bluuebunny/crossref_metadata_2025 huggingface dataset:
Effect of hemodilution on maximal oxygen consumption, blood lactate response to exercise and cerebral blood flow in subjects with a high‐affinity hemoglobin
Authors: Wranne Bengt , Jorfeldt Lennart , Berlin Gosta , Ryding Erik , Lansimies Esko , Kuikka Jyrki , Rautio Pentti , Vainio Pauli , Lahtinen Reino
Published: July 2010

Abstract:  10 subjects with Hb Linkdping (β 36 Pro>Thr), a high‐affinity hemoglobin variant, with a P50 of 2.2 kPa (16.5 mm Hg) were investigated before and 3–4 days after normovolemic hemodilution. Blood hemoglobin concentration decreased from 176 ± 13 (SD) to 146 ± 15 g 1‐1and the red cell volume from 2.77 ± 0.83 to 2.23 ± 0.67 1. Maximal oxygen consumption decreased slightly by 2.7 ± 3.8 ml min‐1kg‐1and maximal exercise power by 11 ± 23 W; these changes were, however, not statistically significant. Maximal heart rate was unchanged (— 1.1 ± 6.4 beats min‐1) while submaximal heart rate was consistently increased on comparable loads after hemodilution compared to before. The exercise ECG was normal both before and after hemodilution. Capillary lactate levels at exercise were always higher after hemodilution than before. Cerebral blood flow was normal both before and after hemodilution in all subjects but one who had a high flow. The grey matter blood flow increased slightly but significantly by 8.6 ± 10.3 ml min‐1100 g‐1from before to after hemodilution. The results indicate that subjects with Hb Linkoping have only limited benefit from their increased blood hemoglobin concentration.
Immune function parameters at diagnosis in patients with myelodysplastic syndromes: Correlation with the FAB classification and prognosis
Authors: Symeonidis Argiris , Kourakli Aleka , Katevas Prokopis , Perraki Maria , Tiniakou Maria , Matsouka Panayota , Georgoulias Vassilis , Zoumbos Nicholas
Published: July 2010

Abstract:  We determined nine immune function parameters at diagnosis in patients with myelodysplastic syndromes (MDS) and correlated the results with the FAB classification and prognosis by univariate and multivariate analyses. Patients with refractory anaemia (RA) and refractory anaemia with ring sideroblasts (RAS) tended to have a higher CD4/CD8 ratio and a lower amount of γ‐globulins and soluble interleukin‐2 receptors in serum in comparison to those suffering from the other three subgroups of MDS. FAB classification, neutrophil and CD8 + T‐cell number had the best discriminatory capacity for predicting survival less than 1 year, and FAB classification, neutrophil number and serum TNF levels were predictors for conversion to acute leukaemia. The frequent occurrence of infections, on the other hand, could be better predicted by the absolute numbers of neutrophils and CD4 + cells and by the skin test score.
Inhibitory effect of cyclosporin A on erythroid and stromal colonies
Authors: Clarke E. , Quinn D. G. , McCann S. R.
Published: July 2010

Abstract:  Cyclosporin A is used to prevent graft‐versus‐host disease (GvHD) following bone marrow transplantation (BMT) and it has been implicated in reducing the time to engraftment for leukaemia and aplastic anaemia patients. To evaluate the effect of cyclosporin A on engraftment, the proliferative capacity of bone marrow progenitors (CFU‐E, CFU‐F and CFU‐C) was assessed both in vitro and following treatment with cyclosporin A over a 9‐week period using an animal model. Cyclosporin had a differential effect on the haemopoietic progenitors, with the myeloid series unaffected at therapeutic concentrations. Both erythroid and stromal progenitors were significantly inhibited at similar concentrations. The mechanism by which cyclosporin A enhances engraftment remains unclear; however, it is not mediated by enhancing any of the haemopoietic progenitors.
Red cell lipid peroxidation and antioxidant enzymes in iron deficiency
Authors: Acharya J. , Punchard N. A. , Taylor J. A. , Thompson R. P. H. , Pearson T. C.
Published: July 2010

Abstract:  Whether iron deficient RBC in humans have a reduced, or an increased, susceptibility to lipid peroxidation was studied in the iron deficiency states of primary proliferative polycythaemia and iron deficiency anaemia and related to changes in the activities of iron‐dependent and non‐iron dependent antioxidant enzymes. Susceptibility of RBCs to lipid peroxidation was increased when expressed per g Hb. However, this was a result of the low RBC Hb giving an increased membrane lipid: Hb ratio in the incubations. Results were normal when expressed either per cell, or per ml, RBC. Glutathione reductase was normal. Increased RBC superoxide dismutase activity in iron deficiency may be explained by the younger RBC population and reductions in glutathione peroxidase and catalase activities by the microcytic hypochromic changes and the lack of availability of iron, respectively. There is no evidence of an increased susceptibility of RBC to lipid peroxidation in iron deficiency.
Iron status markers in hereditary haemochromatosis: Distinction between individuals being homozygous and heterozygous for the haemochromatosis allele
Authors: Milman Nils
Published: July 2010

