bluuebunny/crossref_metadata_2025_split huggingface dataset:
Thrombocytopenia after bone marrow transplantation for leukaemia: changes in megakaryocyte growth and growth‐promoting activity
Authors: Adams J. A. , Gordon A. A. , Jiang Y. Z. , Macdonald D. , McCarthy D. M. , Zuiable A. , Treleaven J. , Powles R. L. , Barrett A. J. 
Published: March 2008

SummaryMegakaryocyte growth‐promoting activity (MK‐GPA) was scored on a scale of 0‐3 in the serum of 23 patients up to 120 d following bone marrow transplantation (BMT) for leukaemia. Nine of] 9 allografts and two of four autografts had thrombocytopenia requiring platelet transfusion more than 30 d after BMT. There was a close correlation between MK‐GPA and platelet count. MK‐GPA reached a maximum before day 30 after BMT but remained elevated in patients with persisting thrombocytopenia secondary to poor engraftment, graft‐versus‐host disease (GVHD) or relapse. Recent platelet transfusion did not suppress serum MK‐GPA. Two of four patients undergoing autologous BMT for acute myeloid leukaemia (AML) showed delayed platelet recovery and persistence of MK‐GPA in the serum. Seven further AML remission marrows were tested for megakaryocyte production before or after autologous BMT, using pooled sera with known MK‐GPA activity. Megakaryocyte generation was reduced before BMT and absent in post transplant samples. This failure of MK production was not corrected by T‐cell depletion or by the presence of adherent cells from normal marrow. We conclude that thrombocytopenia after BMT is associated with an appropriate increase in MK‐GPA levels in response to a reduction in the megakaryocyte pool rather than the platelet pool, and that persisting thrombocytopenia after autologous BMT is due to decreased numbers of available megakaryocyte precursors.
Transfusion of ABO‐mismatched platelets leads to early platelet refractoriness
Authors: Carr Robert , Hutton Jane L. , Jenkins Jill A. , Lucas Geoffrey F. , Amphlett Nigel W. 
Published: March 2008

Summary. Forty‐three consecutive patients previously unexposed to platelets and undergoing treatment for acute leukaemia or autografting for relapsed Hodgkin's lymphoma were randomized to receive transfused platelets of either their own ABO group (OG) or of a major mismatched group (MMG). The 26 evaluable patients were equally distributed between the two study groups.Nine of 13 (69%) MMG patients became refractory with a median onset at transfusion 7 (15 d), compared with only one of 13 (8%) OG patients (P=0.001). Refractoriness was associated with the formation of high titre isoagglutinins, anti‐HLA and platelet specific antibodies. In one patient refractoriness appeared to be due to high titre isoagglutinins alone. Six other patients developed an increase in isoagglutinin titre sufficient to adversely affect platelet increments. Patients receiving ABO‐mismatched platelets had a higher incidence of anti‐HLA antibodies (5 v. 1) and platelet specific antibodies (4 v. 1). ABO‐mismatched platelets transfused prior to the onset of refractoriness resulted in increments similar to those achieved by ABO‐matched platelets.The study demonstrates that ABO‐mismatched platelets are as effective as matched platelets in patients with low titre isoagglutinins requiring only few transfusions. However, the greater incidence of early refractoriness induced in MMG patients indicates that ABO‐mismatched platelets should not be given to patients with marrow failure requiring long‐term support.
The role of interleukin‐1 and tumour necrosis factor‐α in human multiple myeloma
Authors: Carter Anna , Merchav Shoshana , Silvian‐Draxler Ilana , Tatarsky Ilana 
Published: March 2008

