bluuebunny/crossref_metadata_2025_split huggingface dataset:
Population pharmacokinetic analysis of meloxicam in rheumatoid arthritis patients
Authors: Meineke Ingolf , Türck Dietrich 
Published: March 2003

Aim  To perform a nonlinear mixed effect modelling (NONMEM) population pharmacokinetic analysis of meloxicam plasma concentrations in rheumatoid arthritis (RA) patients participating in three clinical trials, and to evaluate the effects of age, weight, gender and concomitant medications on meloxicam pharmacokinetics.Methods  Meloxicam was administered to RA patients once daily for 3 weeks or 6 months at doses between 7.5 and 60 mg. Plasma samples were obtained at least 7 days after the first dose and meloxicam plasma concentrations were quantified by h.p.l.c..Results  NONMEM analysis was conducted on plasma samples derived from 586 patients. A one‐compartmental model was found to describe the data adequately. For a typical subject in the population, a clearance of 0.377 l h−1 (95% confidence interval (CI) 0.0304–0.449) in males and 0.347 l h−1 (95% CI 0.274‐0.419) in females was obtained. The volume of distribution was estimated to be 14.9 l. The findings were corroborated by subsequent analysis using WinBUGS. Analysis of covariates showed that age and gender both significantly (P < 0.005) affected clearance. The effect of age was relatively small and a dose adjustment of <10% was deemed unnecessary. Differences between males and females were attributed to differences in weight. No clinically relevant drug‐drug interactions were found, although sulphasalazine and glucocorticoids both significantly (P < 0.005) affected meloxicam clearance (+19% and − 12%, respectively). The mechanisms by which these agents affect meloxicam clearance remain to be elucidated.Conclusions  The population pharmacokinetic meloxicam data from patients with RA gave similar results to those obtained from phase I trials. However, uncommon drug interactions may not be detected in phase I trials because of the small number of observations made.
Slow acetylator phenotype and genotype in HIV‐positive patients with sulphamethoxazole hypersensitivity
Authors: Alfirevic Ana , Stalford Anne C. , Vilar F. Javier , Wilkins Ed G. L. , Park B. Kevin , Pirmohamed Munir 
Published: March 2003

Aims To test the role of acetylator status, and to investigate the reported discrepancy between acetylator phenotype and genotype in HIV‐positive patients with sulphamethoxazole (SMX) hypersensitivity.Methods Forty HIV‐positive patients (32 of whom were SMX‐hypersensitive), and 26 healthy volunteers, were genotyped by polymerase chain reaction–restriction fragment length polymorphism (PCR–RFLP) analysis, and phenotyped using dapsone (50 mg) as a probe, for acetylator status. Sequencing of the NAT2 exon was performed where discrepancy between phenotyping and genotyping was detected. Our results were also pooled with published studies addressing slow acetylator status in HIV‐positive SMX‐hypersensitive patients.Results Slow acetylator genotype and phenotype frequencies did not differ between HIV‐positive SMX‐hypersensitive and nonhypersensitive patients, and healthy controls, which was further confirmed in a meta‐analysis of published studies (pooled odds ratio 2.25, 95% confidence interval 0.45, 11.17). Discordance between phenotype and genotype was resolved in four of the subjects by sequencing of the whole NAT2 exon, which revealed rare mutations, leaving three (9%) HIV‐positive SMX‐hypersensitive patients and one (4%) healthy volunteer who continued to demonstrate the discordance.Conclusions Slow acetylator phenotype or genotype is unlikely to predispose to SMX hypersensitivity in HIV‐positive patients, although a minor role cannot be excluded. Phenotype–genotype discrepancies are partly due to nondetection of all rare alleles by PCR methodology, and can be circumvented by sequencing of the gene in patients showing a discrepancy.
Identification of pancreatic type I secreted phospholipase A2 in human epidermis and its determination by tape stripping
Authors: Mazereeuw-Hautier J. , Redoules D. , Tarroux R. , Charveron M. , Salles J.P. , Simon M.F. , Cerutti I. , Assalit M.F. , Gall Y. , Bonafe J.L. , Chap H. 
Published: March 2003

