopulated by CFU‐D colony‐derived cells as judged by Southern analysis. In some of these mice, the remaining hematopoietic organs contained small CDU‐D‐derived cell populations which could be detected by more sensitive polymerase chain reaction (PCR). In 1 mouse, the presence of CFU‐D‐derived cells in all hematopoietic organs was only demonstrated by PCR. These findings suggest that lethally irradiated mice can be rescued by CFU‐D‐derived daughter cells. They appear to have the potential to give rise to clones containing lymphoid and myeloid cells in all hematopoietic organs, at least temporarily. Thus, it can be concluded that CFU‐D represents a very primitive hematopoietic precursor cell with radioprotective capability.
Cytokine mediators of septic infections in the normal and granulocytopenic host
Authors: Waage Anders , Steinshamn Sigurd
Published: July 2010

Abstract: Cytokines presently known to be involved in systemic bacterial infection are tumour‐necrosis factor (TNF), interleukin (IL)‐1, IL‐6, IL‐8 and interferon‐gamma (IFN‐γ) and the counterregulatory molecules soluble TNF receptor (sTNFR) and IL‐1 receptor antagonist (IL‐1 Ra). In animal models TNF, IL‐1 and IFN‐γ mediate organ damage, low blood pressure and fatality, whereas IL‐6 is involved in infection‐related manifestations, like the production of acute‐phase protein and fever, and IL‐8 is chemotactic to granulocytes. TNF and IL‐1 increase expression of adhesion molecules on endothelial cells and influence a number of components of the haemostatic system in favour of coagulation. The presence of cytokines in the circulation is characterized by sequential releases of TNF, IL‐1 and IL‐6/IL‐8; however, many variations of this pattern exist during human infection. In experiments as well as in human infection TNF, IL‐1, IL‐6, IL‐8 and IFN‐γ have been detected, and levels of TNF, IL‐6 and IL‐8 have been found to be associated with the severity of the disease. Collectively, TNF, IL‐1 and IFN‐γ emerge as mediators of systemic infection and septic shock whereas IL‐6 and IL‐8 are related to other manifestations of infection. Counteracting molecules like sTNFR are released after somewhat of a delay following TNF and IL‐1Ra is released concomitantly with IL‐1. Probably these factors modulate the cytokine effect although their true potency in natural infection has yet to be clarified. In granulocytopenic infections TNF, IL‐1, IL‐6 and IL‐8 can be detected in scrum, and levels of TNF and IL‐6 are even higher than in the normal situation in experimental animals. Antibodies to TNF inhibit bacteria‐induced fatality in granulocytopenic mice. Altogether, few data related to the granulocytopenic situation are available. However, it is reasonable to believe that the altered development of granulocytopenic infections is due to changes in the cellular constitution and not to changes in cytokine production.
The in vitro effects of interferon‐gamma, interferon‐alpha, and tumour‐necrosis factor‐alpha on erythroid burst‐forming unit growth in patients with non‐leukaemic myeloproliferative disorders
Authors: Kanfer Edward J. , Price Cathy M. , Gordon Andrea A. , Barrett A. John
Published: July 2010

Abstract: We have studied the effects of interferons gamma (IFN‐γ) and alpha (IFN‐α), and tumour‐necrosis factor‐alpha (TNF) on circulating 14‐day erythroid progenitor cell (BFU‐E) growth in vitro from patients with non‐leukaemic myeloproliferative disorders (MPD) compared with normal controls. IFN‐γ (1000 U/ml) inhibited BFU‐E growth in all controls studied (mean growth ± SE = 61 % ± 6%, n = 10). In 7 of 11 MPD studied there was no inhibition, and in some cases clear enhancement of BFU‐E growth by IFN‐γ. When cultured in the presence of recombinant erythropoietin (rEpo) 1 U/ml, both IFN‐α and TNF (at 100 and 1000 U/ml) produced a similar degree of inhibition of BFU‐E growth in MPD and controls. The inhibition by 100 U/ml IFN‐α was abrogated, partially in controls but completely in MPD, by increasing the dose of rEpo to 5 U/ml. Similarly, the increase in rEpo dose enhanced BFU‐E growth in cultures with 100 U/ml TNF, but had little effect on cultures containing 1000 U/ml of either IFN‐α or TNF. The aberrant in vitro response to IFN‐γ demonstrated in some of these patients may be of relevance to the pathophysiology of MPD. These results fail to demonstrate a differential in vitro effect for IFN‐α on MPD BFU‐E growth compared with controls and suggest that the in vitro suppression of haemopoiesis by IFN‐α when used in MPD treatment is non‐specific.
Thrombocytopenia induced by human parvovirus B19 infections
Authors: Yoto Yuko , Kudoh Tooru , Suzuki Nobuhiro , Katoh Shizue , Matsunaga Yasuko , Chiba Shunzo
Published: July 2010

