bluuebunny/crossref_metadata_2025 huggingface dataset:
Normal mouse serum contains two erythroid stimulating activities differing by their mode of action
Authors: Mouchiroud Guy , Blanchet Jean Paul
Published: July 2010

Abstract: We have previously shown that normal mouse serum contains two activities that increase the number of erythroid colonies obtained from murine bone marrow colony‐forming units‐erythroid (CFU‐E) cultured in the presence of saturating Epo concentrations (0.2 U/ml). These activities could be separated by gel filtration and were referred to as peak I and peak II. We report here that peak I increases the number of erythroid colonies in cultures of adult bone marrow cells depleted of cells expressing Mac‐1 antigen. On the contrary, peak II has no stimulating effect in these cultures unless Mac‐1‐positive cells are added to the culture. This synergistic effect is mediated by an activity released in the culture medium by Mac‐1‐positive cells.
An immunomorphometric study on megakaryocyte precursor cells in bone marrow tissue from patients with chronic myeloid leukemia (CML)
Authors: Thiele Juergen , Wagner Stephan , Weuste Roland , Dienemann Dieter , Wienhold Stephan , Zankovich Rudolf , Fischer Robert , Stein Harald
Published: July 2010

Abstract: An immunomorphometric study was performed on trephine biopsies of the bone marrow in 41 patients with chronic myeloid leukemia (CML) to determine number and size of megakaryocyte precursor cells (pro‐ and megakaryoblasts). For specific staining, a monoclonal antibody against platelet glycoprotein IIIa (Y2/51) was employed which is applicable on routinely fixed and paraffin embedded tissue. In comparison with control specimens from 15 patients, in CML morphometric analysis revealed an increase in the total amount of megakaryocytes per square and cubic millimeter marrow tissue, but particularly in patients with thrombocythemia. Moreover, a non‐disorderly expansion of the megakaryocyte precursor pool was recognizable by showing a relative frequency of pro‐ and megakaryoblasts in congruence with the normal value. In this context a significant correlation between the counts for Y2/51‐positive megakaryocytic elements and promegakaryoblasts with the corresponding platelet values was encountered. The more mature stages of megakaryopoiesis (pro‐ end megakaryocytes) disclosed a relevant shift to smaller cell forms with rounded cell perimeters and a more compact aspect of their nuclei. Additionally, in 6 patients with CML, evolution into a subacute and manifest (micro)‐megakaryoblastic transformation accompanied by myelofibrosis could be demonstrated by a retrospective review of file material.
Synthesis of a 60 kD nuclear DNA binding protein induced by cytosine arabinoside in the HL 60 leukemic cell line
Authors: Ravazzolo Roberto , Bianchi‐Scarrǎ Giovanna , Capra Valeria , Fiorentini Paola , Garrě Cecilia
Published: July 2010

Abstract: Cytosine arabinoside (ara‐C) is being employed at low dosage as differentiative rather than a cytotoxic agent in the therapy of leukemias. We have analyzed nuclear proteins from HL 60 leukemic cells treated with ara‐C and have observed increased expression of a 60 kD protein in a dose‐dependent fashion. This protein is actively synthesized, as assessed by labeled methionine incorporation. Using DNA cellulose affinity chromatography we could also demonstrate DNA binding properties of the 60 kD protein.
Platelet autoantibodies detected by immunoblotting in systemic lupus erythematosus: Association with the lupus anticoagulant, and with history of thrombosis and thrombocytopenia
Authors: Jouhikainen Taneli , Kekomäki Riitta , Leirisalo‐Repo Marjatta , Bäcklund Tom , Myllylä Gunnar
Published: July 2010

Abstract: 71 patients with systemic lupus erythematosus (SLE) were studied for the occurrence of platelet antibodies by immunoblotting. Binding of IgG antibodies to platelet protein antigens was observed in 39 of the 71 patients. The most frequently detected and exceptionally strongly reacting antibodies were directed against platelet protein antigens with an approximate molecular weight of 65 kDa under nonreducing conditions. These antibodies were autoreactive and, when followed, they usually persisted. Interestingly, in this group of well‐defined SLE patients, platelet antibodies against the most common targets (65 kDa) were significantly associated with the lupus anticoagulant, a history of thrombocytopenia and thrombosis, particularly with arterial occlusions. The lupus anticoagulant, on the other hand, correlated significantly only with venous thrombosis. In addition to the lupus anticoagulant, platelet antibodies against this unknown platelet protein may thus be a marker of a higher risk of thrombosis in SLE patients.
Fibrinogen Milano VI: A heterozygous dysfibrinogenemia (Aα 16 Arg → His) with bleeding tendency
Authors: Bögli C. , Cofrancesco E. , Cortellaro M. , Volpe A. Della , Hofer A. , Furlan M. , Zanussi C.
Published: July 2010

Abstract: Congenital heterozygous dysfibrinogenemia was diagnosed in a young woman with bleeding tendency. 3 other asymptomatic members of her family (mother and the 2 sisters) had abnormal fibrinogen. The proposita's plasma exhibited prolonged thrombin and reptilase times. Plasma fibrinogen concentration determined by functional assay was 0.3 g/l, whereas immunologic assay revealed normal fibrinogen levels. Turbidity curves, representing the rate of thrombin‐induced fibrin formation, were markedly delayed both in the presence and absence of Ca2+. Isoelectric focusing and SDS electrophoresis of reduced fibrinogen showed normal charge and size of the subunit chains. Release of fibrinopeptide B by thrombin was normal, whereas HPLC elution diagrams of fibrinopeptide A showed an abnormal peak A* with a slightly shorter retention time than the normal fibrinopeptide A. The amino acid analysis showed that the arginine in peak A* is replaced by histidine (Aα 16 Arg → His).
Acute lymphoblastic leukemia in the elderly
Authors: Delannoy A. , Ferrant A. , Bosly A. , Chatelain C. , Doyen C. , Martiat P. , Michaux J. L. , Sokal G.
Published: July 2010

