bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population pharmacokinetics of pyrimethamine and sulfadoxine in children with congenital toxoplasmosis
Authors: Trenque T. , Simon N. , Villena I. , Chemla C. , Quereux C. , Leroux B. , Jaussaud R. , Rémy G. , Dupouy D. , Millart H. , Pinon J.‐M. , Urien S. 
Published: May 2004

AimsTo develop a population pharmacokinetic model for pyrimethamine (PYR) and sulfadoxine (SDX) in children with congenital toxoplasmosis.MethodsChildren were treated with PYR (1.25 mg kg−1) and SDX (25 mg kg−1) (Fansidar®) plus folinic acid (Lederfoline® 5 mg). Plasma concentrations, available from a therapeutic drug monitoring database, were determined by high‐performance liquid chromatogrphy. Population pharmacokinetic analysis was performed using a nonlinear mixed effects model.ResultsEighty‐nine children, aged 1 week to 14 years and weighing 2.9–59 kg, were available for evaluation. Both PYR and SDX concentration‐time profiles were best described by a one‐compartment open model. Volume of plasma distribution (V) and clearance (CL) were significantly related to body weight (BW) using an allometric function. Typical CL and V estimates (95% confidence interval), for a child weighing 11 kg were 5.50 (5.28, 5.73) l day−1 and 36 (33, 39) l for PYR and 0.26 (0.25, 0.27) l day−1 and 2.1 (1.9, 2.3) l for SDX. For BW between 3.5 and 60 kg, plasma half‐lives were predicted to vary from 4.0 to 5.2 days for PYR, and from 5.0 to 7.5 days for SDX.ConclusionThis study indicated that body weight influences PYR and SDX pharmacokinetics in children. To optimize PYR/SDX combination treatment in congenital toxoplasmosis, short dosing intervals in very young low‐wight children are probably appropriate.
Purging iron from the heart
Authors: Hershko Chaim , Cappellini Maria D , Galanello Renzo , Piga Antonio , Tognoni Gianni , Masera Giuseppe 
Published: May 2004

SummaryMethods are now available to measure the magnitude of iron accumulation in the heart. Their validation currently relies on indirect evidence and not on chemical estimation in cardiac biopsies. All patients with symptomatic heart disease appear to have abnormal T2* values, but many patients without symptomatic heart disease also have evidence of increased myocardial iron. Although there is no proof to date that increased myocardial iron, as evidenced by abnormal magnetic resonance imaging, carries an adverse prognosis, it is likely that such new information will affect the chelating programme of patients. In these cases, there are a number of options available: (i) ongoing treatment with either desferrioxamine (DFO) or deferiprone may be intensified; (ii) the patient may be switched to the alternative chelator or (iii) combined chelation with both DFO and deferiprone may be started, which is more effective than using either chelator alone. For patients with symptomatic heart disease, continuous intravenous DFO with, or without deferiprone, remains the currently recommended treatment, in view of its documented ability to salvage these patients.
Genetic variants of the extra‐large stimulatory Gs protein alpha‐subunit and risk of thrombotic and haemorrhagic disorders
Authors: González‐Conejero R. , Corral J. , Guerrero J. A. , Iniesta J. A. , Rivera J. , De Arriba F. , Vicente V. 
Published: May 2004