Abstract: Human parvovirus B19 (B19) has a remarkable tissue‐tropism for erythroid elements ‐ from erythroid precursors (BFU‐E, CFU‐E) to erythroblasts. B19 is thought to be incapable of propagating in cells other than erythroid progenitors. Leukocytopenia and thrombocytopenia sometimes occur in addition to erythrocytopenia in patients with B19 infection. We retrospectively investigated the possible cause of thrombocytopenia by B19 infection in 23 patients with thrombocytopenia admitted to our hospital in the past 5 years. Two patients were found to be infected by B19. Mild thrombocytopenia in both cases was thought to be an early event in B19 infection.
Prognostic significance of serum lactic dehydrogenase levels and fraction of S‐phase cells in non‐Hodgkin lymphomas
Authors: Lindh J. , Lenner P. , Osterman B. , Roos G.
Published: July 2010

Abstract: Sixty‐four untreated patients with non‐Hodgkin lymphomas (NHL) were analyzed with respect to fraction of S‐phase cells in tumor material and serum lactic dehydrogenase (LD) levels. A significant correlation between the two variables was found in the low‐grade (LGM) (r = 0.44, p<0.01), but not in the high‐grade (HGM) lymphomas. Shorter survival times were found for patients with tumors showing a high fraction of S‐phase cells (>4%) (p < 0.001) as well as for patients with elevated LD values (≥ 7.5 μkat/l) (p < 0.001). A multivariate analysis showed clinical stage (p < 0.001), S‐phase fraction (p = 0.002) and age (p = 0.002) to be independent prognostic factors. For serum LD a borderline value (p = 0.05) was found, whereas morphology and B‐symptoms were non‐significant. LD level, but not fraction of S‐phase cells, added prognostic information for LGM lymphomas (p < 0.001). For HGM lymphomas, the clinical stage was the strongest factor for prediction of prognosis. We conclude that the fraction of S‐phase cells describes the biological behavior in a more reliable way than morphology (HGM vs LGM) and better identifies lymphomas with poor or good prognosis. The strong additional prognostic information obtained by serum LD within LGM lymphomas is assumed to be due to an association with the tumor burden.
Influence of aspirin on human megakaryocyte prostaglandin synthesis
Authors: van Pampus E. C. M. , Huijgens P. C. , Zevenbergen A. , Twaalfhoven H. , van Kamp G.J. , Langenhuijsen M. M. A. C.
Published: July 2010

Abstract: To evaluate whether currently popular aspirin regimens have an effect on the prostaglandin synthesis in human megakaryocytes we measured thromboxane B2 (TXB2) synthesis in response to thrombin stimulation in human megakaryocytes ex vivo. Human megakaryocytes were purified by Counterflow Centrifugal Elutriation from bone marrow punctures, taken from volunteers before and 2 hours after ingestion of one dose of 500 mg (n = 4), 80 mg (n = 4) or 40 mg (n = 2) aspirin. Subsequently, megakaryocytes were purified before and 12 h after ingestion of 80 mg (n = 3) aspirin twice daily for 1 week and 12 h after 500 mg (n = 3) aspirin. On average, 140 ± 102 × 103 (mean ± 1 SD) megakaryocytes were recovered. We found that aspirin inhibits megakaryocyte cyclooxygenase in a dose‐dependent manner. Two hours after 500 mg of aspirin, TXB2 synthesis in megakaryocytes was inhibited by 96.8 ±2%, whereas one dose of 80 and 40 mg aspirin showed an inhibition of 79.4 ± 13.7% and 80 ± 6.2% respectively. However, the inhibition of TXB2 synthesis seems not to be long‐lasting since, 12 h after the ingestion of aspirin, an increase of megakaryocyte TXB2 production could be observed which reached significance after the 500 mg aspirin dosage (p < 0.048). We conclude that human megakaryocyte cyclooxygenase is sensitive to aspirin inhibition and that low doses of aspirin (40 and 80 mg) enter the systemic circulation and are able to inhibit megakaryocyte cyclooxygenase, but this inhibition is incomplete and megakaryocyte cyclooxygenase seems to recover within 12 h after ingestion of aspirin.
Increased risk of relapse in patients with chronic myelogenous leukemia given T‐cell depleted marrow compared to methotrexate combined with cyclosporin or monotherapy for the prevention of graft‐versus‐host disease
Authors: Aschan J. , Ringdén O. , Sundberg B. , Klaesson S. , Ljungman P. , Lönnqvist B.
Published: July 2010

Abstract: Fifty‐two patients with chronic myelogenous leukemia (CML) who underwent bone marrow transplantation (BMT) at Huddinge Hospital were analyzed retrospectively regarding type of graft‐versus‐host disease (GvHD) prophylaxis. With T‐cell depletion (TCD) (n = 13) the incidence of grade II—IV acute GvHD was 8% compared to 27% among patients given short course methotrexate (MTX) + cyclosporin (CSA) (n = 23) (ns) and 60% in patients who received MTX or CSA alone (n = 16) (p = 0.006 vs TCD and 0.03 vs MTX + CSA). The incidence of chronic GvHD was 56%, 31% and 75%, in the three groups, respectively (p = 0.02 combination vs monotherapy). Probability of relapse differed significantly, with most relapses in the TCD group, 62% compared to 20% in the MTX + CSA group (p = 0.02) and no relapse in the monotherapy group (p = 0.01 TCD vs monotherapy). Patient survival at 6 years was 54%, 59% and 38%, in the three groups, respectively (ns). Relapse‐free survival was 23% in the TCD group, 55% in the combination group (p = 0.06) and 38% in the monotherapy group (ns). We conclude that TCD in patients with CML is correlated with an increased risk of relapse and a tendency towards a decreased long‐term relapse‐free survival compared to patients receiving other kind of GvHD prophylaxis.
Lack of effect of corticosteroids in W/Wv and Sl/Sld mice: These strains are not a model for steroid‐responsive Diamond‐Blackfan anemia
Authors: Alter Blanche P. , Gaston Thomas , Lipton Jeffrey M.
Published: July 2010