Abstract
Phospholipases A2 (PLA2) catalyse the release of fatty acids from the sn-2 position of phospholipids and have been suggested to play a key part in permeability barrier homeostasis. Using a sensitive and versatile fluorometric method, significant PLA2 activity has been detected in both human skin homogenates and tape strippings of stratum corneum. Based on various properties (resistance to heat and sulphuric acid treatment, neutral optimal pH, absolute requirement for millimolar calcium concentrations, inhibition by dithiothreitol and p-bromophenacyl bromide, and resistance to a trifluoromethyl ketone derivative of arachidonic acid, AACOCF3, a specific inhibitor of cytosolic PLA2), this enzyme was characterized as a secretory PLA2 (sPLA2). Immunohistochemistry revealed strong labelling of type I pancreatic sPLA2 at the stratum corneum–stratum granulosum junction, type II sPLA2 being undetectable. An increase in PLA2 activity in tape-stripped material from the deepest level of the stratum corneum was correlated with partial morphological disappearance of type I sPLA2 immunolabelling. Our data thus provide the first convincing evidence that pancreatic sPLA2 is significantly expressed in human epidermis, where it might participate in the accumulation of free fatty acids contributing to the permeability barrier. In addition, our method for determining PLA2 activity in easily available tape strippings should allow further clinical studies aimed to explore possible PLA2 abnormalities in various dermatoses.
Comedogenesis: some new aetiological, clinical and therapeutic strategies
Authors: Cunliffe W.J. , Holland D.B. , Clark S.M. , Stables G.I. 
Published: March 2003

AbstractHypercornification is an early feature of acne and precedes inflammation. It is associated with ductal hyperproliferation and there are many controlling factors such as androgens, retinoids and cytokines. Cycling of normal follicles and of comedones may explain the natural resolution of comedones and, in the longer term, resolution of the disease itself. There is a need to tailor treatment according to comedonal type. Suboptimal therapy can often result from inappropriate assessments of comedones, especially microcomedones, missed comedones, sandpaper comedones, submarine comedones and macrocomedones. Macrocomedones can produce devastating acne flares, particularly if patients are inappropriately prescribed oral isotretinoin. Gentle cautery under topical local anaesthesia is a useful therapy in the treatment of such lesions. The newer retinoids and new formulations of all-trans-retinoic acid show a better benefit/risk ratio. Evidence-based studies are required to allow adequate comparisons.
Very low incidence of p53 antibodies in adult non‐Hodgkin's lymphoma and multiple myeloma
Authors: Preudhomme Claude , Vanrumbeke Mickaël , Detourmignies Laurence , Facon Thierry , Lepelley Pascale , Soussi Thierry , Fenaux Pierre 
Published: March 2003

In several types of solid tumours, circulating antibodies to p53 are seen in about a third of cases with a p53 mutation, but are absent in cases without p53 mutation. Therefore detection of those antibodies has relatively low sensitivity but high specificity in the detection of p53 mutations.We looked for circulating p53 antibodies by ELISA in 56 adult non‐Hodgkin's lymphoma (NHL) and 80 multiple myeloma cases. A certain or highly probable p53 mutation was found by SSCP analysis, immunocyto‐ or immunohisto‐chemistry in 8/35 (23%) NHL cases and 2/19 (10%) MM cases analysed by these techniques. None of the 80 MM cases and only one of the 56 cases of NHL had circulating p53 antibodies. The positive case had Burkitt's lymphoma and a p53 missense mutation at codon 273. Thus, very few MM and NHL patients with a p53 mutation develop p53 antibodies and this test does not appear to be useful in haematological malignancies.
Antibodies to prothrombin crossreact with plasminogen in patients developing myocardial infarction
Authors: Puurunen Marja , Mänttäri Matti , Manninen Vesa , Palosuo Timo , Vaarala Outi 
Published: March 2003

In a prospective study on healthy middle‐aged men, high level of antibodies to prothrombin implied a risk of myocardial infarction. The possible mechanism(s) of these antibodies in coronary thrombosis are not known. Because prothrombin belongs to the kringle proteins and shares structural homology with a fibrinolytic kringle protein plasminogen, we studied whether antibodies to prothrombin crossreact with plasminogen.Sera from 17 healthy middle‐aged men who later developed myocardial infarction were studied. Binding of antibodies to immobilized prothrombin (EIA) was inhibited by using soluble prothrombin, plasminogen and synthetic peptides of 20 amino acids from plasminogen kringle 5 (P304, P305) and from prothrombin kringle 2 (P302) as inhibitors. The peptides contained the conserved pentapeptide CRNPD of the kringle proteins.Soluble prothrombin inhibited up to 50% the binding of antibodies to immobilized prothrombin in all sera. Plasminogen inhibited binding in 9/17 (53%) sera (a decrease of at least 20%). P305 inhibited binding to prothrombin in 8/17 (47%), P304 in 4/17 (23%) and P302 in 6/17 (35%) sera. In structural analysis, presentation of the pentapeptide was conformationally different between the peptides.We conclude that crossreactive antibodies binding to prothrombin and plasminogen occur in sera of patients later developing myocardial infarction. The crossreactive epitope seems to be conformational and include the conserved pentapeptide of the kringle proteins. These antibodies may interfere with the fibrinolytic function of plasminogen and contribute to the development of myocardial infarction.
Essential monoclonal gammopathy with an IgM paraprotein that is a cryoglobulin with cold agglutinin and EDTA‐dependent platelet antibody properties
Authors: Pujol Misericordia , Ribera José Ma , Jimenez Carmen , Ribera Ana , Abad Elena , Feliu Evarist 
Published: March 2003