Abstract:  Iron status markers, serum iron, serum transferrin, transferrin saturation and serum ferritin were analysed in 162 homozygous patients with clinical haemochromatosis, in 12 homozygous relatives with preclinical haemochromatosis, in 84 heterozygous, and in 9 normal subjects. In the distinction between homozygous patients with clinical haemochromatosis and heterozygotes, transferrin saturation and serum ferritin showed the highest diagnostic efficiencies. A diagnostic efficiency of 0.97 was obtained with a transferrin saturation value of 60%. A discriminatory transferrin saturation value of >50% correctly classified 173 out of the 174 individuals with preclinical + clinical haemochromatosis, whereas a discriminatory value of >60% identified 158 out of the 162 patients with clinical haemochromatosis. All patients with clinical haemochromatosis had transferrin saturation values >50%. 10 heterozygotes had transferrin saturation values >50%, and 3 values >60%. Normal subjects had transferrin saturation values <47%. A diagnostic efficiency of 0.99 was obtained using a discriminatory serum ferritin value of 800 ug/1. Patients with clinical haemochromatosis had higher ferritin (p< 0.001) than subjects with preclinical haemochromatosis, who in turn had higher values than heterozygotes (p< 0.001). Iron status markers in heterozygotes and normal subjects displayed no significant differences.
Combining counterflow centrifugal elutriation and glycoprotein lb‐dependent purification of human megakaryocytes: Efficacy and selectivity
Authors: van Pampus E. C. M. , van Geel B. J. M. , Huijgens P. C. , Wijermans P. W. , Ossenkoppele G. J. , Rodriguez F. , Zevenbergen A. , Langenhuijsen M. M. A. C.
Published: July 2010

Abstract:  To estimate the efficacy of human megakaryocyte purification techniques, mixtures of known numbers of megakaryocytes with a known ploidy range and of bone marrow or peripheral blood mononuclear cells were made. These artificial bone marrow samples were submitted to either a counterflow centrifugal elutriation or Percoll density separation followed by the glycoprotein lb‐dependent agglutination procedure. Also crude bone marrow samples were submitted to counterflow centrifugal elutriation directly followed by a glycoprotein Ib‐dependent agglutination. The counterflow centrifugal elutriation resulted in a mean megakaryocyte recovery of 81% (mean 81% ±2.3). Purification by glycoprotein Ib‐dependent agglutination after either a Percoll density separation or counterflow centrifugal elutriation resulted in a recovery of 61% (mean 61%±15%) and 81% (mean 81% ±6) respectively. Purity of the resulting material was 87% (mean 87% ±11) and 83% (mean 83% ±5) respectively. The various isolation procedures did not affect the ploidy distribution of megakaryocytes ≥8N. Counterflow centrifugal elutriation was preferred as the preparing step before glycoprotein Ib‐dependent agglutination because of the lower variability in recovery and purity of megakaryocyte populations. When large numbers of rather pure and mature megakaryocytes are required, counterflow centrifugal elutriation followed by the glycoprotein Ib‐dependent agglutination is a relatively simple method to purify human megakaryocytes without an | appreciable loss in ploidy class ≥8N.
Increased serum neopterin concentration as indicator of disease severity and poor survival in multiple myeloma
Authors: Boccadoro Mario , Battaglio Silvano , Omede Paola , Palumbo Antonio P. , Fusaro Antonella , Frieri Roberto , Gallone Gabriele , Polloni Renato , Mosso Roberto , De Filippi PierGiuseppe , Pileri Alessandro
Published: July 2010

Abstract:  In this study we investigated serum neopterin levels in 73 multiple myeloma (MM) patients (63 determinations at diagnosis, 58 in remission, and 35 at relapse), in 56 monoclonal gammopathies of undetermined significance (MGUS), and in 70 normal controls. Median neopterin level was 5.3 nmol/1 in normal controls* 6.8 nmol/1 in MGUS, and 10.7 nmol/1 in MM patients. In comparison to healthy subjects, significantly higher levels were observed in MM patients (p<0.0001). A statistical difference was observed between MGUS and MM patients at diagnosis (p< 0.007). Compared to diagnosis, a further increase was noticed during relapse, suggesting a correlation between neopterin and disease activity. The prognostic significance of raised neopterin levels was confirmed by a survival analysis. Median survival for patients with high values was 20 months, whereas it was 63.9 months for those with low values (log‐rank test p < 0.003). Serum neopterin concentrations also correlated to β2 microglobulin levels and the percentage of CD38+circulating lymphocytes, indicating a link between neopterin and other myeloma prognostic factors.
Hemopoietic improvement following fetal liver infusion in aplastic anemia
Authors: Kochupillai Vinod , Sharma Subhadra , Sundaram K. R. , Ahuja R. K.
Published: July 2010

Abstract: 41 (38 males, 3 females) patients with aplastic anemia received fetal liver infusion (FLI) from 74 abortuses with gestation periods of 8–32 (Median(M)‐16) weeks and cell dose of 0.004–11.1 times 108 (M‐2.3 times 108) from September, 1976 until November, 1987. 35 persons received single FLI; those with recurrence or no response received two or more FLI. 8 received two; 7, three; 2, four; and 1, six FLI. There was a slow and incomplete autologous hematopoietic improvement in 40% and expected survival of 52% at 1 year, 45% at 2 yr, and 37% at 5 yr (Kaplan Meier estimate). There was rise in fetal hemoglobin (Hb), 0–15.7%, (M‐3.5) among responders in 3–20 (M‐6) months. Patients who survived for more than 12 months had, on average, a longer duration of disease (4 months or more), and higher granulocyte and platelet counts. Statistically, however, these differences were not significant. Reticulocyte count was significantly lower in those who survived beyond 12 months. 1 patient developed acute undifferentiated leukemia 3 yr post‐FLI. The study indicates that fetal liver infusion is likely to benefit about 40% of individuals suffering from severe aplastic anemia. Longer surviving patients, however, may be at risk of developing clonal diseases.
An abnormal pattern of multiple platelet function abnormalities and increased thromboxane generation in patients with primary thrombocytosis and thrombotic complications
Authors: Zahavi J. , Zahavi M. , Firsteter E. , Frish B. , Turleanu R. , Rachmani R.
Published: July 2010

