bluuebunny/crossref_metadata_2025_split huggingface dataset:
Down‐regulation of the nonspecific and antigen‐specific T cell cytokine response in ankylosing spondylitis during treatment with infliximab
Authors: Zou Jianxiang , Rudwaleit Martin , Brandt Jan , Thiel Andreas , Braun Jürgen , Sieper Joachim 
Published: March 2003

AbstractObjectiveTreatment of active ankylosing spondylitis (AS) with the monoclonal tumor necrosis factor α (TNFα) antibody infliximab is highly clinically effective. This study was undertaken to investigate the precise mechanism of action of anti‐TNFα treatment in AS.MethodsCytokine expression of CD4+ and CD8+ T cells was investigated before and 6 and 12 weeks after the start of treatment in 10 patients treated with infliximab, and before and after 6 weeks of treatment and 6 weeks after placebo was switched to infliximab in 10 patients treated initially with placebo. Peripheral blood mononuclear cells (PBMCs) were stimulated for 6 hours either nonspecifically with phorbol myristate acetate (PMA)/ionomycin or antigen specifically with a pool of 46 overlapping 18‐mer peptides derived from the G1 domain of aggrecan. Cells were stained for T cell surface markers CD4 and CD8 and for the intracellular cytokines interferon‐γ (IFNγ), TNFα, interleukin‐4 (IL‐4), and IL‐10. Positive cells were quantified by flow cytometry. For monocyte‐derived cytokines, PBMCs were stimulated with lipopolysaccharide (LPS) for 18 hours and TNFα and IL‐10 in the supernatant were measured by enzyme‐linked immunosorbent assay.ResultsCompared with baseline, infliximab treatment induced a significant decrease at 12 weeks in the number of CD4+ and CD8+ T cells that were positive for IFNγ and TNFα upon PMA/ionomycin stimulation (P = 0.005). A significant reduction had already begun to occur at 6 weeks. No change in the percent IFNγ or TNFα positivity among CD4+ and CD8+ subpopulations was observed after 6 weeks in patients treated with placebo. However, when these patients began infliximab treatment after 6 weeks of receiving placebo, there was a similar significant decrease in IFNγ and TNFα production by CD4+ and CD8+ T cells (P < 0.05). Furthermore, infliximab treatment induced a significant reduction in the number of IFNγ+ and TNFα+ CD8+ T cells (P = 0.005 at week 6 and week 12) after antigen‐specific in vitro stimulation with G1‐derived peptides. Between‐group analysis showed that the change in the expression of IFNγ and TNFα in both CD4+ and CD8+ T cells was significantly different between the infliximab and placebo groups (P = 0.001 for all variables). There was no change in the number of IL‐10+ or IL‐4+ T cells during treatment. No significant change in the production of TNFα and IL‐10 upon in vitro stimulation of PBMCs with LPS was detectable during infliximab treatment.ConclusionInfliximab down‐regulates both IFNγ and TNFα secreted by T cells but does not induce a change in cytokines produced by monocytes during 3 months of treatment. This is likely to be a relevant mechanism for the clinical efficacy of this therapy.
Bacterial peptidoglycans but not CpG oligodeoxynucleotides activate synovial fibroblasts by toll‐like receptor signaling
Authors: Kyburz Diego , Rethage Janine , Seibl Reinhart , Lauener Roger , Gay Renate E. , Carson Dennis A. , Gay Steffen 
Published: March 2003

