bluuebunny/crossref_metadata_2025 huggingface dataset:
Polymer Nanocomposites for Aerospace Applications: Properties
Authors: Njuguna J. , Pielichowski K.
Published: December 2003

Polymer nanocomposites may provide significantly increased modulus, gas barrier, thermal performance, atomic oxygen resistance, resistance to small molecule permeation and improved ablative performance when compared to typical traditional carbon‐fiber‐reinforced polymeric composites. This presentation gives a review on both theoretical and experimental investigations extracting valuable fundamental elements including field emission, thermal stability, and electrical, optical and mechanical properties of polymer nanocomposites for aerospace applicability.
Surface Tension, Phase Separation, and Solidification of Undercooled Cobalt–Copper Alloys
Authors: Egry I. , Herlach D. , Kolbe M. , Ratke L. , Reutzel S. , Perrin C. , Chatain D.
Published: December 2003

By using electromagnetic levitation, liquid Cu–Co alloys can be undercooled below their liquidus temperature into the metastable miscibility gap, leading to a phase separation into a cobalt‐rich L1 phase and a cobalt‐poor L2 phase. This paper reports on experimental and theoretical investigations into the properties of this system, including equilibrium shape, surface, and interfacial tension, phase separation, as well as solidification behavior. Solidification experiments were performed in microgravity in order to minimize the effect of convection on the resulting microstructure.
Electrocatalytic Properties of Thin Mesoporous Platinum Films Synthesized Utilizing Potential‐Controlled Surfactant Assembly
Authors: Choi K.‐S. , McFarland E.W. , Stucky G.D.
Published: December 2003

A new electrochemical strategy has been developed for the production of mesoporous Pt films (see Figure). The method utilizes only a thin interfacial region of surfactant–inorganic assemblies formed on the working electrode to produce nanostructured films. The resulting films possess high surface areas that lead to enhanced electrocatalytic properties toward methanol oxidation compared to those of non‐mesoporous Pt films.
An Electrospun Poly(vinylidene fluoride) Nanofibrous Membrane and Its Battery Applications
Authors: Choi S.W. , Jo S.M. , Lee W.S. , Kim Y.‐R.
Published: December 2003

A polymer nanofibrous matrix suitable for polymer electrolytes in high‐performance lithium polymer batteries is presented. The poly(vinylidene fluoride) (PVdF) nanofibrous membrane (see Figure) was produced by electrospinning, which is briefly outlined. The characterization of the membrane—its porosity, network structure, mechanical strength, and electrochemical properties—is described.
Oligothiophene‐Based Networks Applied for Field‐Effect Transistors
Authors: Huisman B.‐H. , Valeton J.J.P. , Nijssen W. , Lub J. , ten Hoeve W.
Published: December 2003

A new type of semiconducting material based on polymerizable oligothiophenes (see Figure) has been prepared. In field‐effect transistors, a charge‐carrier mobility of 10–3 cm2 V–1 s–1 is observed prior to polymerization. Photopolymerization to a polymer network provides mechanical stability and allows direct photopatterning of the semiconductor. These materials also appear more stable to oxidative doping than polythiophenes.
Three‐Dimensional Nanonetwork Assembled in a Photopolymerized Rod Array
Authors: Sun H.‐B. , Nakamura A. , Shoji S. , Duan X.‐M. , Kawata S.
Published: December 2003

One‐ and two‐photon interferential patterning of photopolymerizable resin is demonstrated to lead to well‐defined two‐dimensional (2D) photonic crystal structures (which beat the diffraction limit) and also 3D nanonetworks, such as that shown in the Figure. The fiber‐like features are probably formed by a novel self‐assembly mechanism during drying. Applications in photonics are foreseen.
Growth of Patterned Nanopore Arrays of Anodic Aluminum Oxide
Authors: Yan J. , Rao G.V.R. , Barela M. , Brevnov D.A. , Jiang Y. , Xu H. , López G.P. , Atanassov P.B.
Published: December 2003

An inexpensive procedure to fabricate highly ordered, patterned through‐hole nanopore arrays of anodic aluminum oxide (AAO, see Figure) with intermittent aluminum supports has been developed. Silica was used as the anodization barrier. Using a two‐step anodization process, straight nanopores of AAO are formed in the unpatterned areas; no pores are found in the patterned areas.
Functionalized Pentacene Active Layer Organic Thin‐Film Transistors
Authors: Sheraw C.D. , Jackson T.N. , Eaton D.L. , Anthony J.E.
Published: December 2003

Organic thin‐film transistors with active layers of five different functionalized pentacene derivatives (see Figure) have been fabricated. The pentacene molecules are functionalized to encourage face‐to‐face molecular interactions and thus increase π‐orbital overlap and carrier field‐effect mobility. Devices fabricated using triisopropylsilyl pentacene have the highest field‐effect mobility (0.4 cm2 V–1 s–1) and on/off current ratio (106).
Photofabrication of Superhelix‐Like Patterns on Azobenzene Polymer Films
Authors: Kim M.‐J. , Kumar J. , Kim D.‐Y.
Published: December 2003

Unusual superhelix‐like patterns on the surface of azopolymer films (see Figure) have been directly photofabricated by exposure to a laser interference pattern. Each superhelix‐like pattern is aligned parallel to the others, with a diameter of micrometer scale that could be controlled by the laser interference periodicity.
New antithrombotic 1‐Phthalazinamines with Serotonin Antagonistic Properties
Authors: Johnsen Matthias , Rehse Klaus , Pertz Heinz , Stasch Johannes Peter , Bischoff Erwin
Published: December 2003

