bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antiinflammatory and analgesic effects of somatostatin released from capsaicin‐sensitive sensory nerve terminals in a Freund's adjuvant–induced chronic arthritis model in the rat
Authors: Helyes Zsuzsanna , Szabó Árpád , Németh József , Jakab Balázs , Pintér Erika , Bánvölgyi Ágnes , Kereskai László , Kéri György , Szolcsányi János 
Published: May 2004

AbstractObjectiveWe previously demonstrated that somatostatin (SOM) released from the activated peripheral terminals of capsaicin‐sensitive primary sensory neurons inhibits acute inflammation and nociception. This study was undertaken to examine this systemic “sensocrine” function of neuronally derived somatostatin in chronic inflammation in the Freund's complete adjuvant (CFA)–induced arthritis model.MethodsArthritis of the tibiotarsal joint of Lewis rats was evoked by subcutaneous injection of CFA into the left hind paw and the tail root. For 3 weeks, the volume of the paws was measured by plethysmometry, and the mechanonociceptive thresholds were measured by esthesiometry. Plasma concentrations of SOM were determined by radioimmunoassay, and histologic studies of the joints were performed. To impair the function of capsaicin‐sensitive afferents, the capsaicin receptor (VR1/TRPV1) agonist resiniferatoxin (RTX) was injected subcutaneously (30, 70, and 100 μg/kg on 3 subsequent days) 7 days before CFA administration. The SOM receptor antagonist cyclosomatostatin (c‐SOM; 20 μg/kg) or, in another group, the synthetic heptapeptide agonist TT‐232 (2 × 50–400 μg/kg) was administered intraperitoneally every day.ResultsRTX pretreatment or c‐SOM injection significantly increased edema and mechanical hyperalgesia of both CFA‐treated and contralateral paws. The histologic score based on synovial thickening, cell infiltration, cartilage destruction, and bone erosion was also significantly higher both in the RTX‐ and the c‐SOM–injected groups. These parameters were dose‐dependently decreased by TT‐232. Plasma SOM‐like immunoreactivity increased 4‐fold on the twenty‐first day, and was inhibited by RTX pretreatment, as well as by daily administration of TT‐232.ConclusionOur data suggest that SOM released into the circulation from capsaicin‐sensitive afferents in response to prolonged activation exerts systemic antiinflammatory and analgesic effects. TT‐232 can open new perspectives in the treatment of chronic arthritis.
Antibodies to guanosine triphosphate misidentified as anti–double‐stranded DNA antibodies in a patient with antinuclear antibody–negative lupus, due to buckling of insolubilized assay DNA
Authors: Ma Chun Hung , Hui Joannie , Tang Janet Tsui Ying , Leung Danny Tze Ming , Chui Yiu Loon , Fok Tai Fai , Lim Pak‐Leong 
Published: May 2004

AbstractObjectiveTo investigate why the serum of a pediatric patient with systemic lupus erythematosus was persistently (>30 months) and strongly positive for antibodies to double‐stranded DNA (dsDNA) as revealed by enzyme‐linked immunosorbent assay (ELISA), but yielded negative results on the antinuclear antibody test (HEp‐2 immunofluorescence [IF]).MethodsThe patient's antibodies were isolated on dsDNA and single‐stranded DNA (ssDNA) supports, which were then examined by dsDNA ELISA and HEp‐2 IF. Tests included the use of various inhibitors to determine the fine specificity of the antibodies. Other tests performed included immunoblotting, immunoprecipitation, Crithidia luciliae IF, and neutrophil IF.ResultsThe antibodies isolated from the dsDNA and ssDNA supports were similar, in that they were of the IgG type, bound well in the dsDNA ELISA, and recognized a normally hidden nucleolar RNA antigen in HEp‐2 cells. With both the dsDNA ELISA and nucleolar antigens, inhibition studies revealed that the epitope recognized was guanosine 5′‐triphosphate (GTP). Binding of the antibodies was better to GTP than to guanosine 5′‐monophosphate or cytidylyl (3′‐5′) guanosine, and, in turn, was better than to guanosine, while N7‐methylated GTP was unreactive. The antibodies did not bind to dsDNA present in solution or in HEp‐2 or Crithidia cells, but bound transfer RNA well and recognized a cytoplasmic RNA antigen in neutrophils.ConclusionA new problem in dsDNA ELISA is revealed in the occurrence of a hitherto‐unknown and unusual buckling of the insolubilized DNA molecule, which, absent in dsDNA found in solution or in whole cells, presumably creates gaps of single‐strandedness in the molecule. A new antibody specific for GTP is described in this patient, which may be clinically important.
Macrophage migration inhibitory factor up‐regulates the expression of interleukin‐8 messenger RNA in synovial fibroblasts of rheumatoid arthritis patients: Common transcriptional regulatory mechanism between interleukin‐8 and interleukin‐1β
Authors: Onodera Shin , Nishihira Jun , Koyama Yoshikazu , Majima Tokifumi , Aoki Yoshimitsu , Ichiyama Hiroki , Ishibashi Teruo , Minami Akio 
Published: May 2004