SummaryA polymorphism of the gene encoding the extra‐large stimulatory G‐protein α‐subunit (XLαs), originally identified in three patients with a bleeding tendency, involved a 36‐bp insertion and two missense changes. A paternally‐inherited insertion displayed a moderate platelet Gsα over‐expression, which lead to platelet hypo‐reactivity. These data prompted us to investigate the genetic, functional and clinical relevance of this polymorphism in the Mediterranean population. We included 414 healthy subjects and three case/control studies: 263 consecutive patients with a first episode of primary intracerebral haemorrhage, 195 patients with deep venous thrombosis, and 104 patients with cerebrovascular disease. Controls were selected by approximating criteria to match selected risk factors to patients. Moreover, we performed studies of platelet function. We developed a simple method to determine the methylated allele, by digestion of genomic DNA with Sma I before polymerase chain reaction amplification. We identified two new rare variants, resulting from the loss of repeat units 7 and 5. The AB genotype was present in 3·6% of healthy population and the prevalence of the B allele was similar among cases and controls. Accordingly, the non‐methylated B allele did not modify either the expression of platelet Gsα or the platelet response to Gs‐agonists. Thus, our study suggests a minor functional role of XLαs polymorphism in thrombotic or in haemorrhagic disorders.
Characterisation of Mcl‐1 cleavage during apoptosis of haematopoietic cells
Authors: Clohessy John G. , Zhuang Jianguo , Brady Hugh J. M. 
Published: May 2004

SummaryMcl‐1 is essential for normal haematopoiesis, being required for lymphocyte development and maintenance. Its role in haematopoietic differentiation and development is associated with its function as an anti‐apoptotic member of the Bcl‐2 family of proteins although the underlining mechanism is poorly understood. We have characterized caspase cleavage of the Mcl‐1 protein during apoptosis. Caspase cleavage resulted in the removal of the PEST regions from the protein and generation of a fragment containing the BH‐1, ‐2 and ‐3 homology domains. Removal of the PEST regions did not appear to alter Mcl‐1 stability, suggesting that these regions are not responsible for Mcl‐1's short half‐life. In addition, unlike cleavage of Bcl‐2 and Bcl‐XL, which resulted in pro‐apoptotic fragments, cleaved forms of Mcl‐1 were unable to induce apoptosis. This novel regulation of Mcl‐1 may have important implications not only for its role in apoptosis but also for the essential role it plays in the differentiation and development of haematopoietic cells.
Early onset hereditary hemochromatosis resulting from a novel TFR2 gene nonsense mutation (R105X) in two siblings of north French descent
Authors: Le Gac G. , Mons F. , Jacolot S. , Scotet V. , Férec C. , Frébourg T. 
Published: May 2004

SummaryThe molecular basis of hereditary hemochromatosis (HH) is more complex than previously expected. More than 80% of hemochromatosis probands of Northern European descent are homozygous for the C282Y HFE gene mutation. However, five novel non‐related‐HFE HH forms have now been identified. The transferrin receptor(TFR2)‐linked form is inherited in an autosomal recessive pattern and is considered to be an adult‐onset syndrome. Until now, it has been associated with five mutations that have only been detected in Japanese and southern European patients. Here, we report the identification of a novel TFR2 nonsense mutation in two related French adolescents. We discuss the phenotype of this sibling pair from precedent biological and clinical findings as well as the expected role of TFR2 in iron homeostasis. Finally, we suggest that iron overload phenotypes associated with mutations in TFR2 may be intermediate between those related to mutations in HFE and those related to mutations in juvenile hemochromatosis genes.
Infused CD34+ cell dose, but not tumour cell content of peripheral blood progenitor cell grafts, predicts clinical outcome in patients with diffuse large B‐cell lymphoma and follicular lymphoma grade 3 treated with high‐dose therapy
Authors: Blystad A. K. , Delabie J. , Kvaløy S. , Holte H. , Vålerhaugen H. , Ikonomou I. , Kvalheim G. 
Published: May 2004