Abstract: W/Wv and Sl/Sld mice with macrocytic anemias are a potential model for human inherited pure red cell anemia, called Diamond‐Blackfan anemia (DBA). The W mutation involves the gene for c‐kit, and the SI mutation the gene for the kit ligand, called mast cell growth factor, steel factor, or stem cell factor. Since many children with DBA respond to treatment with corticosteroids, we administered steroids to these genetically anemic mice, to determine whether they might provide a model for the human disease. There was no improvement in the murine anemia, consistent with other evidence suggesting that mutations in kit or steel may not be involved in Diamond‐Blackfan anemia.
Clinical significance of P‐glycoprotein expression in acute leukaemia as analysed by immunocytochemistry
Authors: Tiirikainen Maarit I. , Elonen Erkki , Ruutu Tapani , Jansson Sten‐Erik , Krusius Tom
Published: July 2010

Abstract: Multidrug resistance, mediated by the overexpression of an energy‐dependent transport protein, P‐glycoprotein, has been one of the major targets of interest in solving the mechanisms of clinical drug resistance of malignant cells. To evaluate the correlation between P‐glycoprotein overexpression and the response to chemotherapy, we analysed cytospin preparations of gradient‐separated blood or bone marrow mononuclear cells from 79 patients with acute leukaemia by means of the P‐glycoprotein‐directed monoclonal antibody JSB‐1 and immunocytochemistry using the alkaline phosphatase‐antialkaline phosphatase technique. P‐glycoprotein expression was detected in all disease phases of acute leukaemia. Thirteen out of 51 patients at diagnosis, 10/29 patients in relapse or during residual disease and 8/27 patients in remission overexpressed P‐glycoprotein. Seven out of the 8 positive remission samples were collected between the cycles of consolidation treatment. Our results suggest that increased P‐glycoprotein expression in samples collected between the cycles of consolidation treatment during remission may be induced in normal leukocytes by cytotoxic drug treatment, infections, or by some physiological mechanisms related to the disease. Patients older than 45 years of age were significantly more often P‐glycoprotein‐positive (11/25) at diagnosis than younger patients (2/26). P‐glycoprotein expression at diagnosis was significantly correlated with a low remission rate after the first cycle of induction therapy. Of 34 P‐glycoprotein‐negative patients, 25 achieved remission after the first cycle as compared to 4/12 of the P‐glycoprotein‐positive patients. Our results indicate that the method used is specific and sensitive enough for the analysis of P‐glycoprotein expression and that the expression at initial presentation is inversely correlated with the outcome of induction therapy.
Point mutation in the band 4.2 gene associated with autosomal recessively inherited erythrocyte band 4.2 deficiency
Authors: Iwamoto S. , Kajii E. , Omi T. , Kamesaki T. , Akifuji Y. , Ikemoto S.
Published: July 2010

Abstract: A patient who represented acute hemolytic crisis was studied. Analysis of the erythrocyte membrane proteins by SDS‐PAGE revealed a deficiency of band 4.2. In the family, the sister of the patient who had been clinically normal was also shown to be deficient in band 4.2. Binding studies showed that the propositus' membranes were able to bind normal band 4.2 protein as much as control. It was suggested that the binding sites for the protein were prepared on the membrane. We analyzed the band 4.2 cDNA of the propositus and detected a mutation that changes a codon for alanine to one for threonine at residue 142. Band 4.2 exon III of genomic DNA which included the mutation site was amplified and sequenced directly in the family members, and it was revealed that only the homozygotes of the mutation allele manifested band 4.2 deficiency and the parents, who were heterozygotes, showed normal amounts of band 4.2. Recently, the same mutation was reported as Protein 4.2NIPPON in another 4 cases (Bouhassira et al. Blood 1992: 79: 1846–1854). This study supports the hypothesis that this mutation is the pathogenetic cause of band 4.2 deficiency and not a polymorphism.
Severe immunodeficiency in patients treated with fludarabine monophosphate
Authors: Wijermans P. W. , Gerrits W. B. J. , Haak H. L.
Published: July 2010

