bluuebunny/crossref_metadata_2025 huggingface dataset:
New and Efficient Method for the Preparation of Medium-sized Lactones from the Corresponding ω-Hydroxycarboxylic Acids
Authors: Mukaiyama Teruaki , Izumi Jun , Shiina Isamu
Published: May 2004

Medium-sized lactones are prepared in good yields on treating monomeric cyclic silyl siloxycarboxylates, prepared in situ from ω-hydroxycarboxylic acids and 1,2-bisdimethylsilylbenzene using RhCl(PPh3)3 catalyst, with an active catalyst of dimethylsilylbis(trifluoromethanesulfonate).
Nanometer Pore Size Dependence of Intraparticle Diffusion in Silica Gel
Authors: Sekine Tomomi , Nakatani Kiyoharu
Published: May 2004

The sorption of rhodamine 6G into single silica gel microparticles possessing pore sizes of 3, 6, 15, and 30 nm was analyzed using single microparticle injection and microabsorption methods. The intraparticle diffusion of the solute was highly influenced by the pore size of the silica gel. The relationship between the intraparticle diffusion coefficient and a hindrance parameter for the diffusion in the pores is discussed on the basis of a pore and surface diffusion model.
Economics of an Information Intermediary with Aggregation Benefits
Authors: Bhargava Hemant K. , Choudhary Vidyanand
Published: May 2004

The widespread use of the Internet has led to the emergence of numerous information intermediaries that bring buyers and sellers together and leverage their knowledge of the marketplace to provide value-added services. Infomediaries offer matching services that facilitate establishment of a buyer-seller agreement, and value-added services that either provide a standalone benefit or enhance benefits from matching services. This paper develops and analyzes economic models of intermediaries to examine their pricing and product line design strategies. Intermediaries provide aggregation benefits: Buyers find an intermediary’s service more valuable if it provides access to more sellers, and sellers value it more if it provides access to more buyers, but also when they compete with fewer sellers. Due to this unique combination of network effects, we find that an intermediary has stronger incentives to provide quality-differentiated versions of its service relative to other information goods sellers. When buyers have constant marginal valuations for service quality, the intermediary should offer only two levels of service. While it is optimal for the intermediary to offer two levels of service, increasing the quality of the low-level service reduces the intermediary’s profits due to increased cannibalization of the premium service. Hence, the optimal menu consists of a basic matching service and a premium service that includes matching and value-added services. The intermediary’s profits are larger when positive network effects are stronger, and lower when negative network effects are stronger.
A Rasch scaling validation of a ‘core’ near‐death experience
Authors: Lange Rense , Greyson Bruce , Houran James
Published: May 2004

For those with true near‐death experiences (NDEs), Greyson's (1983, 1990) NDE Scale satisfactorily fits the Rasch rating scale model, thus yielding a unidimensional measure with interval‐level scaling properties. With increasing intensity, NDEs reflect peace, joy and harmony, followed by insight and mystical or religious experiences, while the most intense NDEs involve an awareness of things occurring in a different place or time. The semantics of this variable are invariant across True‐NDErs' gender, current age, age at time of NDE, and latency and intensity of the NDE, thus identifying NDEs as ‘core’ experiences whose meaning is unaffected by external variables, regardless of variations in NDEs' intensity. Significant qualitative and quantitative differences were observed between True‐NDErs and other respondent groups, mostly revolving around the differential emphasis on paranormal/mystical/religious experiences vs. standard reactions to threat. The findings further suggest that False‐Positive respondents reinterpret other profound psychological states as NDEs. Accordingly, the Rasch validation of the typology proposed by Greyson (1983) also provides new insights into previous research, including the possibility of embellishment over time (as indicated by the finding of positive, as well as negative, latency effects) and the potential roles of religious affiliation and religiosity (as indicated by the qualitative differences surrounding paranormal/mystical/religious issues).
Trials‐to‐criterion latent inhibition in humans as a function of stimulus pre‐exposure and positive‐schizotypy
Authors: Burch Giles St. J. , Hemsley David R. , Joseph Michael H.
Published: May 2004

Latent inhibition (LI) is a phenomenon during which non‐reinforced pre‐exposure to a stimulus retards later learning of associations with that same stimulus. It has been suggested that LI is a positive function of the amount of stimulus pre‐exposure (PE) and that with very small amounts of PE, facilitation rather than inhibition will occur—particularly in high positive‐schizotypes. Although LI has been demonstrated as a function of the amount of pre‐exposure in animals, human findings have not proved to be so uniform or consistent. The primary objective of the present study was to establish LI as a function of numbers of pre‐exposure on visual and auditory trials‐to‐criterion tasks, with a secondary objective to establish latent facilitation (LF) with very low numbers of pre‐exposure in high positive‐schizotypes. Results revealed a uniform pattern of learning across pre‐exposure conditions, including latent facilitation, on the visual, but not the auditory task. LF was also observed in the high, but not low, scorers in positive‐schizotypy with very low numbers of pre‐exposure on the visual task.
Measuring cancer knowledge: Comparing prompted and unprompted recall
Authors: Waller Jo , McCaffery Kirsten , Wardle Jane
Published: May 2004