SummaryPreviously, we have shown that patients with diffuse large B‐cell lymphoma (DLBCL) transplanted with contaminated bone marrow (BM) generally have a poor outcome. Whether this is also the case when peripheral blood progenitor cell (PBPC) grafts are used is not known. Forty‐three patients with chemosensitive DLBCL or follicular lymphoma grade 3 (FLgr3) were treated with high‐dose therapy (HDT) and autologous stem cell support. Nine patients received purged grafts. Quantitative real‐time polymerase chain reaction (QRT‐PCR) for either the BCL2/IgH translocation or allele specific oligonucleotide (ASO) QRT‐PCR for the immunoglobulin heavy chain (IgH) complementarity‐determining region 3 were used. Nine of 25 (36%) PBPC grafts contained tumour cells as tested by QRT‐PCR, including two grafts purged by CD34+ cell enrichment combined with B‐cell depletion. The level of contamination of the PBPC/CD34+ cells ranged from 0 to 8·28%. No relationship could be shown between the total number of tumour cells infused and relapse. Patients receiving PCR‐positive or PCR‐negative PBPC grafts had similar progression‐free survival (PFS) (P = 0·49). However, a significant difference was seen in PFS and overall survival (OS) for the patients given ≥6·1 × 106 CD34+ cells/kg compared with those given <6·1 × 106 CD34+ cells/kg (P = 0·01 and P < 0·05 respectively).
WT1 gene expression: an excellent tool for monitoring minimal residual disease in 70% of acute myeloid leukaemia patients – results from a single‐centre study
Authors: Østergaard Mette , Olesen Lene Hyldahl , Hasle Henrik , Kjeldsen Eigil , Hokland Peter 
Published: May 2004

SummaryFollowing induction chemotherapy for acute myeloid leukaemia (AML), sensitive determination of minimal residual disease (MRD) in patients achieving complete remission (CR) should enable the detection of early relapse and allow intervention at a more favourable stage than at overt relapse. We have determined the expression levels of the Wilms’ tumour gene (WT1) by real‐time quantitative polymerase chain reaction (RQ‐PCR) in peripheral blood and bone marrow in 133 newly diagnosed AML patients and compared them with those in healthy volunteers. At diagnosis, the WT1 level exceeded normal expression in 118 of 133 (89%) patients, and was high enough to allow for detection of a WT1 decrease of least 1000‐fold in 98 of 133 (74%) patients following induction therapy. Concomitant monitoring of fusion transcripts (PML‐RARα, AML1‐ETO, MLL‐MLL, CBFβ‐MYH11, or DEK‐CAN) in 38 patients identified different relationships between WT1 and fusion transcript levels, the AML1‐ETO group showing remarkably low levels of WT1 compared with fusion transcript. In 32 patients analysed longitudinally there was close concordance between relapse and increased WT1 levels. Parallel longitudinal monitoring of WT1 and fusion transcript showed close correlation in 18 of 18 patients. We conclude that WT1 expression by RQ‐PCR may be employed as a tool to detect MRD in the majority of fusion transcript‐negative AML patients.
E4BP4 expression is regulated by the t(17;19)‐associated oncoprotein E2A‐HLF in pro‐B cells
Authors: Yeung Jenny , O'Sullivan Elaine , Hubank Mike , Brady Hugh J. M. 
Published: May 2004

SummaryThe E4BP4 basic leucine zipper (bZIP) transcription factor is regulated by interleukin‐3 (IL‐3) in pro‐B cells and has been reported to promote survival of the murine IL‐3‐dependent pro‐B cell lines, FL5.12 and Baf‐3. The E2A‐HLF oncoprotein arises from a t(17;19) translocation in childhood pro‐B cell acute lymphoblastic leukaemia and acts as an anti‐apoptotic factor in FL5.12 and Baf‐3 cells. To assess the functions of E2A‐HLF and E4BP4 in cell survival, a tetracycline‐inducible system was established in Baf‐3 cells to express E4BP4 or E2A‐HLF. Upon IL‐3 withdrawal, expression of E2A‐HLF conferred resistance to apoptosis whereas overexpression of E4BP4 did not. E4BP4 and E2A‐HLF both recognized the same DNA sequence in reporter gene assays, but had opposite effects on transcription. E2A‐HLF acts as a transcriptional activator and E4BP4 as a transcriptional repressor. Furthermore, E4BP4 is a downstream transcriptional target of E2A‐HLF. Our data suggests that the overexpression of E4BP4 is unable to block apoptosis induced by IL‐3 withdrawal and that the expression of E2A‐HLF does not replace the function of E4BP4 in mediating survival.
Validation and extension of the EBMT Risk Score for patients with chronic myeloid leukaemia (CML) receiving allogeneic haematopoietic stem cell transplants
Authors: Passweg Jakob R. , Walker Irwin , Sobocinski Kathleen A. , Klein John P. , Horowitz Mary M. , Giralt Sergio A. ,   Chronic Leukemia Study Writing Committee of the International Bone Marrow Transplant Registry
Published: May 2004