Abstract: Fludarabine monophosphate (FAMP) has been shown to be highly effective against low‐grade malignant B‐cell lymphoproliferative diseases. Because some opportunistic infections were observed in patients treated with FAMP, we investigated the influence of this drug on several parameters of immunocompetence. For 17 consecutive patients treated with FAMP for CLL or low‐grade malignant lymphoma we studied T‐cell subpopulations during and after therapy by flow cytometry and our findings were correlated with the clinical course of their disease. A pronounced decrease in the various T‐cell subpopulations was seen in all cases, that for CD4+ cells was still present 11–13 months after the end of the therapy. In 7 patients a severe opportunistic infection developed; the outcome was fatal in 2 cases. Only 5 patients did not experience any serious infection. These results show that FAMP therapy in a dose of 25 mg/m2/day for 5 d every 4 weeks might be too toxic for patients with very advanced disease. However, in view of the efficacy of FAMP, the possibility of less intensive schedules for these advanced cases should be explored.
High‐dose cyclophosphamide, etoposide and BCNU (CVB) with autologous stem cell rescue in malignant lymphomas
Authors: Patti C. , Majolino I. , Scimè R. , Indovina A. , Vasta S. , Liberti G. , Gentile S. , Santoro A. , Pisa R. , Caronia F.
Published: July 2010

Abstract: Eighteen patients with malignant lymphoma, 10 non‐Hodgkin's and 8 Hodgkin's, were treated with high‐dose CVB (cyclophosphamide 4 × 1.5 g/m2, etoposide 4 × 250–400 mg/m2, carmustine 4 × 150–200 mg/m2), followed by autologous peripheral blood stem cells (PBSC, 13 patients) or bone marrow (BM, 5 patients) transplantation. At the time of autograft 6 patients were in complete remission (CR), 3 in partial remission (PR) and 5 in relapse (4 sensitive, 1 resistant), whereas 4 had progressive disease. All CR patients had poor prognostic features at presentation. PBSC were collected at the time of rapid hematologic recovery after intense chemotherapy by means of a cell separator. All patients engrafted. Median time to achieve ≥0.5 × 109/1 polymorphonuclear cells (PMN) and ≥50 × 109/1 platelets was 13 days for both cell types in PBSC autografted patients, versus 20 and 28 days respectively in BM autografted patients. A significant advantage of PBSC over BM was found in terms of time needed to recover either PMN ≥0.5 and PMN≥1 × 109/1 (p = 0.01). Autograft‐related toxicity consisted mainly of moderate severity interstitial pneumopathy (3 patients), and veno‐occlusive disease (1 patient) that resolved completely. Of the 12 patients autografted with detectable disease, 6 (50%) obtained a CR. Seven out of 18 autografted patients (39%) had disease progression within 1 to 5 months of autograft. The projected progression‐free survival is over 50% at 4 years and it was significantly longer in patients with sensitive disease than in those with resistant disease (p = 0.01). The efficacy and the low toxicity of CVB suggest that autograft with PBSC may be proposed for the primary treatment of poor prognosis malignant lymphomas.
Cobalamin absorption and serum homocysteine and methylmalonic acid in elderly subjects with low serum cobalamin
Authors: Joosten E. , Pelemans W. , Devos P. , Lesaffre E. , Goossens W. , Criel A. , Verhaeghe R.
Published: July 2010

Abstract: We prospectively studied 41 consecutive elderly patients with serum cobalamin (vitamin B12) levels lower than 125 pmol/l. The protein‐bound cobalamin absorption test (PBAT) was performed in 34 of them and in 27 selected elderly control patients. The lower decision limit was 0.18% and an abnormal test was detected in only 9 (26%) of the 34 patients with low serum cobalamin level. When the PBAT was compared to the Schilling (Dicopac method) test, a concordant result was found in 80 %. Serum methylmalonic acid and/or total homocysteine concentrations were elevated in 75% (26/35) of the patients with low serum cobalamin levels but also in 30% (5/17) of the control patients. Of the 12 and 9 cobalamin‐deficient patients with elevated serum levels of methylmalonic acid and homocysteine, normalization after cobalamin therapy was obtained in 11 and 5 respectively. In conclusion, determination of serum metabolites and their response to cobalamin therapy are a sensitive index of significant cobalamin deficiency and a useful means of distinguishing between cobalamin and folate deficiency. The PBAT offers little advantage over the Schilling test in diagnosing cobalamin malabsorption in elderly patients.
Quantitative and qualitative studies of red cell ferritin in refractory anemia of myelodysplastic syndrome
Authors: Ohhara Yukio
Published: July 2010

Abstract: The red cell ferritin (rFt) level in 10 patients with refractory anemia (RA) was measured and analyzed by column isoelectric focusing (IEF). The levels in 9 of the 10 patients (90.0%) were higher than the upper limit in healthy controls (MV ± SD: male 14.3 ± 10.3 ag/cell, female 7.5 ± 3.6 ag/cell). The isoelectric point (pI) of rFt determined by IEF in healthy subjects ranged from 5.1 to 5.7. However, the pI ranges for RA patients varied widely; the pI value was thought to correlate with the severity of the morphological abnormalities of bone marrow (BM) erythroblasts. That is, the greater the proportion of morphologically abnormal erythroblasts with respect to all erythroid precursors, the lower the pI range for rFt. The rFt content was not related to serum iron, transferrin saturation, serum ferritin, reticulocyte count, red cell iron content, or BM erythroblast count. These data suggest that rFt synthesis in RA patients is influenced by factor(s) other than iron; this is considered an essential feature of erythropoiesis in myelodysplastic syndrome (MDS).
Etoposide, doxorubicin, cyclophosphamide and high‐dose betamethasone (EACB) as outpatient salvage therapy for refractory multiple myeloma
Authors: Ohrling M. , Björkholm M. , Österborg A. , Juliusson G. , Björeman M. , Brenning G. , Carlson K. , Celsing F. , Gahrton G. , Grimfors G. , Gruber A. , Gyllenhammar H. , Hast R. , Johansson B. , Järnmark M. , Kimby E. , Lerner R. , Linder O. , Merk K. , Paul C. , Simonsson B. , Smedmyr B. , Svedmyr E. , Stalfelt A.‐M. , Udén A.‐M. , Ösby E. , Mellstedt H.
Published: July 2010