We report nineteen 4‐aryl‐ and 4‐arylalkyl‐1‐phthalazinamines (5—8) which we prepared and tested for antithrombotic properties. All compounds were assayed for their antiplatelet activity in the “Born test” with collagen as inducer of the aggregation. N‐[4‐(1H‐1, 2, 4‐triazol‐1‐yl)butyl]‐4‐phenyl‐1‐phthalazin‐amine (7 c) was the most potent compound, having an IC50 of 8 μM. When 5‐HT (Serotonin) was used to start aggregation the N‐(furan‐2‐yl‐methyl)‐4‐phenyl‐1‐pthtalazinamine (8 a) had an IC50 of 2 μM. In vivo potencies were highly significant. N‐[5‐(1H‐1, 2, 4‐triazol‐1‐yl)pentyl]‐4‐phenyl‐1‐phthalazinamine (7 d) inhibited thrombus formation by 12% (P < 0.002) in arterioles and 7% (P < 0.01) in venoles as tested with our laser thrombosis model. For compound 8 a we surprisingly found an antagonism to the 5HT2A receptor, which is most likely the mechanism of the inhibition of aggregation by this compound.
Novel 3, 3a, 4, 5, 6, 7‐Hexahydroindazole and Arylthiazolylpyrazoline derivatives as Anti‐inflammatory Agents
Authors: Nasr Magda N. A. , Said Shehta A.
Published: December 2003

A novel series of 7‐benzylidene‐3, 3a, 4, 5, 6, 7‐hexahydro‐3‐phenyl‐2H‐indazole substituted at the 2‐position were synthesized. The reaction of 2, 6‐bis‐benzylidenecyclohexanone (1) with thiosemicarbazide in the presence of NaOH afforded a mixture of the 3‐H, 3a‐H trans 2 and cis 2a diastereoisomers which have been separated by fractional recrystallization. Interaction of the first intermediate 2 with substituted phenacyl bromides, aromatic aldehydes and chloroacetic acid in presence of a mixture of acetic acid and acetic anhydride, and 2, 3‐dichloroquinoxaline yielded the corresponding 7‐benzylidene‐3, 3a, 4, 5, 6, 7‐hexahydro‐3‐phenyl‐2H‐indazole derivatives substituted at the 2‐position with 4‐aryl‐2‐thiazolyl 3a, b, 5‐arylidene‐4, 5‐dihydro‐4‐oxo‐2‐thiazolyl 4a, b and thiazolo[4, 5‐b]quinoxalin‐2‐yl 5, respectively. Moreover, the other intermediates 3, 5‐diaryl‐1‐thiocarbamoyl‐2‐pyrazolines 7a—d were reacted with the previously‐mentioned reagents and gave the corresponding 3, 5‐diaryl‐1‐(4‐aryl‐2‐thiazolyl)‐2‐pyrazolines 8a—h, 3, 5‐diaryl‐1‐(5‐arylidene‐4, 5‐dihydro‐4‐oxo‐2‐thiazolyl)‐2‐pyrazolines 9a—d and 3, 5‐diaryl‐1‐(thiazolo[4, 5‐b]quinoxalin‐2‐yl)‐2‐pyrazoline derivatives 10a, b, respectively. Some of the newly prepared compounds were subjected to evaluation for their anti‐inflammatory activity. The structures of the new compounds were confirmed by elemental analyses as well as 1H‐NMR, IR, and MS data.
Synthesis and In Vitro Antibacterial Evaluation of Novel Imidazo[2′, 1′:5, 1]‐1, 2, 4‐triazolo[4, 3‐c]‐quinazoline Derivatives of 5‐Thioxo‐1, 2, 4‐triazole, 4‐Oxothiazolidine, and their Open‐chain Counterparts
Authors: Nasr Magda N. , Gineinah Magdy M. , El‐Bendary Eman R.
Published: December 2003

Two novel series of imidazo[2′, 1′:5, 1]‐1, 2, 4‐triazolo[4, 3‐c]quinazolines bearing 5‐thioxo‐1, 2, 4‐triazoles, 6a—f, and 4‐oxothiazolidines, 7a—f, were synthesized from corresponding thiosemicarbazide derivatives, 5a—f. The stepwise methodology applied to the preparation of compounds 5a—f was initiated with reaction of the parent 3‐amino‐1, 2, 4‐triazolo[4, 3‐c]quinazolines, 2, with ethyl 2‐chloroacetoacetate resulting in annelation of the imidazole ring to give esters, 3a—c. However, hydrazinolysis of these ester derivatives gave the corresponding acid hydrazides, 4a—c, which on reaction with the appropriate alkyl isothiocyanate yielded compounds 5a—f. In turn, compounds 5, were cyclized with potassium hydroxide or with ethyl bromoacetate to give the corresponding thioxotriazoles 6 and oxothiazolidines 7, respectively. All synthesized compounds were screened for their in vitro antibacterial activity against various Gram‐positive and Gram‐negative bacteria. Some test compounds were found to possess potent antibacterial activities. Compound, 7f, exhibited much higher potency than the reference standard ciprofloxacin, against both types of bacteria, particularly, Gram‐positive organisms.
Preparation of Fluorescent Nonpeptidic Neuropeptide Y Receptor Ligands: Analogues of the Quinazoline‐type Anti‐obesity Y5 Antagonist CGP 71683A
Authors: Li Liantao , Mayer Matthias , Schneider Erich , Schreiber Elvira , Bernhardt Günther , Peng Shiqi , Buschauer Armin
Published: December 2003

As part of a programme to develop fluorescence‐based methods for the study of the interactions between G‐protein coupled receptors (GPCRs) and their ligands the preparation of low molecular weight fluorescence‐labelled neuropeptide Y (NPY) Y5 antagonists is reported. The naphthylsulfonyl group in the potent quinazoline‐type NPY Y5 receptor antagonist CGP 71683A was replaced with a dansyl, nitrobenzoxadiazole (NBD) or acridine‐9‐carbonyl group. In radioligand binding studies on human Y5 receptor expressing HEC‐1B cells the substances labelled with acridine (Ki 311 nM) and NBD (Ki > 1000 nM) proved to be moderately active or inactive, respectively. By contrast, a Ki value of 49 nM was found for the dansyl analogue compared to 2 nM for CGP 71683A. No binding to Y1 receptors (SK‐N‐MC cells, displacement of [3H]propionyl‐NPY) was detected for the new compounds at concentrations ≤ 1 μM.
Suppression of osteoclastogenesis in rheumatoid arthritis by induction of apoptosis in activated CD4+ T cells
Authors: Ogawa Yukie , Ohtsuki Masahiko , Uzuki Miwa , Sawai Takashi , Onozawa Yoshiko , Nakayama Junichi , Yonemura Akiko , Kimura Tomoatsu , Matsuno Hiroaki
Published: December 2003

Objective

To examine the suppressive effect of anti‐human Fas monoclonal antibody (mAb) on osteoclastogenesis in rheumatoid arthritis (RA) both in vitro and in vivo.

