bluuebunny/crossref_metadata_2025_split huggingface dataset:
The population pharmacokinetics of long‐term methotrexate in rheumatoid arthritis
Authors: Godfrey C. , Sweeney K. , Miller K. , Hamilton R. , Kremer J. 
Published: November 2003

Aims Methotrexate is considered by many practitioners to be the agent of choice in the treatment of rheumatoid arthritis. The pharmacokinetics of methotrexate have been reported to exhibit significant intersubject variability. Therefore, this study was undertaken to evaluate the population pharmacokinetics of methotrexate during long‐term administration in adults with rheumatoid arthritis.Methods Methotrexate pharmacokinetics were evaluated in a 36 month study of 62 adults with rheumatoid arthritis. Patients received oral or intramuscular doses of methotrexate weekly with pharmacokinetic studies performed every 6 months. Data were analyzed with nonlinear mixed effects modeling.Results Three thousand two hundred and sixty post oral or intramuscular dose serum methotrexate concentrations comprising 425 individual concentrationvstime profiles were modeled using NONMEM. Covariates that significantly (P<0.005) influenced the disposition of methotrexate were age (AGE, years), body weight (BW, kg), creatinine clearance (CLCR, l h−1 ), gender (GEN; 0=male, 1=female), dose (DOSE, μmol), and fedvsfasted state (FED; 0=fasted, 1=fed). The final model describing the biexponential disposition of methotrexate was clearance(CL, l h−1 )=(0.0810*BW+0.257*CLCR)*(1–0.167*GEN); central volume (V c, l)=0.311*BW; peripheral volume (V p, l)=0.469*BW‐0.169*AGE; intercompartmental clearance (Q, l h−1 )=4.27*(1–0.355*GEN); oral absorption rate constant (kapo, h−1 )=4.70–0.0439*DOSE*(1–0.507*FED); intramuscular absorption rate constant (kaim, h−1 )=0.122*DOSE; relative bioavailability (F )=93.4%; and oral absorption lag time (LAGpo, min)=13.5. Pharmacokinetic parameters (%CV) for a typical fasted male subject in this study were CL, 7.34 l h−1(27%);V c, 23.5 l (28%);V p, 25.3 l (31%); Q, 4.25 l h−1(41%);kapo, 3.67 h−1(77%); andkaim, 3.09 h−1(44%).Conclusions The population pharmacokinetics of methotrexate in adults with rheumatoid arthritis were well described by this investigation. Substantial interpatient variability was explained by incorporating patient specific data into regression equations predicting pharmacokinetic parameters.
Frequency of CBFβ/MYH11 fusion transcripts in patients entered into the U.K. MRC AML trials
Authors: LANGABEER S. E. , WALKER H. , GALE R. E. , WHEATLEY K. , BURNETT A. K. , GOLDSTONE A. H. , LINCH D. C. 
Published: November 2003

It has been established that cytogenetic findings at diagnosis of acute myeloid leukaemia (AML) are a powerful prognostic indicator. Patients who have the inv(16)(p13q22), closely associated with the FAB subtype M4Eo, are deemed to have good‐risk disease. This subtle translocation may be difficult to detect in poor‐quality metaphase preparations and if missed could lead to the incorrect assignment of risk group and influence further treatment strategies.We studied 321 patients with AML at diagnosis for the presence of inv(16)(p13q22) and CBFβ/MYH11 fusion transcripts by cytogenetic and RT‐PCR techniques respectively. Karyotypic analysis detected 21 cases of inv(16) (p13q22), all of which were PCR positive. A further 12 cases were detected at the molecular level only, in FAB types other than M4Eo. The observed frequencies of CBFβ/MYH11 fusion transcripts in our study have been adjusted for the reported incidence of each FAB subtype and we calculate that 10.1% of all new cases of AMLs have molecular evidence of inv(16)(p13q22), only half of which are of the M4Eo subtype.We conclude that molecular screening for the presence of CBFβ/MYH11 fusion transcripts should be mandatory in all cases of AML at diagnosis.
The role of compliance as a cause of instability in oral anticoagulant therapy
Authors: Van der Meer Felix J. M. , BriëT Eenest , Vandenbroucke Jan P. , ŠRámek Dagmar I. , Versluijs Myrthe H. P. M. , Rosendaal Frits R. 
Published: November 2003