Abstract: Platelet aggregation (PA) induced by ADP, collagen and epinephrine, plasma levels of β‐thromboglobulin (βTG) and thromboxane B2 (TXB2) and serum TXB2 generation were studied in 11 patients with primary thrombocytosis (7 with essential thrombocythaemia and 4 with polycythaemia vera) and compared with 16 healthy subjects. 5 patients suffered from peripheral vascular ischaemia and another 3 had venous thrombosis, but none had bleeding complications. The patients showed an abnormal pattern of platelet function and of thromboxane generation distinct from the healthy subjects in three aspects, a) Shape change was 5–26 times greater, the lag‐time of collagen PA was 2.3‐2.9 times longer and the extent of epinephrine PA was nil or very low. ADP‐or collagen‐induced PA was also reduced (p<0.02). b) Plasma TXB2 generation (corrected to a normal platelet concentration) stimulated by the three PA inducers was within the range of the healthy subjects in spite of the reduced extent of PA. c) Plasma βTG level and serum TXB2 generation (both corrected to a normal platelet concentration) were 2.9‐7.1 times higher (p < 0.001) indicating enhanced in vivo platelet activation and possibly increased thrombin generation. These abnormalities were not detected in another 4 patients with secondary thrombocytosis. The abnormal pattern of platelet function and thromboxane generation can be a useful laboratory method in the evaluation of patients with primary thrombocytosis. It might also explain the thrombotic complications which occurred in 8 of the patients in a manner such that increased or normal TXB2 generation overcomes the reduced extent of PA. In this respect, the pronounced serum TXB2 synthesis might be a marker of intravascular thrombosis.
Has the incidence of multiple myeloma in old age been underestimated?
Authors: Wisløff F. , Andersen P. , Andersson T. R. , Brandt E. , Eika C. , Fjæstad K. , Ly B. , Løvåsen K. , Strøm B. Riis , Tjønnfjord G. E.
Published: July 2010

Abstract:All patients in the region with newly discovered M components were registered from 15 Aug. 1984‐31 Dec. 1986. Among a total of 393 patients enrolled, 162 had multiple myeloma (MM). The incidence rate was 6.6 per 100000 population per year (age‐adjusted to the European standard population), which is somewhat higher than previous reports based on hospital and autopsy records. In particular, the incidence rate was higher in the > 70 age group. Thus, the median age was 72 yr, which is the highest reported. As many as 71 (44%) of the 162 MM patients were asymptomatic; these asymptomatic patients had the same age distribution as the symptomatic ones. The stage distribution, occurrence of risk factors, response to chemotherapy, response duration and survival were similar in the age groups below and above the median and, in multivariate survival analysis, age was not an independent risk factor.
Incidence and follow‐up of asymptomatic multiple myeloma.
Authors: Wisløff F. , Andersen P. , Andersson T. R. , Brandt E. , Eika C. , Fjæstad K. , Grønvold T. , Holm B. , Løvåsen K. , Tjønnfjord G. E.
Published: July 2010

Abstract:During a general population follow‐up study in Health Region I in Norway, 162 patients with multiple myeloma (MM) were diagnosed. 71 of these (44%) were asymptomatic, and were observed without chemotherapy. The great majority (90%) were in stage I, and there were only 2 with light chain disease. 45 of the 71 asymptomatic patients developed progressive disease during the 4–5 year follow‐up period. Estimated median time to disease progression was 26 months. The presence at diagnosis of osteolytic lesions and/or at least 20% plasma cells in the bone marrow defined a group with significantly shorter time to progression (median 10vs39 months). Median survival from diagnosis for the asymptomatic patients was 45 months, which is significantly longer than the 26 months of the symptomatic group. However, when estimated from the start of treatment, the survival was similar for the two groups.
Prophylactic heparin does not prevent liver veno‐occlusive disease following autologous bone marrow transplantation
Authors: Marsa‐Vila L. , Gorin N. C. , Laporte J. P. , Labopin M. , Dupuy‐Montbrun M. C. , Fouillard L. , Isnard F. , Najman A.
Published: July 2010

Abstract: Veno‐occlusive disease (VOD) is a major cause of toxic death after autologous bone marrow transplantation (ABMT). We studied the potential role of continuous administration of low‐dose heparin for VOD prevention in 234 consecutive patients who underwent ABMT in our institution. The population consisted of 98 patients autografted before October 1984 who did not receive heparin, and a series of 136 patients autografted from October 1984 to March 1989 containing 98 patients included in a randomized trial comparing heparin administration (n = 52) vs no heparin (n = 46), and an additional group of 38 patients who received non‐randomized heparin in view of high‐risk criteria to develop VOD (n = 31) or other reasons unrelated to VOD (n = 7). Overall, 90 patients (38%) received heparin and 144 (62%) did not. The global incidence of VOD was 13/234 (5–5%). Heparin did not reduce the risk of VOD in all subgroups studied. In particular, in the randomized trial, the incidence of VOD was 2.2% in the group without heparin vs 7–7% in the group receiving heparin. We analyzed in depth the 13 patients who developed VOD and we compared them to a control group of 13 patients pair‐matched for age, sex, diagnosis and preparative regimen, who did not develop VOD. We found that abnormal LFT before ABMT predisposed patients to VOD; refractoriness to platelet transfusion was observed in 85% of the patients in the VOD group vs 15% in the control group (p<0.05). VOD patients had an increased requirement for red cells and platelet transfusions, a lower recovery (R<25%) after the second and third platelet transfusion, and shorter intervals separating the first four platelet transfusions. Further, the platelet reconstitution after ABMT in the VOD group was slower in comparison to the control group (p<0.01). Again, in this pair‐matched analysis continuous infusion of low‐dose heparin did not prevent VOD.
Treatment of myelodysplastic syndromes with recombinant human erythropoietin
Authors: Hellström Eva , Birgegård Gunnar , Lockner Dieter , Helmers Claes , Öst Åke , Wide Leif
Published: July 2010