Studies evaluating public knowledge of the warning signs and risk factors associated with cancer have varied in the question format used. Those using a prompted (recognition) format have tended to find higher levels of knowledge than those using an unprompted, recall format. The aim of this study was to quantify the effect of prompting on knowledge of the seven warning signs of cancer, and risk factors for breast and bowel cancer, using data from large representative samples of the UK population. We also tested for demographic differences in the effect of prompting, hypothesizing that prompting would have the greatest impact on groups with least knowledge, specifically men, older and younger people, and those with least education. Analysis of data from four ONS surveys (total n = 5,863) demonstrated significantly higher knowledge of all signs and risk factors in the prompted compared with the unprompted condition. Contrary to our hypothesis, the pattern of interaction of prompting with gender and level of education was inconsistent, and the effect of prompting decreased with increasing age. Implications for future research on cancer knowledge and the most appropriate question format are discussed.
Policing a Chinese Community in Brisbane, Queensland: An Experiment
Authors: Chui Wing Hong , Ip Regin
Published: May 2004

This article introduces a police-led initiative by the Queensland Police Service (QPS) which was set up in Brisbane in 2001 to try to promote interaction with young people in the Chinese community. In this article, the objectives, design and contents of the initiative will be described. The police's views on different aspects of the Youth Group and the areas for further improvement will be reported.
Police Accountability for Lethal Force
Authors: Wood David
Published: May 2004

The police use of lethal force has always been a controversial subject; and its use in Northern Ireland has attracted particular attention following allegations in the past of a ‘shoot to kill’ policy and the use of plastic bullets.

David Wood is the Executive Director for the Police Ombudsman of Northern Ireland (PONI) and in his article, derived from a speech delivered to a conference in Belfast in November 2003, he explains how independent investigation of the police use of lethal force in Northern Ireland has brought a new dimension to police accountability. The article demonstrates the benefits and impact of external scrutiny in improved procedures adopted by the police, leading to the reduced use of such force, and improved policy for all.
Novel solution approach for optimizing crude oil operations
Authors: Reddy P. Chandra Prakash , Karimi I. A. , Srinivasan R.
Published: May 2004

Scheduling of crude oil operations is a complex nonlinear problem, especially when tanks hold crude mixes. We present a new mixed‐integer nonlinear programming (MINLP) formulation and a novel, mixed‐integer linear programming (MILP)–based solution approach for optimizing crude oil unloading, storage, and processing operations in a multi‐CDU (crude distillation unit) refinery receiving crude from multiparcel VLCCs (very large crude carriers) through a high‐volume, single‐buoy mooring (SBM) pipeline and/or single‐parcel tankers through multiple jetties. Mimicking a continuous‐time formulation, our primarily discrete‐time model allows multiple sequential crude transfers to occur within a time slot. It incorporates several real‐life operational features including brine settling and tank‐to‐tank transfers, and is superior to other reported models. Notably our algorithm avoids concentration discrepancy and MINLP solutions by identifying a part of the horizon, for which its linear relaxation is exact, and then solving this MILP repeatedly with progressively shorter horizons. By using 8 h time slots and a hybrid time representation, an attractive approach to this difficult problem is presented.© 2004 American Institute of Chemical Engineers AIChE J, 50:1177–1197, 2004
Reversible formation of giant and normal‐sized mitochondria in gastric parietal cells of guinea pigs
Authors: Ogawa Kazushige , Tsuji Masashi , Noguchi Hiroyo , Tsuyama Shingo , Sasaki Fumihiko
Published: May 2004

Mitochondria occasionally increase in size in response to metabolic injury. Numerous studies have reported giant mitochondria in patients with various diseases and animals with metabolic injuries, and there are few reports on giant mitochondria in normal cells under physiological conditions. Here, we report a reversible formation of giant and normal‐sized mitochondria in gastric parietal cells of guinea pigs. We morphometrically analyzed the frequency distribution of mitochondrial area on ultrathin sections of parietal cells in guinea pigs fed freely (control group), starved for 60–72 hr (starvation group), and starved and then injected with histamine (histamine group). The distribution was significantly different between the control and starvation group and between the starvation and histamine group: the histogram of the starvation group significantly shifted toward large mitochondria compared with that of the control or histamine group; the frequency of mitochondria more than 2 μm2 in size was significantly higher in the starvation group than that in the control or histamine group. This is the first report that clearly demonstrated the presence of giant mitochondria in gastric parietal cells under the starved condition and a mitochondrial recovery in a normal size after the administration of histamine. Because gastric parietal cells change their membrane system according to the state of gastric acid secretion, the present data may offer new insight into the morphological changes in gastric parietal cells. Anat Rec Part A 278A:533–539, 2004. © 2004 Wiley‐Liss, Inc.
Histochemical similarities of mucins produced by Brunner's glands and pyloric glands: A comparative study
Authors: Schumacher Udo , Duku Moses , Katoh Marcus , Jörns Julia , Krause William J.
Published: May 2004

Mucins of the gastroduodenal junction are secreted by the mucous surface and mucus‐producing glandular cells in the stomach, and by goblet cells and Brunner's glands in the duodenum. Developmental studies have demonstrated that Brunner's glands can arise from undifferentiated gastric epithelium and/or intestinal epithelium in the proximal duodenum. The aim of this study was to investigate the carbohydrate composition of mucins from this region and compare it with that of mucins from Brunner's glands to evaluate the probable evolution of mucins from these glands. Toward that end, paraffin sections from 13 mammalian species were stained by classic carbohydrate histochemistry and treated with 13 lectins. In general, the mucous surface cells of the stomach, pyloric glands, duodenal goblet cells, and Brunner's glands secretory epithelium had different lectin‐binding patterns. However, the lectin‐binding profile of the secretory epithelium of Brunner's glands resembled that of pyloric glands more closely than that of duodenal goblet cells and mucous surface cells of the stomach. Mucins from Brunner's glands and pyloric glands showed a greater terminal carbohydrate residue diversity than those of gastric mucous surface cells or duodenal goblet cells. The lectin‐binding profile argues for the evolution of similar mucins from the epithelia of Brunner's glands and pyloric glands. The greater diversity of carbohydrate residues in mucins secreted by Brunner's glands suggests that their mucus is more adaptable. This may explain why Brunner's glands metaplasia rather than goblet cell metaplasia is seen in the mucosa adjacent to chronic intestinal ulcers. Anat Rec Part A 278A:540–550, 2004. © 2004 Wiley‐Liss, Inc.
Secretion of oncostatin M by neutrophils in rheumatoid arthritis
Authors: Cross Andrew , Edwards Steven W. , Bucknall Roger C. , Moots Robert J.
Published: May 2004

