bluuebunny/crossref_metadata_2025 huggingface dataset:
Biomineralization of Unicellular Organisms: An Unusual Membrane Biochemistry for the Production of Inorganic Nano‐ and Microstructures
Authors: Bäuerlein Edmund
Published: February 2003

With evolution, Nature has ingeniously succeeded in giving rise to an impressive variety of inorganic structures. Every organism that synthesizes biogenic minerals does so in a form that is unique to that species. This biomineralization is apparently biologically controlled. It is thus expected that both the synthesis and the form of every specific biogenic mineral is genetically determined and controlled. An investigation of the mechanism of biomineralization has only become possible with the development of modern methods in molecular biology. Unicellular organisms such as magnetic bacteria, calcareous algae, and diatoms, all of which are amongst the simplest forms of life, are particularly suited to be investigated by these methods. Crystals and composites of proteins and amorphous inorganic polymers are formed as complex structures within these organisms; these structures are not known in conventional inorganic chemistry.
Effects of dowels produced from various materials on withdrawal strength in MDF and Pb
Authors: Uysal Burhanettin , Özçifçi Ayhan
Published: February 2003

Wood dowels are commonly used in the construction furniture, but little information is available about the additive effects of dowels on the ultimate withdrawal strength of single or multidowel joints. This study was carried out to determine the tensile strength of 10‐mm‐diameter dowels produced from medium‐density fiberboard (MDF), plywood, scotch pine (Pinus sylvestris L.), and beech (Fagus orientalis lipsky), bonded parallel and vertical to the surface of MDF and particleboard (Pb) with poly(vinyl acetate) (PVAc) and Desmodur‐VTKA (D‐VTKA). Tensile strength was applied to the dowels according to the procedure in the ASTM‐D 1037 standard. The effects of dowel species, direction of tensile, composite material, and type of adhesive on tensile strength were determined. The results showed that the highest tensile strength was obtained in beech dowels bonded vertically with PVAc adhesive to the surface of MDF at 7.91 N/mm2. If the dowels used in furniture production are subjected to great tensile strength, beech dowels bonded with PVAc adhesive on MDF should be used. However, when dowels produced from MDF and plywood waste are used, they also can produce positive results. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 88: 531–535, 2003
Estimating crystallinity in high density polyethylene fibers using online Raman spectroscopy
Authors: Paradkar R. P. , Sakhalkar S. S. , He X. , Ellison M. S.
Published: February 2003

Online Raman spectra, obtained at different points along the spin line during pilot‐scale nonisothermal melt spinning of high density polyethylene (HDPE) fibers, are presented for the first time. The fraction of the crystalline phase corresponding to each spectrum was determined from the normalized integrated intensity of the 1418 cm−1 Raman band. It is well established that this band represents the orthorhombic crystalline phase in polyethylene. The estimates of percent crystallinity obtained from decomposition of the Raman spectrum were compared with the percent crystallinity from differential scanning calorimetry (DSC) measurements. It is concluded that online Raman spectroscopy can be successfully used to monitor the development of crystallinity in HDPE fibers as a function of distance from the spinneret. © 2003 Wiley Periodicals, Inc. J Appl Polym Sci 88: 545–549, 2003
Listeria monocytogenes infection as a complication of treatment with tumor necrosis factor α–neutralizing agents
Authors: Slifman Nancy R. , Gershon Sharon K. , Lee Jong‐Hoon , Edwards Evelyne T. , Braun M. Miles
Published: February 2003

Objective

Tumor necrosis factor α (TNFα) has been implicated in the pathogenesis of certain inflammatory diseases. Two TNFα‐neutralizing agents are licensed in the US. Infliximab is licensed for the treatment of Crohn's disease (CD) and, when used with methotrexate, for the treatment of rheumatoid arthritis (RA). Etanercept is licensed for the treatment of RA, including juvenile RA, and, more recently, was licensed for the treatment of psoriatic arthritis. Because of the potential for decreased host resistance to infectious agents due to treatment with anti‐TNFα agents, we sought to evaluate postlicensure cases of opportunistic infection, including Listeria monocytogenes, in patients treated with these products.

Methods

The FDA Adverse Event Reporting System, a passive monitoring system, was reviewed to identify all reports of adverse events (through December 2001) associated with L monocytogenes infection in patients treated with infliximab or etanercept.