AbstractObjectiveTo test the hypothesis that bacterial products acting as adjuvants, such as CpG oligodeoxynucleotides (ODNs) and peptidoglycans (PGs), are able to activate synoviocytes, and to determine the involvement of Toll‐like receptors (TLRs) in this activation process.MethodsCultured synovial fibroblasts obtained from patients with rheumatoid arthritis (RA) or osteoarthritis (OA) were stimulated with CpG ODNs or PGs. The expression of various integrins was determined by fluorescence‐activated cell sorting. TLR and matrix metalloproteinase (MMP) messenger RNA (mRNA) was measured by real‐time polymerase chain reaction. Additionally, levels of interleukin‐6 (IL‐6) and IL‐8 in the culture supernatants were assessed by enzyme‐linked immunosorbent assay. Blocking experiments were performed by adding anti–TLR‐2 and anti–TLR‐4 monoclonal antibodies to cultures stimulated with bacterial PGs.ResultsIncubation of synovial fibroblasts with CpG ODNs resulted in neither up‐regulation of the expression of integrins on the cell surface, up‐regulation of MMP mRNA expression, nor IL‐6 and IL‐8 production. However, incubation of RA synovial fibroblasts as well as OA synovial fibroblasts with staphylococcal PGs led to an up‐regulation of CD54 (ICAM‐1) surface expression and to increased expression of MMP‐1, MMP‐3, and MMP‐13 mRNA. Furthermore, production of the proinflammatory cytokines IL‐6 and IL‐8 was increased by treatment with PGs. We demonstrated that cultured synovial fibroblasts express low levels of TLR‐2 and TLR‐9 mRNA. TLR‐2 was up‐regulated after stimulation with PGs, whereas TLR‐9 mRNA remained at baseline levels after stimulation with CpG ODNs. Anti–TLR‐2 monoclonal antibodies significantly inhibited production of IL‐6 and IL‐8 induced by stimulation with PGs.ConclusionWe demonstrate that bacterial PGs activate synovial fibroblasts, at least partially via TLR‐2, to express integrins, MMPs, and proinflammatory cytokines. Inhibition of TLR signaling pathways might therefore have a beneficial effect on both joint inflammation and joint destruction.
Microenvironment regulation of extracellular signal–regulated kinase activity in chondrocytes: Effects of culture configuration, interleukin‐1, and compressive stress
Authors: Li Kelvin W. , Wang Aaron S. , Sah Robert L. 
Published: March 2003

AbstractObjectiveTo compare extracellular signal–regulated kinase (ERK) activity in response to interleukin‐1 (IL‐1) in chondrocytes under various culture configurations designed for the study of cartilage biology and repair, and also in response to dynamic load for chondrocytes in cartilage.MethodsIsolated bovine articular chondrocytes were maintained in serum‐supplemented medium under 4 culture configurations: high‐density monolayer, attached to a cut surface of cartilage, within tissue‐engineered constructs, or within intact cartilage explants. Samples were subjected to a change of medium with or without IL‐1. Cartilage explants were also subjected to dynamic compression.ResultsIn chondrocyte monolayers, both basal and IL‐1–stimulated ERK activities were similarly elevated at 0.5 hours after medium change, diminishing by 74% after 16 hours. In contrast, chondrocytes in other culture configurations exhibited lower basal levels of ERK activity and a moderate activation of ERK in response to IL‐1 that was sustained over the 16‐hour treatment time. The dynamic component of loading of cartilage explants led to a 5‐fold activation of ERK, compared with free‐swelling controls, that was indistinguishable from the effects of IL‐1.ConclusionERK signaling in response to IL‐1 in chondrocyte monolayers exhibited a pattern that was distinct from that in other culture systems, suggesting that the extracellular matrix plays an important regulatory role in modulating the response to extracellular stimuli. Since IL‐1 and dynamic loading have distinct effects on chondrocyte biosynthesis, signaling pathways other than ERK participate in the chondrocyte responses to these stimuli.
Placental immunomodulator ferritin, a novel immunoregulator, suppresses experimental arthritis
Authors: Weinberger Abraham , Halpern Marisa , Zahalka Muayad A. , Quintana Francisco , Traub Leonid , Moroz Chaya 
Published: March 2003

AbstractObjectiveTo determine the effect of treatment with C48, the recombinant cytokine‐like domain of the novel human placental immunomodulator ferritin (PLIF) immunoregulator, on zymosan‐induced arthritis (ZIA) in mice and on adjuvant‐induced arthritis (AIA) in rats.MethodsThe in vitro effect of PLIF/C48 was tested in mixed lymphocyte cultures (MLCs) of allogeneic mouse splenocytes. Arthritis was induced by intraarticular injection of zymosan into naive mice and by subcutaneous injection of Mycobacterium tuberculosis into rats. C48 was injected intraperitoneally daily from day 3 to day 9 or from day 7 to day 13 after induction of synovitis by zymosan, and every other day from day 2 to day 14 after induction of AIA. Swelling of the joints and histologic features of the synovium were assessed. Th1 and Th2 cytokines were quantified by enzyme‐linked immunosorbent assay.ResultsBoth PLIF and C48 significantly inhibited the in vitro immunoreactivity of mouse splenocytes in MLCs. Treatment of ZIA mice and AIA rats with C48 effectively reduced joint swelling. C48 treatment reduced synovial lining thickening, numbers of mononuclear cells and histiocytes, as well as cartilage destruction and bone erosions. In vitro, activated splenocytes from C48‐treated ZIA and AIA animals produced significantly higher levels of interleukin‐10 (IL‐10). In animals with ZIA, this was accompanied by lower levels of tumor necrosis factor and IL‐2.ConclusionHuman PLIF and C48 were shown to exert cross‐species immunosuppressive activity in vitro. The in vivo suppression of articular inflammation in the experimental models of ZIA and AIA was the result of treatment with the antiinflammatory human C48. These results suggest that treatment with C48 may offer an effective immunotherapeutic means of controlling inflammatory polyarthritis.
Attenuation of autoimmune disease in fas‐deficient mice by treatment with a cytotoxic benzodiazepine
Authors: Bednarski Jeffrey J. , Warner Roscoe E. , Rao Tharaknath , Leonetti Francesco , Yung Raymond , Richardson Bruce C. , Johnson Kent J. , Ellman Jonathan A. , Opipari Anthony W. , Glick Gary D. 
Published: March 2003