Methods

For in vitro analysis, activated CD4+ T cells derived from peripheral blood mononuclear cells were left untreated or were treated with humanized anti‐human Fas mAb (R‐125224) and cocultured with human monocytes. On day 12, the number of tartrate‐resistant acid phosphatase (TRAP)–positive multinucleated cells was counted. For in vivo analysis, tissue derived from human RA pannus was implanted with a slice of dentin subcutaneously in the backs of SCID mice (SCID‐HuRAg‐pit model). R‐125224 was administered intravenously once a week for 3 weeks. The implanted tissue and dentin slice were removed, and the pits formed on the dentin slice were analyzed.

Results

In vitro, coculture of activated CD4+ T cells and peripheral monocytes induced osteoclastogenesis. The number of TRAP‐positive multinucleated cells was reduced when activated CD4+ T cells were treated with R‐125224. We established a new animal model for monitoring osteoclastogenesis, SCID‐HuRAg‐pit. We found that with R‐125224 treatment, the number of pits formed on the implanted dentin slices was significantly reduced and the number of lymphocytes in the implanted RA synovial tissue was dramatically reduced in this model.

Conclusion

This is the first study to demonstrate the suppressive effect of anti‐human Fas mAb on osteoclastogenesis in RA synovial tissues through the induction of T cell apoptosis. Induction of apoptosis of infiltrated lymphocytes could be a useful therapeutic strategy for RA, in terms of suppressing both inflammation and bone destruction.
G1 domain of aggrecan cointernalizes with hyaluronan via a CD44‐mediated mechanism in bovine articular chondrocytes
Authors: Embry Jennifer J. , Knudson Warren
Published: December 2003

Objective

To determine whether aggrecan fragments bound to hyaluronan (HA) can be retained and internalized by articular chondrocytes and whether these events are dependent on HA and its receptor, CD44. An additional objective was to determine whether partial degradation of aggrecan is a prerequisite for internalization.

Methods

Binding and internalization of a variety of fluorescein isothiocyanate (FITC)– or biotin‐labeled HA/proteoglycan probes were investigated on normal bovine articular cartilage chondrocytes, bovine articular chondrocytes transfected with a dominant‐negative construct of CD44, or COS‐7 cells transfected with wild‐type CD44. The probes were defined as being internalized by the presence of label associated with the cells following extensive trypsinization of the cell surface.

Results

Biotinylated aggrecan fragments bound to FITC‐HA were cointernalized in bovine articular chondrocytes or COS‐7 cells transfected with CD44. Intracellular vesicles containing FITC‐HA colocalized with a fluorescent probe for lysosomes. The internalization of the aggrecan fragments was dependent on the presence of HA as well as the presence of functional CD44. Intact aggrecan/FITC‐HA complexes bound to the cell surface but were not internalized. However, following brief trypsin digestion of the aggrecan/HA complex, the remaining proteoglycan fragments were bound and internalized.

Conclusion

Partially degraded aggrecan fragments (e.g., aggrecan G1 domains bound to HA) can be internalized by articular chondrocytes via a mechanism involving HA/CD44‐mediated endocytosis. Further, the presence of an intact aggrecan monomer bound to HA inhibits the internalization of HA as well as HA‐bound fragments.
Reduction of osteophyte formation and synovial thickening by adenoviral overexpression of transforming growth factor β/bone morphogenetic protein inhibitors during experimental osteoarthritis
Authors: Scharstuhl Alwin , Vitters Elly L. , van der Kraan Peter M. , van den Berg Wim B.
Published: December 2003

Objective

Osteoarthritis (OA) is a joint disease characterized by osteophyte development, fibrosis, and articular cartilage damage. Effects of exogenous transforming growth factor β (TGFβ) isoforms and bone morphogenetic proteins (BMPs) suggest a role for these growth factors in the pathogenesis of OA. The aim of this study was to elucidate the role of endogenous TGFβ and BMP during papain‐induced OA‐like changes in mice.

Methods

We used adenoviral overexpression of TGFβ and BMP antagonists to block growth factor signaling. An adenovirus expressing a secreted, pan–specific TGFβ antagonist called murine latency‐associated peptide 1 (mLAP‐1) was used. In addition, we used intracellular inhibitory Smad6 as a BMP antagonist and Smad7 as a TGFβ/BMP inhibitor. Papain was injected into the knee joints of C57BL/6 mice to induce osteophyte development, synovial thickening, and articular cartilage proteoglycan (PG) loss.

Results

Intraarticular injection of papain caused increased protein expression of several TGFβ and BMP isoforms in synovium and cartilage. Adenovirus transfection into the joint resulted in a strong expression of the transgenes in the synovial lining. Overexpression of mLAP‐1, Smad6, and Smad7 led to a significant reduction in osteophyte formation compared with that in controls. Smad6 and Smad7 overexpression also significantly decreased synovial thickening. Furthermore, the secreted TGFβ inhibitor mLAP‐1 increased articular cartilage PG loss.

