bluuebunny/crossref_metadata_2025_split huggingface dataset:
The site of platelet destruction in thrombocytopenic purpura as a predictive index of the efficacy of splenectomy
Authors: Najean Y. , Dufour V. , Rain J. D. , Toubert M. E. 
Published: March 2008

Summary The significance of the site of platelet sequestration in determining the indication for splenectomy in idiopathic thrombocytopenic purpura (ITP) is a controversial subject. However, most of the negative conclusions are based on 51chromium labelling of homologous platelets. We report here the results of an analysis of 222 cases in which the kinetic study of 111indium‐oxinate‐labelled autologous platelets was performed under homogeneous technical conditions. 103 of these patients subsequently underwent splenectomy.This study demonstrates that the site of platelet sequestration in active ITP constitutes a variable independent of the patient's age, history of the disease and its severity (platelet count, lifespan). The sequestration site is a good predictive element of the short‐term efficacy of splenectomy (71/76 cases with splenic sequestration obtained a platelet count exceeding 100 × 109/1 versus 7/13 cases with mixed sequestration and 1/14 cases with hepatic sequestration), and the long‐term results (6 months to 5 years after splenectomy) do confirm the clinical value of this study.
Quantification of platelet‐bound immunoglobulins of different class and subclass using radiolabeled monoclonal antibodies: assay conditions and clinical application
Authors: Tijhuis G. J. , Klaassen R. J. L. , Modderman P. W. , Ouwehand W. H. , Kr. vondem Borne A. E. G. 
Published: March 2008

Summary. Quantification of platelet‐bound immunoglobulins (PBIg) with radiolabelled murine monoclonal antibodies (mAbs) has been described only for IgG so far. Here we describe some modifications of this mAb radioimmunoassay (MARIA) and show that by using a panel of radiolabelled specific mAbs it is possible to quantify not only PBIgG but also PBIgG subclasses and PBIgM. Analysis by gel filtration showed that all anti‐IgG and anti‐IgG‐subclass mAbs bound to their respective antigens in a ratio of about 1:1. However, the binding ratio for the anti‐IgM Mab could not be established. There was a good correlation between the antibody‐density per platelet as determined with the anti‐IgG mAb and determined as the sum of the IgG molecules of different subclass per platelet (r= 0·90). Platelet fragments did not interfere in the assay. 89 normal healthy controls had 140 IgG molecules per platelet and bound 269 anti‐IgM molecules per platelet (geometric means).In a study on the detection of PBIg in 147 thrombocytopenic patients, it appeared that the MARIA had a sensitivity of 61% and a specificity of 45% for the diagnosis of idiopathic thrombocytopenic purpura (ITP). Both in ITP and in secondary thrombocytopenia (STP), PBIgG1 and PBIgG3 were found more frequently (60% and 61%, respectively) than PBIgG2and PBIgG4 (13% and 9%, respectively). There was no relation between the amount of total PBIgG or PBIgM and the platelet count in either ITP or STP. Also, if IgG antibodies of only one subclass were found, there was no relation between the severity of the thrombocytopenia and the amount of PBIgG.By applying the MARIA, it is possible to quantify PBIgG, all four PBIgG‐subclasses and PBIgM in ITP and STP in a reliable way.
The priming effects of the products of stimulated mononuclear cells on the response of neutrophils to C5a des arg
Authors: Crouch Sharon , Fletcher John 
Published: March 2008