AbstractObjectiveElimination of autoreactive cells relies on Fas‐dependent activation‐induced cell death mechanisms, an important component of peripheral tolerance. Defects in Fas or its cognate ligand lead to inefficient activation‐induced cell death and are specific causes of lymphoproliferative and autoimmune diseases. The present study was undertaken to investigate a novel 1,4‐benzodiazepine (Bz‐423) that induces apoptosis and limits autoimmune disease in NZB/NZW mice, to determine its activity against lupus‐like disease associated with defective Fas expression. We investigated the Fas‐dependence of its cytotoxic actions, its therapeutic potential in mice deficient in Fas, and its therapeutic mechanism of action.MethodsPrimary lymphocytes isolated from Fas‐deficient MRL/MpJ‐Faslpr (MRL‐lpr) mice were tested for sensitivity to Bz‐423. Bz‐423 was administered to MRL‐lpr mice for short (1‐week) or long (14‐week) periods, and its effects on cell survival were determined along with measures of nephritis, arthritis, antibody titers, and Th subpopulations. BALB/c mice were similarly treated to determine if Bz‐423 alters normal immune functions in vivo.ResultsAdministration of Bz‐423 to MRL‐lpr mice significantly reduced autoimmune disease including glomerulonephritis and arthritis. Treatment was associated with decreases in CD4+ T cells and an alteration in the Th1/Th2 balance. At the therapeutic dosage, Bz‐423 did not interfere with normal T and B cell responses in BALB/c mice, suggesting that this agent is not globally immunosuppressive.ConclusionBz‐423 is a novel immunomodulatory agent that is active against disease even in the context of defective Fas signaling. It is a leading compound for further investigation into the development of selective therapies for lupus.
Why do we need algorithmic historiography?
Authors: Garfield Eugene , Pudovkin A. I. , Istomin V. S. 
Published: March 2003

AbstractThis article discusses the rationale for creating historiographs of scholarly topics using a new program called HistCite™, which produces a variety of analyses to aid the historian identify key events (papers), people (authors), and journals in a field. By creating a genealogic profile of the evolution, the program aids the scholar in evaluating the paradigm involved.
Indicator‐assisted evaluation and funding of research: Visualizing the influence of grants on the number and citation counts of research papers
Authors: Boyack Kevin W. , Börner Katy 
Published: March 2003

AbstractThis article reports research on analyzing and visualizing the impact of governmental funding on the amount and citation counts of research publications. For the first time, grant and publication data appear interlinked in one map. We start with an overview of related work and a discussion of available techniques. A concrete example—grant and publication data from Behavioral and Social Science Research, one of four extramural research programs at the National Institute on Aging (NIA)—is analyzed and visualized using the VxInsight® visualization tool. The analysis also illustrates current existing problems related to the quality and existence of data, data analysis, and processing. The article concludes with a list of recommendations on how to improve the quality of grant‐publication maps and a discussion of research challenges for indicator‐assisted evaluation and funding of research.
Human cytochromes mediating gepirone biotransformation at low substrate concentrations
Authors: Greenblatt David J. , von Moltke Lisa L. , Giancarlo Gina M. , Garteiz Daniel A. 
Published: March 2003