Abstract: 12 patients with myelodysplastic syndromes were treated with recombinant human erythropoietin (r‐epo). 5 patients had stable anemia, 78–92 g/l, and 7 were transfusion‐dependent. In 11 patients, r‐epo was given intravenously three times a week, with dose escalation after 4 and 8 wk if hemoglobin did not increase more than 15 g/l. The doses were 600, 1500 and 3000 U/kg body weight/wk. The 12th patient was treated subcutaneously with a dose of 560 U/kg/wk. 3 patients showed a significant response with an increase in hemoglobin of ≥ 15 g/l. 2 of these had stable anemia before treatment and increased in hemoglobin from 87 to 116 g/l and from 80 to 99 g/l, respectively. The 3rd patient was transfusion‐dependent and rose to a stable hemoglobin level between 76 and 80 g/l without transfusions. 2 patients showed a reduction of their transfusion need. Mean initial serum erythropoietin in the responding group was 366 U/l compared to 1049 among the non‐responders (p = 0.367). Response was observed in 5/7 patients without bone marrow sideroblasts and in 0/5 patients with sideroblasts (p = 0.027). Erythropoietin seems to be an effective and well‐tolerated treatment for a certain proportion of patients with MDS. A larger patient material might provide a model for predicting responses.
Phenotyping of peripheral blood hemopoietic progenitor cells – in vitro cultures using CD34‐/CD33‐immunomagnetic purging
Authors: Serke Stefan , Abe Yoshikazu , Kirsch Andreas , Huhn Dieter
Published: July 2010

Abstract: In contrast to many detailed studies on the antigenic profile of hemopoietic progenitor cells from human bone marrow, sparse information, so far, has been gathered with regard to the antigen expression of hemopoietic progenitors present in peripheral blood. Previous studies by multiparameter flow‐cytometry have revealed substantial differences of the coexpression of the CD33‐, CD19‐, and CD74‐ antigens, respectively, on CD34‐positive cells from blood versus those from bone marrow, respectively. Immunomagnetic purging with monoclonal antibodies detecting the CD34‐, and the CD33‐ antigen, respectively, has been used to further characterize the expression of these antigens on day 8 and d‐14 granulocyte/macrophage and erythroid colonies as grown from circulating progenitor cells. Purging with CD34 monoclonal antibody abrogated all colony formation, whereas purging with CD33 antibody led to differential inhibition of the various progenitors. Purging bone marrow cells with CD34 antibody, an inhibition of only about 25 % was observed with regard to erythroid colonies, whereas an inhibition of about 85 % was observed for CFU‐GM. These findings reinforce the view that circulating progenitor cells represent relatively immature stages of differentiation, when compared to bone marrow progenitors. Particularly, d‐8 erythroid colonies from blood do not represent the equivalent of the genuine CFU‐E as described from bone marrow, but they seem to be early stages of BFU‐E development.
Diagnostic utility of the pre‐incubated acidified glycerol lysis test in haemolytic and non‐haemolytic anaemias
Authors: Hoffmann J. J. M. L. , Swaak‐Lammers N. , Breed W. P. M. , Strengers J. L. M.
Published: July 2010

Abstract: The usefulness of the pre‐incubated acidified glycerol lysis test (AGLT), a laboratory test for spherocytosis, has been investigated in a selected hospital population of 348 patients with haemolytic and non‐haemolytic anaemia. The AGLT was positive in 58 out of 59 patients with hereditary spherocytosis. In all 32 patients with other types of hereditary haemolytic anaemia the AGLT was normal or equivocal, but clearly different from spherocytosis. Adults with a positive AGLT, but without hereditary spherocytosis, had auto‐immune haemolytic anaemia, myelodysplastic syndrome or were pregnant women. In newborn infants the AGLT was positive, in the first week of life, in those babies having hereditary spherocytosis or immune haemolysis due to blood group incompatibility; no positive AGLT results were seen if no haematological explanation for neonatal hyperbilirubinaemia could be found. At the optimal cut‐off point the sensitivity of the AGLT for hereditary spherocytosis was 98.3% and the specificity 91.1%, under the most unfavourable conditions. The AGLT is a very useful and simple test for the diagnosis of hereditary spherocytosis.
Prophylaxis of cytomegalovirus infection with ganciclovir in allogeneic marrow transplantation
Authors: Yau Jonathan C. , Dimopoulos Meletios A. , Huan Susan D. , Tarrand Jeffrey J. , Spencer Verneeda , Spitzer Gary , Meneghetti Carole M. , Wallerstein Ralph O. , Andersson Borje S. , LeMaistre C. Frederick
Published: July 2010

Abstract: Cytomegalovirus (CMV) infection is one of the most common causes of morbidity and mortality after allogeneic marrow transplantation. We studied 14 consecutive CMV‐seropositive patients adding ganciclovir (2.5 mg/kg i.v. every 8 hours for 7 days prior to transplant and 6 mg/kg three times a week after neutrophils became > 0.5 times 109/1 and the patients were platelet transfusion‐independent until d 70) to our previous prophylaxis regimen which consisted of intravenous immunoglobulin and acyclovir. The result was compared with 30 consecutive patients whom we studied with our previous regimen. The addition of ganciclovir did not cause any extra toxicities. The incidence of interstitial pneumonitis and cumulative probability of CMV excretion in the first 100 d post‐transplantation was significantly reduced (p = 0.038 and p = 0.035 respectively). The result shows that addition of ganciclovir significantly decreased the incidence of CMV infection in the early post‐transplantation period.
Effectiveness of partial splenic embolization as treatment for hypersplenism in thalassaemia major: A 7‐year follow up
Authors: Pinca A. , Soriani S. , Di Palma A. , Sprocati M. , Vullo C. , Mannella P. , Georgacopulo P. , Bagni B.
Published: July 2010