SummaryCertain recombinant human cytokines have been shown to enhance polymorphonuclear leucocyte (PMN) responses to subsequent stimulation. Mononuclear cells (MNC) from normal healthy individuals were stimulated for 5 h with 1 μg/ml bacterial lipopolysaccharide (LPS) in order to induce production and secretion of inflammatory cytokines into the surrounding medium. These mononuclear cell conditioned media (MNCM) were then used to prime PMN isolated from healthy volunteers. Preincubating the PMN with MNCM for 15 min at 4°C followed by washing and warming to 37°C caused a 344% increase (n= 26) in the rate of superoxide anion production in response to zymosan‐activated serum (ZAS), a source of C5a des arg. This effect could not be reproduced with recombinant human forms of interleukin 1 beta (Il‐1 beta) or granulocyte‐macrophage‐colony stimulating factor (GM‐CSF), although, with the latter, there was some effect when the preincubation stage was carried out for 60 min at 37°C. Only recombinant human tumour necrosis factor‐alpha (rh‐TNF‐alpha) gave a similar PMN priming effect to that seen with MNCM. This effect could not be reversed by washing away either the MNCM or rh‐TNF‐alpha. The priming effect could be markedly reduced (74.8%, n= 6) by employing the use of polyclonal antibody to TNF‐alpha in the preincubation step; assaying for TNF‐alpha in these MNCMs showed that the degree of priming corresponded to the amount of TNF‐alpha present. Rh‐TNF‐alpha alone appeared to have very little direct stimulatory effect on respiratory burst activity.The results show that TNF‐alpha produced by LPS stimulated MNC after 5 h binds to a PMN surface receptor in the cold and warming of the cells to 37°C allows for an immediate and dramatic response to ZAS stimulation. This suggests that TNF‐alpha is the important cytokine upregulating PMN responses to other physiological mediators, including C 5 a des arg during the early phases of an inflammatory reaction.
A fibroblast cell culture model to study vitamin K metabolism and the inhibition of vitamin K epoxide reductase by known and suspected antagonists
Authors: Ross P. J. , Shearer M. J. , Diplock A. T. , Schey S. A. 
Published: March 2008

SummaryThe metabolism and antagonism of vitamin K has been studied in cultured fibroblasts. Monolayers of 3T3 mouse fibroblasts (grown in the absence or presence of warfarin or other putative antagonists) were incubated for 24 h with [1′, 2′‐3H2]phylloquinone (K1) or [1′,2′‐3H2]phylloquinone epoxide (K1O), the cells harvested and lipid extracts fractionated by high performance liquid chromatography. [3H]K1 was converted to [3H]K1O (about 20% of [3H] lipids) and to unidentified polar metabolites (30%). [3H]K1O was converted to [3H]K1 (3%) and to polar metabolites (50%). Cells grown with warfarin showed a marked increase in the [3H]K1O:K1 ratio and in the proportion of polar metabolites. The metabolic interconversion of K1 and K1O and inhibitory response to warfarin provide evidence for a fibroblast pathway analogous to the vitamin K‐epoxide cycle in the liver. From the K1O:K1 ratios it was possible to grade the antagonism of vitamin K epoxide reductase activity by known and suspected inhibitors. Inhibitory ratios were seen for racemic warfarin down to 10−8m. S‐warfarin was a more potent antagonist than the R‐enantiomer. Consistently low K1O:K1 ratios were observed for N‐methyl‐thiotetrazole and antibiotics with (moxalactam) or without (cefotaxime) this side chain suggesting that none of these compounds are direct inhibitors of vitamin K epoxide reductase. Fibroblasts grown in cell culture provide a useful model to study the extrahepatic role of vitamin K and the mode of action of vitamin K antagonists.
Interleukin 2 infusion induces haemopoietic growth factors and modifies marrow regeneration after chemotherapy or autologous marrow transplantation
Authors: Heslop Helen E. , Duncombe Andrew S. , Reittie Joyce E. , Bello‐Fernandez Concha , Gottlieb David J. , Prentice H. Grant , Mehta Atul B. , Hoffbrand A. Victor , Brenner Malcolm K. 
Published: March 2008

SummaryAdministration of interleukin 2 (IL2) to patients with minimal residual malignant disease following myelo‐ablative chemo‐radiotherapy may augment immune reconstitution and reduce the risk of relapse by increasing cytotoxic effector function and cytokine dependent killing directed at residual malignant cells. The ability of IL2 generated activated killer cells to inhibit haemopoietic progenitor cells and to release gamma‐interferon (γIFN) and tumour necrosis factor (TNF) may, however, retard haemopoietic recovery, as both TNF and γIFN inhibit normal myelopoiesis in vitro. To determine the effect of IL2 infusion on myeloid regneration in vivo, we have examined haemopoietic recovery in patients receiving this cytokine following autologous marrow transplantation or ablative chemotherapy. We find that IL2 infusion accelerates neutrophil recovery and that granulocyte‐macrophage colony stimulating factor (GMCSF) and IL3 mRNA become detectable in circulating mononuclear cells. Induction of TNF by IL2 may also contribute to subsequent acceleration of myelopoiesis by initiation of GM‐CSF mRNA synthesis in patient marrow fibroblasts. These results show that IL2 infusion may facilitate myeloid recovery when administered during the period of haemopoietic regeneration following ablative chemoradiotherapy.
IL‐2 abolishes fibroblast proliferation in long‐term bone marrow culture by inhibition of an accessory cell
Authors: Carron J. A. , Cawley J. C. 
Published: March 2008