Conclusion

Our results indicate a pivotal role of endogenous TGFβ in the development of osteophytes and synovial thickening, implicating endogenous TGFβ in the pathogenesis of OA. In contrast, the prevention of cartilage damage by endogenous TGFβ signifies the protective role of TGFβ in articular cartilage. This is the first study to demonstrate that endogenous BMPs are involved in osteophyte formation and synovial thickening in experimental OA.
Oncostatin M in combination with tumor necrosis factor α induces cartilage damage and matrix metalloproteinase expression in vitro and in vivo
Authors: Hui W. , Rowan A. D. , Richards C. D. , Cawston T. E.
Published: December 2003

Objective

To determine the effects of the proinflammatory cytokine combination of oncostatin M (OSM) and tumor necrosis factor α (TNFα) on cartilage destruction in both in vitro and in vivo model systems.

Methods

The release of collagen and proteoglycan was assessed in bovine cartilage explant cultures, while messenger RNA (mRNA) from bovine chondrocytes was analyzed by Northern blotting. Immunohistochemistry was performed on sections prepared from murine joints following injection of adenovirus vectors encoding murine OSM and/or murine TNFα.

Results

The combination of OSM + TNFα induced significant collagen release from bovine cartilage, accompanied by high levels of active collagenolytic activity. Northern blot analysis indicated that this cytokine combination synergistically induced matrix metalloproteinase 1 (MMP‐1), MMP‐3, and MMP‐13 mRNA. The in vivo data clearly indicated that OSM + TNFα overexpression increased MMP levels and decreased levels of tissue inhibitor of metalloproteinases 1 (TIMP‐1). Specifically, OSM + TNFα induced marked synovial hyperplasia, inflammation, and cartilage and bone destruction with a concomitant increase in MMP expression in both cartilage and synovium and decreased TIMP‐1 expression in the articular cartilage. These effects were markedly greater than those seen with either cytokine alone.

Conclusion

This study demonstrates that OSM + TNFα represents a potent proinflammatory cytokine combination that markedly induces MMP production in both cartilage and synovium, thus promoting joint destruction.
Prognostic factors for radiographic progression, radiographic damage, and disability in juvenile idiopathic arthritis
Authors: Magni‐Manzoni Silvia , Rossi Federica , Pistorio Angela , Temporini Francesca , Viola Stefania , Beluffi Giampiero , Martini Alberto , Ravelli Angelo
Published: December 2003

Objective

To investigate the rate of radiographic progression and identify prognostic factors of radiographic progression, radiographic damage, and physical disability in juvenile idiopathic arthritis (JIA).

Methods

Ninety‐four JIA patients with a median disease duration of 1.1 years were followed up prospectively for a median of 4.5 years. Bilateral wrist radiographs were obtained at baseline, at 1 year, and at the last followup visit. Radiographic damage was assessed by the carpal length (Poznanski score), and physical disability by the Childhood Health Assessment Questionnaire (C‐HAQ). Yearly radiographic progression, the Poznanski score at the final visit, and the C‐HAQ score at the final visit were used as outcome measures. Baseline parameters included demographic, clinical, laboratory, and radiographic data.

Results

The mean ± SD Poznanski score was −1.2 ± 1.3 at baseline, −1.7 ± 1.8 at the 1‐year visit, and −1.9 ± 2.2 at the final visit (P < 0.0001). Radiographic progression was greater during the first year (mean ± SD −0.5 ± 1.1) than between the 1‐year visit and the final visit (−0.2 ± 1.3). The mean yearly radiographic progression during the entire study period was −0.1 ± 0.4. Logistic regression analysis revealed that radiographic progression during the first year was the only baseline parameter that was predictive of all 3 study outcomes. The final Poznanski score was also predicted by the baseline Poznanski score, whereas female sex was protective against radiographic progression.

Conclusion

We identified the prognostic factors for poorer outcome in polyarticular‐course JIA. The changes in the early Poznanski score can be used to predict long‐term joint damage and physical disability.
Patterns of interphalangeal hand joint involvement of osteoarthritis among men and women: A British cohort study
Authors: Poole Jason , Sayer Avan Aihie , Hardy Rebecca , Wadsworth Michael , Kuh Diana , Cooper Cyrus
Published: December 2003

Objective

To characterize the pattern of involvement of osteoarthritis (OA) of the hand among men and women of the same age.

Methods

Structured hand examinations were performed on 1,467 men and 1,519 women who were age 53 years and born in England, Scotland, or Wales during the first week of March 1946 (identified through the United Kingdom National Survey of Health and Development). OA at each joint site was characterized using a previously validated examination schedule. The interrelationship of involvement of different hand joints was analyzed by logistic regression and cluster analyses.

Results

There was clear evidence of polyarticular involvement in the hand joints of both the men and the women. Among the women, 161 subjects had ≥4 joints involved, compared with only 41 subjects expected in this category (P < 0.001). Among the men, 87 subjects were observed to have ≥4 joints involved, in contrast with only 7 subjects expected (P < 0.001). The pattern of hand joint involvement (characterized by clustering primarily by row and symmetric joint involvement, rather than clustering by ray) was found to be almost identical between the men and the women.

Conclusion

This study confirms the existence of a polyarticular subset of OA among men that has characteristics similar to those of the variant observed among women. The data suggest that the genetic or metabolic influences underlying this particular variant of OA acts similarly in both sexes.
Molecular phenotyping of human chondrocyte cell lines T/C‐28a2, T/C‐28a4, and C‐28/I2
Authors: Finger F. , Schörle C. , Zien A. , Gebhard P. , Goldring M. B. , Aigner T.
Published: December 2003

Objective

Because the immortalized chondrocyte cell lines C‐28/I2, T/C‐28a2, and T/C‐28a4 have become a common tool in cartilage research, permitting investigations in a largely unlimited and standardized manner, we investigated the molecular phenotype of these cell lines by gene expression profiling.

Methods

Complementary DNA–array analysis as well as online quantitative polymerase chain reaction were used to identify the gene expression profiles of the 3 cell lines cultured in monolayer and alginate beads, as compared with the expression profiles of cultured human adult primary chondrocytes.