We report our findings in 18 patients with acute lymphoblastic leukemia (ALL) aged 60 years or older. A preleukemic syndrome was observed in 2 patients. Compared to younger adults with ALL, L3 morphology was unexpectedly frequent (4/16) T‐ALL was not observed. Other criteria of poor prognosis (high white blood cell count, CNS involvement, organomegaly, high serum LDH) were similar to those reported in young adults. 12 patients were treated with an OPAL‐derived regimen, 4 with the MAV regimen, 1 with vincristine and prednisone, 1 with 6‐mercaptopurine. Complete remission was achieved in 8 patients but proved short‐lived. 5 patients died in aplasia and 5 failed to achieve remission. Median survival for the whole group was 3 months. ALL in the elderly raises the dilemma of an aggressive disease in patients with poor tolerance to intensive therapy.
High‐dose cytosine arabinoside and amsacrine or mitoxantrone in relapsed and refractory acute myeloid leukaemia: a prospective randomized study
Authors: Martiat P. , Ghilain J. M. , Ferrant A. , Doyen C. , Delannoy A. , Chatelain C. , Bosly A. , Michaux J. L. , Sokal G.
Published: July 2010

52 patients with refractory or relapsed acute myeloid leukaemia (AML) were randomly assigned to receive a combination of high‐dose cytosine arabinoside (HD Ara‐C), 3 g/m2/d and either mitoxantrone (MTX), 7 mg/m2/d (5 mg if older than 60 yr) or m‐amsacrine (AMSA), 120 mg/m2/d (90 mg if older than 60 yr) for 5 d. The overall response rate was 50% and did not differ significantly in the two groups (46% for AMSA and 56% for MTX, p = 0.415). The median survival was 11 months (8 months for AMSA and 12 months for MTX, p = 0.326) and the median duration of complete remission (CR) was 11 months for AMSA and 12 months for MTX (p = 0.643). In relapsed patients, the only significant predictive factor for obtaining a complete response was the length of first complete remission. Patients with a first CR shorter than 6 months had a CR rate of 36% while it was 65% if the first CR lasted more than 6 months (p = 0.03). Severe (WHO grade III‐IV) gastro‐intestinal toxicity was more frequent in the AMSA group (27% vs 4%, p = 0.021). Treatment‐related death occurred in 4 patients in the AMSA group and in 2 patients in the MTX group (p = 0.097). We conclude that neither of these two treatment modalities was shown to be superior in terms of CR rate and survival, with a better tolerance for MTX.
Treatment of myelodysplastic syndromes with retinoic acid and 1α‐hydroxy‐vitamin D3 in combination with low‐dose ara‐C is not superior to ara‐C alone. Results from a randomized study
Authors: Hellström Eva , Robert Karl‐Henrik , Samuelsson Jan , Lindemalm Christina , Grimfors Gunnar , Kimby Eva , Öberg Gunnar , Winqvist Ingemar , Billström Rolf , Carneskog Jan , Dahlén Magnus , Stockner Mette , Wislöff Finn , Dybedal Ingunn , Dahl Inger‐Marie , Öst Åke ,   Scandinavian Myelodysplasia Group (SMG)
Published: July 2010

Abstract: 63 evaluable patients with myelodysplastic syndromes (MDS) and 15 with acute myelogenous leukemia (AML) were randomized between low‐dose ara‐C (arm A) and low dose ara‐C in combination with 13‐cis‐retinoic acid (13‐CRA) and 1α‐hydroxy‐vitamin D3 (1α D3) (arm B). 69 patients were evaluable and 18 (26.1%) responded to therapy. The addition of 13‐CRA and 1α D3 had no positive influence on survival of the patients, remission rates or duration of remissions. 12/27 patients in arm A and 6/29 patients in arm B progressed from MDS to AML during the course of the study (p = 0.0527). Arm B gave significantly more side‐effects than arm A (p = 0.005). Therapeutic effects of 13‐CRA and 1α D3 on MDS is not supported by this study. However, an inhibiting effect on AML development in some MDS subgroups cannot be excluded.
Recombinant human erythroid potentiating activity enhances the effect of erythropoietin in mice
Authors: Niskanen Eero , Gasson Judy C. , Egrie Joan , Wipf Kaarina , Golde David W.
Published: July 2010

Abstract: Endotoxin‐free purified recombinant human erythroid potentiating activity (EPA) was administered to mice either alone or concomitantly with recombinant human erythropoietin (Epo). Epo treatment alone caused an increased hematocrit and reticulocyte count in the peripheral blood. In the spleen, the number of morphologically recognizable erythroid cells, CFU‐E and BFU‐E was also increased. Concomitant administration of EPA with Epo further enhanced erythropoiesis as judged by the same parameters. No significant effect on granulopoiesis was observed in association with Epo or combined Epo and EPA treatment. Our data indicates that EPA is active in vivo in augmenting the erythropoietic response to Epo.
Relationship between immunological phenotype and hematological response to α‐IFN treatment in 35 patients with hairy cell leukemia
Authors: Lauria F. , Zinzani P. L. , Raspadori D. , Foà R. , Buzzi M. , Gugliotta L. , Bocchia M. , Benfenati D. , Tura S.
Published: July 2010