AbstractObjectiveInterleukin‐8 (IL‐8) plays an important role in the migration of inflammatory cells into the synovium and joint fluids in rheumatoid arthritis (RA). This study was undertaken to investigate the IL‐8 inductive activity of the macrophage migration inhibitory factor (MIF) in RA synovial fibroblasts. The regulatory mechanism of IL‐8 was compared with that of IL‐1β.MethodsMIF‐induced IL‐8 and IL‐1β transcriptional activation was studied in RA synovial fibroblasts by Northern blot analysis, enzyme‐linked immunosorbent assay, and electromobility shift assay. The effect of anti‐MIF antibody administration on murine passive collagen‐induced arthritis (CIA) was also evaluated by histologic examination and reverse transcriptase–polymerase chain reaction.ResultsMIF up‐regulated the IL‐8 messenger RNA (mRNA) and protein levels in a dose‐dependent manner. The IL‐8 mRNA up‐regulation started 1 hour poststimulation by MIF, and reached a maximum level at 6 hours. IL‐1β mRNA was also up‐regulated by MIF. The mRNA up‐regulation of IL‐8 and IL‐1β by MIF was inhibited by 2 tyrosine kinase inhibitors, a protein kinase C (PKC) inhibitor, an activator protein 1 (AP‐1) inhibitor, and by an NF‐κB inhibitor. A cAMP‐dependent kinase inhibitor did not inhibit it. MIF enhanced AP‐1 and NF‐κB binding activities in a dose‐dependent manner. Passive CIA enhanced mRNA levels of macrophage inflammatory protein 2 and cytokine‐induced neutrophil chemoattractants and, moreover, migration and proliferation of inflammatory cells within the synovium, which were suppressed by administration of an anti‐MIF antibody.ConclusionMIF may play an important role in the migration of inflammatory cells into the synovium of rheumatoid joints via induction of IL‐8. MIF up‐regulates IL‐8 and IL‐1β mRNA via tyrosine kinase–, PKC‐, AP‐1–, and NF‐κB–dependent pathways.
Progression of radiographic hip osteoarthritis over eight years in a community sample of elderly white women
Authors: Lane Nancy E. , Nevitt Michael C. , Hochberg Marc C. , Hung Yun‐Yi , Palermo Lisa 
Published: May 2004