SummaryThis study investigates the capacity of interleukin‐1α (IL‐1α), interleukin‐1β (IL‐1β) and tumour necrosis factor‐α (TNF‐α) to induce interleukin‐6 (IL‐6) production in freshly isolated myeloma cells (MC) and bone marrow‐derived stromal cells (MSC). Recombinant human (rh) IL‐1α, IL‐1β and TNF‐α augmented production of IL‐6 in human MC.IL‐6 was determined on a factor‐dependent Cess cell line. This activity was completely abrogated by anti‐IL‐6 antibodies. Prior incubation of IL‐1α, IL‐1β and TNF‐α with their respective antibodies inactivated the ability of recombinant cytokines to stimulate the release of IL‐6 from myeloma cells. IL‐1α, IL‐1β and TNF‐α enhanced 3H‐TdR uptake in myeloma cells through IL‐6, as antibodies to IL‐6 completely abolished the DNA synthesis induced by culture supernatants of MC exposed to these cytokines. rhIL‐6 reversed the inhibitory action of anti‐IL‐6 antibodies and reinduced DNA synthesis in MC. Next we found that IL‐lα, IL‐1β and TNF‐α induced MSC to produce IL‐6. In contrast, supernatants of unstimulated MSC did not contain detectable IL‐6 biologic activity. Further data demonstrated that human MC were able to induce IL‐6 production in MSC. The stimulatory activities of MC appeared to be mediated through endogenously released IL‐1, as the addition of antibodies towards IL‐1 at the initiation of cocultures completely abrogated the IL‐6 production. We conclude from our data that IL‐1 and TNF‐α may play an important role in the pathogenesis of human multiple myeloma.
Calpain proteolysis of von Willebrand factor enhances its binding to platelet membrane glycoprotein IIb/IIIa: an explanation for platelet aggregation in thrombotic thrombocytopenic purpura
Authors: Moore Jane C. , Murphy William G. , Kelton John G. 
Published: March 2008

SummaryWe have previously observed calpain activity (calcium‐dependent cysteine protease) in sera from patients with acute thrombotic thrombocytopenic purpura (TTP). The calpain activity was not present following recovery and was not detected in other thrombocytopenic disorders. We postulated that this enzyme could participate in the pathogenesis of TTP. Because other investigators have demonstrated abnormalities of von Willebrand factor (vWF) in patients with TTP, we proposed that calpain might interact with vWF in TTP. To challenge this hypothesis, we measured the binding of untreated and calpain‐treated vWF to normal and ADP or calpain activated platelets. Untreated vWF bound in a specific and saturable fashion to activated platelets, but only at low (30 μm) calcium concentrations. Von Willebrand factor did not bind to activated platelets at physiological (2 mm) calcium concentrations. Calpain proteolysis of vWF changed the binding characteristics of the vWF so that it had greatly increased binding to both ADP and calpain activated platelets. The calpain‐proteolysed vWF bound to activated platelets at both low and physiological calcium concentrations, and was capable of causing platelet aggregation. The calpain‐proteolysed vWF bound to the activated platelets via glycoproteins IIb/IIIa as demonstrated by inhibition studies using monoclonal antibodies against glycoproteins IIb/IIIa and Ib. It also had a high binding affinity and was capable of inhibiting the binding of radiolabelled fibrinogen to the activated platelets at physiological calcium concentrations. Calpain also proteolysed fibrinogen, but the calpain altered fibrinogen had normal platelet reactivity.These studies provide further insight into the pathogenesis of the platelet aggregation of thrombotic thrombocytopenic purpura. Calpain proteolyses vWF and can produce the characteristic loss of large multimers seen on sodium dodecyl sulphate (SDS)‐agarose gel electrophoresis. The altered vWF is highly reactive with activated platelets and binds to platelet glycoproteins IIb/IIIa and participates in formation of the platelet aggregates that characterize this disease.
Post‐hepatitic aplastic anaemia in children in Taiwan, a hepatitis prevalent area
Authors: Liang Der‐Cherng , Lin Kai‐Hsin , Lin Dong‐Tsamn , Yang Chao‐Ping , Hung Kun‐Long , Lin Kuo‐Sin 
Published: March 2008

SummaryAplastic anaemia is a rare but serious complication of hepatitis, and hepatitis is an unusual cause of aplastic anaemia in children in the West. However, the relative frequencies of acquired aplastic anaemia in children in Taiwan, a hepatitis prevalent area, differ from those in the West, in the very high frequency of post‐hepatitic aplastic anaemia (23.9% of all cases of aplastic anaemia). This may account for the higher incidence of aplastic anaemia in children in Taiwan. Although the prognosis of post‐hepatitic severe aplastic anaemia was very poor, the present study using bone marrow transplantation, antithymocyte (or antilymphocyte) globulin, high‐dose methylprednisolone and cyclosporin, etc., has improved the response rate and the survival.
Erythropoietin production in kidney tubular cells
Authors: Maxwell Alexander P. , Lappin Terence R. J. , Johnston Colin F. , Bridges John M. , McGeown Mary G. 
Published: March 2008