Results

A similar, but not identical, gene expression profile was established for all 3 cell lines. SOX9 was expressed at a significant level in all 3 cell lines. Extracellular matrix proteins and matrix‐degrading proteases were rarely expressed. In contrast, genes involved in the cell cycle were strongly up‐regulated, as compared with the expression levels in physiologic chondrocytes.

Conclusion

The expression of SOX9, the master gene of chondrocytic cell differentiation, reflects the basically chondrocytic phenotype of these cells. However, the major issue appears to be that these cell lines mainly proliferate and show less expression of genes involved in matrix synthesis and turnover. In this respect, C‐28/I2 cells display the highest levels of matrix‐anabolic and matrix‐catabolic genes and thus are presumably preferable for use in investigating chondrocyte anabolic and catabolic activity and its regulation. None of the 3 cell lines appears to be a direct substitute for primary chondrocytes. A successful approach will have to validate the findings obtained with chondrocyte cell lines by using primary chondrocytes or cartilage‐tissue cultures. This would permit the establishment of reproducible in vitro models and subsequently allow investigators to relate the findings to the physiologic situation.
The genetic control of rheumatoid factor production in a rat model of rheumatoid arthritis
Authors: Wernhoff Patrik , Olofsson Peter , Holmdahl Rikard
Published: December 2003

Objective

To investigate the genetic regulation of rheumatoid factor (RF) in a rat model of rheumatoid arthritis, in order to gain understanding of the enigmatic role of RF in the disease.

Methods

IgM‐RF and IgG‐RF, as well as total levels of immunoglobulins of different subclasses, were measured in sera from rats with pristane‐induced arthritis (PIA). The major gene regions were identified by linkage analysis of genetically segregating crosses.

Results

The production of RF was found to correlate with development of arthritis and to be higher in females than in males. Surprisingly, the relatively arthritis‐resistant E3 strain had higher levels of RF than the arthritis‐susceptible DA strain. In an (E3 × DA)F2 cohort a major locus controlling the levels of IgM‐RF in serum was identified on chromosome 11 (Rf1) and another on chromosome 16 (Rf3), and these were not related to arthritis susceptibility. However, the Rf2 locus on chromosome 4 controlled IgG‐RF levels, IgG2a levels, and chronic arthritis in males (Pia5). Some previously defined arthritis loci (Pia4, Pia6, Pia7, and Pia8) were found to also control immunoglobulin levels in serum.

Conclusion

RFs are produced in the rat PIA model and correlate with development of arthritis. Gene regions controlling RF and serum immunoglobulin levels were identified, of which some cosegregated with arthritis. This suggests a new focus of study to elucidate the role of RF in the pathogenesis of arthritis.
Antiidiotypic antibodies neutralize autoantibodies that inhibit cholinergic neurotransmission
Authors: Cavill Dana , Waterman Sally A. , Gordon Tom P.
Published: December 2003

Objective

Functional autoantibodies that inhibit M3 muscarinic receptor (M3R)–mediated neurotransmission have been reported in patients with Sjögren's syndrome (SS) and in patients with scleroderma. Because of limited reports that intravenous immunoglobulin (IVIG) improves dysautonomia in primary SS, we investigated whether IVIG neutralizes the effect of anti‐M3R antibodies on colon smooth muscle contractions, in an in vitro functional assay.

Methods

IgG obtained from patients with primary SS, patients with rheumatoid arthritis and secondary SS, and patients with scleroderma was tested, before and after coincubation with equimolar amounts of IVIG or its F(ab′)2 and Fc fractions, for the ability to inhibit carbachol‐evoked colon smooth muscle contractions. In addition, patient IgG was passed through an IVIG F(ab′)2 column, and unretained IgG was tested for functional activity on colon smooth muscle strips. Purified IgG obtained from healthy adults was also examined for a neutralizing effect on anti‐M3R antibody activity.

Results

Inhibition of colon contractions was mediated by the Fab fraction of patient IgG. Coincubation of IgG from the 3 patient groups with IVIG or its F(ab′)2 fragment neutralized anti‐M3R antibody–mediated inhibition of cholinergic smooth muscle contractions. Preabsorption of patient IgG with Sepharose‐bound IVIG F(ab′)2 removed the anti‐M3R inhibitory activity. In addition, purified IgG from each of 4 healthy adults neutralized the functional autoantibodies.

Conclusion

Anti‐M3R antibody activity does not require receptor crosslinking. Antiidiotypic antibodies present in pooled IgG neutralize patient IgG–mediated inhibition of M3R cholinergic neurotransmission, providing a rationale for IVIG as a treatment of autonomic dysfunction in patients with SS and patients with scleroderma. Furthermore, antiidiotypic antibodies in healthy individuals may prevent the emergence of pathogenic anti‐M3R autoantibodies.
Chemokine receptor expression and in vivo signaling pathways in the joints of rats with adjuvant‐induced arthritis
Authors: Shahrara Shiva , Amin Mohammad A. , Woods James M. , Haines G. Kenneth , Koch Alisa E.
Published: December 2003

Objective

This study was undertaken to characterize the role of CC chemokines and their receptors in rat adjuvant‐induced arthritis (AIA), a model for rheumatoid arthritis (RA). Furthermore, we investigated the signaling pathways associated with CC receptors as well as the cell type distribution of the receptors.

Methods

Using TaqMan real‐time reverse transcription–polymerase chain reaction, Western blot analysis, and immunohistochemistry, we defined chemokine and chemokine receptor messenger RNA (mRNA) expression, CC chemokine receptor (CCR) protein activation during the disease course, CCR‐associated signaling pathways, and immunopositive CCR5, phosphorylated signal transducer and activator of transcription 1 (p‐STAT‐1), and p‐STAT‐3 cells in rat AIA versus control joints.