A patient with apparent anaemia and thrombocytopenia caused by a monoclonal paraprotein is described. The patient's serum contained a monoclonal IgM kappa, a cryoglobulin and a cold agglutinin. The cryoglobulin, similar to the serum paraprotein, was a monoclonal IgM kappa. Serum was studied to determine the relationship of the cryoglobulin with the cold agglutinin. The cryoglobulin and cold agglutinin were found to be the same paraprotein. Moreover, with absorption and elution techniques the reactivity of the autoantibody with both erythrocytes and platelets was demonstrated.Reports of cryoprecipitable cold agglutinins are rare and therefore this case is exceptional given that the IgM kappa paraprotein was found to be a cold agglutinin which was also reactive with platelets.
Successful use of protease inhibitors in HIV‐infected haemophilia patients
Authors: Merry Concepta , Mcmahon Corrina , Ryan Mairin , O'shea  , Mulcahy Fiona , Smith Owen P. 
Published: March 2003

The haemophilias are a group of inherited haemostatic disorders that require regular clotting factor replacement therapy in the severe and moderately severe subgroups. Prior to the introduction of adequate viral inactivation methods in 1985, haemophilia patients were at exceptionally high risk of contracting blood‐borne viruses from factor concentrates as each batch was derived from the plasma of thousands of donors. As a result, approximately 60% of these patients were infected with HIV between 1979 and 1985, and HIV infection now contributes significantly to the morbidity and mortality seen in this group.Protease inhibitors (PIs) have been shown to significantly log reduce viral loads and increase CD4 cell counts in HIV‐infected individuals. Recently, there has been concern about their use in HIV‐infected haemophilia patients following increased bleeding episodes in some patients during PI therapy. We prospectively studied the effect of PI therapy in 20 HIV‐infected haemophilia patients at our centre over a 6‐month period. The mean increase in CD4 cell count was 70 × 106/l and the mean log decrease in viral load was 1.59 over the study period. Gastrointestinal side‐effects (nausea and vomiting in five, diarrhoea in two) were the most frequent and resulted in discontinuation of the medication in two patients. Factor concentrate usage for the group on and off study was similar. One severe FVIII patient reported a single episode of an unusual bleed which responded promptly to FVIII concentrate infusion. The significant clinical and laboratory benefits in terms of HIV disease and the paucity of added bleeding complications suggest that PI therapy should not be withheld from HIV‐infected haemophilics. Further prospective studies evaluating the efficacy and possible haemostatic complications related to these promising inhibitors of the HIV protease are needed.
Immunophenotype of adult and childhood acute promyelocytic leukaemia: correlation with morphology, type of PML gene breakpoint and clinical outcome. A cooperative Italian study on 196 cases
Authors: Guglielmi Cesare , Paola Martelli Maria , Diverio Daniela , Fenu Susanna , Luce Vegna Maria , CantÙ‐Rajnoldi Angelo , Biondi Andrea , Grazia Cocito Maria , Del Vecchio Luigi , Tabilio Antonio , Avvisati Giuseppe , Basso Giuseppe , LO Coco Francesco 
Published: March 2003