Results

Fifteen cases of L monocytogenes infection associated with infliximab or etanercept treatment were identified. In 14 of these cases, patients had received infliximab. The median age of all patients was 69.5 years (range 17–80 years); 53% were female. Six deaths were reported. Among patients for whom an indication for use was reported, there were 9 patients (64%) with RA and 5 patients (36%) with CD (information was not reported for 1 patient). All patients for whom information was reported were receiving concurrent immunosuppressant drugs.

Conclusion

Postlicensure surveillance suggests that L monocytogenes infection may be a serious complication of treatment with TNFα‐neutralizing agents, particularly infliximab.
Articular cartilage repair by gene therapy using growth factor–producing mesenchymal cells
Authors: Gelse Kolja , von der Mark Klaus , Aigner Thomas , Park Jung , Schneider Holm
Published: February 2003

Objective

To investigate the repair of partial‐thickness lesions in rat articular cartilage by combining cell transplantation with transfer of growth factor complementary DNA (cDNA).

Methods

Mesenchymal cells isolated from rib perichondrium were infected ex vivo with adenoviral vectors carrying bone morphogenetic protein 2 (BMP‐2) or insulin‐like growth factor 1 (IGF‐1) cDNA. The cells were suspended in fibrin glue and applied to mechanically induced partial‐thickness cartilage lesions in the patellar groove of the rat femur. The filling of the defects was quantified and the quality and integration of the newly formed tissue were assessed by histochemical and immunohistochemical methods. Uninfected cells or cells infected with a LacZ reporter gene vector served as controls.

Results

Transplanted cells were able to attach to the wounded articular cartilage and were not displaced from the lesions by joint movement. Cells infected with both adenoviral vectors AdBMP‐2 and AdIGF‐1 produced repair cartilage of hyaline morphology containing a type II collagen–positive but type I collagen–negative proteoglycan‐rich matrix that restored the articular surface in most lesions. Uninfected cells either failed to fill up the defects or formed fibrous tissue mainly composed of type I collagen. Excessive cells were partially dislocated to the joint margins, leading to osteophyte formation there if AdBMP‐2–infected cells were used. These adverse effects, however, were not seen with AdIGF‐1–infected cells.

Conclusion

Stimulation of perichondrium‐derived mesenchymal cells by transfer of growth factor cDNA in a partial‐thickness defect model allows for satisfactory cartilage restoration by a repair tissue comparable with hyaline articular cartilage.
Synthesis of insulin‐like growth factor binding protein 3 in vitro in human articular cartilage cultures
Authors: Eviatar Tamar , Kauffman Hannah , Maroudas Alice
Published: February 2003

Objective

To quantify the rate of synthesis of insulin‐like growth factor binding protein 3 (IGFBP‐3) and insulin‐like growth factor 1 (IGF‐1) by in vitro cultures of normal and osteoarthritic (OA) human articular cartilage.

Methods

Levels of IGF‐1 and IGFBP‐3 in media from in vitro cultures of human cartilage were determined by radioimmunoassay (RIA). IGFBPs were characterized by immunoblots and ligand blots. Ultrafiltration and RIA analysis of synovial fluid (SF) samples and washings of cartilage samples ex vivo were used to calculate partition coefficients and to estimate the amount of IGF‐1 and IGFBP‐3 in cartilage in vivo.

Results

OA cartilage synthesized 150 ng of IGFBP‐3 per gm of cartilage per day, compared with 50 ng synthesized by normal cartilage. The surface zone of normal cartilage produced more IGFBP‐3 than did the deep zone. Immunoblots and ligand blots confirmed the presence of IGFBP‐3. IGFBP‐3 synthesis was stimulated by exogenous IGF‐1. No freshly synthesized IGF‐1 was detected. The quantities of IGF‐1 and IGFBP‐3 present ex vivo were 11.3 and 78.7 ng/gm of cartilage in normal cartilage and 21.6 and 225.4 ng/gm in OA cartilage.