Results

We showed significant up‐regulation of CCR1, CCR2, CCR5, and macrophage inflammatory protein 1β/CCL4 mRNA in AIA on post–adjuvant injection day 18, coincident with peak inflammation. Additionally, increases in tyrosine phosphorylation of CCR1 (days 14, 18, 21, and 24), CCR2 (days 14 and 18), and CCR5 (days 14, 18, and 21) were detected in AIA rats compared with control (nonarthritic) rats. JAK‐1, STAT‐1, and STAT‐3 were associated with CCR1 and were highly tyrosine phosphorylated on days 14 and 18. Moreover, CCR2 was associated with JAK‐2, STAT‐1, and STAT‐3 on day 18. The association of STAT‐1 and STAT‐3 with CCR5 on days 18 and 21 correlated with JAK‐1 phosphorylation and binding on day 18. However, the activation of JNK was not associated with CCR5 activation in rat AIA. Immunohistochemical analysis demonstrated that the expression of CCR5, p‐STAT‐1, and p‐STAT‐3 was detected on synovial lining cells, macrophages, and endothelial cells in arthritic rat ankles on post–adjuvant injection day 18. While the majority of the CCR5 and p‐STAT‐1 immunostaining was on synovial lining cells and macrophages, p‐STAT‐3 was predominantly expressed on endothelial cells.

Conclusion

CCR1, CCR2, and CCR5 mRNA expression and tyrosine phosphorylation increased with peak inflammation in the AIA model. CCR1, CCR2, and CCR5 tyrosine phosphorylation are associated with the JAK/STAT‐1/STAT‐3 pathway at different stages of rat AIA, as well as with macrophage and endothelial cell infiltration. However, their signaling activation overlaps with peak inflammation. Up‐regulation and activation of CCRs may play a role in macrophage and endothelial cell infiltration in rat AIA joints in addition to activating the associated signaling pathways. The downstream intermediate signaling proteins associated with CC receptors may be used as potential tools to control inflammation in RA.
N‐terminal pro–brain natriuretic peptide as a diagnostic marker of early pulmonary artery hypertension in patients with systemic sclerosis and effects of calcium‐channel blockers
Authors: Allanore Y. , Borderie D. , Meune C. , Cabanes L. , Weber S. , Ekindjian O. G. , Kahan A.
Published: December 2003

Objective

To evaluate N‐terminal pro–brain natriuretic peptide (NT‐proBNP) as a marker of early pulmonary artery hypertension (PAH) and to study changes in the levels of this marker following treatment with dihydropyridine‐type calcium‐channel blocker (DTCCB) in patients with systemic sclerosis (SSc).

Methods

We evaluated 40 consecutive SSc patients who had been hospitalized for followup care (mean ± SD age 56 ± 11 years and mean ± SD duration of cutaneous disease 9 ± 9 years; 27 with limited cutaneous and 13 with diffuse cutaneous disease) but who had no clinical symptoms of heart failure and had a normal left ventricular ejection fraction. At baseline, 10 patients had PAH, defined as a systolic pulmonary artery pressure (sPAP) >40 mm Hg, as measured by echocardiography. Levels of NT‐proBNP were determined at baseline (after discontinuation of DTCCB treatment for 72 hours), after taking 3 doses of DTCCB following treatment reinitiation (assessment 1), and after 6–9 months of continuous DTCCB treatment (assessment 2) in the 20 patients who attended regular appointments (including the 10 patients with PAH at baseline).

Results

At baseline, 13 patients had high NT‐proBNP values for their ages. High NT‐proBNP levels identified patients with PAH with a sensitivity of 90%, a specificity of 90.3%, a positive predictive value of 69.2%, and a negative predictive value of 96%. The NT‐proBNP level correlated with the sPAP (r = 0.44; P = 0.006). By assessment 1, the number of patients with PAH and high levels of NT‐proBNP had decreased from 9 of 10 to 2 of 10 (P = 0.02). This decrease was partially sustained at assessment 2 (4 of 10 patients; P = 0.06).

Conclusion

NT‐proBNP is a useful biologic marker that can be used to diagnose early PAH in SSc patients without clinical heart failure. Measurement of NT‐proBNP may be valuable for the evaluation of treatment with DTCCB and vasodilators in patients with PAH.
Intravenous immunoglobulin abrogates dendritic cell differentiation induced by interferon‐α present in serum from patients with systemic lupus erythematosus
Authors: Bayry Jagadeesh , Lacroix‐Desmazes Sébastien , Delignat Sandrine , Mouthon Luc , Weill Bernard , Kazatchkine Michel D. , Kaveri Srini V.
Published: December 2003

Objective

Alterations in the function of dendritic cells (DCs) may explain the systemic autoimmune responses that characterize systemic lupus erythematosus (SLE). Even though several reports have documented the beneficial effect of intravenous immunoglobulin (IVIG) in SLE, the underlying mechanisms of action remain poorly understood. Considering the effect of serum factors, including interferon‐α (IFNα), on the activity of DCs, we investigated the effects of IVIG on the differentiation of DCs mediated by serum from SLE patients.

Methods

DCs were differentiated from peripheral blood monocytes obtained from SLE patients and from healthy blood donors, in the presence of SLE serum. IVIG was used at a concentration of 0.15 mM. A functional assay was performed to assess the inhibitory effect of IVIG on the uptake of nucleosomes by DCs.

Results

IVIG interfered with the differentiation of DCs from SLE patients and healthy donors cultured in the presence of SLE serum. Treatment of DCs with IVIG inhibited the ingestion of nucleosomes by immature DCs, by up to 36%.

Conclusion

The present findings indicate that IVIG, by down‐regulating the IFNα‐mediated differentiation of DCs and by inhibiting uptake of nucleosomes, may exert an essential immunoregulatory effect in SLE patients at the onset of the immune response, at the DC level. Given the critical role of HLA molecules and the costimulatory signals delivered by CD80 and CD86 in optimal antigen presentation and T cell activation, inhibition of expression of HLA and CD80/CD86 on DCs by IVIG offers a plausible explanation for the efficacy of IVIG in SLE and other immune‐mediated inflammatory conditions.
Indentation testing of human cartilage: Sensitivity to articular surface degeneration
Authors: Bae Won C. , Temple Michele M. , Amiel David , Coutts Richard D. , Niederauer Gabriele G. , Sah Robert L.
Published: December 2003

Objective

To determine, for clinical indentation testing of human articular cartilage, the effects of aging and degeneration on indentation stiffness and traditional indices of cartilage degeneration; the relationship between indentation stiffness and indices of degeneration; and the sensitivity and specificity of indentation stiffness to cartilage degeneration.