Acute promyelocytic leukaemia (APL), characterized by a specific PML‐RARα fusion gene resulting from translocation t(15;17) and by a high response rate to differentiation therapy with all‐trans retinoic acid, presents clinical (varying WBC counts, age and treatment outcome), morphological (hypergranular M3 and hypogranular M3V) and molecular (three isoforms of PML breakpoint) heterogeneity.We correlated leukaemic immunophenotype with these aspects in 196 molecularly confirmed APLs (63 children and 133 adults) in Italy. The bcr3 isoform (P = 0.05) and FAB M3V (P = 0.05) were more frequent in children. We confirmed in APL an immunophenotype characterized by frequent expression of CD13, CD33 and CD9 and rare expression of HLA‐DR, CD10, CD7 and CD11b. However, we recognized CD2 in 28%, CD34 in 23% and CD19 in 11% of cases and demonstrated by double labelling that CD34 and CD2 may be co‐expressed. CD2, CD34 and CD19 were significantly intercorrelated, and variably associated to other features: CD2 and CD34 with PML bcr3 (P < 0.001 and P < 0.001, respectively) and with M3V (P < 0.001 and P = 0.002), whereas only CD19 was directly correlated with WBC counts and only CD2 positively influenced CR rate (logistic model) and event‐free survival (Cox model). We conclude that immunophenotype plays a role in the determination of the biological and clinical heterogeneity of childhood and adult APL.
Cost‐minimization analysis of CHOP, fludarabine and rituximab for the treatment of relapsed indolent B‐cell non‐Hodgkin's lymphoma in the U.K.
Authors: Sweetenham John , Hieke Klaus , Kerrigan Matthew , Howard Paul , Smartt Pamela F. M. , McIntyre Ann‐Marie , Townshend Sarah 
Published: March 2003

The optimal therapy for patients with relapsed indolent B‐cell non‐Hodgkin's lymphoma is unclear. Combination chemotherapy such as CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) or purine analogues including fludarabine are frequently used and the anti‐CD20 monoclonal antibody rituximab has recently been licensed for use. However, no comparative studies of these therapies have been reported. Since relapsed indolent B‐cell NHL is generally regarded as incurable with current therapies, the place of each of these therapies is likely to be determined by their relative efficacy, toxicity and cost. We undertook a literature review and a retrospective analysis of patients receiving combination chemotherapy for relapsed indolent B‐cell NHL at our institution to determine the response rates and the duration of response when treated with CHOP or fludarabine. Reported response rates and median response duration for these regimens are similar, and similar to those reported in phase II studies of rituximab. A cost minimization analysis was therefore conducted.The per patient costs for the treatment of drug‐related adverse events were £5049 for CHOP, £2953 for fludarabine and £109 for rituximab. When costs of a full course of each treatment were compared, the costs per patient for CHOP, fludarabine and rituximab were £7210 (£5975–8445), £10022 (£8917–11126) and £6080 (£5892–6267) respectively. In this preliminary analysis, rituximab appeared to have a similar efficacy rate to CHOP and fludarabine, but had significantly fewer adverse events and a lower total cost per patient. These data require confirmation in a prospective randomized study with formal assessment of cost‐effectiveness.
Circulating platelet–neutrophil complexes represent a subpopulation of activated neutrophils primed for adhesion, phagocytosis and intracellular killing
Authors: Peters M. J. , Dixon G. , Kotowicz K. T. , Hatch D. J. , Heyderman R. S. , Klein N. J. 
Published: March 2003

Platelets play a prominent role in linking the processes of inflammation, haemostasis and thrombosis. Recent studies have shown that platelets form heterotypic aggregates with leucocytes via platelet CD62P and leucocyte β2 integrins. These interactions have been observed in vitro in blood taken from healthy volunteers and in clinical conditions in which thrombosis and inflammation are prominent.This study investigated the properties of platelet–neutrophil complexes (PNCs) in anticoagulated whole blood. At rest, neutrophils in PNCs exhibit a significantly more activated adhesion molecule profile than free neutrophils with increased CD11b expression and activation (increased binding of the CD11b/CD18 ‘activation reporter’ monoclonal antibody 24) and decreased CD62L expression. In addition, neutrophils in PNCs phagocytosed significantly more Neisseria meningitidis and produced more toxic oxygen metabolites than free neutrophils.Stimulation with the platelet agonist adenosine diphosphate (ADP) led to further increases in CD11b expression and activation, loss of CD62L as well as increased phagocytosis and toxic oxygen metabolite production throughout the whole neutrophil population. When these experiments were repeated with the CD62P blocking antibody G1 the effects were inhibited to a variable extent, dependent upon the parameter under investigation. These results indicate that both soluble and contact‐dependent factors contribute to platelet‐mediated neutrophil activation.Platelet neutrophil complexes represent a large subpopulation of neutrophils with a more activated adhesion molecule profile, and a greater capacity for phagocytosis and toxic oxygen metabolite production. This study provides further support for a role for PNCs in both health and disease.
A combination of megakaryocyte growth and development factor and interleukin‐1 is sufficient to culture large numbers of megakaryocytic progenitors and megakaryocytes for transfusion purposes
Authors: Van Den Oudenrijn Sonja , De Haas Masja , Calafat Jero , Van Der Schoot C. Ellen , Von Dem Borne Albert E. G. KR. 
Published: March 2003