AbstractBiotransformation of gepirone to 1‐(2‐pyrimidinyl)‐piperazine (1‐PP) and 3'‐OH‐gepirone, as well as two other hydroxylated metabolites, was studied in vitro using a human liver microsomal preparation and heterologously expressed human CYP3A4 and CYP2D6. The focus was on a low range of gepirone concentrations (1000 nM and below). Liver microsomes formed 1‐PP and 3'‐OH‐gepirone with similar reaction velocities. Two other hydroxylated metabolites (2‐OH‐ and 5‐OH‐gepirone) were also formed, but pure reference standards were not available for purposes of quantitative analysis. The CYP3A inhibitor ketoconazole completely eliminated 1‐PP formation, reduced 3'‐OH‐gepirone formation to less than 20% of control, and reduced 2‐OH‐gepirone formation to 7% of control. All metabolites were formed by expressed CYP3A4; however, CYP2D6 formed 3'‐OH‐ and 5‐OH‐gepirone, but not 1‐PP or 2‐OH‐gepirone. Based on estimated relative abundances of the two isoforms in human liver, CYP3A4 was predicted to account for more than 95% of net clearance of gepirone in vivo at low concentrations approaching the therapeutic range. CYP2D6 would account for less than 5% of net clearance. The findings are consistent with previous in vitro studies of gepirone using higher substrate concentrations. Copyright © 2003 John Wiley & Sons, Ltd.
Are there teratogenic risks associated with antidotes used in the acute management of poisoned pregnant women?
Authors: Bailey Benoit 
Published: March 2003

AbstractOBJECTIVEWe reviewed evidence suggesting teratogenic risk associated with the use of antidotes in the acute management of poisoned pregnant women.METHODSMedline, Toxline, and DART/ETIC searches; references of retrieved articles, pertinent databases and textbooks were also searched.RESULTSThere are case reports or case series of women who received antidotes for poisoning during (*) or after (+) the period of organogenesis who showed no fetal adverse effects. Some antidotes, however, have no teratogenic risk: atropine (cohort/surveillance studies)+, calcium (oral supplement: cohort study)+ and pyridoxine (Bendectin studies). Also, ethanol+, methylene blue (intra‐amniotic injection but not oral) and penicillamine* can be considered teratogens but their risks in the treatment of poisonings are unknown. There is no epidemiologic study evaluating the risk of the following antidotes during pregnancy: N‐acetylcysteine*+, BAL (dimercaprol)+, black widow spider antivenin+, calcium EDTA+, crotalidae antivenin, crotalidae polyvalent immune FAB, cyanide antidote kit (amyl and sodium nitrate, sodium thiosulfate), deferoxamine*+, digoxin immune FAB+, DMSA+, flumazenil+, fomepizole, methylene blue (IV), naloxone, physostigmine, pralidoxime+, protamine+; and parenteral pharmacologic doses of calcium+, folinic acid*, glucagon+, hydroxycobalamin, phytonadione (vitamin K), and pyridoxine.CONCLUSIONSDespite the limited evidence supporting the risk of antidote use during pregnancy, antidotes should be used when there is a clear maternal indication to decrease the morbidity or mortality associated with poisoning. The only exception may be penicillamine, which is a teratogen. Better antidotes exist for most poisonings that penicillamine could potentially treat. At this time, there is no known fetal indication for all antidotes. Reporting the use of an antidote during pregnancy should be encouraged, especially if used during the critical period of organogenesis. Birth Defects Research (Part A) 67:133–140, 2003. © 2003 Wiley‐Liss, Inc.
Birth prevalence and pattern of osteochondrodysplasias in an inbred high risk population
Authors: Al‐Gazali Lihadh I. , Bakir Mahmood , Hamid Zuhair , Varady Elizabeth , Varghes Mani , Haas Danialla , Bener Abdulbari , Padmanabhan Rengasamy , Abdulrrazzzaq Yeusef M. , Dawodu Aden Kula 
Published: March 2003

AbstractBACKGROUNDDefine the pattern and birth prevalence of the different types of osteochondrodysplasias in newborn infants in the United Arab Emirates (UAE) population, which is highly inbred and where termination of pregnancy is not accepted.METHODSAll infants with a birth weight of 500 gm and above in the three hospitals in Al Ain Medical District of the UAE were studied prospectively over a period of 5 years. For each live birth or stillbirth with suspected skeletal dysplasia, a detailed clinical and radiological examination was carried out. Pregnancy history and information regarding parental age, ethnic origin, family history, and level of consanguinity were obtained and a pedigree was constructed.RESULTSAmong the 38,048 births during the study period, 36 (9.46/10,000 births) had some type of skeletal dysplasia. Eighteen cases were attributed to autosomal recessive genes (4.7/10,000 births), 10 were due to apparent new dominant mutations (2.62/10,000), five were autosomal dominant type (1.3/10,000) and one was X‐linked dominant type (0.26/10,000). In three cases, inheritance was unknown. The most common recessive type of skeletal dysplasia in our series was fibrochondrogenesis (1.05/10,000), followed by chondrodysplasia punctata (0.78/10,000). The birth prevalence rate of skeletal dysplasia doubled in the last 2 years of the 5‐year observation period (6.74/10,000 in 1996 vs. 12.86/10,000 in 1999, and 13.45/10,000 in 2000). This increase involved cases caused by new dominant mutations, and occurred mainly in the first half of 1999.CONCLUSIONThis prospective study has identified a high birth prevalence of skeletal dysplasia, and risk factors are postulated. These findings represent an accurate birth prevalence figure and a useful baseline for this group of birth defects in the UAE. Birth Defects Research (Part A) 67:125–132, 2003. © 2003 Wiley‐Liss, Inc.
Bendectin and birth defects II: Ecological analyses
Authors: Kutcher Jeffrey S. , Engle Arnold , Firth Jacqueline , Lamm Steven H. 
Published: March 2003