Abstract: Partial splenic embolization is an alternative procedure to total splenectomy in patients with hypersplenism, and was performed in 10 patients with beta‐thalassaemia major who were then followed for 5 to 7 years. The results were compared with those of a 7‐yr follow‐up of 6 splenectomized thalassaemics. The blood consumption decreased and the leucocyte counts increased in both groups of patients. However, after partial splenic embolization, severe thrombocytosis — which is typical of splenectomized patients — did not develop and there were no severe complications from the operation, such as infections or reappearance of hypersplenism. In addition, the minor surgical injury and avoidance of abdominal scars were further advantages of partial splenic embolization over total splenectomy.
Treatment of acute lymphoblastic leukaemia (ALL)
Authors: Jacobs Peter , Wood Lucille
Published: July 2010

Abstract: Forty‐six consecutive patients with acute lymphoblastic leukaemia (ALL), having a median age of 23 years (range 14 to 64), underwent induction and consolidation chemotherapy with weekly parenteral vincristine, adriamycin, 1‐asparaginase and daily oral prednisone (VAAP), followed by standard central nervous system (CNS) prophylaxis. Maintenance therapy was given for 3 years and consisted of daily 6‐mercaptopurine, weekly methotrexate, and monthly intrathecal chemotherapy, with drug intensification comprising either vincristine, adriamycin and 1‐asparaginase (VAA) or cyclophosphamide, vincristine, cytosine arabinoside and prednisone (COAP). Complete remission (CR) was achieved in 36 patients (78%) and only the FAB L1 morphology was a significant predictive factor (Chi‐squared = 3.91: p < 0.05). Eight of the 10 non‐responders had significant drug resistance and 3 deaths were associated with marrow hypoplasia. Median follow‐up is 52 months. Median duration of CR is 28 months, median survival of all patients is 16 months, and for those who achieved CR is 44 months. There was no difference between the two maintenance arms. Significant prognostic factors for survival are French‐American‐British (FAB) subtype, in which the L1 is better than L2 (p = 0.05), and age (p = 0.035). Nineteen patients have experienced medullary relapse and 7 (37%) achieved subsequent CR; this is durable in a single patient who underwent allogeneic bone marrow transplantation. Eight patients (17%) had CNS disease at diagnosis; 5 achieved CR and 1 is alive and disease‐free at 65 + months. There has been 1 CNS relapse. These results demonstrate that prolonged remissions and survival can be achieved with this protocol and many patients possibly cured. The level of toxicity is acceptable and the pattern of induction failure indicates that a margin exists for intensifying chemotherapy and thereby possibly further improving results.
Erythropoietin response in anaemic patients with multiple myeloma and other lymphoid malignancies infiltrating the bone marrow
Authors: Ariad S. , MacPhail A. P. , Bezwoda W. R. , Clifford D. , Penfold G.
Published: July 2010

Abstract: Immunoreactive erythropoietin levels were measured in 42 patients with lymphoid malignancies with anaemia and bone marrow involvement. Results were compared to a control group of 16 patients suffering from anaemia due to other causes. Significant inverse correlations between serum erythropoietin level and haemoglobin concentration were shown for the patients with lymphoid malignancies and also for the control subjects. Overall, the erythropoietin levels of patients with lymphoid malignancies with bone marrow infiltration and with normal renal function did not differ significantly from erythropoietin levels of the anaemic controls. We conclude that anaemia in patients with lymphoproliferative disorders with bone marrow infiltration and normal renal function is caused primarily by a diminished/inadequate response to erythropoietin at the level of the target cell.
Initial cytoreduction by mitoxantrone and cytarabine has no impact on the outcome of interferon‐alfa‐2b therapy in chronic myelogenous leukemia
Authors: Nielsen Henrik , Nielsen Johan Lanng , Karle Hans
Published: July 2010

Abstract: Eleven previously untreated patients with chronic‐phase Philadelphia‐chromosome‐positive chronic myelogenous leukemia were treated with cytotoxic chemotherapy followed by interferon‐alfa‐2b (IFN‐α) maintenance. Initial chemotherapy consisted of three cycles of mitoxantrone 10 mg/m2 on day 1 and 2, and cytarabine 100 mg/m2 daily for 5 d. Complete hematological response was obtained in 9 (82%) patients with moderately associated toxicity. However, cytogenetic responses after three cycles were poor and transient (1 partial suppression and 2 minor suppression of Ph chromosome). Maintenance therapy with IFN‐α was started in 10 patients at 5 × 106 U/m2 daily with dose reduction if hematologic toxicity or severe side‐effects occurred. Of 9 evaluable patients treated for more than 3 months, 6 patients maintained a complete hematological response, whereas 1 patient remained in partial remission and 2 patients showed progressive disease. Cytogenetic evaluation showed partial suppression of Ph chromosome in 1 patient, whereas 1 patient had a minor response and 5 patients had no change or evolution of new chromosome abnormalities. As the results are not superior to IFN‐α treatment alone, it is concluded that initial cytoreduction by mitoxantrone and cytarabine has no impact on the outcome of therapy in CML.
Antiviral nucleoside toxicity in canine bone marrow progenitor cells and its relationship to drug permeation
Authors: Chan Thomas C. K. , Shaffer Lauren , Boon G. Daniel , Redmond Robert
Published: July 2010