To assess the role of non‐compliance as a cause of instability in patients on oral anticoagulant therapy, a follow‐up study of stably and instably anticoagulated patients and of patients beginning oral anticoagulant therapy was performed. Compliance was assessed by pill counting and with the use of pill bottles in the cap of which a microprocessor registered the exact date and time of opening of the bottle. (In)stability of oral anticoagulant therapy was expressed as the number of INRs and as the time spent within the target range and by squared sigma. Subsequently, as a pilot study, a randomized intervention study in instable, non‐compliant patients was performed in which these patients were or were not informed about the real nature of the cap of the pill bottle.Nineteen stable and 19 unstable patients and 30 patients beginning therapy were followed for 3 months or less until therapy stopped. Compliance was better in the previously stably anticoagulated patients, although differences were small. Poor compliance was not a major cause of instability in patients starting therapy. Although the pilot intervention study was too small to assess the role of the special pill bottle, it was shown that compliance can be positively affected.
Protection from concanavalin A (Con A)-induced T cell-dependent hepatic lesions and modulation of cytokine release in mice by sodium fusidate
Authors: NICOLETTI F , BELTRAMI B , RASCHI E , DI MARCO R , MAGRO G , GRASSO S , BENDTZEN K , FIORELLI G , MERONI P L 
Published: November 2003

SUMMARY
The immunomodulatory effects of the antibiotic sodium fusidate (SF) were tested in a model of T cell-dependent hepatic injury that can be induced in normal mice by a single i.v. injection of Con A. Signs of hepatitis with elevated transaminase activities in plasma, severe infiltration of the liver by neutrophil granulocytes, lymphocytes and monocytes, and necrotic areas were observed in control mice treated intraperitoneally with PBS 24 h and 1 h before Con A challenge. T cell- and macrophage-derived cytokines (IL-2, interferon-gamma (IFN-γ), tumour necrosis factor-alpha (TNF-α), IL-1β, IL-6) were released with different kinetics in the circulation of these mice. SF, 20, 40 or 80 mg/kg, administered 24 h and 1 h before Con A challenge, protected the mice against the hepatitic effects of Con A. The protective effects of SF were dose-dependent and accompanied by profound modifications of blood levels of cytokines induced by Con A, so that, relative to control mice, SF (80 mg/kg)-treated animals showed markedly diminished plasma levels of IL-2, IFN-γ and TNF-α, along with augmented levels of IL-6. These results suggest that SF might be useful in the treatment of immunoinflammatory liver diseases in humans.
Analysis of T cell receptor Vβ usage in the autoimmune sialadenitis of non-obese diabetic (NOD) mice
Authors: YANAGI K , HANEJI N , ISHIMARU N , SAITO I , HAYASHI Y 
Published: November 2003

SUMMARY
The NOD mouse develops spontaneous autoimmune sialadenitis besides a well characterized T cell-mediated autoimmune insulitis. We used reverse transcriptase-polymerase chain reaction (RT-PCR) to analyse the repertoire of T cell receptor (TCR) Vβ chain genes expressed in the isolated infiltrating cells from affected salivary glands. Immunohistochemical analysis showed that the vast majority of inflammatory infiltrates in the salivary glands were CD4+Vβ8+ and CD4+Vβ6+ T cells, whereas CD8+T cells and B220+ B cells were fewer in number. Predominant expression of the Vβ8 and Vβ6 gene segment was detected in the infiltrating cells in the salivary glands very early, and age-related diversity of TCR Vβ gene usage was observed. Single-strand conformation polymorphism (SSCP) analysis demonstrated a strikingly symmetrical distribution of expanded clones in the PCR products of the Vβ8 and Vβ6 gene in the cells infiltrating the salivary glands. Nucleotide sequencing of amplified TCR Vβ cDNA revealed that T cell clonotypes had a high incidence of identical clones, indicating that the immune response in NOD sialadenitis is driven by common stimuli. These findings suggest that in spontaneous autoimmune sialadenitis of NOD mice, there may be a restricted usage of TCR Vβ elements in the early stage of the autoimmune lesion to recognize self-antigen in organ-specific autoimmune sialadenitis.
Analysis of VH genes rearranged by individual B cells in dermal infiltrates of patients with mycosis fungoides
Authors: FÖRSTE N , GELLRICH S , GOLEMBOWSKI S , RUTZ S , AUDRING H , STERRY W , JAHN S 
Published: November 2003