Addition of interleukin‐2 (IL‐2 (>250 U/ml) during the first 3 d of long‐term bone marrow culture (LTBMC) permanently abolished the fibroblast component of the stromal layer, even when IL‐2 was removed after the 3 d culture period. When IL‐2 was added at more than 72 h after initiation of culture, no effect was observed. Stromal growth in IL‐2‐treated culture was restored by addition of irradiated bone marrow, indicating that the IL‐2 inhibited an accessory cell rather than the fibroblast directly. Accessory cells were shown to be necessary for fibroblast proliferation at low cell densities and were also inhibited by IL‐2. The accessory cell effect could not be replaced by LTBMC supernatants or extracellular matrix. It is suggested that these observations are relevant to the suppression of haemopoiesis observed in patients receiving IL‐2.Addition of interleukin‐2 (IL‐2 (>250 U/ml) during the first 3 d of long‐term bone marrow culture (LTBMC) permanently abolished the fibroblast component of the stromal layer, even when IL‐2 was removed after the 3 d culture period. When IL‐2 was added at more than 72 h after initiation of culture, no effect was observed. Stromal growth in IL‐2‐treated culture was restored by addition of irradiated bone marrow, indicating that the IL‐2 inhibited an accessorycell rather than the fibroblast directly. Accessory cells were shown to be necessary for fibroblast proliferation at low cell densities and were also inhibited by IL‐2. The accessory cell effect could not be replaced by LTBMC supernatants or extracellular matrix. It is suggested that these observations are relevant to the suppression of haemopoiesis observed in patients receiving IL‐2.
Iron metabolism in patients with the anaemia of end‐stage renal disease during treatment with recombinant human erythropoietin
Authors: Kooistra M. P. , Es A. Van , Struyvenberg A. , Marx J. J. M. 
Published: March 2008

Iron metabolism was studied in 21 patients with the anaemia of end‐stage renal disease during 40 weeks of treatment with recombinant human erythropoietin (rhEPO). Oral iron was prescribed to all patients. Initial serum iron concentrations and transferrin saturation levels were subnormal, decreased during the correction period of treatment, and increased thereafter. In 81% of patients in whom pretreatment transferrin saturation was below 0–25, transferrin saturation decreased below 0–16, despite sufficiently high serum ferritin levels. Serum ferritin concentrations decreased significantly. There was no correlation between serum ferritin levels and serum iron or transferrin saturation.Ferrokinetic studies, performed before and during treatment, showed an increase in plasma iron turnover, in erythron transferrin uptake, and in the flux of iron binding sites through the plasma.The rhEPO dose needed to keep the haematocrit at the target level during the maintenance period of treatment was significantly correlated with transferrin saturation, and iron binding capacity, but not with serum ferritin concentrations. This suggests that the functional availability of iron in plasma, rather than the size of body iron stores, is a major factor in the determination of the response to rhEPO treatment in end‐stage renal disease.
The molecular pathology of chronic myelogenous leukaemia
Authors: Kurzrock Razelle , Talpaz Moshe 
Published: March 2008

The first consistent karyotypic abnormality found to be associated with neoplastic disease was the Philadelphia (Ph) chromosome (Nowell & Hungerford, 1960). Furthermore, the best‐studied example of translocation‐mediated gene activation occurs in leukaemia patients bearing this abnormality (reviewed by Kurzrock et al, 1988). In these individuals, the Ph translocation (t(9;22)(q34;q11)) results in transposition of the ABL proto‐oncogene from chromosome 9q34 to 22q11, where it is fused with part of the BCR gene. It is now known that as a result of the Ph translocation, p160BCR and p145ABL (the normal BCR and ABL gene products) are replaced by p210BCR‐ABL. This aberrant protein constitutes the molecular fingerprint of CML. The enhanced tyrosine phosphokinase enzymatic activity (a property possessed by some growth factor receptors and transformation‐inducing oncogenes) of p210BCR‐ABL implicates a direct role for this molecule in the pathogenesis of CML. Because the Ph translocation is present in the early chronic phase, the union of the BCR and ABL genes is probably involved in the initiation of the leukaemic process. The secondary molecular forces driving progression of CML to blast crisis are however unknown, and may differ from patient to patient.Approximately 10% of CML patients lack a Ph chromosome. One‐half of these individuals have bcr rearrangement and express p210BCR‐ABL. Ph + and Ph ‐ bcr + (p210 +) CML are identical and should be treated the same. Molecular follow‐up of diploid bcr + CML patients is essential for detection of persistent malignancy after therapy.The presence of a specific marker—the BCR‐ABL message—permits the development of new diagnostic approaches for CML. For instance, detection of a BCR‐ABL message with the use of the highly sensitive polymerase chain reaction, a technique capable of detecting up to one leukaemia cell amongst one million normal cells, yields important information about minimal residual disease. Finally, the use of therapy directed against the BCR‐ABL product may be a worthwhile strategy which deserves investigation, and may prompt a new era of tumour‐specific treatment.
Interferon in essential thrombocythaemia
Authors: Gisslinger Heinz , Chott Andreas , Scheithauer Werner , Gilly Bettina , Linkesch Werner , Ludwig Heinz 
Published: March 2008