Objective

Neutrophils are known to express and release a large number of proinflammatory cytokines when they are stimulated by inflammatory stimuli. The objective of this study was to determine whether neutrophils express oncostatin M (OSM), a member of the interleukin‐6 family of cytokines that has been implicated in the pathogenesis of inflammatory joint disease.

Methods

Neutrophils were isolated from the blood of healthy volunteer donors and from the blood and synovial fluid of patients with rheumatoid arthritis (RA). OSM levels were measured in cell extracts and in culture supernatants by Western blotting. Total RNA was isolated from control and granulocyte–macrophage colony‐stimulating factor (GM‐CSF)–treated neutrophils, and OSM messenger RNA levels were quantified by hybridization of a radiolabeled probe.

Results

GM‐CSF stimulated a rapid and transient expression and release of OSM from blood neutrophils, which was more rapid than the expression and release from blood monocytes. A 28‐kd protein was identified in cell extracts, but an additional 25‐kd isoform was detected in culture supernatants. Synovial fluid neutrophils could not be stimulated to express OSM, but this cytokine was detected in cell‐free supernatants at various levels.

Conclusion

Blood neutrophils can be stimulated to express and rapidly release large quantities of OSM. We propose that this important cytokine is released from neutrophils as they infiltrate rheumatoid joints and, thus, contribute to the complex cytokine network that characterizes RA.
Midkine, a heparin‐binding growth factor, is fundamentally involved in the pathogenesis of rheumatoid arthritis
Authors: Maruyama Kiyoko , Muramatsu Hisako , Ishiguro Naoki , Muramatsu Takashi
Published: May 2004

Objective

Midkine (MK), a heparin‐binding growth factor, promotes growth, survival, and migration of various cells. The essential role of MK in migration of inflammatory cells has been shown using mice deficient in the MK gene (Mdk−/− mice). We undertook this study to investigate the role of MK in the pathogenesis of rheumatoid arthritis (RA).

Methods

MK levels in specimens from patients were determined by enzyme‐linked immunosorbent assay, and localization of MK was revealed by immunohistochemical analysis. Susceptibility to antibody‐induced arthritis was compared between Mdk−/− and wild‐type (WT) mice. Osteoclast differentiation was monitored using macrophage‐like cells isolated from human synovial tissue and macrophages from mouse bone marrow.

Results

MK levels in sera and synovial fluid were increased in most RA patients, indicating a strong correlation between MK expression and RA. MK was expressed in macrophage‐like cells and fibroblast‐like cells in synovial membranes from the patients. In antibody‐induced arthritis, Mdk−/− mice seldom developed the disease, while most of the WT mice did. Administration of MK to the Mdk−/− mice increased the frequency of antibody‐induced arthritis. Migration of inflammatory leukocytes to the synovial membranes in the disease model was suppressed in the Mdk−/− mice. Furthermore, MK was found to promote the differentiation of osteoclasts from macrophages.

Conclusion

MK participates in each of the two distinct phases of RA development, namely, migration of inflammatory leukocytes and osteoclast differentiation, and is a key molecule in the pathogenesis of RA.
Achievement of a synergistic adjuvant effect on arthritis induction by activation of innate immunity and forcing the immune response toward the Th1 phenotype
Authors: Hanyecz Anita , Berlo Suzanne E. , Szántó Sándor , Broeren Chris P. M. , Mikecz Katalin , Glant Tibor T.
Published: May 2004

Objective

To apply and analyze the mechanisms of action of dimethyldioctadecylammonium bromide (DDA), a powerful adjuvant that does not have the side effects of the conventionally used Freund's adjuvants, in proteoglycan‐induced arthritis (PGIA) and collagen‐induced arthritis (CIA).

Methods

PGIA and CIA were generated using standard immunization protocols with cartilage proteoglycan aggrecan (PG) or human type II collagen (CII) emulsified with Freund's complete adjuvant (CFA), and compared with PGIA and CIA generated using immunization protocols in which the same antigens were used in combination with the adjuvant DDA. Immune responses to immunizing and self PGs and CII, and the incidence, severity, and onset of arthritis were monitored throughout the experiments. In addition, a new, inexpensive, and powerful method of inducing arthritis using crude cartilage extracts is described.

Results

A significantly reduced onset period and a more severe arthritis were achieved in BALB/c mice immunized with cartilage PGs in DDA. PGs from bovine, ovine, and porcine cartilage, which otherwise have no effect or have only a subarthritogenic effect, and crude extracts of human osteoarthritic cartilage induced a 100% incidence with a very high arthritis score in BALB/c mice. The overall immune responses to either CII or PG were similar in antigen/CFA‐immunized and antigen/DDA‐immunized animals, but the Th1/Th2 balance shifted significantly toward a Th1 bias in DDA‐injected animals with either PGIA or CIA.