Abstract: Fifty‐six patients with refractory multiple myeloma were treated with intermittent courses of etoposide, doxorubicin, cyclophosphamide and high‐dose betamethasone (EACB) every 4th week. The overall response rate was 30%. Durable remissions exceeding 1 year were obtained in 12 of the 17 responding patients. A significant prolongation of the survival time was found for responding patients (median 13 months) compared to those patients who did not respond (median 9 months) to EACB therapy (p = 0.01). A low frequency of neutropenic fever episodes was noted compared to other salvage treatment regimens. The EACB regimen was usually well tolerated and could be administered safely on an out‐patient basis. This regimen might be an alternative especially for elderly patients unresponsive to initial therapy.
S100 protein and neuron‐specific enolase on monocytic leukemic CD1+ cells, probable precursors of Langerhans cells
Authors: Misery L. , Campos L. , Sabido O. , Kanitakis J. , Dezutter‐Dambuyant C. , Guyotat D. , Schmitt D.
Published: July 2010

Abstract: Langerhans cells are characterized by specific markers, such as Birbeck granules and CD1a antigen. S100 protein and neuron‐specific enolase are less specific but are expressed only on Langerhans cells among the cells of the phagocytic mononuclear system. In this study, the expression of these two antigens on many monocytic leukemic cells is shown. These cells could be precursors of Langerhans cells which have been transformed into malignant cells.
Epidemiological and clinical study of sickle cell disease in France, French Guiana and Algeria
Authors: de Montalembert Mariane , Guilloud‐Bataille Monique , Feingold Josué , Girot Robert
Published: July 2010

Abstract: The main clinical and haematological features of sickle cell patients were compared in 618 French, 50 Guianese and 87 Algerian patients. In homozygous sickle cell patients, the proportion of icteric subjects rises with age in all centres; the prevalence of splenomegaly reaches a peak in children from 1 to 5 years and then decreases; jaundice and splenomegaly are more often noted in Algerian and Guianese than French patients. The prevalence of painful crisis is comparable in the 3 centres. In 465 French SS children, having a mean age of 7.3 ± 5.9 years, the prevalence of a past history of meningitis is 7.3%, of septicaemia 4.1% of osteomyelitis 8.8%. These percentages do not differ significantly between countries. Prevalence of a past history of cerebrovascular accident is 3.2% in French SS patients; 1.2% in SC, 3.8% in Sβ thalassaemia. A past history of acute splenic sequestration was noted significantly more often in SS (11.75%) and Sβ thalassaemia (14.3%) than SC (3.6%) in French children (p < 0.05). Proportions of subjects transfused at least once do not differ between countries; SS children are more transfused (64%) than SC (15.6%) and Sβ thalassaemic (66%) (p < 10–4). Haemoglobin and reticulocyte counts do not differ significantly between countries. In conclusion, no major differences were detected between French, Guianese and Algerian homozygous sickle cell patients: this may be due to the fact that France is in itself a mosaic of ethnic origins.
G‐CSF enhances the immunoglobulin generation rather than the proliferation of human B lymphocytes
Authors: Morikawa Keiko , Miyawaki Toshio , Oseko Fumimaro , Morikawa Shigeru , Imai Katsuyuki
Published: July 2010

Abstract: The effect of granulocyte‐colony stimulating factor (G‐CSF) on human B‐cell function was studied in in vitro cultures. G‐CSF alone had no effect on the proliferative response of resting B cells, but it slightly enhanced the proliferative response of these cells in the presence of polyclonal B‐cell mitogen, Staphylococcus aureus Cowan strain I (SAC) at concentrations of 0.2 to 25 μg/ml (1.5‐fold increase in the DNA synthesis). In contrast, immunoglobulin (Ig) secretion of activated B cells was increased approximately three‐fold to four‐fold by adding G‐CSF to the cultures. The neutralization of G‐CSF bioactivity with anti‐G‐CSF antibody abrogated this effect. Though cytoplasmic Ig‐positive cells or plasma cell marker‐positive cells did not change, the expression of IgM mRNA in antibody‐producing B cells increased in the presence of G‐CSF in the cultures. Interestingly, human B lymphocytes are shown to express the binding to biotin‐conjugated G‐CSF preparation, but not to biotin‐conjugated GM‐CSF preparation when examined by flow cytometry. These data suggest that G‐CSF may influence B‐cell function in special circumstances.
Functional capacity of transfused platelets estimated by the Thrombostat 4000/2
Authors: Kristensen Jörgen , Eriksson Lars , Olsson Karin , Killander Andreas , Högman Claes
Published: July 2010