Conclusion

The results show that while IGFBP‐3 is synthesized in explant cultures, IGF‐1 is not. The rate of IGFBP‐3 synthesis is 3 times higher in OA than in normal cartilage. Both IGFBP‐3 and IGF‐1 penetrate into cartilage from SF in vivo. We estimate that the quantities of IGFBP‐3 produced in culture by human cartilage are small compared with the amount supplied in the form of “small complexes” from the circulation. The high value of the partition coefficient of IGFBP‐3 implies binding to the matrix.
Identification and characterization of SmD183–119‐reactive T cells that provide T cell help for pathogenic anti–double‐stranded DNA antibodies
Authors: Riemekasten Gabriela , Langnickel Dirk , Ebling Fanny M. , Karpouzas George , Kalsi Jatinderpal , Herberth Gunda , Tsao Betty P. , Henklein Peter , Langer Sven , Burmester Gerd‐R. , Radbruch Andreas , Hiepe Falk , Hahn Bevra H.
Published: February 2003

Objective

The C‐terminal peptide of amino acids 83–119 of the SmD1 protein is a target of the autoimmune response in human and murine lupus. This study was undertaken to test the hypothesis that SmD183–119‐reactive T cells play a crucial role in the generation of pathogenic anti–double‐stranded DNA (anti‐dsDNA) antibodies.

Methods

Splenic or lymph node T cells derived from unmanipulated as well as SmD183–119‐immunized NZB/NZW mice were analyzed in vitro by enzyme‐linked immunospot (ELISpot) assay to determine T cell help for anti‐dsDNA generation induced by the SmD183–119 peptide. Cytokines expressed by these T cells were measured by ELISpot assay, enzyme‐linked immunosorbent assay, and flow cytometry. SmD183–119‐ and ovalbumin‐specific T cell lines were generated and characterized.

Results

The SmD183–119 peptide, but not the control peptides, significantly increased the in vitro generation of anti‐dsDNA antibodies in cultures from unmanipulated NZB/NZW mice. Interferon‐γ (IFNγ), interleukin‐2 (IL‐2), IL‐4, transforming growth factor β, and IL‐10 production increased in response to the peptide in young mice; only IFNγ and IL‐2 were increased in older, diseased mice. Activation of SmD183–119‐reactive T cells by immunization of NZB/NZW mice resulted in elevated anti‐dsDNA synthesis and, later, increased antibodies to SmD183–119. Most cells in SmD183–119‐specific CD4+ T cell lines helping both antibodies had increased intracellular expression of IFNγ, and most expressed both IFNγ and IL‐4.

Conclusion

The SmD183–119 peptide plays an important role in generating T cell help for autoantibodies, including anti‐dsDNA, and activates different subsets of T cells as defined by distinct cytokine expression. This peptide is an interesting target structure for the modulation of autoreactive T cells, and its characterization may contribute to our understanding of the role of autoantigen‐reactive T cells in the pathogenesis of SLE.
LJP 394 for the prevention of renal flare in patients with systemic lupus erythematosus: Results from a randomized, double‐blind, placebo‐controlled study
Authors: Alarcón‐Segovia Donato , Tumlin James A. , Furie Richard A. , McKay James D. , Cardiel Mario H. , Strand Vibeke , Bagin Robert G. , Linnik Matthew D. , Hepburn Bonnie ,   LJP 394 Investigator Consortium
Published: February 2003

Objective

To determine whether LJP 394 delays or prevents renal flare in patients with systemic lupus erythematosus (SLE) and a history of renal disease.

Methods

In a 76‐week, double‐blind, placebo‐controlled study, 230 SLE patients were randomized to receive 16 weekly doses of 100 mg of LJP 394 or placebo, followed by alternating 8‐week drug holidays and 12 weekly doses of 50 mg of LJP 394 or placebo. An assay measuring the affinity of the serum IgG fraction for the DNA epitope of LJP 394 identified a high‐affinity population of patients (189 of 213 patients; 89% taking LJP 394 and 90% taking placebo). Analyses were performed on both the intent‐to‐treat population and the high‐affinity population.

Results

Anti–double‐stranded DNA antibodies decreased and C3 levels tended to increase during treatment with LJP 394. In the intent‐to‐treat population, the time to renal flare was not significantly different between treatment groups, but patients taking LJP 394 had a longer time to institution of high‐dose corticosteroids and/or cyclophosphamide (HDCC) and required 41% fewer treatments with HDCC. In the high‐affinity population, the LJP 394 group experienced a longer time to renal flare, 67% fewer renal flares, longer time to institution of HDCC, and 62% fewer HDCC treatments compared with the placebo group. In patients with serum creatinine levels ≥1.5 mg/dl at study entry, those taking LJP 394 had 50% fewer renal flares; no renal flares were observed in the high‐affinity group taking LJP 394. Serious adverse events were observed in 25 of the 114 LJP 394–treated patients (21.9%) and 34 of the 116 placebo‐treated patients (29.3%).