Methods

Osteochondral cores from femoral condyles of cadaveric human donors were harvested. Samples were distributed into experimental groups based on donor age (young [20–39 years], middle [40–59 years], and old [≥60 years]), and a macroscopic articular surface appearance that was either normal or mildly degenerate, without deep erosion. Samples were analyzed for indentation stiffness, cartilage thickness, India ink staining (quantitated as the reflected light score), and Mankin‐Shapiro histopathology score.

Results

Indentation stiffness, India ink staining, and the histopathology score each varied markedly between normal‐sample and degenerate‐sample groups but varied relatively little between normal samples obtained from different age groups. A decrease in indentation stiffness (softening) correlated with a decrease in the reflectance score and an increase in the overall histopathology score, especially the surface irregularity component of the histopathology score. Receiver operating characteristic analysis suggested that the indentation testing could accurately detect cartilage degeneration as indicated by macroscopic appearance, India ink staining, and histopathology score.

Conclusion

The indentation stiffness of the normal to mildly degenerate samples tested in this study was sensitive to mild degeneration at the articular surface and was insensitive to changes associated with normal aging or to slight variations in cartilage thickness. This suggests that indentation testing may be a useful clinical tool for the evaluation of early‐stage degenerative changes in articular cartilage.
Rheumatoid arthritis of the shoulder joint: Comparison of conventional radiography, ultrasound, and dynamic contrast‐enhanced magnetic resonance imaging
Authors: Hermann Kay‐Geert A. , Backhaus Marina , Schneider Udo , Labs Karsten , Loreck Dieter , Zühlsdorf Svenda , Schink Tania , Fischer Thomas , Hamm Bernd , Bollow Matthias
Published: December 2003

Objective

To determine the role of ultrasound and magnetic resonance imaging (MRI) compared with conventional radiography in the detection of chronic and acute inflammatory manifestations of rheumatoid arthritis (RA) of the shoulder joint.

Methods

Forty‐three consecutive patients with known RA prospectively underwent clinical examination, radiography, ultrasound, and MRI of the shoulder joints. Each patient was assigned a clinical/laboratory score consisting of 7 parameters, including measurements of shoulder mobility, the erythrocyte sedimentation rate, and C‐reactive protein level. Conventional radiography was standardized and performed in 2 planes. Ultrasound was performed in 10 predefined planes using a 7.5‐MHz linear transducer. MRI at 1.5T comprised transverse and oblique coronal T1‐ and T2*‐weighted fast spin‐echo, gradient‐echo (GRE), and inversion‐recovery sequences with a matrix size of up to 512 pixels. A dynamic T1‐weighted GRE sequence was acquired with intravenous administration of contrast medium. Erosions were assessed using all 3 imaging techniques on a 4‐point scale. Soft‐tissue involvement was evaluated according to the presence of synovitis, tenosynovitis, and bursitis on ultrasound and MRI. The results in the study group were compared with those obtained in a control group of 10 patients with shoulder pain.

Results

In the study group, erosions of the humeroscapular joint were detected by conventional radiography in 26 patients, by ultrasound in 30 patients, and by MRI in 39 patients; the differences were statistically significant for the comparisons of conventional radiography with MRI and for ultrasound versus MRI (P < 0.0001). Conventional radiography detected 12 erosions of the scapula and MRI detected 15. Synovitis was demonstrated in 12 patients by ultrasound and in 27 patients by MRI (P = 0.0003). Tenosynovitis was observed in 15 patients by ultrasound and in 28 patients by MRI (P = 0.0064). Bursitis was detected in 13 patients by ultrasound and in 18 patients by MRI. The findings on dynamic contrast‐enhanced MRI correlated significantly with the detection of synovitis by ultrasound and erosions by static MRI (P < 0.05).

Conclusion

Ultrasound and MRI supplement conventional radiography in assessing the shoulder joint. Although conventional radiography can be used as the sole method of following up known joint destruction in RA, ultrasound and, preferably, MRI are recommended as additional techniques in the initial diagnostic evaluation when radiography yields negative results.
Incidence and predictors of large‐artery complication (aortic aneurysm, aortic dissection, and/or large‐artery stenosis) in patients with giant cell arteritis: A population‐based study over 50 years
Authors: Nuenninghoff Dirk M. , Hunder Gene G. , Christianson Teresa J. H. , McClelland Robyn L. , Matteson Eric L.
Published: December 2003

Objective

To determine the incidence and predictors of large‐artery complication (aortic aneurysm, aortic dissection, and/or large‐artery stenosis) in patients with giant cell arteritis (GCA).

Methods

The cohort of all residents of Olmsted County, Minnesota, in whom GCA was diagnosed between January 1, 1950, and December 31, 1999, was followed up. The incidence of aortic aneurysm, aortic dissection, and large‐artery stenosis was determined. Possible predictors and correlates of large‐artery complication were assessed.

Results

Forty‐six incident cases of large‐artery complication (representing 27% of the 168 patients in the cohort) were identified. These included 30 incident cases (18%) of aortic aneurysm and/or aortic dissection. Of these cases, 18 (11%) involved the thoracic aorta, with aortic dissection developing in 9 (5%). There were 21 incident cases (13%) of large‐artery stenosis. Fifteen patients (9%) had incident cervical artery stenosis, and 6 (4%) had incident subclavian/axillary/brachial artery stenosis. One patient (0.6%) had incident iliac/femoral artery stenosis attributable to GCA. Hyperlipidemia and coronary artery disease were associated with aortic aneurysm and/or dissection (P< 0.05 for both). Cranial symptoms (headache, scalp tenderness, abnormal temporal arteries) were negatively associated with large‐artery stenosis (hazard ratio [HR] 0.10 [95% confidence interval (95% CI) 0.03–0.35,P< 0.0005]), as was a higher erythrocyte sedimentation rate (HR 0.80 [95% CI 0.67–0.95,P< 0.05] per 10 mm/hour).