Conclusion

DDA, which was first used in autoimmune models, is a potent nonirritant adjuvant, which eliminates all undesired side effects of the Freund's adjuvants. DDA exerts a strong stimulatory effect via the activation of nonspecific (innate) immunity and forces the immune regulation toward Th1 dominance. These lines of evidence also suggest the possibility that seemingly innocuous compounds may exert an adjuvant effect in humans and may create the pathophysiologic basis of autoimmunity in susceptible individuals via the activation/stimulation of innate immunity.
Antiangiogenic effects of anti–tumor necrosis factor α therapy with infliximab in psoriatic arthritis
Authors: Cañete Juan D. , Pablos José L. , Sanmartí Raimon , Mallofré Carmen , Marsal Sara , Maymó´ Joan , Gratacós Jordi , Mezquita Jovita , Mezquita Cristobal , Cid Maria C.
Published: May 2004

Objective

Neovascularization, with an increased number of synovial vessels with a characteristic morphology, seems to contribute to the progression of psoriatic arthritis (PsA). Accordingly, angiogenesis may be an important therapeutic target in PsA. The aim of this study was to analyze the effects of infliximab on angiogenesis in the synovial membrane of patients with PsA who responded to this therapy.

Methods

The study group comprised 9 patients with PsA who were selected for the presence of active polyarthritis (including knee synovitis) despite methotrexate therapy. Clinical and biologic evaluations were performed at each visit. Arthroscopy and synovial biopsies were performed at week 0, before infliximab therapy was initiated, and at week 8, after administration of 3 intravenous infusions of infliximab (5 mg/kg). We used immunohistochemistry to identify changes in infiltrating cells and in the angiogenesis modulators αvβ3 integrin, vascular endothelial growth factor (VEGF), angiopoietin 2 (Ang‐2), flt‐1 (VEGF receptor 1 [VEGFR‐1]), kinase insert domain receptor [KDR]/flk‐1 (VEGFR‐2), and stromal cell–derived factor 1 (SDF‐1). Neovascularization was assessed by automated histomorphometry of CD31+ vessels and by measuring αvβ3 expression.

Results

Rapid and significant clinical and biological improvement were observed after treatment in all patients. In the synovium, infliximab therapy induced a significant reduction in macrophages, the CD31+ vascular area, αvβ3+ neovessels/Ulex europaeus agglutinin+ vessels, VEGF and its receptor KDR/flk‐1 (VEGFR‐2), and SDF‐1+ vessels. Expression of flt‐1 (VEGFR‐1), and SDF‐1 in lining cells showed a nonsignificant reduction, whereas expression of Ang‐2 increased. In 3 patients, reverse transcription–polymerase chain reaction confirmed the changes in some of these markers at the messenger RNA level.

Conclusion

These results show consistent changes in several factors involved in angiogenesis regulation, in parallel with the clinical response to infliximab in patients with PsA. The pattern of reduced VEGF with increased Ang‐2 suggests vascular regression as a potential mechanism underlying the antiangiogenic effect of infliximab.
Ribozymes that inhibit the production of matrix metalloproteinase 1 reduce the invasiveness of rheumatoid arthritis synovial fibroblasts
Authors: Rutkauskaite Edita , Zacharias Wolfgang , Schedel Jörg , Müller‐Ladner Ulf , Mawrin Christian , Seemayer Christian A. , Alexander Dorothea , Gay Renate E. , Aicher Wilhelm K. , Michel Beat A. , Gay Steffen , Pap Thomas
Published: May 2004

Objective

To investigate whether retroviral gene transfer of ribozymes targeting matrix metalloproteinase 1 (MMP‐1) inhibits the production of MMP‐1 in rheumatoid arthritis synovial fibroblasts (RASFs) and reduces the invasiveness of these cells in vivo.

Methods

MMP‐1–specific ribozymes (RzMMP‐1) were designed and cloned into the pLNSX retroviral vector. Cleavage of MMP‐1 was determined in vitro, and the most effective ribozyme was selected for further investigation. RASFs were transduced with replication‐deficient viruses carrying RzMMP‐1 or with empty viruses (mock). Quantitative polymerase chain reaction with cleavage site–spanning fluorescent probes was used to measure the levels of MMP‐1, MMP‐9, and MMP‐13 messenger RNA. In addition, protein levels of MMP‐1 in cell culture supernatants were determined by enzyme linked immunosorbent assay. The effects of stimulation with lipopolysaccharide (LPS) and tumor necrosis factor α (TNFα) on the production of MMP‐1 were assessed accordingly. The invasiveness of RzMMP‐1–transduced, mock‐transduced, and untransduced RASFs was analyzed in the SCID mouse in vivo model of RA.

Results

Transduction of RASFs with RzMMP‐1 significantly decreased the production of MMP‐1 in RASFs without affecting other MMPs, such as MMP‐9 and MMP‐13. RzMMP‐1 not only reduced the spontaneous production of MMP‐1, but also prevented the LPS‐ and TNFα‐induced increase in MMP‐1 production. Inhibition of MMP‐1 was maintained for at least 2 months and was accompanied by a significant reduction of the invasiveness of RASFs in the SCID mouse model of RA.