Abstract: During the past 6 years, clinical trials employing α‐interferon (α‐IFN) in hairy cell leukemia (HCL) have shown dramatic improvement in the management of this disease. Complete remissions (CR), however, are relatively rare (10–15%) and a minority of patients (10–25%) do not respond adequately to α‐IFN. The possibility that the poor response to α‐IFN treatment could be related to a peculiar immunological phenotype of the hairy cell (HC) was investigated in this study. The results demonstrated that, in the majority of patients who failed to respond to α‐IFN, HC showed an immunological phenotype characterized by positivity with the CD5 monoclonal antibody which is usually absent on HC and characteristically expressed on B‐chronic lymphocytic leukemia cells. In fact, among the 10 HCL patients who presented with this phenotype, only 5 partial remissions (PR) and 5 minor responses (MR) were achieved, as opposed to the 3 complete remissions (CR), 19 PR and 3 MR observed in the 25 CD5‐negative patients. The possibility that a more extensive immunological analysis of HCL patients at diagnosis may be predictive of the response to IFN treatment is postulated.
II. Comparison of Automated Haematology Analysers
Authors: Stølsnes B. , Skare E. V. , Taverner P. , Ommundsen T. , Aga I.B. , Sandberg S.
Published: July 2010

A comparison of the differential white blood cell count using the Technicon H1, the Tech‐nicon H6000 and the Coulter VCS

Abstract:  One hundred blood samples were analysed on Technicon HI, Technicon H6000, and Coulter VCS hematology analysers, and the white cell differential counts were compared. All three instruments showed very good agreement for neutrophiles and lymphocytes, good agreement for eosinophiles, and acceptable agreement for monocytes. For the material analysed there were no disparities of clinical significance between the results obtained from the three instruments. Eur J Haematol 1990: 45 suppl. 53: 37–39.
Splenic irradiation in chronic lymphocytic leukemia
Authors: Chisesi T. , Capnist G. , Fior S. Dal
Published: July 2010

Abstract: 52 patients with CLL, presenting primarily with splenomegaly, stage II‐IV according to the Rai stage system, were treated with a regime of low‐dose splenic irradiation (SI) between January, 1979 and December 1987. The treatment modality consisted of 1 Gy, from 1 to 10 doses, given at weekly intervals. The median given dose was 700 cGy (100–1000). CHR occurred in 23/52 (44%), PR in 20/52 (38%) and no reponse (NR) in 9/52 (17%) of the patients. The median duration of remission was 9 months (range 3–24), 15 and 7 months for patients achieving CHR and PR, respectively. At relapse, 14 patients received a second course of SI by the same modalities: 2 ot them obtained a second CHR, 9 a PR and 3 NR. The median duration of remission was 4 months. In conclusion, SI represents a suitable therapy for CLL patients presenting primarily with splenomegaly. The low rate of response and the short remission duration after the second treatment suggest that SI should be combined either with splenectomy or with other therapeutic approaches.
Congenital haemolytic anaemia in a low birth weight infant due to congenital stomatocytosis
Authors: Huppi Petra S. , Ott Peter , Amato Maurizio , Schneider Henning
Published: July 2010

Abstract: A baby girl born at 31 weeks gestation showed severe haemolytic anaemia and hyperbilirubinaemia which led to exchange transfusion within the first 12 hours of life. There was no blood group incompatibility between mother and child but there was a marked stomatocytosis of the baby's red blood cells. Family history revealed a congenital stomatocytosis in the mother. Biochemical characterization of the defect was performed. Phospholipid analysis of the erythrocyte membrane of mother and child showed an increase in phosphatidylserine with a compensatory decrease in phosphatidylcholine and phosphatidylethanolamine. SDS‐electrophoresis showed multiple modifications of the protein pattern with a decrease in band 6, an increased content of band 4.lb, a slight decrease in band 7 and a clear change in the shape of the protein band 3 pattern. The results suggest that the basis of the observed abnormalities is a common defect in protein posttranslational modification, rather than multiple genetic defects in the synthesis of several proteins. Haematologic, biochemical and clinical course of the disease in this preterm infant are discussed.
Bernard‐Soulier syndrome in two Swedish families: Effect of DDAVP on bleeding time
Authors: Waldenström Erik , Holmberg Lars , Axelsson Uno , Winqvist Ingemar , Nilsson Inga Marie
Published: July 2010

Abstract: We present 2 patients with Bernard‐Soulier syndrome from two different families. The parents of one of the patients were found to have had common ancestors in the 17th century. The platelet membrane content of glycoprotein (GP)Ib was measured in the patients and their first‐degree relatives with an ELISA technique based on monoclonal antibodies. Both patients had very low levels of GPIb. In one of the families the heterozygotes had reduced expression of GPIb but in the other the obligate heterozygotes had normal values, suggesting that the molecular pathology differs between the two families. In both patients, bleeding time was shortened by infusion of DDAVP (1‐deamino‐8‐D‐arginine vasopressin), although it was not completely normalised. DDAVP may be of some therapeutic value in cases of Bernard‐Soulier syndrome.
Plasma kininogen concentration: the low level in cord blood plasma and age dependence in adults
Authors: Kleniewski J. , Czokato M.
Published: July 2010

Abstract:  Antigenic concentration of total kininogen, kinin liberated in vitro, and the antigenic concentration of high molecular weight (HMW) kininogen was measured in 58 different samples of cord blood plasma and in plasma samples from 67 healthy blood donors. Total kininogen and kinin concentration in cord blood plasma was more than twice as low as in pooled plasma of adult persons, and the concentration of HMW‐kininogen in cord blood plasma was close to one‐third of normal. The concentration of total kininogen and of HMW‐kininogen increased with age in adults. All. these findings were highly statistically significant.
An Arg545→ Cys545 substitution mutation of the von Willebrand factor in type IIB von Willebrand's disease
Authors: Donnér Mikael , Andersson Ann‐Mari , Kristoffersson Ann‐Charlotte , Nilsson Inga Marie , Dahlbäck Björn , Holmberg Lars
Published: July 2010