AbstractObjectiveTo describe progression over 8 years in a community‐based sample of elderly women with radiographic findings of hip osteoarthritis (RHOA) with or without hip pain.MethodsBaseline and followup anteroposterior pelvic radiographs were obtained at a mean ± SD 8.3 ± 0.4 years of followup in women age ≥65 years at the baseline examination of the Study of Osteoporotic Fractures. We evaluated progression in 936 hips of 745 women with one or more baseline findings of RHOA: summary OA grade ≥2, minimum joint space (MJS) ≤1.5 mm, definite femoral or acetabular osteophytes, definite superolateral joint space narrowing (JSN), or moderate or worse superomedial JSN. We separately examined progression in hips with an MJS between 1.5 mm and 2.5 mm. Hip pain and lower extremity disability were assessed by questionnaire and examination. Measures of progression included an increase in summary grade of radiographic findings, increase in total osteophyte score, decrease in MJS of ≥0.5 mm, total hip replacement (THR), and increase in lower extremity disability score. Odds ratios (ORs) and 95% confidence intervals (95% CIs) for baseline radiographic predictors of progression were estimated using general estimating equations.ResultsDuring followup, 12.9% of women with baseline RHOA underwent THR, and 22.8% had substantial worsening of lower extremity disability, while 64.6% of hips with RHOA showed radiographic progression or were replaced. Progression was greater by all measures in the 37% of hips and 47% of women with both RHOA and hip pain at baseline. Of hips with pain, 23.6% progressed to THR compared with 2.7% of hips without pain (OR 8.1 [95% CI 4.2, 15.4], P < 0.001), and MJS decreased ≥0.5 mm in 53.7% of hips with pain compared with 30.7% of hips without pain (OR 1.9 [95% CI 1.4, 2.6], P < 0.001). Women with hip pain were more likely to have worsened lower extremity disability (29.3% versus 17.6%; OR 1.8 [95% CI 1.2, 2.8], P = 0.0053). Hips with an MJS >1.5 mm and ≤2.5 mm (n = 1,868) had primarily superomedial narrowing and comparatively low rates of progression that did not differ by hip pain. Femoral osteophytes, superolateral JSN, and subchondral bone changes were independent predictors of progression.ConclusionAmong women recruited from the community, radiographic and clinical progression was greater in those with symptomatic RHOA, but still substantially less frequent than previously reported for hip OA patients in clinical settings. Asymptomatic RHOA and hips with an isolated finding of mild JSN (MJS of 1.5 mm to 2.5 mm) were unlikely to progress over 8 years.
Association of killer cell immunoglobulin‐like receptors with scleroderma
Authors: Momot T. , Koch S. , Hunzelmann N. , Krieg T. , Ulbricht K. , Schmidt R. E. , Witte T. 
Published: May 2004

AbstractObjectiveScleroderma is an autoimmune disorder of unknown etiology. A genetic contribution has been demonstrated, and genes influencing activation of the immune system have been potentially identified as candidate genes in this process. The repertoire of killer cell immunoglobulin‐like receptors (KIRs) that are involved in the activation of T cells and natural killer cells is highly variable. Recently, an association of KIR2DS2 with vasculitis in patients with rheumatoid arthritis has been reported. Because scleroderma is characterized by an involvement of the vascular system, we sought to determine whether KIR2DS2 is associated with scleroderma.MethodsWe typed 9 KIR genes in 102 patients with scleroderma and in 100 blood donors, using polymerase chain reaction on genomic DNA.ResultsTwelve patients with scleroderma, compared with only 2 blood donors, had KIR phenotypes characterized by the presence of the activating KIR2DS2 and the absence of the corresponding inactivating KIR2DL2 (P = 0.005).ConclusionThe genetic combination of KIR2DS2+ and KIR2DL2− is associated with scleroderma.
Expression of interleukin‐21 receptor, but not interleukin‐21, in synovial fibroblasts and synovial macrophages of patients with rheumatoid arthritis
Authors: Jüngel Astrid , Distler Jörg H. W. , Kurowska‐Stolarska Mariola , Seemayer Christian A. , Seibl Reinhart , Forster Adrian , Michel Beat A. , Gay Renate E. , Emmrich Frank , Gay Steffen , Distler Oliver 
Published: May 2004