SummaryThe erythropoietin gene has been cloned in three mammalian species including man and recombinant erythropoietin is now used to treat the anaemia of chronic renal failure. Despite the isolation of the gene the precise cellular location of erythropoietin synthesis remains controversial. We present studies which demonstrate erythropoietin production by kidney tubular cells. Erythropoietin gene expression (messenger RNA) was detected by in situ hybridization using an oligonucleotide gene probe and the translated protein product by immunohistochemistry employing antibodies raised to pure recombinant DNA derived erythropoietin.
Alpha‐2a‐interferon/melphalan/prednisone versus melphalan/prednisone in previously untreated patients with multiple myeloma
Authors: Montuoro Aldo , De Rosa Luca , De Blasio Angelo , Pacilli Leonardo , Petti Nicola , De Laurenzi Antonio 
Published: March 2008

SummaryAlpha‐2a‐interferon (IFN) has demonstrable activity in advance and refractory multiple myeloma (MM), because of the in vitro synergism between IFNs and cytotoxic agents we report the preliminary results of a therapeutic trial of 50 patients with MM. Twenty‐eight patients were randomized to receive melphalan plus prednisone (MP) and 22 were randomized to receive IFN plus MP (IFN‐MP). Criteria for response, progression and relapse were those of the South‐western Oncology Group. 95% of the patients receiving IFN‐MP responded to therapy as opposed to 68% of the patients receiving MP (P<0·05). Response was independent of M‐component immunoglobulin class but in stage III it was higher in the IFN‐MP group than in the MP group (P<0·05). The combination IFN‐MP was well tolerated without unusual or unexpected toxic effects. The response duration time was longer in the IFN‐MP group than in the MP group (P<0·025). The median survival was 80 weeks in the MP group and in the IFN‐MP group the 93% of patients were still alive after 90 weeks (P<0·025). Our results show that the use of the IFN as an adjuvant to MP improves the percentage of responders, the response duration time and the median survival of untreated patients with MM.
Evidence for a von Willebrand factor defect in factor VIII binding in three members of a family previously misdiagnosed mild haemophilia A and haemophilia A carriers: consequences for therapy and genetic counselling
Authors: Mazurier Claudine , Gaucher Christine , Jorieux Sylvie , Parquet‐Gernez Armelle , Goudemand Maurice 
Published: March 2008

SummaryA plasma von Willebrand factor (vWf) defect limited to its failure to bind factor VIII (FVIII) was previously characterized in a woman with FVIII deficiency and normal primary haemostasis. By usingin vitrotests we found a similar pattern in three siblings of another family previously thought to be affected with mild haemophilia A. Furthermore, a decrease in vWf ability to bind FVIII was found in the parents and the brother of the three patients. This decrease was consistent with heterozygous expression of a recessive vWf gene abnormality. FVIII deficiency was corrected by infusion with a vWf concentrate almost devoid of FVIII coagulant activity. FVIII recovery and half‐life thus obtained showed that this treatment was more effective than a FVIII infusion performed by way of comparison. These results indicate that this vWf defect may account for FVIII deficiency in patients without the usual laboratory and clinical features of von Willebrand's disease. Changes in therapy and genetic counselling following the new diagnosis in this family emphasize the need to search for such a vWf defect in patients in whom FVIII deficiency is not obviously X‐linked.
Measurement of fibrinogen binding to platelets in whole blood by flow cytometry: a micromethod for the detection of platelet activation
Authors: Warkentin Theodore E. , Powling M. J. , Hardisty R. M. 
Published: March 2008

SummaryPlatelet fibrinogen binding in whole blood has been measured in vitro by flow cytometry using a commercially available, fluorescein isothiocyanate (FITC)‐conjugated polyclonal antifibrinogen antibody. Fibrinogen–antifibrinogen immune complexes were formed in experimental conditions approaching antigen–antibody equivalence, but optimal reaction conditions in which their formation was prevented or minimized could be achieved. Immune complex formation was associated with fibrinogen binding to unstimulated platelets but did not significantly affect ADP‐induced fibrinogen binding. Half‐maximal fibrinogen binding occurred at about 0·4 μm ADP, and ADP‐induced fibrinogen binding continued progressively during 20 min incubation with 10 μm ADP. Fibrinogen binding correlated closely with platelet glycoprotein IIb–IIIa expression in members of a family with Glanzmann's thrombasthenia, and, in double labelling experiments, with the binding of PAC1, a monoclonal antibody that binds to GP lib–IIIa only after the exposure of fibrinogen receptors. These studies show that platelet fibrinogen binding can be reliably measured in whole blood by means of a polyclonal antifibrinogen antibody which does not discriminate between plasma and platelet‐bound fibrinogen, despite the presence of an approximately 100‐fold excess of the former.
Effects of recombinant human erythropoietin on haemolytic anaemia in mice
Authors: Cynshi Osamu , Shimonaka Yasushi , Higuchi Masato , Imai Nobuo , Suzuki Hiroshi , Togashi Mamoru , Okamoto Michio T. , Hirashima Kunitake 
Published: March 2008