Chemotherapy‐induced thrombocytopenia is a major risk factor in cancer treatment. The transfusion of autologous ex vivo expanded megakaryocytes could be a new therapy to shorten the period of thrombocytopenia. Therefore we investigated, in a liquid culture system, the effect of various cytokine combinations composed of pegylated megakaryocyte growth and development factor (PEG‐rHuMGDF), interleukin‐1 (IL‐1), IL‐3, IL‐6, IL‐11 and stem cell factor (SCF) on the proliferation and differentiation of CD34+ cells, in order to define the most optimal and minimum levels of cytokine combinations for megakaryocyte expansion.Besides PEG‐rHuMGDF, IL‐1 was found to be important for optimal megakaryocyte expansion. Depletion of either SCF, IL‐6 or IL‐11 did not exert a large effect, but the absence of IL‐1 strongly diminished the number of megakaryocytic cells. Addition of IL‐3 to the combination PEG‐rHuMGDF, IL‐1, IL‐6, IL‐11 and SCF significantly reduced the number of megakaryocyte progenitors (CD34+CD41+ cells) and the number of CFU‐Meg. Furthermore, we found a strong correlation between the number of CD34+CD41+ cells and the number of CFU‐Meg obtained after 8 d culture.Our study shows that optimal ex vivo expansion of megakaryocytes is achieved by the combination of PEG‐rHuMGDF and IL‐1. The numbers of megakaryocytes and megakaryocyte progenitors (CD34+CD41+) obtained in our liquid culture system with the growth factor combination PEG‐rHuMGDF and IL‐1 are suitable for transfusion purposes.
Stem cell transplantation from HLA‐matched related donor for Fanconi's anaemia: a retrospective review of the multicentric Italian experience on behalf of Associazione Italiana di Ematologia ed Oncologia Pediatrica (AIEOP)–Gruppo Italiano Trapianto di Midollo Osseo (GITMO)
Authors: Dufour Carlo , Rondelli Roberto , Locatelli Franco , Miano Maurizio , Di Girolamo Gabriele , Bacigalupo Andrea , Messina Chiara , Porta Fulvio , Balduzzi Adriana , Iorio Anna Paola , Buket Erer , Madon Enrico , Pession Andrea , Dini Giorgio , Di Bartolomeo Paolo 
Published: March 2003

Twenty‐seven consecutive Italian patients with Fanconi's anaemia (FA) underwent stem cell transplantation (SCT) from an HLA‐matched related donor in 10 Italian centres of the Associazione Italiana Ematologia ed Oncologia Pediatrica (AIEOP), Gruppo Italiano di Trapianto di Midollo Osseo (GITMO). Twenty‐two patients (81·5%) were conditioned with low‐dose (median 20 mg/kg) cyclophosphamide (Cy) and thoraco‐abdominal or total body irradiation (median dose 500 cGy), five patients (18·5%) with high‐dose Cy (median 120 mg/kg). Graft‐vs.‐host disease (GVHD) prophylaxis was carried out with cyclosporin A in 26 cases; methotrexate (MTX) was added in eight cases. One patient received MTX alone. The median follow‐up was 36 months. Ninety‐two percent of patients (25 out of 27) engrafted, grade II and III acute GVHD occurred in 28% and 8% of patients, respectively, with chronic GVHD in 12·5%. Conditioning‐related toxicity was mild: 4% of patients had grade III mucositis, 7·4% had grade II haemorrhagic cystitis, 14·8% had grade III liver toxicity and 11·1% had grade III renal toxicity. Transplant‐related mortality at 12 months was 19·2%, survival at 36 months was 81·5%, with a median Karnofsky score of 100%. No late tumours occurred after a mean follow‐up of the survivors of 5 years. None of the studied variables significantly affected the survival, including conditioning regimen, acute GVHD and clinical non‐haematological phenotype. Among the studied variables, only conditioning regimens containing high‐dose Cy and the presence of genital abnormalities were significantly (P < 0·05) associated with an increased rate of acute GVHD. Our study demonstrates that the Italian FA patients undergoing SCT from an HLA‐matched related donor have a very good outcome. These patients, when compared with others of different ethnic origin who underwent allogeneic bone marrow transplantation, showed a less severe non‐haematological phenotype, raising the possibility that this milder phenotype may have, at least in part, contributed to the outcome. Our data may provide a useful tool for further studies aiming to correlate genotype with phenotype.