Abstract: Type IIB is a special variant of von Willebrand's disease, characterized by an abnormal von Willebrand factor which shows an increased interaction with platelets. This interaction sometimes causes platelet aggregation and thrombocytopenia in vivo. It involves the glycoprotein‐Ib (GPIb) receptor on platelets and corresponding GPIb‐binding sites in the von Willebrand factor. We here demonstrate a C ± T mutation at codon 1308 of the von Willebrand factor gene in 2 related patients with IIB von Willebrand's disease. The transition gives rise to a substitution of arginine by cysteine at position 545 of the mature von Willebrand factor subunit. This position is close to the GPIb‐ as well as the collagen‐ and heparin‐binding domains of the von Willebrand factor. The mutation may change the conformation of the molecule in this region and activate the GPIb‐binding domain, which is normally not exposed in the von Willebrand factor of circulating blood.
Validation of a serum‐free growth factor‐replenished in vitro culture system for hematopoietic progenitor cells in healthy donors and recipients of an allogeneic bone marrow graft
Authors: van den Berg H. , van Tol M. J. D. , Oudeman‐Gruber N. J. , Waaijer J. L. M. , Wagemaker G. , Vossen J. M.
Published: July 2010

Abstract: The in vitro colony formation of hematopoietic progenitor cells of bone marrow samples, taken before and early after allogeneic bone marrow transplantation (BMT), was investigated prospectively. In order to circumvent culture‐related and sample‐related variations, a serum‐free recombinant growth factor‐replenished culture system was developed using T cell‐ and monocyte‐depleted bone marrow samples. Samples of healthy bone marrow donors were used to validate the technique. The standardized culturing technique gave reproducible results, with numbers of colonies above those in conventional conditioned‐medium technique. Colony formation in vitro of myelomonocytic precursor cells was found decreased in graft recipients, also after addition of growth factors, in comparison with healthy donors. The growth‐promoting effect of the combination of IL‐3 + GM‐CSF was superior to that of either growth factor alone or conditioned medium. No effect was observed of T lymphocytes and monocytes on in vitro colony formation after bone marrow transplantation, probably as a result of functional impairment of these cells at that period after transplantation.
Evolution of Ig‐ and T‐cell receptor gene configuration in a Ph1+ hybrid leukemia patient
Authors: Jensen Arne Willy , Hokland Peter , Kristensen Jgrgen Schøler , Justesen Just , Hokland Marianne
Published: July 2010

Abstract: In a longitudinal study of a 32‐year‐old male with Ph1+ hybrid leukemia we have followed the immunophenotype and configuration of Ig‐and TCR genes during the course of different chemotherapy regimens directed first against the myeloid and later against the lymphoid components of the disease. We identified changes in all parameters, interpretable as an evolution of the malignant clone resulting in a leukemic switch towards a more lymphoid character. Thus, while the expression of the myeloid antigens CD13 and CD33 decreased, that of CD10 (CALLA) and CD20 (B1) increased. Moreover, while the configuration of the Ig heavy and light chain λ genes remained constant during the whole period of treatment, that of the Ig light chain κ gene and TCR (3 gene displayed extensive rearrangements after initiation of ALL therapy. Since this patient represents a de novo acute leukemia as evaluated by location of the translocation‐breakpoint on chromosome 22, our data clearly indicate that Ig‐ and TCR gene rearrangements might prove a valuable addition in monitoring Ph1+ hybrid leukemias, providing guidelines for optimizing chemotherapy.
Interferon‐α‐induced changes in surface antigens in a hairy‐cell leukemia (JOK‐1)‘ and a Burkitt's lymphoma cell line (Daudi) during in vitro culture
Authors: Nielsen Bendt , Madsen Peder Skov , Jensen Arne Willy , Hokland Peter , Hokland Marianne
Published: July 2010

Abstract: In further studying the mechanism of action of IFN‐α in HCL, we cultured the HCL cell line JOK‐1 and the IFN‐sensitive Burkitt cell line Daudi with and without IFN‐a and investigated the changes in density of a number of surface antigens by use of mAb and flow cytometry analyses. During culture with IFN‐α, reproducible changes were induced in both cell lines, which were qualitatively similar but differed quantitatively with small and transient changes in JOK‐1. Significant decreases in surface antigen expression were observed for CD 19, 23, 37, and for IgM on both cell lines. Moreover, decreases were seen for CD 10, 22, 45, and MHC class I1 on Daudi, and for CD 20, 21, 27, and 40 on JOK‐1. By contrast, only a few antigens increased in density, including CD 39, A96/G8 and SC9, on both cell lines, CD 22 on JOK‐1, and CD 21 on Daudi. The increase in CD 39, A96/G8 and SC9 was probably directly related to the mechanism of action of IFN‐a, whereas the other changes were most consistent with an unspecific inhibition of protein synthesis, possibly due to an accumulation of cells in Go, even though a differentiating effect cannot be ruled out. Thus, the unique in vivo effect of IFN‐α in HCL was not parallelled by a specific direct effect on JOK‐1 in vitro. Our findings therefore do not support the theory that IFN's mechanism of action in vivo is a direct effect on HC, but suggest that indirect effects are involved.
Recombinant interleukin‐2 (rIL‐2) in acquired immune deficiency syndrome (AIDS): Preliminary report in patients with lymphoma associated with HIV infection
Authors: Mazza P. , Bocchia M. , Tumietto F. , Costigliola P. , Coronado O. , Bandini G. , Conte R. , Ricchi E. , Vianelli N. , Raise E. , Fondacaro A. , Re M. C. , Vignoli N. , Chiodo F. , Tura S.
Published: July 2010