Conclusion

Treatment with LJP 394 in patients with high‐affinity antibodies to its DNA epitope prolonged the time to renal flare, decreased the number of renal flares, and required fewer HDCC treatments compared with placebo. The study drug appeared to be well tolerated.
The relationship of FcγRIIIa genotype to degree of B cell depletion by rituximab in the treatment of systemic lupus erythematosus
Authors: Anolik Jennifer H. , Campbell Debbie , Felgar Raymond E. , Young Faith , Sanz Inaki , Rosenblatt Joseph , Looney R. John
Published: February 2003

Objective

Despite wide use of the anti‐CD20 monoclonal antibody rituximab in the treatment of B cell lymphomas, the mechanism by which it causes B cell depletion remains a subject of controversy. As part of an ongoing phase I/II trial of rituximab in the treatment of systemic lupus erythematosus (SLE), we sought to determine whether the effectiveness of B cell depletion was influenced by polymorphisms of Fc receptors (FcR) on effector cells.

Methods

During rituximab treatment of 12 SLE patients, B cell depletion was monitored as a function of the serum rituximab level and FcγRIIa and FcγRIIIa genotypes at baseline and at 1 month and 2 months after treatment. FcR genotypes were determined by polymerase chain reaction. Serum levels of rituximab were measured by enzyme‐linked immunosorbent assay (ELISA). B lymphocyte percentages were assessed by flow cytometry.

Results

B cell depletion was highly variable in this patient cohort, with B cell percentages at the 1–2‐month posttreatment nadir ranging from undetectable (<0.1 cell/μl) to 16% (∼30 cells/μl) of the total peripheral blood lymphocytes. At 2 months posttreatment, B cell percentages were highly correlated with both the serum rituximab level and the FcγRIIIa genotype (R2 = 0.75, P = 0.002). The FcγRIIIa genotype was a significant independent predictor of the efficacy of B cell depletion (P = 0.019).

Conclusion

These results highlight the potential variability of B cell depletion by rituximab in the treatment of autoimmune disease and indicate that Fc receptors are an important determinant of that variability. The findings further suggest the importance of antibody‐dependent cell‐mediated cytotoxicity and/or apoptosis induction via FcγRIIIa‐expressing effector cells in the mechanism of B cell depletion by this widely used monoclonal antibody.
Detection of radiographic joint space narrowing in subjects with knee osteoarthritis: Longitudinal comparison of the metatarsophalangeal and semiflexed anteroposterior views
Authors: Mazzuca Steven A. , Brandt Kenneth D. , Buckwalter Kenneth A.
Published: February 2003

Objective

Although recent protocols for standardized knee radiography afford highly reproducible radioanatomic alignment of the joint and measurement of joint space width (JSW) in repeat radiographs acquired on the same day, the sensitivity of these techniques to joint space narrowing (JSN) over time in subjects with knee osteoarthritis (OA) is unknown. The present study was undertaken to compare the metatarsophalangeal (MTP) view and the semiflexed anteroposterior (AP) view with respect to sensitivity to JSN in knee OA.

Methods

In 49 subjects with definite knee OA, 2 MTP radiographs and 1 semiflexed AP radiograph were obtained at baseline. Each examination was repeated 14 months later. In MTP views, minimum JSW and the distance between the anterior and posterior margins of the medial tibial plateau (intermargin distance [IMD], an indicator of parallel alignment of the tibial plateau and the x‐ray beam) were measured with a pair of calipers and a magnifying lens fitted with a graticule. JSW in semiflexed AP views was measured by digital image analysis.

Results

The mean of within‐knee standard deviations of JSW in the baseline MTP examinations (n = 52 OA knees) was 0.24 mm (coefficient of variation 5.8%). Although IMDs in the 2 baseline MTP views were very highly correlated (+0.88), IMDs in the serial examinations were only moderately correlated (+0.45). Serial MTP views showed a small increase in mean JSW over 14 months that was not significantly greater than zero (mean ± SD +0.09 ± 0.66 mm; P not significant). In contrast, concurrent semiflexed AP examinations showed a marginally significant decrease in mean JSW (−0.09 ± 0.31 mm; P = 0.10).