AbstractObjectiveTo determine the role and expression of the cytokine/receptor pair interleukin‐21 (IL‐21)/IL‐21 receptor (IL‐21R) in rheumatoid arthritis (RA).MethodsThe expression of IL‐21R and IL‐21 was analyzed by TaqMan real‐time polymerase chain reaction (PCR) and in situ hybridization of synovial biopsy samples from patients with RA and osteoarthritis (OA). Double labeling by immunohistochemistry after in situ hybridization was performed with anti‐CD68 antibodies. The expression of IL‐21R at the protein level was confirmed by Western blotting. Stimulation experiments were performed with recombinant IL‐1β, tumor necrosis factor α (TNFα), platelet‐derived growth factor (PDGF), and transforming growth factor β (TGFβ). The role of IL‐21R in cartilage destruction was analyzed in the SCID mouse coimplantation model of RA.ResultsIL‐21R was found in total RNA extracts and in synovial biopsy samples from RA patients, whereas no expression or only minimal expression was seen in samples from OA patients. Double labeling indicated that both synovial macrophages and synovial fibroblasts expressed IL‐21R. Western blotting with anti–IL‐21R antibodies confirmed the expression of IL‐21R protein in RA synovial fibroblasts (RASFs). Of note, IL‐21 was not detectable by real‐time PCR and in situ hybridization in the same samples in vivo as in vitro. The level of expression of IL‐21R messenger RNA (mRNA) was not altered by stimulation with IL‐1β, TNFα, PDGF, or TGFβ. Interestingly, in the SCID mouse coimplantation model, RASFs did not maintain their expression of IL‐21R at sites of invasion into the cartilage. Similarly, IL‐21R mRNA was not expressed at sites of invasion into cartilage and bone in RA synovium.ConclusionOur data demonstrate that IL‐21R is expressed in RA synovium by RASFs and synovial macrophages. IL‐21R is associated with the activated phenotype of RASFs independently of the major proinflammatory cytokines IL‐1β and TNFα, but correlates negatively with the destruction of articular cartilage and bone.
Combination therapy with etanercept and anakinra in the treatment of patients with rheumatoid arthritis who have been treated unsuccessfully with methotrexate
Authors: Genovese Mark C. , Cohen Stanley , Moreland Larry , Lium Deborah , Robbins Sean , Newmark Richard , Bekker Pirow ,   for the 20000223 Study Group
Published: May 2004

AbstractObjectiveTo determine the potential for additive or synergistic effects of combination therapy with the selective anti–tumor necrosis factor α agent etanercept and the anti–interleukin‐1 agent anakinra.MethodsTwo hundred forty‐four patients in whom rheumatoid arthritis (RA) was active despite methotrexate therapy were treated with subcutaneous etanercept only (25 mg twice weekly), full‐dosage etanercept (25 mg twice weekly) plus anakinra (100 mg/day), or half‐dosage etanercept (25 mg once weekly) plus anakinra (100 mg/day) for 6 months in a double‐blind study at 41 centers in the US. Patients had never previously received anticytokine therapy. Patient response was measured with the American College of Rheumatology (ACR) core set criteria, a health‐related quality‐of‐life questionnaire, and the Disease Activity Score. Safety was assessed by the number of adverse events and clinical laboratory values. Plasma concentrations of both agents and antibody formation against both agents were also assessed.ResultsCombination therapy with etanercept plus anakinra provided no treatment benefit over etanercept alone, regardless of the regimen, but was associated with an increased safety risk. Thirty‐one percent of the patients treated with full‐dosage etanercept plus anakinra achieved an ACR 50% response, compared with 41% of the patients treated with etanercept only. This result was not statistically significant (P = 0.914). The incidence of serious infections (0% for etanercept alone, 3.7–7.4% for combination therapy), injection‐site reactions, and neutropenia was increased with combination therapy. Combination therapy had no effect on the pharmacokinetics or immunogenicity of either agent.ConclusionCombination therapy with etanercept and anakinra provides no added benefit and an increased risk compared with etanercept alone and is not recommended for the treatment of patients with RA.
Markers for type II collagen breakdown predict the effect of disease‐modifying treatment on long‐term radiographic progression in patients with rheumatoid arthritis
Authors: Landewé Robert , Geusens Piet , Boers Maarten , van der Heijde Désirée , Lems Willem , te Koppele Johan , van der Linden Sjef , Garnero Patrick 
Published: May 2004