Abstract: Post‐transfusion platelet increment is a useful test for the evaluation of transfusion efficacy. It does not, however, give information about the in vivo platelet function. We have evaluated the in vitro bleeding time (IVBT) using the Thrombostat 4000/2 with ADP as activating agent in 60 platelet transfusions given to 17 chemotherapy‐induced severely thrombocytopenic patients. Determinations were performed before and after transfusion of platelet concentrates (PC) prepared from buffy coat. Both fresh and stored platelets resulted in significant reductions of the IVBT already 10 minutes after completed platelet transfusion. In the majority of patients there was a correspondence between IVBT and platelet increment. However, in 30% of the cases there was no improvement of the IVBT despite an increase of the platelet count. Fresh PCs were more effective I than stored. The IVBT seems to represent a clear‐cut improvement in the possibilities for evaluating and monitoring the effect of platelet transfusion.
Improved survival from fungaemia in patients with haematological malignancies: Analysis of risk factors for death and usefulness of early antifungal therapy
Authors: Iwama Atsushi , Yoshida Minoru , Miwa Akiyoshi , Obayashi† Taminori , Sakamoto Shinobu , Miura Yasusada
Published: July 2010

Abstract: Fourty‐three episodes of fungaemia encountered from 1978 to 1991 in 43 patients with haematological malignancies are reviewed here to analyse the risk factors for death and to evaluate the efficacy of early antifungal therapy. Low serum cholinesterase and elevated serum blood urea nitrogen were significantly associated with fungaemic death, defined as death occurring within 2 weeks after documentation of fungaemia. Overall death rate from fungaemia was 62.8%. Before the introduction of early antifungal therapy in 1986, however, fungaemic mortality was 85.7%; it was reduced to 51.7% thereafter (p = 0.01). Determination of plasma (1→3)‐β‐D‐glucan was helpful in detecting deep fungal infections and initiating antifungal therapy early.
Neutrophils from patients with secondary haemosiderosis contain excessive amounts of autotoxic iron
Authors: Cantinieaux B. , Boelaert J. R. , De Meuleneire J. , Kerrels V. , Fondu P.
Published: July 2010

Abstract: Secondary haemosiderosis may be accompanied by a decrease in the phagocytic function of neutrophils (PMNs). This dysfunction has been attributed to an exaggerated generation of oxidants induced by intracellular iron. However, an accumulation of iron has so far not been reliably demonstrated in neutrophils harvested from iron‐overloaded patients. Six polytransfused haemodialysed patients, with a serum ferritin level higher than 1000 μg/l, and 10 healthy controls were investigated. The iron status of PMNs was evaluated by iron determination using atomic absorption spectrometry and by ferritin measurement using radioimmunoassay. The phagocytic performance was measured by cytofluorometry. The results confirm that PMNs from the haemosiderosis patients have a decreased phagocytosis. Moreover, they demonstrate for the first time that these PMNs have an increased cellular iron and ferritin content. Both latter concentrations were 4 to 5 times more elevated in secondary haemosiderosis than in healthy controls. This iron accumulation may be toxic for the PMNs and may, at least partially, explain the three‐fold higher risk of bacteraemia which has been reported in those patients.
Ultrastructural and ultracytochemical alteration of rat neutrophils induced by G‐CSF
Authors: Azakami Saiki , Eguchi Mitsuoki
Published: July 2010

Abstract: Recombinant human granulocyte colony‐stimulating factor (G‐CSF) was administered intravenously to rats, and its effects on the neutrophils from bone marrow and peripheral blood were examined by electron microscopy. Immature cells such as the promyelocytes in the bone marrow of the rats 12 hours after G‐CSF administration revealed more irregular nuclei than those in untreated rats. Forty‐eight hours after G‐CSF administration, these changes became more marked. In the peripheral blood, the number of cytoplasmic granules was increased 12 hours after administration of G‐CSF. The nuclei of mature neutrophils at 48 hours showed hypersegmentation with slight chromatin aggregation. The peroxidase reaction observed by electron microscopy revealed an increase in the number of positive granules in the immature neutrophils 48 hours after G‐CSF administration, and some of the granules tended to be large. Different from untreated mature granulocytes, a positive peroxidase reaction was observed in the perinuclear space and rough endoplasmic reticulum of mature cells in the peripheral blood 48 hours after G‐CSF administration. These granules also tended to be large. The present electron microscopic investigations demonstrated alterations of the neutrophils in G‐CSF‐administered rats, and these cells retained ultracytochemical evidence of prematurity even at their mature stage.
Human neutrophil granules and secretory vesicles
Authors: Borregaard Niels , Lollike Karsten , Kjeldsen Lars , Sengeløv Henrik , Bastholm Lone , Nielsen Morten H. , Bainton Dorothy F.
Published: July 2010