AbstractBACKGROUNDBendectin was the primary pharmaceutical treatment of nausea and vomiting of pregnancy (NVP) in the United States until the early 1980s. Its manufacture was then discontinued after public allegations that it was causing birth defects. Subsequently, meta‐analyses of the many epidemiological cohort and case/control studies used to examine that hypothesis have demonstrated the absence of a detectable teratogenic effect. This study presents an ecological analysis of the same hypothesis that examines specific malformations.METHODSAnnual birth defect prevalence data for the 1970s to the 1990s have been obtained for specific birth defects from the Center for Disease Control's nationwide Birth Defect Monitoring Program. These data for the US have been compared graphically to the annual US Bendectin sales for the treatment of NVP. Data have also been obtained for annual US rates for hospitalization for NVP. The three data sets have been temporally compared in graphic analysis.RESULTSThe temporal trends in prevalence rates for specific birth defects examined from 1970 through 1992 did not show changes that reflected the cessation of Bendectin use over the 1980–84 period. Further, the NVP hospitalization rate doubled when Bendectin use ceased.CONCLUSIONSThe population results of the ecological analyses complement the person‐specific results of the epidemiological analyses in finding no evidence of a teratogenic effect from the use of Bendectin. Birth Defects Research (Part A) 67:88–97, 2003. © 2003 Wiley‐Liss, Inc.
Estimation of Treatment Difference and Standard Deviation with Blinded Data in Clinical Trials
Authors: Chen Michael , Kianifard Farid 
Published: March 2003

AbstractIn an ongoing clinical trial and while the randomized treatment codes remain blinded, it is often desirable to estimate the treatment difference and standard deviation for a normally‐distributed response variable. This is particularly useful for estimating the sample size for future trials or for adjusting the sample size for the ongoing trial. We describe the limitations of an available EM algorithm‐based procedure to reestimate the standard deviation without unblinding the codes for the two treatments. We introduce a new procedure and propose a clinical trial design for estimating both the treatment difference and standard deviation without unblinding. The performance of the proposed procedure is evaluated in a simulation study.
Estimation and Confidence Intervals after Adjusting the Maximum Information
Authors: Lawrence John , Hung H.M. James 
Published: March 2003

AbstractIn a comparative clinical trial, if the maximum information is adjusted on the basis of unblinded data, the usual test statistic should be avoided due to possible type I error inflation. An adaptive test can be used as an alternative. The usual point estimate of the treatment effect and the usual confidence interval should also be avoided. In this article, we construct a point estimate and a confidence interval that are motivated by an adaptive test statistic. The estimator is consistent for the treatment effect and the confidence interval asymptotically has correct coverage probability.
Cumulative Damage Survival Models for the Randomized Complete Block Design
Authors: Gregory Gavin G. 
Published: March 2003

AbstractA continuous time discrete state cumulative damage process {X(t), t ≥ 0} is considered, based on a non‐homogeneous Poisson hit‐count process and discrete distribution of damage per hit, which can be negative binomial, Neyman type A, Polya‐Aeppli or Lagrangian Poisson. Intensity functions considered for the Poisson process comprise a flexible three‐parameter family. The survival function is S(t) = P(X(t) ≤ L) where L is fixed. Individual variation is accounted for within the construction for the initial damage distribution {P(X(0) = x) | x = 0, 1, …,}. This distribution has an essential cut‐off before x = L and the distribution of L – X(0) may be considered a tolerance distribution. A multivariate extension appropriate for the randomized complete block design is developed by constructing dependence in the initial damage distributions. Our multivariate model is applied (via maximum likelihood) to litter‐matched tumorigenesis data for rats. The litter effect accounts for 5.9 percent of the variance of the individual effect. Cumulative damage hazard functions are compared to nonparametric hazard functions and to hazard functions obtained from the PVF‐Weibull frailty model. The cumulative damage model has greater dimensionality for interpretation compared to other models, owing principally to the intensity function part of the model.