Conclusion

Intracellular expression of ribozymes constitutes a feasible tool for inhibiting the production of matrix‐degrading enzymes. Inhibition of MMP‐1 alone results in a significant reduction of cartilage invasion by RASFs.
Requirement of dying cells and environmental adjuvants for the induction of autoimmunity
Authors: Bondanza Attilio , Zimmermann Valérie S. , Dell'Antonio Giacomo , Cin Elena Dal , Balestrieri Genesio , Tincani Angela , Amoura Zahir , Piette Jean‐Charles , Sabbadini Maria Grazia , Rovere‐Querini Patrizia , Manfredi Angelo A.
Published: May 2004

Objective

Cells commonly die without eliciting autoimmunity. However, dying cells are a potential initiating stimulus for systemic lupus erythematosus (SLE). Our goal was to verify whether immune adjuvants influence the autoimmunity induction that ensues following in vivo injection of dying cells.

Methods

Mice were immunized with apoptotic thymocytes in the presence of artificial moieties, such as Freund's incomplete adjuvant (IFA), or natural adjuvants, such as dendritic cells (DCs). Renal involvement and the development of autoantibodies were monitored.

Results

Apoptotic cells failed to induce clinical disease or to sustain production of autoantibodies in (NZB × NZW)F1 mice. In contrast, autoimmunity developed in the presence of IFA or DCs. The characteristics of the adjuvant influenced the array of autoantibodies, the kinetics of their development, and the severity of the disease. DCs were required for induction of anti–β2‐glycoprotein I IgG. Adjuvants alone did not elicit disease.

Conclusion

A “two‐hit” signal composed of autoantigens and adjuvants initiates systemic autoimmunity. Moreover, environmental signals at the site of clearance of dead cells shape the features and the severity of the autoimmune disease. Strategies aimed at preventing the accumulation of dying cells and at modulating endogenous adjuvants may be beneficial for the treatment of SLE.
Proteomic surveillance of autoimmunity in osteoarthritis: Identification of triosephosphate isomerase as an autoantigen in patients with osteoarthritis
Authors: Xiang Yang , Sekine Taichi , Nakamura Hiroshi , Imajoh‐Ohmi Shinobu , Fukuda Hiroyuki , Nishioka Kusuki , Kato Tomohiro
Published: May 2004

Objective

Autoimmunity to proteins, such as type II collagen and cartilage intermediate layer protein, that are produced by chondrocytes has been reported in patients with osteoarthritis (OA) as well as in patients with rheumatoid arthritis (RA). However, it remains to be determined whether the overall specificities of the autoimmunity differ between OA and RA patients. This study sought to clarify the differences by applying proteomic surveillance for the detection of autoantigens comprehensively.

Methods

Serum samples were obtained from 20 patients with OA, 20 patients with RA, and 20 healthy volunteers. Human chondrocyte proteins were separated from the sera by 2‐dimensional electrophoresis, and antigenic protein spots were detected by Western blotting. The antigenic proteins were then identified by mass fingerprinting. The antigenicity of the identified proteins was confirmed and the prevalence of the autoantibodies in the OA, RA, and other disease groups was determined with the use of recombinant proteins. In addition, autoepitopes were mapped on the antigens.

Results

Nineteen protein spots were recognized only by the OA sera, but not by the RA sera. One of these proteins was identified as triosephosphate isomerase (TPI). IgG‐type anti‐TPI autoantibodies were detected in 24.7% of the serum samples and 24.1% of the synovial fluid samples from the patients with OA, whereas <6% of the RA and systemic lupus erythematosus samples were positive for anti‐TPI. In addition, multiple autoepitopes were identified on TPI.

Conclusion

The overall profile of autoimmunity in OA differs from that in RA, which may reflect the OA‐specific pathologic role of autoimmunity. The autoantibody to TPI, detected predominantly in the OA samples and produced by the antigen‐driven mechanism, has the potential to be used as a diagnostic marker for OA.
Defective costimulatory function is a striking feature of antigen‐presenting cells in an HLA–B27–transgenic rat model of spondylarthropathy
Authors: Hacquard‐Bouder Cécile , Falgarone Géraldine , Bosquet Antoine , Smaoui Faïza , Monnet Dominique , Ittah Marc , Breban Maxime
Published: May 2004

Objective

A disease resembling the human spondylarthropathies develops in HLA–B27–transgenic rats. This disease in rats is mediated by CD4+ T cells, but antigen‐presenting cells (APCs) may also play a role. Dendritic cells (DCs) have been reported to be defective in allogeneic mixed lymphocyte culture in this model. Here, we further investigated the functional defect of APCs.

Methods

DCs and B cells from nontransgenic, HLA–B27 (33–3)–transgenic, and HLA–B7 (120–4)–transgenic rats were used to stimulate T cells. Surface expression of HLA–B transgene and rat molecules on APCs and the formation of conjugates between DCs and T cells were monitored by flow cytometry.

Results

We observed a strikingly defective stimulation of allogeneic and syngeneic T lymphocytes by APCs from HLA–B27 but not HLA–B7 rats, even if stimulation was driven in the presence of anti–T cell receptor (TCR) antibody. We found no evidence that HLA–B27 DCs were immature, lacked production of some diffusible factor, or produced an inhibitory factor for T cells. When comparing the levels of expression of class II major histocompatibility complex, CD2, intercellular adhesion molecule 1, lymphocyte function–associated antigen 1, B7, and CD40 molecules at the surface of DCs from 33‐3, 120‐4, and nontransgenic rats, we found little difference. However, HLA–B27–transgenic DCs formed fewer conjugates with T cells than did nontransgenic DCs. Furthermore, the proportion of conjugates formed between DCs and T cells, as well as the difference between nontransgenic and HLA–B27–transgenic DCs, were in large part reduced by blocking CD86 on DCs.