AbstractObjectiveTo investigate in a randomized clinical trial setting with an aggressive combination‐therapy arm and a mild‐monotherapy arm, whether therapy‐induced changes in urinary C‐terminal crosslinking telopeptide of type I collagen (CTX‐I) and type II collagen (CTX‐II) predict 5‐year radiographic progression in patients with rheumatoid arthritis (RA).MethodsPatients had participated in the COBRA (Combinatietherapie Bij Reumatoïde Artritis) trial comparing aggressive step‐down combination therapy (the COBRA regimen, including temporary high‐dose prednisolone, temporary low‐dose methotrexate, and sulfasalazine [SSZ]) and mild monotherapy (SSZ). Urinary CTX‐I and CTX‐II levels were measured at baseline and 3, 6, 9, and 12 months after initiation of treatment. Radiographs were scored according to the modified Sharp/van der Heijde method (mean of 2 independent readers who were aware of the sequence). Individual long‐term radiographic progression was estimated, using baseline radiographs and all radiographs obtained during the followup period, by simple linear regression analysis (curve fitting).ResultsBoth COBRA therapy and SSZ monotherapy produced a significant decrease in urinary CTX‐I and CTX‐II levels at 3 months, and this decrease was amplified at 6 months. COBRA therapy suppressed CTX‐II (change from baseline levels −36% and −43% at 3 and 6 months, respectively), but not CTX‐I, significantly better than did SSZ (−17% and −21% at 3 and 6 months, respectively) at 3 and 6 months. The magnitude of the decrease in urinary CTX‐II levels at 3 months significantly predicted long‐term (5‐year) radiographic progression (β = 0.48 [95% confidence interval (95% CI) 0.13, 0.83]). This effect was independent of the change in disease activity and inflammation indices at 3 months. Patients whose CTX‐II levels were normalized (<150 ng/mmoles of urinary creatinine) at 3 months had a significantly higher chance of radiographic stability (no progression over 5 years) than did patients whose CTX‐II levels were increased both at baseline and at 3 months (odds ratio 4.5 [95% CI 1.5, 13]).ConclusionThe individual CTX‐II response measured after 3 months of therapy in patients with active RA who had increased CTX‐II levels at baseline independently predicts long‐term radiographic progression. Urinary CTX‐II levels may be used as early markers of treatment efficacy in patients with RA.
Familial Paget's disease in The Netherlands: Occurrence, identification of new mutations in the sequestosome 1 gene, and their clinical associations
Authors: Eekhoff E. W. M. , Karperien M. , Houtsma D. , Zwinderman A. H. , Dragoiescu C. , Kneppers A. L. J. , Papapoulos S. E. 
Published: May 2004

AbstractObjectiveTo estimate the occurrence of familial Paget's disease of bone in The Netherlands, to examine the prevalence of mutations of the sequestosome 1 gene (SQSTM1) in identified families, and to assess potential genotype–phenotype associations.MethodsWe performed a case–control study of patients with Paget's disease and a mutation analysis of the SQSTM1 gene of index patients with familial disease and of the relatives of those with a mutation. Serum alkaline phosphatase (AP) activity was assessed, and bone scintigraphy was performed.ResultsFive percent of patients had at least 1 first‐degree relative with the disease, compared with 0.5% of the controls (relative risk 10; 95% confidence interval 1.3–75.6). In 38.9% of patients with familial disease, heterozygous mutations in the SQSTM1 gene were identified. These were the previously described P392L mutation, which was present in 22.2% of patients, and 3 new mutations, S399P, G425R, M404T, 9 of which were present in 3 different families. All mutations were located in the ubiquitin‐associated domain of the gene. There was a relationship between serum AP activity, as a marker of the disease, and the presence or absence of the G425R and P392L mutations, the subject's age, and the presence of Paget's disease.ConclusionOur data provide further evidence of a causal role of SQSTM1 gene mutations in the pathogenesis of Paget's disease and allow the design of a strategy based on measurements of serum AP activity and age for investigating asymptomatic relatives of patients with familial Paget's disease of bone.
Suppressive oligonucleotides protect against collagen‐induced arthritis in mice
Authors: Dong Li , Ito Shu‐ichi , Ishii Ken J. , Klinman Dennis M. 
Published: May 2004