Abstract:The most promising nucleoside analogs that are currently undergoing preclinical and clinical testing for anti‐HIV activity belong to the dideoxynucleoside group. We have studied the toxicity of 3′‐azido,3′‐deoxythymidine (AZT), 2′,3′‐dideoxycytidine (DDC), and 2′,3′‐dideoxyinosine (DDI) in canine bone marrow progenitor cells in culture. AZT potently inhibited both canine CFU‐GM and CFU‐E with IC50values of 2 and 8 μmol/l respectively, while DDC was relatively non‐toxic to either progenitor with IC50of > 200μmol/l and 80μmol/l respectively. DDI was mildly toxic to the bone marrow progenitors, with IC50values of 62 μmol/l for CFU‐GM and 70 μmol/l for CFU‐E. Dipyridamole, a nucleoside transport inhibitor, did not influence the toxicity of these dideoxynucleosides in either progenitor at concentrations up to 10 μmol/l. Using uridine as the prototype endogenous nucleoside, we have demonstrated that there is a saturable “zero‐trans” nucleoside transport system in canine bone marrow mononuclear cells, which is completely inhibited by 1 μmol/l dipyridamole (Ki = 0.02 μmol/l). None of the dideoxynucleosides appeared to be a substrate for this transport system, and dipyridamole did not alter their influx. Permeation of radiolabeled AZT into bone marrow mononuclear cells was slow and non‐saturable, while the permeation of DDI was even slower. DDC did not permeate bone marrow cells well, with very little cell accumulation even after 2 hours of equilibration. Our toxicity data from canine bone marrow progenitor cells paralleled the clinical hematotoxicity profiles of these dideoxynucleosides in AIDS patients and suggest that the myelotoxicity of a nucleoside analog is related to its ability to permeate the progenitor cells in question. Canine bone marrow progenitor cultures may serve well as anin vitromodel for drug hematotoxicity studies.
A randomized trial comparing the use of fresh and stored platelets in the treatment of bone marrow transplant recipients
Authors: Shanwell A. , Larsson S. , Aschan J. , Ringdén O.
Published: July 2010

Abstract: Patients undergoing allogeneic bone marrow transplantation (BMT) were randomized into two groups. One group (n = 21) received single donor platelet concentrates (PC) that were as fresh as possible, the other group (n = 18) received single donor PC stored for 2 to 5 days. Actual mean storage times for PC were 1.12 ± 1.25 (mean ± SD) and 2.67 ± 1.30 d, respectively (p < 0.001). The total need for platelets during 60 d after BMT in patients receiving fresh PC was 22.1 ± 17.8 × 109 platelets/liter blood volume/d, and for stored PC 29.2 ± 19.2 × 109 platelets/liter blood volume/d (n.s.). A multiple regression analysis of the data showed no correlation between PC storage time and the PC requirement (p = 0.85). Posttransfusion corrected count increment (CCI) at 1 hour was 10.4 ± 5.1 for PC stored 0–1 d, 10.3 ± 7.0 for PC stored 2–3 d, and 11.4 ± 9.2 for PC stored 4–5 d. The corresponding CCI, at 18 h were 6.5 ± 4.4, 5.4 ± 3.3 and 6.8 ± 4.6. We conclude that there is no major difference between fresh and stored single donor PC.
Erythrocyte pyruvate kinase deficiency: Relations of residual enzyme activity, altered regulation of defective enzymes and concentrations of high‐energy phosphates with the severity of clinical manifestation3
Authors: Lakomek Max , Neubauer Bernd , Lühe Andreas von d. , Hoch Gerhard , Schröter Werner , Winkler Heinz
Published: July 2010

Abstract: The defective enzymes of 54 patients with pyruvate kinase (PK) deficiency were characterized according to the recommendations of the International Committee for Standardization in Haematology (ICSH). The erythrocyte PK activity in whole blood was calculated considering the 16‐fold higher activity of the reticulocyte enzyme (AR) compared to the erythrocyte enzyme (AE). The following parameters turned out to give a good correlation to the degree of haemolytic anaemia and can therefore serve as a prognostic tool: All patients with a severe course of the disease had residual erythrocyte PK activities less than 33% of the normal enzymes (percentage activity), and patients with mild haemolytic anaemia exhibited residual activity values below and above this threshold value. Studies of enzyme cooperativity showed that positive cooperative or mixed cooperative phosphoenolpyruvate (PEP) binding with a predominant positive cooperative part appeared in all cases with a mild clinical course, and about one‐third of the severe ones. Negative cooperativity or mixed cooperativity with predominant negative cooperative part was observed only with severe haemolytic anaemia. Furthermore, the determination of glucose‐6‐phosphate (G‐6‐P) turned out to be a good prognostic criterion, i.e. all patients with mild clinical course exhibited G‐6‐P‐concentrations lower than 0.11 μmol/l red blood cells. In the case of patients with severe haemolytic anaemia, about 80% showed values higher than 0.11 μmol/l RBC.
Multiple myeloma: Intensified maintenance therapy with recombinant interferon‐α‐2b plus glucocorticoids
Authors: Palumbo Antonio , Boccadoro Mario , Garino Lucia A. , Gallone Gabriele , Frieri Roberto , Pileri Alessandro
Published: July 2010