Conclusion

We confirmed defective stimulation of T cells by APCs in HLA–B27 rats, the mechanism of which appears to implicate APC/T cell contact, independent of TCR engagement. In addition, decreased use of the CD86 costimulatory molecule by B27 DCs was observed. Impaired costimulatory function could result in a loss of tolerance toward microbial flora in this model.
Increased tyrosine phosphorylation mediates the cooling‐induced contraction and increased vascular reactivity of Raynaud's disease
Authors: Furspan Philip B. , Chatterjee Soumya , Freedman Robert R.
Published: May 2004

Objective

Increased levels of protein tyrosine kinase (PTK) are mechanistically associated with increased contractile responsiveness to cooling. This study tests the hypothesis that increased PTK activity mediates the increased vascular reactivity to agonists and cooling associated with primary Raynaud's disease (RD).

Methods

The response of dermal arterioles isolated from control (n = 29) and RD (n = 29) subjects to contractile and dilatory agents at 37°C and 31°C was characterized using the microvessel perfusion technique. Fluorescence immunohistochemistry was used to measure tyrosine phosphorylation.

Results

At 37°C, arteries from RD patients exhibited similar sensitivity to the specific α2‐adrenergic agonist UK 14,304, to serotonin, and to angiotensin II. At 31°C, however, the response to all 3 agonists was greater in the arterioles from the RD patients than in those from the control subjects. Agonist‐induced contraction at both temperatures was reversed by cumulative addition of the PTK inhibitors genistein (1–30 μM) and tyrphostin 47 (0.1–10 μM). All arterioles from control subjects relaxed slightly in response to cooling, whereas more than half of those from RD patients contracted. This cooling‐induced contraction was reversed by the cumulative addition of genistein. The 3 agonists elicited large increases in tyrosine phosphorylation only in arterial segments from RD patients at 31°C. Cooling from 37°C to 31°C elicited a large increase in tyrosine phosphorylation in arterioles from RD patients, but not those from control subjects. All increases in tyrosine phosphorylation could be prevented by genistein.

Conclusion

Increased tyrosine phosphorylation mediates cooling‐induced contraction and the increased vascular reactivity of skin arterioles from individuals with RD.
Expression of toll‐like receptor 2 on CD16+ blood monocytes and synovial tissue macrophages in rheumatoid arthritis
Authors: Iwahashi Mitsuhiro , Yamamura Masahiro , Aita Tetsushi , Okamoto Akira , Ueno Akiko , Ogawa Norio , Akashi Sachiko , Miyake Kensuke , Godowski Paul J. , Makino Hirofumi
Published: May 2004

Objective

CD16 (IgG Fcγ receptor type IIIA [FcγRIIIA])–expressing CD14+ monocytes express high levels of Toll‐like receptor 2 (TLR‐2) and are able to efficiently produce proinflammatory cytokines such as tumor necrosis factor α (TNFα). To understand the role of CD16 and TLR‐2 in monocyte and macrophage activation in rheumatoid arthritis (RA), we investigated the expression of TLR‐2 on CD16+ blood monocytes and synovial tissue macrophages and the effect of CD16 and TLR‐2 activation on cytokine production.

Methods

The expression of CD14, CD16, TLR‐2, and TLR‐4 on blood monocytes was measured by flow cytometric analysis. CD16 and TLR‐2 expression in RA synovial tissue was detected by 2‐color immunofluorescence labeling. CD16+ mature monocytes were prepared by incubating blood monocytes in plastic plates for 24 hours. These adhered monocytes were stimulated with lipoteichoic acid (LTA), anti‐FcγRIII antibody, and Hsp60 for 5 hours, and culture supernatants were measured for various cytokines by immunoassay. The activation of NF‐κB was detected by electrophoretic mobility shift assay.

Results

The frequency of CD16+ cells in all blood monocytes was significantly increased in patients with RA compared with healthy controls. TLR‐2 was expressed at higher levels on CD16+ monocytes than on CD16− monocytes, while TLR‐4 was expressed similarly on both monocytes. In RA synovial tissue, CD16+/TLR‐2+ cells were distributed mainly in the lining layer. TLR‐2 expression on monocytes was enhanced by macrophage colony‐stimulating factor (M‐CSF) and interleukin‐10 (IL‐10), but was reduced by transforming growth factor β1, while CD16 expression was inducible by these cytokines. Adhered monocytes (∼50% CD16+) produced TNFα, IL‐1β, IL‐6, IL‐8, IL‐12 p40, IL‐1 receptor antagonist, and IL‐10 after LTA stimulation. This cytokine response was inhibited significantly by anti–TLR‐2 antibody and partly by anti–TLR‐4 antibody. Anti‐FcγRIII antibody stimulation markedly enhanced the LTA‐induced TNFα response. Hsp60 could stimulate TNFα production by adhered monocytes, which was inhibited similarly by anti–TLR‐2 antibody and anti–TLR‐4 antibody. NF‐κB activation in adhered monocytes was induced by LTA, but this NF‐κB activity was not augmented by anti‐FcγRIII antibody stimulation.