Abstract: The traditional classification of neutrophil granules as peroxidase‐positive (azurophil, or primary) and peroxidase‐negative (specific or secondary) has proven to be too simple to explain the differential exocytosis of granule proteins and incorporation of granule membrane into the plasma membrane which is an important aspect of neutrophil activation. Combined subcellular fractionation and immunoelectron microscopy has revealed heterogeneity among both peroxidase‐positive and peroxidase‐negative granules with regard to their content, mobilization and time of formation. Peroxidase‐negative granules may be classified according to their content of lactoferrin and gelatinase: 15% of peroxidase‐negative granules contain lactoferrin, but no gelatinase. 60% contain both lactoferrin and gelatinase. The term specific or secondary granule should be reserved for these two subsets. In addition, 25% of peroxidase‐negative granules contain gelatinase but no lactoferrin. These should be termed gelatinase granules or tertiary granules. Gelatinase granules are formed later than specific granules and mobilized more readily. In addition, a distinct, highly mobilizable intracellular compartment, the secretory vesicle, has now been recognized as an important store of surface membrane‐bound receptors. This compartment is formed in band cells and segmented cells by endocytosis. This heterogeneity among the neutrophil granules is of functional significance, and may also be reflected in the dysmaturation which is an important feature of myeloproliferative and myelodysplastic disorders.
Heart transplantation in a case of juvenile hereditary haemochromatosis followed up by MRI and endomyocardial biopsies
Authors: Jensen P.D. , Bagger J.P. , Jensen F.T. , Baandrup U. , Christensen T. , Ellegaard J.
Published: July 2010

Abstract: Cardiac involvement in hereditary haemochromatosis (HH) is a poor prognostic sign and is the main cause of death in the juvenile form. The treatment of choice is iron removal therapy by phlebotomy, but treatment by iron chelation (desferrioxamine) has been recommended in cases with severe cardiac symptoms. We describe here the first case of juvenile HH undergoing heart transplantation, which became necessary despite intensive iron removal therapy by phlebotomy and treatment by desferrioxamine. Throughout the course the myocardial iron content was monitored by endomyocardial biopsies and by magnetic resonance imaging (MRI). At the last follow‐up, 18 months after transplantation, the myocardial iron content in the transplanted heart was still within reference ranges by biochemical determination and MRI and the patient's condition was completely satisfactory. In conclusion, heart transplantation should be considered in cases of severe juvenile HH. In the follow‐up of these patients MRI may be a useful supplement.
Therapeutic potential of intravenous 67‐gallium in non‐Hodgkin's lymphoma
Authors: Huijgens P. C. , Jonkhoff A. R. , Hoekstra O. S. , Ossenkoppele G. J. , Teule G. J. J.
Published: July 2010

Abstract: 67‐gallium accumulates rather selectively in malignant lymphoid tissue. The isotope has a substantial cytotoxic effect in human‐derived cell‐lines. 67‐gallium was given intravenously to 3 patients with end‐stage, resistant large‐cell lymphoma. Evaluation of tumour response was done by physical measurements, and CT‐scanning together with gallium scintigraphy. Three weekly doses of 20, 40 and 60 mCi respectively caused persistent pancytopenia in 1 patient. Panycytopenia was not observed in 2 other patients given two 40 mCi doses 4 weeks apart. In all 3 patients, some response was noted, be it shortlived and different from site to site. 67‐gallium has some cytostatic effect in large cell lymphoma. It seems feasible to start a phase I study to find a tolerable dose to be given every 4 weeks.
Synergistic cytotoxicity of AZT plus alpha and gamma interferon in chronic myeloid leukemia cell line K562*
Authors: Tosi Patrizia , Visain Giuseppe , Ottaviani Emanuela , Gamberi Barbara , Cenacchi Annarita , Tura Sante
Published: July 2010

Abstract: We have previously reported that the antineoplastic activity of 3′ ‐azido 3′ deoxythymidine (AZT) can be increased by drugs that inhibit “de novo” thymidylate synthesis, such as 5‐fluorouracil, methotrexate and hydroxyurea. In the present study we tested the combinations AZT + alpha interferon (IFN) and AZT + gamma IFN on in vitro growth of the human acute‐phase chronic myeloid leukemia (CML) cell line K562. After 72 hours incubation, not only AZT + α‐IFN but also AZT + γ‐IFN were synergistic in inhibiting K562 growth, as demonstrated by isobologram analysis of the data. This enhanced cytotoxicity was confirmed by the evaluation of [3H]AZT incorporation into cellular DNA, that was increased by 50% and 222% in the presence of α‐ and γ‐IFN, respectively. The addition of 50 μmol/l thymidine to the culture medium was able to reduce the cytotoxicity of the drug combinations to the degree observed with each compound alone; furthermore, the increased incorporation of AZT into DNA was completely reversed. These data indicate the existence of a biochemical interaction between AZT and IFNs that results in an increased cytotoxic effect. While the combination AZT + α‐IFN is currently being tested in HIV‐related malignancies, AZT + γ‐IFN is new and deserves further study in human CML acute and chronic phase models, in view of possible clinical applications.
B‐chronic lymphocytic leukaemia in Latvia: Epidemiological aspects
Authors: Yavorkovsky L. I. , Terebkova Z. F. , Nikulshin S. V. , Yavorkovsky L. L.
Published: July 2010