SummaryThe effects of repeated administration of recombinant human erythropoietin (rHuEPO) were investigated in mice with haemolytic anaemia. Mice with haemolytic anaemia induced by phenylhydrazine (PHZ mice) were examined as an acute model and New Zealand black mice (NZB mice) at 13 months of age were examined as a chronic model. The plasma erythropoietin (EPO) level in PHZ mice was high and showed a strong inverse correlation with the Hb in the anaemia development period. However, it was relatively low in the recovery period from anaemia. On the other hand, the plasma EPO level in NZB mice showed a simple inverse correlation with the Hb. The rHuEPO was injected every day for a week into these mice. While a high plasma EPO level was maintained in PHZ mice, no significant effect was observed by injection with rHuEPO at dose of 600 IU/kg. However, in the recovery period from anaemia, RBC and haemoglobin in PHZ mice were increased by the rHuEPO treatment and recovered more quickly to their normal levels. In NZB mice, RBC and haemoglobin were also increased by treatment with rHuEPO at dose of 600 IU/kg. Anti‐RBC autoantibodies and anti‐EPO antibodies did not increase, while RBC and plasma EPO levels were increased by the rHuEPO treatment. These results suggest that some types of haemolytic anaemia are not always combined with high endogenous EPO levels and that exogenous rHuEPO may be effective for use in the treatment of haemolytic anaemia.
ABL proteins in Philadelphia‐positive acute leukaemias and chronic myelogenous leukaemia blast crises
Authors: Ponzetto Carola , Guerrasio Angelo , Rosso Claudia , Avanzi Giancarlo , Tassinari Angela , Zaccaria Alfonso , LoCoco Francesco , Foa Robin , Basso Giuseppe , Abate Maria Lorena , Comoglio Paolo M. , Saglio Giuseppe 
Published: March 2008

Summary. The Philadelphia chromosome (Ph1) is present in 95% of chronic myelogenous leukaemias (CML) and 15% of acute lymphoblastic leukaemias (ALL). This cytogenetic marker is due to a t(9;22) translocation, which causes a rearrangement of the ABL oncogene. In order to better define the relationship between type of genomic rearrangement, variant ABL protein expressed and haematological phenotype, a series of Phl‐positive acute leukaemias, both myeloblastic (AML) and lymphoblastic, and several CML lymphoid blast crises have been analysed at the DNA and protein level.The results confirm the presence of the ABL protein P210 in all cases of CML, ALL and AML positive for rearrangement in the bcr region of chromosome 22, and, surprisingly, in one AML case apparently negative for bcr rearrangement. The ABL protein P190 was found to be present only in cases of ALL negative for bcr rearrangement. Polymerase chain reaction (PCR) analysis of the types of 9/22 junctions present in the mRNA of CML lymphoid blast crises showed no evidence of‘ALL‐type’transcripts.
Antithrombotic potencies of heparins in relation to their antifactor Xa and antithrombin activities: an experimental study in two models of thrombosis in the rabbit
Authors: Amar J. , Caranobe C. , Sie P. , Boneu B. 
Published: March 2008