Abstract: In an ongoing phase I1 study, 12 patients with lymphoma and HIV infection were treated with zidovudine (ZDV) and recombinant interleukin‐2 (rIL‐2) to evaluate if this association may produce beneficial effect on the immunologic status and the outcome of lymphoma. The protocol included daily doses of rIL‐2 at 6 MIU/m2 over 5 days in c.i. per week for a total 4 courses; ZDV was associated at 600 mg/d in the period under study. An improved CD4 count, exceeding 2‐ to 4‐fold the basal count, was obtained in patients with a basal CD4 number > 100/μl accompanied by a significant increase of NK and LAK activity (p< 0.001). From the clinical point of view the reduction of tumor manifestation was proportional to CD4 basal number; 2 patients from those with CD4> 100/μl obtained a complete remission after rIL‐2 and ZVD. The p24 antigen, taken as parameter of viral replication, remained invariably negative after rIL‐2 and ZDV in patients already negative and became negative in 1 patient previously positive. Our conclusion is that the association of rIL‐2 and AZT is safe and useful in patients with lymphoma and HIV infection.
Normal mouse serum‐derived factor(s) which inhibits growth of the interleukin‐2‐dependent cell line CTLL
Authors: Lindqvist Christer , Dahl Carol , Back Carita , Oker‐Blom Christian , Akerman Karl , Wigzell Hans
Published: July 2010

Abstract: Evidence is presented for the existence of a serum factor(s) (SF), which inhibits the growth of both the interleukin‐2 (IL‐2)‐dependent cell line CTLL and the 2‐day generation of CTL cells. This activity is found in the serum of both nude and euthymic mice and its suppressive effect can be detected about 18 hours after addition to CTLL cultures. The inhibitory activity elutes from a Sepharose 6B gel after the gamma globulin fraction (100–150 kD), and is precipitated by ammonium sulfate at 60 wjv % saturation. IL‐3‐mediated bone marrow colony formation is not inhibited by SF. It also does not suppress the growth of a panel of different tumor cell lines. The spleen cell responsiveness to both Con A and LPS activation is greatly reduced in the presence of SF. However, binding of radiolabelled IL‐2 to CTLL cells was not blocked by SF, although the activity was greatly reduced by absorption to these cells. Our data support the existence of factor(s) in sera that may have a regulatory role on IL‐2‐mediated functions.
Reduced erythropoietin response to anaemia in elderly patients with normocytic anaemia
Authors: Carpenter M. A. , Kendall R. G. , O'Brien A. E. , Chapman C. , Sebastian J.P. , Belfield P. W. , Norfolk D. R.
Published: July 2010

Abstract: We studied the effect of age on the relationship between haemoglobin and serum erythropoietin (EPO) levels in anaemic patients. 568 patients over 70 years of age were compared with 137 patients under 70 and a reference group of 144 patients of all ages with proven iron deficiency. EPO was measured using a radioimmunoassay. We found that elderly patients with a normocytic anaemia (N = 375) had a statistically lower EPO response than younger patients with normocytic anaemia (N = 61) (p < 0.05) or patients of all ages with iron‐deficiency anaemia (p < 0.05). There was no difference between the sexes. Elderly patients with microcytic or macrocytic anaemia had a normal EPO response as compared to the “gold standard” of iron deficiency. These findings suggest that a proportion of elderly patients with normocytic anaemia has an impaired EPO response.
IL2‐ and IL4‐dependent proliferation of T‐cell clones derived early after allogeneic bone marrow transplantation: Studies of patients with chronic myelogenous leukaemia
Authors: Bruserud Ø. , Hamann W. , Patel S. , Ehninger G. , Pawelec G.
Published: July 2010

Abstract:  In an attempt to explore T‐cell functions shortly after allogeneic bone marrow transplantation more fully, IL2‐ and IL4‐dependent proliferation was assessed on CD4+ TCRαβ+ T‐cell clones derived 4–6 weeks after transplantation. Both allogeneic pooled peripheral blood mononuclear cells and Epstein‐Barr virus‐transformed B‐cell lines (BCL) could function as accessory cells (AC) for PHA activation of T‐cell clones. Although minimal clonal proliferation was seen when the T‐cell activation signal was BCL + PHA + IL4, a majority of the clones could undergo IL4‐dependent proliferation after previous activation with AC + PHA + IL2. For certain clones, IL4 also showed an additive effect with IL2. Thus, IL4 was a growth factor for a majority of the investigated posttransplant T‐cell clones, and in vivo modulation of IL4‐dependent T‐cell functions may thus become a future therapeutic possibility to enhance graft‐versus‐leukaemia effects in bone marrow transplant recipients.
Altered function and surface marker expression of neutrophils induced by rhG‐CSF treatment in severe congenital neutropenia
Authors: Elsner Jörn , Roesler Joachim , Emmendörffer Andreas , Zeidler Cornelia , Lohmann‐Matthes Marie‐Luise , Welte Karl
Published: July 2010