Conclusion

These results suggest that CD16+ monocytes and synovial tissue macrophages with high TLR‐2 expression may be induced by M‐CSF and IL‐10, and their production of TNFα could be simulated by endogenous TLR ligands such as Hsp60 and FcγRIIIA ligation by small immune complexes in RA joints.
Down‐regulation of the aberrant expression of the inflammation mediator high mobility group box chromosomal protein 1 in muscle tissue of patients with polymyositis and dermatomyositis treated with corticosteroids
Authors: Ulfgren Ann‐Kristin , Grundtman Cecilia , Borg Kristian , Alexanderson Helene , Andersson Ulf , Harris Helena Erlandsson , Lundberg Ingrid E.
Published: May 2004

Objective

High mobility group box chromosomal protein 1 (HMGB‐1) is an endogenous nuclear protein that can be translocated to the cytoplasm and then released extracellularly. It can induce tumor necrosis factor and interleukin‐1 production in myeloid cells. Increased expression of these 2 cytokines has been observed in muscle tissue of patients with polymyositis (PM) and dermatomyositis (DM). The present study was therefore undertaken to investigate how HMGB‐1 is expressed in muscle tissue of patients with myositis and, if so, whether such expression is modulated by prednisolone therapy.

Methods

Muscle biopsy specimens from 5 patients with PM and 4 patients with DM, obtained before and 3–6 months after initiation of prednisolone therapy, were assessed by conventional microscopic evaluation and computerized image analysis, and HMGB‐1 expression was investigated by immunohistochemical staining. Muscle biopsy specimens from 7 healthy controls were also studied.

Results

Cytoplasmic HMGB‐1 expression was detected in infiltrating rounded mononuclear cells, vascular endothelial cells, and muscle fibers of PM and DM patients. Extracellular staining surrounding the inflammatory cells was also observed. After treatment with high‐dose prednisolone, cytoplasmic and extracellular HMGB‐1 expression was significantly reduced, coinciding mainly with a decreased number of infiltrating inflammatory cells. Cytoplasmic HMGB‐1 expression was still evident in endothelial cells and muscle fibers. No HMGB‐1 expression was observed in muscle tissue from healthy controls.

Conclusion

The cytoplasmic and extracellular distribution of HMGB‐1 in muscle tissue may indicate an important role of this proinflammatory molecule in the pathogenesis of PM and DM. Furthermore, our findings indicate that systemically administered high‐dose corticosteroids selectively down‐regulate aberrant expression of HMGB‐1 in mononuclear inflammatory cells in vivo.
An increased transforming growth factor β receptor type I:Type II ratio contributes to elevated collagen protein synthesis that is resistant to inhibition via a kinase‐deficient transforming growth factor β receptor type II in scleroderma
Authors: Pannu Jaspreet , Gore‐Hyer Elizabeth , Yamanaka Masayoshi , Smith Edwin A. , Rubinchik Semyon , Dong Jian‐Yun , Jablonska Stefania , Blaszczyk Maria , Trojanowska Maria
Published: May 2004

Objective

Aberrant transforming growth factor β (TGFβ) signaling has been implicated in the pathogenesis of scleroderma (systemic sclerosis [SSc]), but the contribution of specific components in this pathway to SSc fibroblast phenotype remains unclear. This study was undertaken to delineate the role of TGFβ receptor type I (TGFβRI) and TGFβRII in collagen overexpression by SSc fibroblasts.

Methods

Primary dermal fibroblasts from SSc patients and healthy adults were studied (n = 10 matched pairs). Adenoviral vectors were generated for TGFβRI (AdTGFβRI), TGFβRII (AdTGFβRII), and kinase‐deficient TGFβRII (AdΔkRII). TGFβRI basal protein levels were analyzed by 35S‐methionine labeling/immunoprecipitation and immunohistochemistry. Type I collagen and TGFβRII basal protein levels were analyzed by Western blot and newly secreted collagen by 3H‐proline incorporation assay.

Results

Analysis of endogenous TGFβRI and TGFβRII protein levels revealed that SSc TGFβRI levels were increased 1.7‐fold (P = 0.008; n = 7) compared with levels in healthy controls, while TGFβRII levels were decreased by 30% (P = 0.03; n = 7). This increased TGFβRI:TGFβRII ratio correlated with SSc collagen overexpression. To determine the consequences of altered TGFβRI:TGFβRII ratio on collagen expression, healthy fibroblasts were transduced with AdTGFβRI or AdTGFβRII. Forced expression of TGFβRI in the range corresponding to elevated SSc TGFβRI levels increased basal collagen expression in a dose‐dependent manner, while similar TGFβRII overexpression had no effect, although transduction of fibroblasts at higher multiplicities of infection led to a marked reduction of basal collagen levels. Blockade of TGFβ signaling via AdΔkRII resulted in ∼50% inhibition of basal collagen levels in healthy fibroblasts and in 5 of 9 SSc cell lines. A subset of SSc fibroblasts (4 of 9 cell lines) was resistant to this treatment. SSc fibroblasts with the highest levels of TGFβRI were the least responsive to collagen inhibition via ΔkRII.

Conclusion

This study indicates that an increased TGFβRI:TGFβRII ratio may underlie aberrant TGFβ signaling in SSc and contribute to elevated basal collagen production, which is insensitive to TGFβ signaling blockade via ΔkRII.
Exercise and dietary weight loss in overweight and obese older adults with knee osteoarthritis: The arthritis, diet, and activity promotion trial
Authors: Messier Stephen P. , Loeser Richard F. , Miller Gary D. , Morgan Timothy M. , Rejeski W. Jack , Sevick Mary Ann , Ettinger Walter H. , Pahor Marco , Williamson Jeff D.
Published: May 2004

Objective

The Arthritis, Diet, and Activity Promotion Trial (ADAPT) was a randomized, single‐blind clinical trial lasting 18 months that was designed to determine whether long‐term exercise and dietary weight loss are more effective, either separately or in combination, than usual care in improving physical function, pain, and mobility in older overweight and obese adults with knee osteoarthritis (OA).