SUMMARY
In patients with cutaneous T cell lymphomas such as mycosis fungoides B cells can frequently be detected in the lymphocytic dermal infiltrate. To analyse their immunoglobulin heavy chain gene repertoire, single B cells were obtained from tissue sections of two typical patients with mycosis fungoides using hydraulic micromanipulation followed by specific amplification of the respective gene segments by single-cell polymerase chain reaction (PCR) technique. A total of 21 VHDJH genes was sequenced. From each individual B cell a single productive VHDJH rearrangement was obtained. There was no clonal relationship detected between any of these rearrangements suggesting polyclonality of the infiltrating B cells. The representation of VH families was in accordance with the germ-line complexity. A remarkably high number of VH genes (5/13 in patient 1; 3/8 in patient 2) was completely or nearly germ-line-identical. Five of seven VH4 family genes were nearly unmutated. On the other hand, most of the VH3 gene family members were somatically mutated in an antigen-driven manner. The proportion of germ-line-identical VH genes, the usage of individual VH, D, JH gene elements, and the pattern of somatic mutations found in the B cells infiltrating skin lesions of patients with mycosis fungoides resembles the peripheral blood repertoire, suggesting a bystander role of these cells.
In vitro effects of mercuric chloride (HgCl2) on human mononuclear cells
Authors: LOFTENIUS A , EKSTRAND J , MÖLLER E 
Published: November 2003

SUMMARY
Due to the release of the toxic compounds of mercury from amalgam fillings, dental amalgam has been questioned as an adequate restoration material for tooth fillings. HgCl2 has been found to be mitogenic for human blood lymphocytes in vitro. However, activation required much higher concentrations than are ever found in vivo. This study has been initiated to evaluate further the influence of HgCl2 on human immunocompetent cells in vitro. It is found that HgCl2 in a narrow concentration range has the ability to preferentially stimulate the CD4+ T cell subset to blast transformation and DNA synthesis. The reaction, when monitored during days 2–6, is maximal at day 6, and most blasts express the IL-2 receptor (IL-2R), indicating in vitro activation. The CD8+ T cell subset is not affected to the same extent. In addition, HgCl2-induced lymphocyte reactivity is dependent on accessory cells, i.e. CD14+ cells.
Relevance of local Th2-type cytokine mRNA expression in immunocompetent infiltrates in inflamed gingival tissue to periodontal diseases
Authors: Tokoro Y , Matsuki Y , Yamamoto T , Suzuki T , Hara K 
Published: November 2003

Abstract
It has been suggested that the types of inflammatory round cell infiltrates and the divergence in the cytokine production profile by macrophages and helper T cells regulate the course of infectious or inflammatory diseases, including periodontitis and gingivitis. We examined the expression of IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-6 and tumour necrosis factor-alpha (TNF-α) mRNA in the inflamed gingiva by in situ hybridization. The results of single-cell analysis were used as data sets for statistical analyses. The density of cells expressing IL-1α, IL-4 and IL-5 mRNA was higher in periodontitis than in gingivitis. IL-2 mRNA-expressing cells were almost absent in gingivitis specimens. Principal component analysis disclosed three factors explaining 84.8% of the variance: one accounting for 40.5% of the variance and mainly regulated by IL-1α, IL-1β, IL-6 and TNF-α, and two others, explaining 29.9% and 14.4% of the variance, describing the relationship between the types of cytokines derived from macrophages or Th2 type. These results suggest that the cytokines produced by inflammatory cells infiltrating in the gingival tissue are influential on the progression of gingivitis, an acute and reversible inflammatory condition, to chronic and destructive periodontitis. Thus, periodontal disease progression may be regulated by the local cytokine network, and the bias in this network towards a Th2-type cytokine dominance could be an exacerbating factor.
Increased proinflammatory cytokine gene expression in the colonic mucosa of coeliac disease patients in the early period after gluten challenge
Authors: Chowers Y , Marsh M N , De Grandpre L , Nyberg A , Theofilopoulos A N , Kagnoff M F 
Published: November 2003