SummaryThe European Group for Blood and Marrow Transplantation (EBMT) devised a scoring system to predict survival after allogeneic haematopoietic stem cell transplantation (HSCT) for chronic myeloid leukaemia (CML). The present International Bone Marrow Transplant Registry study of 3211 patients tested the EBMT Risk Score in a independent population, investigated the value of adding other variables, evaluated a new risk score specifically for chronic phase and compared the allograft risk scores with risk scores established by Sokal in 1984 and Hasford in 1998 for survival with non‐transplant treatments. The primary outcome was 5‐year survival after HSCT; survival curves, regression models and measurements of explained variation were used to compare scores. Using the EBMT scoring system, survival in the independent dataset was almost identical to those in the original EBMT publication, thus validating the EBMT Risk Score. Adding one extra variable, performance status, or designing a score specifically for early chronic phase by using the original five variables with different breakpoints gave results only slightly better than the original EBMT Score. Sokal and Hasford Scores did not predict survival after HSCT. We concluded that the EBMT Risk Score does not currently require modification.
Depletion and impaired interferon‐α‐producing capacity of blood plasmacytoid dendritic cells in human T‐cell leukaemia virus type I‐infected individuals
Authors: Hishizawa Masakatsu , Imada Kazunori , Kitawaki Toshio , Ueda Maki , Kadowaki Norimitsu , Uchiyama Takashi 
Published: May 2004

SummaryDendritic cells (DCs) play an important role in innate and adaptive immunity. There are two major populations of blood DCs, myeloid DCs (myDCs) and plasmacytoid DCs (pcDCs). pcDCs are particularly important in antiviral as well as in general host defence, as they are the principal producers of type I interferons (IFNs). In this study, we analysed myDCs and pcDCs in healthy controls, human T‐cell leukaemia virus type I (HTLV‐I)‐infected asymptomatic carriers (ACs), and patients with adult T‐cell leukaemia (ATL). ATL patients had significantly decreased number of pcDCs and myDCs compared with controls. IFN‐α production by peripheral blood mononuclear cells (PBMCs) was markedly reduced in ATL patients. Purified pcDCs from ACs were found to have impaired IFN‐α‐producing capacity, suggesting a functional defect in pcDCs in HTLV‐I‐infected individuals. Interestingly, pcDCs were shown to be susceptible to HTLV‐I infection. Thus, impaired IFN‐α production by pcDCs may contribute to the immunodeficiency observed in ATL. Furthermore, IFN‐α‐producing capacity was inversely correlated with HTLV‐I proviral load in PBMCs from ACs, suggesting a role for pcDCs in maintaining the carrier state. Taken together, we hypothesize that the depletion and impaired IFN‐α‐producing capacity of blood DCs may contribute to the immunodeficiency in ATL and/or the development of ATL.
Secretion of functional plasma haemostasis proteins in long‐term primary cultures of human hepatocytes
Authors: Biron‐Andréani Christine , Bezat‐Bouchahda Corinne , Raulet Edith , Pichard‐Garcia Lydiane , Fabre Jean‐Michel , Saric Jean , Baulieux Jacques , Schved Jean‐François , Maurel Patrick 
Published: May 2004