Methods

Three hundred sixteen community‐dwelling overweight and obese adults ages 60 years and older, with a body mass index of ≥28 kg/m2, knee pain, radiographic evidence of knee OA, and self‐reported physical disability, were randomized into healthy lifestyle (control), diet only, exercise only, and diet plus exercise groups. The primary outcome was self‐reported physical function as measured with the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC). Secondary outcomes included weight loss, 6‐minute walk distance, stair‐climb time, WOMAC pain and stiffness scores, and joint space width.

Results

Of the 316 randomized participants, 252 (80%) completed the study. Adherence was as follows: for healthy lifestyle, 73%; for diet only, 72%; for exercise only, 60%; and for diet plus exercise, 64%. In the diet plus exercise group, significant improvements in self‐reported physical function (P < 0.05), 6‐minute walk distance (P < 0.05), stair‐climb time (P < 0.05), and knee pain (P < 0.05) relative to the healthy lifestyle group were observed. In the exercise group, a significant improvement in the 6‐minute walk distance (P < 0.05) was observed. The diet‐only group was not significantly different from the healthy lifestyle group for any of the functional or mobility measures. The weight‐loss groups lost significantly (P < 0.05) more body weight (for diet, 4.9%; for diet plus exercise, 5.7%) than did the healthy lifestyle group (1.2%). Finally, changes in joint space width were not different between the groups.

Conclusion

The combination of modest weight loss plus moderate exercise provides better overall improvements in self‐reported measures of function and pain and in performance measures of mobility in older overweight and obese adults with knee OA compared with either intervention alone.
Mechanical injury and psychosocial factors in the work place predict the onset of widespread body pain: A two‐year prospective study among cohorts of newly employed workers
Authors: Harkness Elaine F. , Macfarlane Gary J. , Nahit Elizabeth , Silman Alan J. , McBeth John
Published: May 2004

Objective

Mechanical injury has been postulated as a risk factor for widespread pain, although to date, the evidence is weak. The aim of this study was to determine whether repeated exposure to mechanical trauma in the work place predicts the onset of widespread pain and to determine the relative contribution of mechanical trauma compared with psychosocial factors.

Methods

In this prospective cohort study of 1,081 newly employed subjects in 12 diverse occupational settings, we collected detailed information on mechanical exposure, posture, physical environment, and psychosocial risk factors in the work place. Study questionnaires were completed at baseline and at 12 and 24 months. Individuals free of widespread pain at baseline and 12 months were eligible for followup. Generalized estimating equations were used to determine which factors predicted the new onset of widespread pain.

Results

Of the 1,081 baseline respondents, 896 were free of widespread pain and were eligible for further study. Of these 896 subjects, 708 and 520 responded at 12 months and 24 months, respectively. The rates of new‐onset widespread pain were 15% at 12 months and 12% at 24 months. Several work place mechanical and posture exposures predicted the new onset of widespread pain: lifting >15 lbs with 1 hand, lifting >24 lbs with 2 hands, pulling >56 lbs, prolonged squatting, and prolonged working with hands at or above shoulder level. Of the psychosocial exposures, those who reported low job satisfaction, low social support, and monotonous work had an increased risk of new‐onset widespread pain. In multivariate analysis, monotonous work and low social support were found to be the strongest independent predictors of symptom onset.

Conclusion

Our findings demonstrate that the prevalence of new‐onset widespread pain was high, but among this young, newly employed work force, both physical and psychosocial factors played an important role.
Identification of mesenchymal progenitor cells in normal and osteoarthritic human articular cartilage
Authors: Alsalameh Saifeddin , Amin Rayya , Gemba Takefumi , Lotz Martin
Published: May 2004

Objective

To determine the presence of mesenchymal progenitor cells (MPCs) in human articular cartilage.

Methods

Primary cell cultures established from normal and osteoarthritic (OA) human knee articular cartilage were analyzed for the expression of CD105 and CD166, cell surface markers whose coexpression defines mesenchymal stem cells (MSCs) in bone marrow and perichondrium. The potential of cartilage cells to differentiate to adipogenic, osteogenic, and chondrogenic lineages was analyzed after immunomagnetic selection for CD105+/CD166+ cells and was compared with bone marrow–derived MSCs (BM‐MSCs).

Results

Up to 95% of isolated cartilage cells were CD105+ and ∼5% were CD166+. The mean ± SEM percentage of CD105+/CD166+ cells in normal cartilage was 3.49 ± 1.93%. Primary cell cultures from OA cartilage contained significantly increased numbers of CD105+/CD166+ cells. Confocal microscopy confirmed the coexpression of both markers in the majority of BM‐MSCs and a subpopulation of cartilage cells. Differentiation to adipocytes occurred in cartilage‐derived cell cultures, as indicated by characteristic cell morphology and oil red O staining of lipid vacuoles. Osteogenesis was observed in isolated CD105+/CD166+ cells as well as in primary chondrocytes cultured in the presence of osteogenic supplements. Purified cartilage‐derived CD105+/CD166+ cells did not express markers of differentiated chondrocytes. However, the cells were capable of chondrocytic differentiation and formed cartilage tissue in micromass pellet cultures.

Conclusion

These findings indicate that multipotential MPCs are present in adult human articular cartilage and that their frequency is increased in OA cartilage. This observation has implications for understanding the intrinsic repair capacity of articular cartilage and raises the possibility that these progenitor cells might be involved in the pathogenesis of arthritis.