Abstract: Interferon‐α‐2b has been demonstrated to prolong remission duration and survival in responding multiple myeloma patients. The aim of this study was to evaluate intensification of this maintenance therapy through the addition of glucocorticoids. Eighteen myeloma patients at diagnosis received six‐12 courses of conventional chemotherapy and then interferon + glucocorticoids. This treatment included 3 megaunits of interferon three times a week, plus 4 days of pulsed high‐dose dexamethasone (40 mg/d for 4 d every 28 d for 6 months/year) in patients < 70 yr old, or oral prednisone (50 mg three times a wk) in patients > 70 yr old. Conventional chemotherapy induced an objective response in 13/18 patients and a further reduction of the M component (> 50%) was achieved during interferon + glucocorticoids treatment in 7/13. 4/18 patients relapsed with a median follow‐up of 22 months (range 13–40). These findings indicate that interferon + glucocorticoids, after inductional chemotherapy, further reduces tumor burden and may prolong remission.
Elastase activity in leukaemic cells and plasma in patients with acute leukaemia
Authors: Törnebohm E. , Lockner D. , Paul C. , Egberg N. , Sablica H. , Wallin R.
Published: July 2010

Abstract: Proteolysis of coagulation factors and inhibitors resulting in haemorrhage can be mediated by elastase. Indirect signs of this are elevated levels of elastase complexed to its inhibitor in plasma, α1‐antitrypsin (Eα1‐AT). We have measured intracellular elastase activity in leukaemic cells from 60 patients with acute leukaemia. Elastase activity was detected in 92% of the patients with acute nonlymphoblastic leukaemia (ANL), no activity was found in the patients with acute lymphoblastic leukaemia (ALL). High levels were found in cells from patients with promyelocytic leukaemia. Moderate to high total circulating blast elastase activity was measured in 70 % of the ANL patients with haemorrhage compared with 36% of the patients without bleeding complications (p < 0.05). The available intracellular elastase activity was correlated to the level of Eα1‐AT (rs = 0.42, p < 0.01) but not to the elastase specific split product of fibrinogen, Bβ 30–43. In complete remission the levels of Eα1AT were normalized. Intracellular elastase activity might be a useful supplement to differentiate ANL and ALL.
Evaluation of bone marrow cellularity by magnetic resonance imaging in patients with myelodysplastic syndrome
Authors: Depaoli L. , Ficara F. , Priotto C. , Resegotti L. , Davini O. , Foggetti M. D. , Cirillo R.
Published: July 2010

Abstract: Magnetic resonance imaging (MRI) is a safe modality for examining the bone marrow and it is quite effective in revealing marrow involvement in hematological malignancies. MRI has been compared with needle marrow biopsy in 22 patients with myelodysplastic disorders. A fairly good concordance has been demonstrated in 79% of cases. However, in 5 patients MRI revealed that bone marrow hyperplasia was not generalized. Therefore in elderly patients with MDS, MRI of the spine allows the quantification of bone marrow hyperplasia with a greater accuracy than bone marrow biopsy and this may be useful for monitoring the effect of cytostatic treatment.
Porcine plateletsin vitroandin vivostudies: Relevance to human thrombosis research
Authors: Søfteland Eirik , Framstad Tore , Thorsen Terje , Holmsen Holm
Published: July 2010

Abstract: This review summarizes present knowledge on porcine plateletsin vitroand recent studies onin vivoactivation of platelets in the pig. There are certain differences compared to human platelets: Platelet aggregation and secretion cannot be achieved by epinephrine, and the arachidonate pathway seems poorly developed in porcine platelets. Genetic models for von Willebrand disease (vWD) and storage pool deficiency (SPD) have been developed in the pig. Several models for the study ofin vivoplatelet deposition and early thrombus formation have been developed. Platelet radio‐labeling techniques (with111In) have been used extensively. We conclude that the pig seems to be a good choice for the investigation ofin vivoplatelet activation and deposition based on present knowledge of porcine platelets and on already established animal models.
Three years' continuous low‐dose interferon‐α treatment of hairy‐cell leukaemia: Evaluation of response and maintenance dose
Authors: Nielsen Bendt , Braide Inger
Published: July 2010

Abstract:  Thirty‐six HCL patients were treated with 2 × 106 U/m2 IFN‐α‐2b three times weekly for 24 months, followed by 12 months of treatment with one of three doses ranging from 0.5 × 106 U to 2 × 106 U/m2. For most patients the response continued to improve during the whole treatment period, and there were no cases of disease progression during treatment. Patients with disease of short duration before IFN treatment and/or non‐splenectomized patients seemed to respond more slowly than others, but there were no differences between patients treated with the different IFN doses. Toxicity was usually WHO grade 1 or 2. The continued improvement in a large number of patients even with very small IFN doses might indicate that only a small number of true complete responses are reached after 24 months of treatment, thus explaining the reported high relapse rate after early discontinuation of treatment. It therefore seems worthwhile — also from a cost/benefit point of view — to test long‐term or continuous IFN‐α treatment at other centres.
Human neutrophil gelatinase: A marker for circulating blood neutrophils. Purification and quantitation by enzyme linked immunosorbent assay
Authors: Kjeldsen Lars , Bjerrum Ole Weis , Hovgaard Doris , Johnsen Anders H , Sehested Maxwell , Borregaard Niels
Published: July 2010

Abstract:  Human neutrophil gelatinase was purified to apparent homogeneity. The N‐terminal amino‐acid sequence of the purified enzyme could be aligned to an internal part of the cDNA‐derived amino‐acid sequence of 92‐kDa type IV collagenase from SV 40‐transfected human lung fibroblasts and from a TPA differentiated monocytic cell line, U937. Total amino‐acid composition of U937 and neutrophil gelatinases was identical. Gelatinase was susceptible to treatment with o‐ and n‐glycanase, indicating that posttranslational addition of oligosaccharide side chains occurs. An enzyme‐linked immunosorbent assay for gelatinase was developed using specific polyclonal rabbit antibodies. The assay was specific, sensitive, accurate, and reproducible. Ninety percent range for plasma gelatinase from normal subjects was 17.3 to 102.9 ng/ml. In patients treated with cytostatic agents for non‐Hodgkin's lymphoma, there was a parallel drop in plasma gelatinase and peripheral granulocyte count. This indicates that plasma gelatinase is a marker for circulating neutrophils. Plasma gelatinase does not seem to reflect bone marrow cellularity.
Abnormal bone remodelling in patients with myelomatosis and normal biochemical indices of bone resorption
Authors: Taube Taina , Beneton Monique N. C. , McCloskey Eugene V. , Rogers Susan , Greaves Mike , Kanis John A.
Published: July 2010