Abstract: Neutrophils from patients suffering from severe congenital neutropenia (SCN), who were receiving recombinant human granulocyte colony‐stimulating factor (rhG‐CSF), were investigated in order to analyze the previously described decrease in chemotaxis. This study demonstrated the decreased chemotaxis to five well‐known chemoattractants, FMLP, C5a, IL‐8, LTB4 and PAF. To further investigate this impairment of patients' neutrophils, receptors and receptor turnover for chemoattractants were examined using flow cytometry. We found 1) increased FMLP receptor and decreased C5a receptor expression, 2) a normal expression of intracellular FMLP receptors after incubation with PMA, 3) increased loss and decreased re‐expression of FMLP receptors after incubation with this peptide, 4)normal expression of adhesion glycoproteins CR3 (CD11b/CD18) and LFA1 (CD11a/CD18), 5) further signs of in vivo preactivation: high expression of Fcγ‐RI (CD64) and Fcγ‐RII (CD32), decreased expression of Fcγ‐RIII (CD16), increased expression of CD14, and low expression of HLA‐DR. These data demonstrate that the decrease of chemotaxis of neutrophils from SCN patients is not due: a) to a decrease in the number of intra‐ or extracellular FMLP receptors; b) to a decrease of adhesion molecules. However, the decreased chemotaxis could result from an altered FMLP receptor turnover. The relevance of the altered Fcγ‐receptor pattern for the in vivo occurrence of side‐effects, e.g. the necrotic vasculitis, of G‐CSF treatment is discussed.
Incidence of polycythemia vera in a defined population
Authors: Berglund Stig , Zettervall Olle
Published: July 2010

Abstract: In this retrospective investigation from Malmö, a city well‐suited for epidemiologic studies, 177 patients (88 males and 89 females) with polycythemia vera (PV) were identified between 1950 and 1984. The incidence rate (number of cases/100 000/yr) in both sexes increased significantly, being 1.0 in 1950–1959 and 2.6 in 1980–1984 (adjusted to the European age‐standardized population). This is the highest rate reported to date. In 1970–1984 the highest age‐specific incidence rates (number of cases/100 000/yr) were found in males ≥ 80 yr and females 70–79 yr of age, being 18.3 and 14.6, respectively. A subgroup of 12 (7%) was identified where the PV diagnosis was not obvious on entry into the study but where it became clear during follow‐up. 16 PV patients (9%) had verified or suspected arterial hypoxemia caused by a concomitant condition. We conclude that the increasing PV incidence rates, mainly confined to older age groups, are probably due to better case ascertainment.
Pentoxifylline at clinically achievable levels inhibits FMLP‐induced neutrophil responses, but not priming, upregulation of cell‐adhesion molecules, or migration induced by GM‐CSF
Authors: Roberts Pamela J. , Yong Kwee L. , Khwaja Asim , Johnson Beryl V. , Pizzey Arnold R. , Carver Julia E. , Addison Ian E. , Linch David C.
Published: July 2010

Abstract: Pentoxifylline (PTX) administered after bone‐marrow transplantation reduces procedure‐related organ damage mediated by TNFα. GM‐CSF is also given post‐transplant to stimulate earlier neutrophil recovery. Because PTX has been shown to inhibit neutrophil function, we sought to determine whether it also inhibited the effects of GM‐CSF on neutrophil activity. The study confirmed that PTX at clinically achievable concentration (5–10 μmol/l) attenuated the responses of human neutrophils to chemotactic peptide, whereas it did not inhibit the effect of GM‐CSF on neutrophil function even at high concentrations. In experiments with human neutrophils, neither the direct effects of GM‐CSF such as stimulation of migration and increased expression of CD11b, nor the priming effects of GM‐CSF on the respiratory burst, were inhibited by PTX. In experiments with monkeys, intravenous administration of PTX did not block subsequent GM‐CSF‐induced neutrophil CD11b upregulation or phagocyte margination, even when near millimolar plasma levels of pentoxifylline were obtained. The retention of cytokine‐stimulated activities suggests that PTX will not compromise the response of neutrophils to stimuli from infectious foci.
Expression of interleukins 1, 3, 6, stem cell factor and their receptors in acute leukemia blast cells and in normal peripheral lymphocytes and monocytes
Authors: Ferrari Sergio , Grande Alexis , Manfredini Rossella , Tagliafico Enrico , Zucchini Patrizia , Torelli Giuseppe , Torelli Umberto
Published: July 2010

Abstract: Reverse transcriptase‐polymerase chain reaction amplification (RT‐PCR) and Southern blot analysis were used to evaluate ligand and receptor expression of interleukin 1α (IL‐1α), interleukin 3 (IL‐3), interleukin 6 (IL‐6) and stem cell factor (SCF) in peripheral blood lymphocytes and monocytes and in several acute leukemia blast cell populations. Resting peripheral lymphocytes and monocytes expressed both ligand and receptor of the four cytokines at considerable levels. The leukemic blast cells of the M1‐M4 phenotypes are characterized by almost complete lack of expression of IL‐1α, IL‐3 and IL‐6 and the constant and usually high expression of SCF. On the other hand, these myeloid blast cells express generally high levels of the four cytokine receptors. The data suggest that the regulation of the expression of IL‐1α, IL‐3 and IL‐6, at least in our limited number of leukemic cell populations studied, is independent of that of SCF. The results indicate that, at least in most of the leukemic myeloid blasts cells, the expression of SCF and its receptor, the c‐kit oncogene, may permit an autocrine regulation of cell cycling.
Plasma and cellular pharmacokinetics of m‐AMSA related to in vitro toxicity towards normal and leukemic clonogenic bone marrow cells (CFU‐GM, CFU‐L)
Authors: Linssen P. , Brons P. , Knops G. , Wessels H. , de Witte T.
Published: July 2010