Summary. Our purpose was to determine the relative contribution of the antifactor Xa and antithrombin activities of heparin to its antithrombotic potency. The antithrombotic activities of unfractionated heparin (UH), two low molecular weight heparins (LMWH, CY 216 and CY 222) with increasing anti‐factor Xa/antithrombin ratio and a synthetic pentasaccharide (PS) with high affinity to antithrombin III and no antithrombin activity were evaluated. In the Wessler‐thromboplastin model, the most potent antithrombotic agent, on a weight basis, was UH followed by CY 216. CY 222 and the PS which was 40 times less potent than UH. On an antithrombin unit basis, the antithrombotic potencies of UH, CY 216 and of CY 222 were equivalent. Thus, in this model, the antithrombotic effect results from the catalytic action of UH or LMWH on thrombin inhibition. In the Wessler‐serum model, on a weight basis, the antithrombotic effectiveness of UH was unchanged, those of CY 216 and CY 222 were doubled, and that of the PS was increased 10 times. On an anti‐factor Xa unit basis, CY 216 was as effective as UH, and PS as effective as CY 222. On an antithrombin unit basis, CY 216 and CY 222 were equivalent and more potent than UH. Thus, in this model, the antifactor Xa activity of heparin becomes important for its antithrombotic property.After a single subcutaneous injection of 1000 antifactor Xa U/kg, the antithrombotic effects of UH were maintained for more than 14 h in the two models. After injection of the same dose of CY 216 significant antithrombotic effects were observed only for 9 h, in the Wessler‐thromboplastin model but for 18 h in the Wessler‐serum model. At that time, no detectable antithrombin activity was measurable in the plasma while 0.11 units of antifactor Xa activity/ml was detected. Thus, the relative contribution of the anti‐factor Xa and antithrombin activities to the antithrombotic effect of a LMWH differs according to the nature of the thrombogenic stimulus.
Molecular charge heterogeneity of human serum erythropoietin
Authors: Wide L. , Bengtsson C. 
Published: March 2008

Summary. The charge heterogeneity of human serum erythropoietin (S‐Epo) was studied in 89 serum specimens from 78 subjects by zone electrophoresis in 0.17% agarose suspension at pH 8.6. The electrophoretic elution profiles of S‐Epo were determined with a radioimmunoassay for Epo. The number of Epo peaks indicated that at least 20–30 different forms of Epo were present in a single serum specimen. The median charge of Epo, estimated as its median electrophoretic mobility, was determined for each serum specimen. This median charge was measured in 10 healthy adults, 46 patients with anaemia, six patients with secondary polycythaemia, one patient with polycythaemia Vera treated by phlebotomy, and six healthy newborn infants (cord sera). Forty‐four of the patients with anaemia had a median charge of S‐Epo within the reference range for healthy adults, while all the patients with polycythaemia and the newborn infants had less negatively charged forms of S‐Epo. In nine patients in whom the S‐Epo level had a circadian rhythm, the forms of S‐Epo in the evening were less negative than those in the morning. The median charge of recombinant preparations was much less negative than that of S‐Epo in healthy individuals, while that of the 2nd International Reference Preparation was more negative than in any of the 78 subjects analysed. A significant change to less negatively charged S‐Epo forms was observed 24 h after a subcutaneous injection of recombinant Epo in one patient, who before the injection had a normal median charge and concentration of S‐Epo.In conclusion, Epo exhibits a considerable charge heterogeneity in individual serum specimens, the forms of S‐Epo in the morning may differ from those in the evening, those in adults differ from those in newborn infants, and those in patients with anaemia differ from those in polycythaemia. The results also suggest that the methods used in this study may be useful for detecting the presence of injected recombinant Epo in the blood in persons with a normal endogenous Epo production.
Serum erythropoietin changes in autologous and allogeneic bone marrow transplant patients
Authors: Ireland R. M. , Atkinson K. , Concannon A. , Dodds A. , Downs K. , Biggs J. C. 
Published: March 2008

Summary. Sequential changes in serum erythropoietin (sEPO) levels were measured by radioimmunoassay in six patients receiving autologous rescue (AR) and 11 patients receiving an allogeneic bone marrow transplant (BMT) for malignant disease.Longitudinal studies showed an inverse relationship between sEPO and haemoglobin levels in the autologous rescue and allogeneic transplant patients throughout the 130 d post‐transplant study period. Early post‐conditioning EPO responses were normal for the haemoglobin level in both groups, but after day 14 post‐transplant, erythropoietin production in response to anaemia became impaired in one autologous rescue patient and eight of the 11 allogeneic transplant patients.There was no clear association between late impairment of sEPO production and conditioning therapy, infection, graft‐versus‐host disease, immunosuppressive therapy or serum creatinine.Blood transfusion requirements were similar for both groups in the first month after transplantation, but from days 31 to 90 post‐transplant, BMT patients required an average of 5.5 units per patient compared with 1 unit per patient for the autologous group.Marrow transplant procedures do not affect early EPO responses but may diminish late responses. The potential value of exogenous rHuEPO in hastening engraftment and decreasing transfusion requirements, particularly for those patients who appear to have impaired EPO responses, remains to be shown by clinical trials.