AbstractObjectiveTo examine whether systemic administration of oligonucleotides (ODNs), known to inhibit the production of proinflammatory cytokines, alters host susceptibility to collagen‐induced arthritis (CIA), a murine model of rheumatoid arthritis (RA).MethodsCIA was induced by injecting DBA/1 mice with type II collagen (CII) in Freund's complete adjuvant, followed 3 weeks later by CII in Freund's incomplete adjuvant. The effect of suppressive ODNs on the incidence and severity of disease was monitored, as were immune correlates of CIA.ResultsSuppressive ODNs administered during the inductive phase of CIA significantly reduced the incidence and severity of arthritis. Treatment with suppressive ODNs significantly decreased serum titers of pathogenic IgG anti‐CII autoantibodies and interferon‐γ production by collagen‐reactive T cells.ConclusionSuppressive ODNs may be of therapeutic value in the treatment of RA, and potentially other autoimmune diseases.
International greenhouse gas emissions when global warming is a stochastic process
Authors: Wirl Franz 
Published: May 2004

AbstractThis paper integrates two different but crucial aspects of global warming: free riding and uncertainty. Although certainty equivalence does not hold, an analytical solution is obtained if ‘clean up’ (e.g. reforestation) is possible. Assuming realistically irreversible emissions, numerical methods are necessary to obtain the value function and the implied strategies, which are shown to be unique (for the calibrated parameters). Although uncertainty stresses the importance of conservation, the incentives to free ride are almost the same. Beyond the particular application, the paper shows how to analyze stochastic, dynamic games. Copyright © 2004 John Wiley & Sons, Ltd.
Structural characterization of the N‐terminal mineral modification domains from the molluscan crystal‐modulating biomineralization proteins, AP7 and AP24
Authors: Wustman Brandon A. , Morse Daniel E. , Evans John Spencer 
Published: May 2004

AbstractThe AP7 and AP24 proteins represent a class of mineral‐interaction polypeptides that are found in the aragonite‐containing nacre layer of mollusk shell (H. rufescens). These proteins have been shown to preferentially interfere with calcium carbonate mineral growth in vitro. It is believed that both proteins play an important role in aragonite polymorph selection in the mollusk shell. Previously, we demonstrated the 1–30 amino acid (AA) N‐terminal sequences of AP7 and AP24 represent mineral interaction/modification domains in both proteins, as evidenced by their ability to frustrate calcium carbonate crystal growth at step edge regions. In this present report, using free N‐terminal, Cα‐amide “capped” synthetic polypeptides representing the 1–30 AA regions of AP7 (AP7‐1 polypeptide) and AP24 (AP24‐1 polypeptide) and NMR spectroscopy, we confirm that both N‐terminal sequences possess putative Ca (II) interaction polyanionic sequence regions (2 × —DD— in AP7‐1, —DDDED— in AP24‐1) that are random coil‐like in structure. However, with regard to the remaining sequences regions, each polypeptide features unique structural differences. AP7‐1 possesses an extended β‐strand or polyproline type II‐like structure within the A11–M10, S12–V13, and S28–I27 sequence regions, with the remaining sequence regions adopting a random‐coil‐like structure, a trait common to other polyelectrolyte mineral‐associated polypeptide sequences. Conversely, AP24‐1 possesses random coil‐like structure within A1–S9 and Q14–N16 sequence regions, and evidence for turn‐like, bend, or loop conformation within the G10–N13, Q17–N24, and M29–F30 sequence regions, similar to the structures identified within the putative elastomeric proteins Lustrin A and sea urchin spicule matrix proteins. The similarities and differences in AP7 and AP24 N‐terminal domain structure are discussed with regard to joint AP7–AP24 protein modification of calcium carbonate growth. © 2004 Wiley Periodicals, Inc. Biopolymers 2004