In the present investigation, 20 patients with ET were treated with recombinant interferon alfa‐2c (IFN) for up to 4 years. Initially, IFN was administered subcutaneously at a dosage of 6–45 MU/week. The dosage was adjusted according to individual tolerance and response. The median dose during induction was 20 MU/week, 10 MU/week during the remaining first year, 6 MU/week during the second year and 2 MU/week thereafter.13 patients (65%) achieved complete remission (platelet count <440/nl), four patients (20%) had partial remission (>440/nl but a reduction by more than 50% of the initial count). The median platelet count remained steady throughout the 4‐year period of treatment, in spite of extreme dose reductions. After withdrawal of IFN, however, platelet counts again increased. The white blood cells showed a marked decrease similar to that of platelet counts, whereas the haemoglobin level remained fairly stable. In the bone marrow, a significant decrease in megakaryocyte density and size could be observed.Concurrently with the improvement of haematological parameters, clinical symptoms improved, but reappeared after withdrawal of IFN. During induction, fever, bone and/or muscle pain, fatigue, lethargy and psychological symptoms were the most prominent side‐effects in the majority of patients. In three patients these symptoms led to discontinuation of the treatment. With repeated dose reductions, excellent long‐term tolerance was achieved, and during late maintenance treatment the only observed side‐effect was an induction of thyroid autoimmunity in three patients.IFN is an effective, well‐tolerated alternative in the long‐term treatment of symptomatic ET. However, since withdrawal of IFN leads to recurrence of thrombocytosis, continued treatment is to be recommended.
Rational basis for the metabolic modulation of 5‐fluorouracil by leucovorin and interferon alpha
Authors: Rustum Youcef M. 
Published: March 2008

Although 5‐fluorouracil (FUra) has been the drug of choice for the treatment of patients with advanced colorectal carcinoma, the response rates are in the range of 15% and the median survival times do not exceed 9 months. Interferon alpha (IFNα) has limited antitumour activity in this disease. Recent clinical trials have demonstrated that both the response rate and the survival time of patients with advanced colorectal cancer can be significantly improved by the addition of leucovorin (CF) to FUra. In a randomized phase III trial, the median response to FUra and CF was about 30% with a range of 20–55%, dependent on the dose and schedule of administration of CF. Due to multiplicity of mechanisms of action postulated for IFNα, the role of IFNα in the modulation of the cytotoxicity and therapeutic efficacy of FUra alone and in combination with CF has been evaluated in patients with advanced colorectal cancer and also in a variety of human cell lines in culture, including human colorectal cell lines, HCT‐8, human bladder cell line RT‐4 and leukaemia CEM cells.The results obtained in patients demonstrated that indeed the antitumour activity of FUra can be improved by the addition of IFNα with a response range from 26% to 76%. The initial clinical use of this combination, however, has been limited in some cases by the severe host toxicity. In vitro results demonstrated that: (1) in vitro cytotoxicity potentiation by IFNα is cell‐type dependent; (2) in these cells where modulation was possible, αIFN was used as a low and noncytotoxic doses (10–50 μg/ml for 3–5 d exposure), and (3) the cytotoxicity of IFNα was dose dependent, indicating a direct antiproliferative cellular effect.
The role of interferons in the management of carcinoid tumours
Authors: ÖBerg K. , Eriksson B. 
Published: March 2008