Abstract
Activation of T cells in the intestinal mucosa in response to gluten exposure is thought to play a key role in the pathogenesis of coeliac disease. Moreover, the response of the rectal mucosa to gluten challenge has been considered a useful predictor of gluten sensitivity in coeliac disease. In the present study, we assessed early changes in the expression of proinflammatory cytokine genes and the T cell receptor (TCR) Vβ repertoire in the rectal mucosa of coeliac disease patients following experimental gluten challenge. Cytokine gene expression was assessed in rectal mucosal biopsies from coeliac disease subjects and controls before and after rectal gluten challenge using quantitative reverse transcription polymerase chain reaction analysis, and the TCR Vβ repertoire was characterized using a multiprobe RNase protection assay. Marked up-regulation of expression of the C-X-C chemokine IL-8, the proinflammatory cytokine IL-1β, and the C-C chemokine monocyte chemotactic protein-1 occurred within 2–4 h of rectal gluten challenge in coeliac disease subjects, but not in controls. Furthermore, these changes occurred in the absence of parallel changes in the expressed repertoire of TCR Vβ genes in the rectal mucosa. Thus, an increased expression of proinflammatory cytokine genes precedes the expansion of antigen-specific T cell populations in the early period following experimental exposure of the rectal mucosa of coeliac disease patients to gluten. These findings provide new insights into pathways that may be involved in the activation or reactivation of coeliac disease.
The effects of vitamin A derivatives on in vitro antibody production by peripheral blood mononuclear cells (PBMC) from normal blood donors and patients with common variable immunodeficiency (CVID)
Authors: Zhang J-G , Morgan L , Spickett G P 
Published: November 2003

Abstract
The underlying nature of the defect of CVID is not understood, and the treatment at present is life-long infusion of replacement immunoglobulin. Attempts have been made to use other therapeutic agents, such as IL-2 and retinoic acid (RA), with mixed results. RA is a morphogenetic signalling molecule related to vitamin A and involved in vertebrate development. We report here our in vitro evaluation of the effects of three vitamin A analogues, 9-cis retinal, 13-cis RA and all-trans RA, on antibody production of PBMC from normal donors and patients with CVID. At 10−5 m, 9-cis retinal strongly augmented IgM production of lymphocytes from normal individuals and to a much lesser extent, mild, non-granulomatous (group C) CVID patients, but IgG production was not affected. In the presence of anti-human IgM and IL-2, 9-cis retinal at 10−5 m elevated IgM and IgG production by normal PBMC, but the effect on PBMC of mild CVID was minimal. The effect of 9-cis retinal was significantly reduced at 10−7 and 10−9 m. Only minimal effects were found using 13-cis RA and all-trans RA under these conditions. No detectable antibody production was found in severe, granulomatous (group A) CVID patients under any conditions tested. Taking all data into account, 9-cis retinal is the most potent stimulator for antibody production compared with 13-cis RA and all-trans RA as tested in this in vitro study.
Antibodies to endothelial cells in Kawasaki disease lyse endothelial cells without cytokine pretreatment
Authors: Fujieda M , Oishi N , Kurashige T 
Published: November 2003

Abstract
Kawasaki disease (KD) is characterized by diffuse vasculitis and marked immune activation. To confirm the presence of antiendothelial cell antibodies (AECA) and cytotoxicity of AECA, we investigated the presence of AECA using ELISA and cytotoxicity of AECA in KD. Sera from patients with acute KD were assessed for binding to human umbilical vein endothelial cells (HUVEC) using a cell-based ELISA, and for cytotoxicity against HUVEC as indicated by the conversion of a tetrazolium salt (MTT) into a coloured product. IgM AECA were detected in 8/19 KD sera, IgG AECA were detected in 5/19 KD sera. Significant differences in both AECA titres existed between patients and febrile and afebrile controls. Six out of 19 patients showed complement-dependent cytotoxicity against HUVEC. Cytotoxicity was significantly enhanced by pretreating HUVEC with tumour necrosis factor (TNF), and reduced by incubation with gammaglobulin. Serum titres of IgM AECA in the KD patients were positively correlated with cytotoxicity. Findings suggest that IgM AECA mediates complement-dependent cytotoxicity against endothelial cells in patients with KD, and gammaglobulin may reduce complement-dependent cytotoxicity of AECA against endothelial cells.
Experimental acute glomerulonephritis induced in the rabbit with a specific streptococcal antigen
Authors: Yoshizawa N , Oshima S , Takeuchi A , Kondo S , Oda T , Shimizu J , Nishiyama J , Ishida A , Nakabayashi I , Tazawa K , Sakurai Y 
Published: November 2003