Conclusion

Large‐artery complication is common in GCA. Increased awareness of large‐artery complication in GCA, particularly early‐occurring aortic dissection, may decrease associated mortality.
B lymphocyte stimulator overexpression in patients with systemic lupus erythematosus: Longitudinal observations
Authors: Stohl William , Metyas Samy , Tan Soon‐Min , Cheema Gurtej S. , Oamar Bonifacia , Xu Dong , Roschke Viktor , Wu Youmei , Baker Kevin P. , Hilbert David M.
Published: December 2003

Objective

To assess the overexpression of B lymphocyte stimulator (BLyS) over time in patients with systemic lupus erythematosus (SLE).

Methods

Sixty‐eight SLE patients were followed up longitudinally for a median 369 days. At each physician encounter, disease activity was assessed by the Systemic Lupus Erythematosus Disease Activity Index, and blood was collected for determination of the serum BLyS level, blood BLyS messenger RNA (mRNA) level, and cell surface BLyS expression. Twenty normal control subjects underwent similar laboratory evaluations.

Results

In contrast to the uniformly normal serum BLyS and blood BLyS mRNA phenotypes in control subjects, SLE patients displayed marked heterogeneity, with 50% and 61% of patients manifesting persistently or intermittently elevated serum BLyS and blood BLyS mRNA phenotypes, respectively. Surface BLyS expression by SLE peripheral blood mononuclear cells was also often increased. Treatment of patients who had elevated serum BLyS levels with intensive courses of high‐dose corticosteroids resulted in marked reductions in serum BLyS levels, and tapering of the corticosteroid dosage often resulted in increases in serum BLyS levels. Serum BLyS levels generally correlated with anti–double‐stranded DNA (anti‐dsDNA) titers (in those with detectable anti‐dsDNA titers), but changes in serum BLyS levels did not correlate with changes in disease activity in individual patients. Serum BLyS phenotype did not associate with specific organ system involvement.

Conclusion

Dysregulation of BLyS over extended periods of time is common in patients with SLE. Neutralization of BLyS activity with an appropriate BLyS antagonist may be therapeutically beneficial.
Gene deletion of either interleukin‐1β, interleukin‐1β–converting enzyme, inducible nitric oxide synthase, or stromelysin 1 accelerates the development of knee osteoarthritis in mice after surgical transection of the medial collateral ligament and partial medial meniscectomy
Authors: Clements Kristen M. , Price Joanne S. , Chambers Mark G. , Visco Denise M. , Poole A. Robin , Mason Roger M.
Published: December 2003

Objective

To investigate the development of osteoarthritis (OA) after transection of the medial collateral ligament and partial medial meniscectomy in mice in which genes encoding either interleukin‐1β (IL‐1β), IL‐1β–converting enzyme (ICE), stromelysin 1, or inducible nitric oxide synthase (iNOS) were deleted.

Methods

Sectioning of the medial collateral ligament and partial medial meniscectomy were performed on right knee joints of wild‐type and knockout mice. Left joints served as unoperated controls. Serial histologic sections were obtained from throughout the whole joint of both knees 4 days or 1, 2, 3, or 4 weeks after surgery. Sections were graded for OA lesions on a scale of 0–6 and were assessed for breakdown of tibial cartilage matrix proteoglycan (aggrecan) and type II collagen by matrix metalloproteinases (MMPs) and aggrecanases with immunohistochemistry studies using anti‐VDIPEN, anti‐NITEGE, and Col2‐3/4Cshort neoepitope antibodies. Proteoglycan depletion was assessed by Alcian blue staining and chondrocyte cell death, with the TUNEL technique.

Results

All knockout mice showed accelerated development of OA lesions in the medial tibial cartilage after surgery, compared with wild‐type mice. ICE‐, iNOS‐, and particularly IL‐1β–knockout mice developed OA lesions in the lateral cartilage of unoperated limbs. Development of focal histopathologic lesions was accompanied by increased levels of MMP‐, aggrecanase‐, and collagenase‐generated cleavage neoepitopes in areas around lesions, while nonlesional areas showed no change in immunostaining. Extensive cell death was also detected by TUNEL staining in focal areas around lesions.

Conclusion

We postulate that deletion of each of these genes, which encode molecules capable of producing degenerative changes in cartilage, leads to changes in the homeostatic controls regulating the balance between anabolism and catabolism, favoring accelerated cartilage degeneration. These observations suggest that these genes may play important regulatory roles in maintaining normal homeostasis in articular cartilage matrix turnover.
Successful tumor necrosis factor α blockade treatment in therapy‐resistant sarcoidosis
Authors: Ulbricht Kai U. , Stoll Matthias , Bierwirth Janine , Witte Torsten , Schmidt Reinhold E.
Published: December 2003

Sarcoidosis is a multisystemic disorder histologically characterized by a noncaseating granulomatous inflammatory process. The etiology remains unclear, but tumor necrosis factor α seems to play a crucial role. Herein we describe a patient with severe sarcoidosis involving the lung and liver. Various treatment regimens with azathioprine, methotrexate, cyclophosphamide, and pentoxifylline failed to control the disease. Therefore, salvage therapy with infliximab was commenced. Arthritis and pulmonary and liver involvement improved. We were then able to taper the corticosteroid treatment to a lower‐dose regimen with no need for additional immunosuppressive treatment. To our knowledge, this is the first reported case of successful treatment of multiorgan sarcoidosis that was previously resistant to conventional therapy.