SummaryThis study was designed to investigate the ability of long‐term primary cultures of adult human hepatocytes to secrete the main haemostasis proteins. Factors II, V, VII, VIII, PIVKA‐II (protein induced by vitamin K 1 absence or antagonist II), fibrinogen and antithrombin were quantified in culture medium by immunological methods and by measuring the coagulant activity of factors II, V and VII. All the haemostasis protein antigens except the factor VIII antigen (FVIII:Ag) were found in the culture medium throughout the culture period. The clotting activity of each factor correlated well with antigen level. In addition, fibrinogen and fibrin were detected in the fibrillar material following incubation of the culture medium with thromboplastin. Moreover, adding vitamin K 1 to the culture medium resulted in a significant increase of factors II and VII and a reciprocal decrease of the PIVKA‐II, and adding von Willebrand factor resulted in a drastic increase of the level of FVIII:Ag. We conclude that, in our culture system, normal adult human hepatocytes retain their capacity to secrete haemostasis proteins for at least 30 days.
Gene expression profiling in the myelodysplastic syndromes using cDNA microarray technology
Authors: Pellagatti Andrea , Esoof Noor , Watkins Fiona , Langford Cordelia F. , Vetrie David , Campbell Lisa J. , Fidler Carrie , Cavenagh James D. , Eagleton Helen , Gordon Peter , Woodcock Barrie , Pushkaran Beena , Kwan Mark , Wainscoat James S. , Boultwood Jacqueline 
Published: May 2004

SummaryThe myelodysplastic syndromes (MDS) comprise a heterogeneous group of clonal disorders of the haematopoietic stem cell and primarily involve cells of the myeloid lineage. Using cDNA microarrays comprising 6000 human genes, we studied the gene expression profiles in the neutrophils of 21 MDS patients, seven of which had the 5q‐ syndrome, and two acute myeloid leukaemia (AML) patients when compared with the neutrophils from pooled healthy controls. Data analysis showed a high level of heterogeneity of gene expression between MDS patients, most probably reflecting the underlying karyotypic and genetic heterogeneity. Nevertheless, several genes were commonly up or down‐regulated in MDS. The most up‐regulated genes included RAB20, ARG1, ZNF183 and ACPL. The RAB20 gene is a member of the Ras gene superfamily and ARG1 promotes cellular proliferation. The most down‐regulated genes include COX2, CD18, FOS and IL7R. COX2 is anti‐apoptotic and promotes cell survival. Many genes were identified that are differentially expressed in the different MDS subtypes and AML. A subset of genes was able to discriminate patients with the 5q‐ syndrome from patients with refractory anaemia and a normal karyotype. The microarray expression results for several genes were confirmed by real‐time quantitative polymerase chain reaction. The MDS‐specific expression changes identified are likely to be biologically important in the pathophysiology of this disorder.
Variant MYST4‐CBP gene fusion in a t(10;16) acute myeloid leukaemia
Authors: Murati Anne , Adélaïde José , Mozziconacci Marie‐Joëlle , Popovici Cornel , Carbuccia Nadine , Letessier Anne , Birg Françoise , Birnbaum Daniel , Chaffanet Max 
Published: May 2004

SummaryWe report a novel fusion of the MYST4 and CBP genes in an acute myeloid leukaemia (AML)‐M4 patient exhibiting t(10;16)(q22;p13) and t(11;17)(q23;q21). The t(10;16)(q22;p13) resulted in a rearrangement, where MYST4‐CBP and CBP‐MYST4 chimaeric transcripts were products of in‐frame fusions of MYST4 exon 17 to CBP exon 6 and CBP exon 4 to MYST4 exon 18 respectively. The potential resulting chimaeric proteins showed similarities with MYST3‐CBP, MYST3‐P300 and MYST3‐NCOA2 putative fusion proteins found in other cases of AML.
The prevalence of, and molecular defects underlying, inherited protein S deficiency in the general population
Authors: Beauchamp Nicholas J. , Dykes Anne C. , Parikh Nirzari , Campbell Tait R. , Daly Martina E. 
Published: May 2004