Abstract
FITC-labelled IgG obtained from patients convalescing from acute poststreptococcal glomerulonephritis (APSGN) stains glomeruli of patients with early APSGN. We previously reported a streptococcal antigen (preabsorbing antigen (PA-Ag)) that preabsorbed the stain out of sera from the convalescent patients and thus prevented glomerular staining. To confirm the nephritogenicity of PA-Ag, we administered up to 40 mg of this antigen to rabbits for 8 days and observed them for up to 9 weeks. Immunohistological analysis showed diffuse and global glomerular staining for C3 without notable staining for γ-globulin. Light microscopic examinations revealed slight to moderate proliferative glomerulonephritis with exudative change. Control rabbits, which received similar doses of bovine serum albumin, did not show significant staining for C3. A transient and significant decrease in CH50 was observed from weeks 3 to 7 (9.7 ± 0.3 U/ml at week 3; normal range 12.9 ± 0.6 U/ml). This experimental model showed a resemblance to immunological and immunohistological features of APSGN in humans. Although the precise mechanisms are yet to be determined, complement activation by PA-Ag seems to hold a key position in this model and in the human disease.
Gender, light and water effects in carbon isotope discrimination, and growth rates in the dioecious tree Ilex aquifolium
Authors: Retuerto R. , Lema B. Fernandez , Roiloa S. Rodriguez , Obeso J. R. 
Published: November 2003

Abstract1. Detailed understanding of the specific physiology of sexes in dioecious species is required to explain patterns in gender dimorphism. Under controlled‐environment conditions we tested the hypothesis that sexes of the dioecious tree holly Ilex aquifolium L. (Aquifoliaceae) differed in growth and long‐term potential water‐use efficiency, as measured by carbon isotope discrimination (Δ13C), and that these differences were dependent on the environmental context.2. Patterns of response in Δ13C to the various combinations of light and water were gender‐specific. Under more xeric conditions, females maintained significantly higher Δ13C than males.3. Female plants exhibited significantly greater relative diameter growth rates than male plants.4. As expected, Δ13C significantly increased with decreasing irradiance, and decreased with increasing limitation in water supply. Light and water effects were not independent, with a more pronounced drought effect in decreasing leaf Δ13C under unshaded than under shaded conditions.5. Our results suggest that between‐sex differences in physiology are context‐dependent. Future studies attempting to assess gender dimorphism should take more account of gender‐specific interactions with the environment. Gender‐specific efficiency in water use could play a decisive role in explaining gender differences in growth and ecological interactions.
The small GTP‐binding protein Rho1 is a multifunctional protein that regulates actin localization, cell polarity, and septum formation in the fission yeast Schizosaccharomyces pombe
Authors: Nakano Kentaro , Arai Ritsuko , Mabuchi Issei 
Published: November 2003

Background:The small GTP‐binding protein Rho has been shown to regulate the formation of the actin cytoskeleton in animal cells. We have previously isolated two rho genes, rho1+ and rho2+ , from the fission yeast Schizosaccharomyces pombe in order to investigate the function of Rho using genetic techniques. In this paper, we report the cellular function of Rho1.Results:We found that Rho1 is essential for cell viability and cell polarity using gene disruption and by exogenous expression of botulinum C3 ADP‐ribosyltransferase. In cells expressing either a constitutively active Rho1 or a dominant‐negative Rho1, actin patches were delocalized. Both the cell wall and secondary septum were thick and stratified in cells expressing the constitutively active Rho1, while the cell wall of cells expressing the dominant‐negative Rho1 seemed to be loosely organized. Furthermore, inactivation of Rho1 is apparently required for the separation of daughter cells. Cell fractionation studies suggested that Rho1 is predominantly membrane‐bound. Moreover, we observed that Rho1 is localized to the cell periphery and to the septum.Conclusions:Rho1 is involved in actin patch localization, the control of cell polarity, the regulation of septation, and cell wall synthesis.