Malignant carcinoid tumours with the carcinoid syndrome has over the years presented a therapeutic challenge. The patients might not only die from tumour progression but also from symptoms relating to hormone overproduction and the specific cardiac disease, e. g. right heart fibrosis and failure. Surgery has been the treatment of choice in local disease, but when liver metastases have developed other treatment procedures must be considered. Conventional chemotherapy has been of little beneficial value, with response rates of only 10–30%, whereas a new somatostatin analogue, octreotid, is effective in controlling clinical symptoms but not tumour progression. Interferon treatment was introduced in 1982 by our group, and we are now presenting treatment results of 130 patients with histologically verified malignant carcinoid tumours and liver metastases. One hundred and eleven patients were treated with a median dose of 6 mega units (MU) of interferon alpha, five times weekly (dose range 3–9 MU), whereas 29 patients received conventional chemotherapy. Forty‐seven out of 111 patients (42%) treated with interferon alpha demonstrated a significant biochemical response and 15% demonstrated more than 50% reduction in tumour size. In another 43 (39%) patients stabilization of the carcinoid disease have been noted, whereas 21(19%) showed progressive disease. The median duration of response was 34 months. Subjective responses with improvement of diarrhoea, flush and/or bronchocon‐striction were noticed in 76 patients (68%). The 19 patients treated with chemotherapy demonstrated only 10% biochemical response, lasting for only 3–5 months. The survival analysis demonstrates a median survival of only 8 months in the group of patients treated with chemotherapy, compared to 80+ months (P<0·001) in the groups treated with interferon alpha. Interferon adverse reactions of fatigue, weight loss and anaemia were manageable. Neutralizing interferon antibodies were documented in 5–15% of the patients.Interferon alphas are active in patients with malignant carcinoid tumours. Clinical symptoms are significantly reduced following reduction of circulating hormones. Interferon might also have an impact on survival in this group of patients. The side‐effects are moderate and managed by dose adjustments.
Lactoferrin inducible monocyte cytotoxicity defective in esterase deficient monocytes
Authors: McCormick Julie A. , Markey Geraldine M. , Morris T. C. M. , Auld P. W. , Alexander H. D. 
Published: March 2008

SummaryWe recently demonstrated a higher incidence of monocyte esterase deficiency in patients with lymphoproliferative neoplasia and gastrointestinal carcinoma than in the normal population. Using lactoferrin to stimulate monocyte cytotoxicity we have now compared the abilities of esterase positive and esterase deficient monocytes to lyse K562 cells. The esterase deficient monocytes were from normal subjects whose monocytes have consistently failed to show cytoche‐mical esterase staining over 30–72 months and which lack specific monocyte isoenzymes. The esterase positive monocytes were from age and sex matched control subjects. Esterase positive monocytes responded to lactoferrin stimulation by a five‐fold increase in cytotoxicity whereas deficient monocytes failed to produce any response.These results indicate a possible defect in cytotoxicity of esterase deficient monocytes and together with the epidemiological findings suggest a link between monocyte esterase deficiency and neoplasia.
Autologous blood stem cell transplantation for chronic granulocytic leukaemia in transformation: a report of 47 cases
Authors: Reiffers J. , Trouette R. , Marit G. , Montastruc M. , Fabères C. , Cony‐Makhoul P. , David B. , Bourdeau M. J. , Bilhou‐Nabera C. , Lacombe F. , Feuillatre‐Fabre F. , Vezon G. , Bernard Ph. , Broustet A. 
Published: March 2008

SummaryForty‐seven patients with chromosome Philadelphia‐positive (Ph1) chronic granulocytic leukaemia (CGL) in transformation underwent autologous transplantation of peripheral blood stem cells (ABSCT) collected at the original diagnosis before any treatment. They were treated with three consecutive strategies: single transplant (group I=17 patients), double transplant (group II = 13 patients), double transplant followed by recombinant alpha interferon (group III=17 patients). Forty‐three patients were restored to a second chronic phase with a cytogenetic conversion (more than 10%, Ph1‐negative marrow metaphases) occurring in 14 of the 29 evaluable patients. Most patients had a recurrent transformation occurring 2‐43 months after ABSCT and finally eight patients are still alive in second chronic phase 4‐49 months after ABSCT (median = 24 months). The actuarial median duration of second chronic phase was 3 months, 10 months and 18 months for group I. group II and group III patients (P < 0·0001). The encouraging results observed for group III patients prompt us to propose ABSCT for patients in chronic phase with initial prognostic factors, suggesting that recombinant alpha interferon will not be effective if administered as front‐line therapy.