Abstract: Plasma and cellular pharmacokinetics of m‐AMSA were investigated in 5 patients with acute leukemia, using HPLC. The pharmacokinetic data served as a guideline for in vitro toxicity tests on clonogenic bone marrow cells. m‐AMSA was administered as a 3‐hour intravenous infusion of 100 mg/m2. Median plasma and nucleated blood cell peak concentrations were 1.25 and 6.36 μg/ml followed by biphasic elimination with a median T1/2αα of 1.6 h and 0.3 h and a median T1/2β of 5.0 h and 5.0 h respectively. Median plasma and cellular area under the curve (AUC) for a 24‐h period amounted 6.2 μug·h/ml and 49.8 μg·h/ml respectively. In vitro cellular uptake was maximal at least within 30 minutes. No differential toxicity for CFU‐GM and CFU‐L was observed in relation to exposure time. Median IC50 for CFU‐GM and CFU‐L was 2.2, 1.8 and 1.6 μg/ml after incubation periods of resp. 0.08, 4 and 24 h. The corresponding m‐AMSA concentration × time products to achieve 50% inhibition (IAUC50) were 0.18, 7.2 and 38.4 μg·h/ml, respectively. 48‐h prestimulation of the clonogenic bone marrow cells with Human Placenta Conditioned Medium increased sensitivity (median 1.7 ×) after 4 h incubation with mAMSA. Short exposure provides maximal, concentration‐related, cellular uptake, resulting in effective inhibition of growth of clonogenic bone marrow cells.
High incidence of leukemic phase in follicular lymphoma in Akita, Japan: Clinicopathologic, immunological and cytogenetic studies
Authors: Chubachi A. , Miura I. , Hashimot K. , Hamanaka S. C. , Saitoh M. , Watanuki T. , Miura A. B.
Published: July 2010

Abstract:  A leukemic phase occurred in 7 of 11 (64%) Japanese patients with follicular lymphoma. The clinical and hematologic features at the onset of this phase were splenomegaly, anemia, and thrombocytopenia. The lymphoma cells expressed monoclonal surface immunoglobulins with moderate to strong intensity in all 7 of the patients diagnosed as leukemic. Various B‐cell associated antigens were expressed as follows: CD19 (5/6), CD20 (7/7), and CD 10 (6/7). The reactivity to these markers was comparable in the lymph node and blood samples. The expression of CD38 antigen was much lower in the lymphoma cells of the blood than in those of the lymph nodes. Cytogenetic studies of the lymph nodes of follicular lymphoma in leukemic phase revealed a common chromosomal aberration, of t(14;18)(q32;q21) and + 18, in 2 patients successfully analyzed. Although the follicular lymphomas in the leukemic phase in these patients in Akita, Japan, were consistent with those in the West with respect to morphology, immunology and cytogenetics, the high incidence of leukemic manifestations may be a salient feature of Japanese cases.
In vitro inhibition of interleukin‐2‐induced defective polymorphonuclear chemotaxis by TNF inhibitor
Authors: Fossat C. , Sainty D. , Stoppa A. M. , Blaise D. , David M. , Maraninchi D. , Juhan‐Vague I.
Published: July 2010

Abstract: Patients undergoing immunotherapy with interleukin‐2 experience multiple side effects and are highly susceptible to bacteremia. In a previous study, we confirmed that a profound deficiency of neutrophil chemotaxis is induced by interleukin‐2 therapy. Migration in response to N‐formyl‐methionyl‐leucyl‐phenylalanine (FMLP), being normal before therapy, was markedly impaired after the first cycle and further decreased after the third cycle of treatment. A direct effect of interleukin‐2 on neutrophil chemotaxis is controversial. However, peripheral blood cells exposed to interleukin‐2 secrete secondary cytokines. In particular, the release of tumor necrosis factor after interleukin‐2 injection has been proposed as an important regulatory mechanism. When testing random migration and chemotaxis of neutrophils from normal subjects after incubation with the serum from treated patients, we found that this serum induced a defective chemotaxis similar to that of neutrophils from interleukin‐2‐treated patients. In order to assess the influence of tumor necrosis factor, we tested the effect of anti‐tumor necrosis factor‐alpha antibody on the chemotactic response of cells after incubation with the serum, and we observed a dose‐dependent reduction of neutrophil chemotaxis deficiency. These data suggest that TNF is counteracting the neutrophil chemotactic deficiency observed during IL‐2 treatment.
Two new candidate mutations in type IIA von Willebrand's disease (ARG834→GLY, GLY846→ARG) and one polymorphism (TYR821→CYS) in the A2 region of the von Willebrand factor
Authors: Donnér M. , Kristoffersson A‐C. , Berntorp E. , Scheibel E. , Thorsen S. , Dahlbäck B. , Nilsson I. M. , Holmberg L.
Published: July 2010

Abstract: Recently, several von Willebrand factor gene mutations resulting in type IIA von Willebrand's disease have been reported. We examined 8 patients from Sweden and Denmark with this phenotype and found two new candidate mutations and a hitherto unknown amino acid polymorphism. One patient had a de novo occurring mutation resulting in substitution of glycine for arginine 834. Previous reports have demonstrated conversion of arginine 834 to tryptophan or glutamine in IIA patients. A 2nd patient had a G(4825)→A transition, substituting arginine for glycine 846. The transition produces a sequence congruent with that of the pseudogene but several lines of evidence indicate that a sequencing error due to influence by the latter could be excluded. The remaining 6 patients had one of the earlier described substitution mutations: Ser743→Leu and Ile865→Thr. In addition, two sequence variations not linked to the phenotype were found, namely Tyr821→Cys and Val802→Leu.
Apparent polycythaemia: diagnosis, pathogenesis and management
Authors: Messinezy Maria , Pearson Thomas C.
Published: July 2010