Abstract: As in western Europe and the USA, chronic lymphocytic leukaemia (CLL) in Latvia is the most prevalent type of leukaemia. A total of 1509 newly diagnosed cases of B‐cell chronic lymphocytic leukaemia entered the study, 440 of whom were followed up at the Latvian Haematology Centre. The main peculiarities of the study were: 1) the higher incidence of the disease in Latvia as compared with other regions of the former USSR and with western countries, 2) a lower male‐to‐female ratio than in most other countries and 3) a higher morbidity among the Latvian population in comparison with the Russian. A positive correlation between the disease stage and survival was confirmed, but no precise individual prognosis in an early stage of the disease was possible.
Production of oxygen radicals by fibroblasts and neutrophils from a patient with x‐linked chronic granulomatous disease
Authors: Emmendörffer Andreas , Roesler Joachim , Eisner Jörn , Raeder Evilyn , Lohmann‐Matthes Marie‐Luise , Meier Beate
Published: July 2010

Abstract: Recently, a superoxide‐generating NADPH‐oxidase system in human fibroblasts has been described. Therefore, we reassessed the possible use of this cell type for prenatal diagnosis of CGD patients comparing normal and CGD peripheral blood neutrophils (PMN) and skin fibroblasts in their reactive oxygen intermediate (ROI)‐producing capacity. While PMN of the CGD patient showed a clearly reduced respiratory burst activity, which correlated well with the measured content of cytochrome b558, fibroblasts of the same individual showed no impaired production of superoxide anion or H2O2 upon stimulation by cytokines (TNF and IL‐1) or other agents (Ca2+ ionophores and PAF, unpublished results). Furthermore, fibroblasts of the CGD patient or of normal donors could be inhibited in ROI production by diphenylene iodonium (DPI) and 2‐iodobiphenyl. In contrast to PMN, no inhibition of the fibroblast NADPH‐oxidase system was observed using staurosporin, an inhibitor of proteinkinase C. These data demonstrate, in contrast to previous studies, that fibroblasts are able to produce ROI. Nevertheless, since fibroblasts obtained from a CGD patient exhibited no difference in ROI production compared with fibroblasts obtained from healthy donors, they are not suitable for prenatal diagnosis of CGD.
Primary polycythaemia: diagnosis by non‐conventional positive criteria
Authors: Westwood N. , Dudley J. M. , Sawyer B. , Messinezy M. , Pearson T. C.
Published: July 2010

Abstract: Patients with polycythaemia and normal controls have been studied to establish and subsequently test non‐conventional criteria for the diagnosis of primary polycythaemia (primary proliferative polycythaemia, polycythaemia vera) as compared with conventional Polycythaemia Vera Study Group (PVSG) assessment. One criterion was erythroid colony formation from peripheral blood in a serum‐free system, assayed alone and with the addition of recombinant human erythropoietin (Epo), interleukin 3 (IL3), or α interferon (α‐IFN) (Dudley et al. 1990). The remaining criteria were non‐culture associated and comprised platelet distribution width (PDW), platelet nucleotide ratio (ATP:ADP), serum erythropoietin and clinical evidence of ischaemic vascular disease. The combination of culture associated and non‐culture associated variables, by use of a simple additive scoring system, gave no false positive and only 6% false negative results in distinguishing primary polycythaemia from other polycythaemias and normal controls in those (34 patients Group A) used in its derivation. Testing the scoring system in a newly presenting group (25 patients Group B) was highly satisfactory with no false positives and only a few false negative results (14%). Use of these non‐conventional criteria should allow more confident diagnosis of primary polycythaemia, where conventional clinical and laboratory assessment is inconclusive.
Circulating megakaryocytes: Delivery of large numbers of intact, mature megakaryocytes to the lungs
Authors: Levine R. F. , Eldor A. , Shoff P. K. , Kirwin S. , Tenza D. , Cramer E. M.
Published: July 2010

Abstract: To determine the locus of platelet production, we sought to determine if sufficient megakaryocytes reach the lungs in a state that could produce platelets. Elutriation was used to isolate megakaryocytes from blood reaching and leaving the lungs of 20 patients undergoing routine cardiac catheterizations. A mean of 5.0 intact megakaryocytes/ml were found in pulmonary artery blood, compared to only 0.5 megakaryocytes/ml, with partial cytoplasmic content, in aortic samples. The megakaryocytes in central venous and aortic samples were all mature. The identity of these cells as megakaryocytes, their maturity and normal morphology were confirmed by standard and immunoelectron microscopy. Cardiac outputs were obtained for each patient at the time of blood sampling, allowing an extrapolation that 40 × 106 intact, mature megakaryocytes were being delivered to the lungs every day in the average patient, compared to only 4.0 × 106 partially spent megakaryocytes exiting the lungs daily. About 98% of megakaryocyte cytoplasm reaching the lungs did not exit as recognizable megakaryocytes or fragments. The number and state of the megakaryocytes apparently filtered in the lungs is consistent with the hypothesis that megakaryocytes may shed platelets within the pulmonary microvasculature, which may be the primary site of platelet production.