SummaryThe molecular basis of protein S (PS) deficiency was investigated in seven of eight donors identified with persistently low plasma PS levels from a survey of PS levels in 3788 Scottish blood donors. PROS1 gene analysis identified at least one defect in six donors. Five were heterozygous for the Heerlen polymorphism predicting a Ser460Pro substitution. Haplotype analysis revealed the possibility that this allele was inherited with the same haplotype in four of the five donors, suggesting a founder effect for the Heerlen allele in this population. One Heerlen allele carrier was also heterozygous for a 3 bp deletion 68–72 bp upstream of exon 2. Platelet PROS1 transcript analysis showed no reduction in mRNA expression from the affected allele in this donor. A T to G transversion 3 bp upstream of exon 12 was identified in one donor, which is predicted to reduce the efficiency of PS mRNA splicing. However, PROS1 transcript analysis showed no evidence of exon skipping or cryptic splicing. No PROS1 gene defect was detected in the remaining donor. This genetic information enabled us to refine our estimate of the prevalence of heritable PS deficiency in the Scottish population to between 0·16% and 0·21%, predominantly resulting from the presence of the Heerlen allele.
ChlVPP/ABVVP, a first line ‘hybrid’ combination chemotherapy for advanced Hodgkin's lymphoma: a retrospective analysis
Authors: Martinelli G. , Cocorocchio E. , Peccatori F. , Zucca E. , Saletti P. C. , Calabrese L. , Pastano R. , Pruneri G. , Mazzetta C. , Ghielmini M. , Cavalli F. 
Published: May 2004

SummaryWe retrospectively analysed toxicities and clinical results of 61 Hodgkin's lymphoma patients treated with chlorambucil, vinblastine, procarbazine, doxorubicin, bleomycin, vincristine and etoposide (ChlVPP/ABVVP), delivered in a weekly alternate schedule. Of 61 patients, 33 were in stages III–IV, 21 in stage IIB and seven in stage IIA with bulky disease or extranodal presentation. ChlVPP/ABVVP was administered for 6–8 cycles. Involved field radiotherapy (IFRT) (30–35 Gy) was delivered to 31 patients with residual disease after chemotherapy or bulky disease at diagnosis. Of 61 patients, 58 (95%) achieved complete clinical or radiological remission after chemotherapy and IFRT. With a median follow‐up of 60 months, 5‐year overall survival, relapse‐ and event‐free survival were 78·8% (95% CI 68·2–91·1%), 81% (95% CI 70·6–92·2%) and 71·9% (95% CI 68·2–82·2%) respectively. Grades 3–4 neutropenia was the most relevant haematological toxicity and occurred in 82% of patients. Non‐haematological toxicities were mild and reversible. No toxic deaths were recorded. One patient developed secondary acute myeloid leukaemia 1 year after ChlVPP/ABVVP. Due to the retrospective nature of this study, no definitive conclusions could be drawn about the clinical activity of ChlVPP/ABVVP. Nonetheless, clinical results seem better than those reported with standard regimens [ABVD (doxorubicin, bleomycin, vincristine, dacarbazine), MOPP (methotrexate, vincristine, procarbazine, prednisone), MOPP/ABVD] and as good as those reported using standard or escalated BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone), with a lower degree of haematological and non‐haematological toxicity. Long‐term results of the ongoing randomized trial, comparing ABVD versus high‐dose intensity weekly regimens will be useful to confirm our results.
Role of Toll‐like receptor 4 in the initiation and progression of atherosclerotic disease
Authors: Pasterkamp G. , Van Keulen J. K. , De Kleijn D. P. V. 
Published: May 2004

AbstractThe family of Toll‐like receptors (TLRs) initiates an innate immune response after recognition of pathogen‐associated molecular patterns (PAMPs). Evidence is accumulating that TLRs, and particularly TLR4, are important players in the initiation and progression of atherosclerotic disease. Not only exogenous ligands but also endogenous ligands that are expressed during arterial injury are recognized by TLR4. Mouse knockout studies and epidemiological studies of human TLR4 polymorphisms have demonstrated that the TLR4 might play a role in the initiation and progression of atherosclerosis. This review will summarize the latest progression in research on the role of TLR4 in arterial occlusive disease In addition, the potential of intervention in TLR4 signalling to influence progression of atherosclerotic disease is discussed.