Abstract:The term “apparent polycythaemia” is applied to a group of patients who have a raised PCV (<0.51 in males, <0.48 in females) but a normal red cell mass (less than 25% above their predicted mean normal value). Some have additionally a marked reduction in plasma volume and can be defined as a subgroup: relative polycythaemia. Smoking, hypertension and to a lesser extent obesity, excessive alcohol, low‐dose diuretic therapy and hypoxaemia have all been associated with apparent polycythaemia but the mechanism is both uncertain and likely to be complex. This group of patients is unlikely to be uniform in pathogenesis and may well include some normal individuals. Investigation requires exclusion of factors associated with other types of polycythaemia. The possibility of an increased vascular occlusive risk is uncertain in these patients except at the higher PCV values. Reduction of PCV by venesection is sensible at PCV < 0.54 or where there is perceived to be an increased risk of vascular occlusion. The remaining patients should be managed by regular observation to detect further rise in PCV or evolution to absolute polycythaemia (raised red cell mass). In some, the PCV returns to normal.
Measurement of spleen size using gamma camera scintigraphy in essential thrombocythaemia
Authors: Revesz Peter , Carneskog Jan , Wadenvik Hans , Jarneborn Lennart , Kutti Jack
Published: July 2010

Abstract: By using gamma camera imaging the spleen size was determined in 33 consecutive patients with essential thrombocythaemia (ET) and in 33 consecutive patients with reactive thrombocytosis (RT). All ET patients were newly diagnosed and had not received myelosuppressive treatment prior to study; they all fulfilled the criteria for ET as established by the Polycythemia Vera Study Group. In both posterior and lateral projections, the spleen area in the group of ET patients was significantly larger than in the RT patients. The present study has shown that 39% of ET patients at diagnosis have splenic enlargement. Evaluation of spleen size is therefore a useful diagnostic test in patients presenting with unexplained thrombocytosis.
A 40‐base‐pair duplication in the gp91‐phox gene leading to X‐linked chronic granulomatous disease
Authors: Rabbani Hodjattallah , de Boer Martin , Åhlin Anders , Sundin Ulf , Elinder Göran , Hammarström Lennart , Palmblad Jan , Smith C. I. Edvard , Roos Dirk
Published: July 2010

Abstract: Chronic granulomatous disease (CGD) is characterized by the inability of the patients' phagocytic leukocytes to generate superoxide. Therefore, these cells fail to kill certain bacteria and fungi. As a result, patients with CGD suffer from recurrent, life‐threatening infections with these micro‐organisms. Superoxide is produced by NADPH oxidase, a multicomponent enzyme exclusively present in phagocytic leukocytes. The most common form of CGD is X‐linked, originating from a deficiency of the high‐molecular‐weight subunit of cytochrome b558 (gp91‐phox). Here we describe a patient suffering from X‐linked CGD due to a 40‐base‐pair duplication in exon 7 of the CYBB gene coding for gp91‐phox, predicting a frameshift, substitution of 22 amino acids and a premature stop codon at amino‐acid position 253. The mother as well as the grandmother of this patient were proven to be heterozygous for this mutation; the father and sister were normal. However, the great‐grandmother proved to have normal oxidative functions, suggesting that the mutation occurred three generations ago. This is the first description of a nucleotide duplication leading to CGD.
Lethal infections in patients with hematological malignancies
Authors: Salonen Juha , Nikoskelainen Jukka
Published: July 2010

Abstract:  The hospital files of 410 patients with hematological malignancy treated at our clinic between 1977 and 1990 were reviewed to determine the importance of infections as a cause of death. The total number of infections was 203 (49.5%). A microbiologically documented infection was detected in 27.3%, a clinically documented infection in 9.5% and a possible infection in 12.7% of the patients. Gram‐positive bacteria were responsible for 25.9%, gram‐negative bacteria for 31.3%, anaerobic baeteria for 2.7%, viruses for 4.5% and fungi for 25.9% of the microbiologically documented infections. Of 29 systemic fungal infections only 2 were diagnosed before the patients died. The remaining diagnoses rested on autopsy findings. Empiric antifungal therapy was introduced in 1983; still, 74.2% of systemic fungal infections in 1977–1990 were detected after 1982. Patients with a verified infection had statistically significantly higher CRP concentrations than patients who died of other causes (152 mg/l vs. 117.5 mg/l, p = 0.018). We conclude that infection is a significant cause of death in patients with these diseases. The number of systemic fungal infections is increasing, despite the widespread use of antifungal medication and thus better diagnostic methods and more effective treatment are needed. –
Increased colony growth in peripheral blood cultures from patients with ALL depends on immunological subtype*
Authors: Betticher D. C. , Huxol H. , Müller R. , Speck B. , Nissen C.
Published: July 2010

Abstract:  The proliferative capacity of precursor cells in bone marrow and peripheral blood of 19 patients with acute lymphoblastic leukaemia (ALL) at diagnosis was studied and results were compared with the immunophenotype of the leukaemic population. Bone marrow proliferative capacity in these patients was strongly diminished, low or absent, independent of the immunophenotype, compared with control values (p<0.0002). In contrast, the growth pattern in peripheral blood cultures from the same patients varied widely according to the subtype of ALL: whereas in patients with undifferentiated ALL [TdT+, HLA‐DR+, CD19+ or−, CD10−, (n=4) or CD7+, CD5+, CD1−, CD4− and CD8− (n=1)] PB had strongly reduced proliferative capacity compared with control (p < 0.05), there was excess growth of normal neutrophil and erythroid colonies in BP cultures from patients with a more mature immunophenotype of either B‐[CD10+, (n=11)] or T [CD1+, CD4+ and/or CD8+, (n=3)] phenotype. This phenomenon was only seen in patients who had circulating lymphoblasts: If their number was low, growth was so prolific that single colonies could not be identified. In the presence of a high blast count, colony growth was less prolific ‐ probably due to a “dilution” effect ‐ but still higher than normal (p<0.05). We conclude that, in relatively mature ALL of the B‐ and the T‐cell line, the presence of circulating lymphoblasts is associated with increased PB proliferative capacity.