Abstract:  We studied bone biopsies from 26 patients with myelomatosis with apparently normal skeletal metabolism. Quantitative histomorphometric measurements suggested that skeletal disease was progressive despite normocalcaemia and normal urinary excretion rates of calcium and hydroxyproline. When biopsies were divided according to the involvement of marrow by plasma cells, bone resorption — as judged by the eroded surface — increased significantly the greater plasma cell burden. Osteoclasts were frequent with moderate tumour burdens, but there was no further increase in the number of osteoclasts when plasma cell infiltration increased by more than 50% of bone marrow. Contrary to expectation, the numbers of osteoblasts and bone formation rates were increased with bone biopsies with moderate tumour burden, but were markedly lower when plasma cell infiltration occupied more than 50% of bone marrow, due to a decreased functional capacity of osteoblasts. We conclude that skeletal bone disease in myeloma is commonly progressive despite apparently stable bone disease as judged by biochemical measurements. The major mechanism of bone loss in myelomatosis is increased osteoclastic resorption but decreased bone formation contributes to bone loss with heavy plasma cell burdens. Urinary excretion of calcium and hydroxyproline provide insensitive indices of bone resorption in myelomatosis.
Granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) and granulocyte colony‐stimulating factor (G‐CSF) secretion by adherent monocytes measured by quantitative immunoassays
Authors: Sallerfors Bengt , Olofsson Tor
Published: July 2010

Abstract:  The kinetics of GM‐CSF and G‐CSF secretion by purified adherent human monocytes were studied by quantitative immunoassays. Interleukin‐1 (IL‐1); 4–40 ng/ml and E. coli lipopolysaccharide (LPS); 0.1–100 ng/ml, were the most effective stimuli and induced dose‐dependent secretion of both GM‐CSF and G‐CSF. Secretion of newly synthesized CSF was detectable 3–6 hours after stimulation and continued for approximately 24 h. Twenty minutes pulse exposure to LPS was sufficient to induce half maximum secretion of GM‐CSF, and after 24–36 h the adherent monocytes could not be restimulated. Neither GM‐CSF nor TNF could down‐regulate the secretion of GM‐CSF. IL‐3 induced a minor secretion of GM‐CSF whereas TNF, G‐CSF, M‐CSF and IFN‐gamma were unable to induce GM‐CSF secretion. In addition to LPS and IL‐1, GM‐CSF and to a minor degree TNF induced G‐CSF secretion. Enriched T lymphocytes secreted GM‐CSF, but not G‐CSF, after stimulation with PHA or staphylococcal enterotoxin A (SEA), whereas LPS and IL‐1 were without stimulatory effects. We also noted that enriched T lymphocytes added to LPS‐stimulated adherent monocytes at ratios of 1:10 or more inhibited, in a dose‐dependent fashion, GM‐CSF secretion by 13–55%. These findings add new quantitative data on CSF secretion by human monocytes.
Phenylarsine oxide augments tyrosine phosphorylation in hematopoietic cells
Authors: Oetken Christina , von Willebrand Maria , Autero Matti , Ruutu Tapani , Andersson Leif C. , Mustelin Tomas
Published: July 2010

Abstract:  Tyrosine phosphorylation and dephosphorylation are implicated in the regulation of cell growth and differentiation. A diverse identification of key regulatory proteins by their content of phosphotyrosine has been hampered by the very low level of tyrosine phosphorylation. This is presumably caused by the relative preponderance of phosphotyrosine phosphatase activity in many cells. We report that treatment of hematopoietic cells with phenylarsine oxide (PAO), a membrane‐permeable phosphotyrosine phosphatase inhibitor, induced a dramatic accumulation of phosphotyrosine in a number of cellular proteins. No changes in serine or threonine phosphorylation were detected. The PAO‐induced accumulation of phosphotyrosine occurred well before any signs of toxicity or irreversible damage to the cells were seen. Addition of dithiotreitol reversed the effect of PAO. Our data demonstrate that phosphotyrosine phosphatase activity has a major impact on the level of phosphotyrosine in cellular proteins, even in cells with high protein tyrosine kinase activity. Cells with constitutively elevated tyrosine kinase activity are easily detected following treatment with PAO and substrates with an otherwise too low phosphotyrosine content or too rapid phosphate turnover can be studied. This effect of PAO allows determinations of tyrosine phosphorylation‐dependent complex formation between proteins.
Antenatal diagnosis of haemophilia B by amplification and electrophoresis of an exon fragment with a short deletion
Authors: Ljung R. , Green P. , Sjörin E. , Giannelli F. , Nilsson I. M.
Published: July 2010

Abstract:  Carrier identification and antenatal diagnosis were performed in 2 sisters by electrophoretic separation of the normal and abnormal bands obtained after amplification of a fragment of exon h in the factor IX gene. The mutation in the family had been characterised as an 8‐base pair (bp) deletion in exon h. By amplification of a 326 bp fragment containing the site of deletion, the shorter 318 bp band of the haemophilia B gene could be separated by electrophoresis of the fragments. The comprehensive data collection at the Haemophilia Centre is of vital importance in the genetic counselling of haemophilia families, and was a crucial step for the successful diagnoses in these sisters.