Conclusion

These results demonstrate that evidence of the short‐term reproducibility of a radiographic protocol is an insufficient basis on which to predict the quality of its longitudinal performance.
Cartilage‐like gene expression in differentiated human stem cell spheroids: A comparison of bone marrow–derived and adipose tissue–derived stromal cells
Authors: Winter Anja , Breit Stephen , Parsch Dominik , Benz Karin , Steck Eric , Hauner Hans , Weber Renate M. , Ewerbeck Volker , Richter Wiltrud
Published: February 2003

Objective

To compare the chondrogenic potential of human bone marrow–derived mesenchymal stem cells (BMSC) and adipose tissue–derived stromal cells (ATSC), because the availability of an unlimited cell source replacing human chondrocytes could be strongly beneficial for cell therapy, tissue engineering, in vitro drug screening, and development of new therapeutic options to enhance the regenerative capacity of human cartilage.

Methods

Quantitative gene expression of common cartilage and cell interaction molecules was analyzed using complementary DNA array technology and reverse transcription–polymerase chain reaction during optimization of cell differentiation, in order to achieve a molecular phenotype similar to that of chondrocytes in cartilage.

Results

The multilineage potential of BMSC and ATSC was similar according to cell morphology and histology, but minor differences in marker gene expression occurred in diverse differentiation pathways. Although chondrogenic differentiation of BMSC and ATSC was indistinguishable in monolayer and remained partial, only BMSC responded (with improved chondrogenesis) to a shift to high‐density 3‐dimensional cell culture, and reached a gene expression profile highly homologous to that of osteoarthritic (OA) cartilage.

Conclusion

Hypertrophy of chondrocytes and high matrix‐remodeling activity in differentiated BMSC spheroids and in OA cartilage may be the basis for the strong similarities in gene expression profiles between these samples. Differentiated stem cell spheroids represent an attractive tool for use in drug development and identification of drug targets in OA cartilage–like tissue outside the human body. However, optimization of differentiation protocols to achieve the phenotype of healthy chondrocytes is desired for cell therapy and tissue engineering approaches.
Immature articular cartilage is more susceptible to blood‐induced damage than mature articular cartilage: An in vivo animal study
Authors: Hooiveld Michel J. J. , Roosendaal Goris , Vianen Marieke E. , Van Den Berg H. Marijke , Bijlsma Johannes W. J. , Lafeber Floris P. J. G.
Published: February 2003

Objective

Cartilage of young but skeletally mature dogs is more susceptible to blood‐induced damage than that of old dogs. The aim of the present study was to investigate whether cartilage of skeletally immature individuals is even more adversely affected by exposure to blood than that of mature individuals, as suggested by clinical practice experience with humans.

Methods

Right knees of 3 groups of 6 beagle dogs (skeletally immature, young mature, and old animals) were injected with autologous blood on days 0 and 2. On day 4, cartilage matrix proteoglycan turnover (content, synthesis, and release), synovial inflammation, and cartilage‐destructive properties of the synovial tissue were determined and compared with those of the left uninjected control knees.

Results

Subsequent to intraarticular bleeding, cartilage proteoglycan content decreased in an age‐dependent manner, with the largest decrease occurring in cartilage of immature animals. Proteoglycan synthesis per cell also decreased in an age‐dependent manner, with the largest decrease occurring in the immature animals. Cartilage proteoglycan release increased in all 3 groups, but the decrease was not age dependent. Interestingly, immature animals showed a large increase in cartilage DNA content upon exposure to blood, whereas mature animals did not. Histologic analysis showed a mild synovitis in animals of all ages, but catabolic inflammatory activity was found only in immature animals.

Conclusion

Joints of skeletally immature dogs appeared to be more susceptible than joints of mature dogs to the adverse effects of a joint hemorrhage. These data suggest that for humans, specifically young children are at risk for joint damage after a joint hemorrhage.
Valine/valine genotype at position 247 of the β2‐glycoprotein I gene in Mexican patients with primary antiphospholipid syndrome: Association with anti–β2‐glycoprotein I antibodies
Authors: Prieto G. Aleph , Cabral Antonio R. , Zapata‐Zuñiga Martín , Simón Abraham J. , Villa Antonio R. , Alarcón‐Segovia Donato , Cabiedes Javier
Published: February 2003

Objective

To determine the polymorphism at position 247 of the β2‐glycoprotein I (β2GPI) gene in Mexican patients with antiphospholipid syndrome (APS) and to compare these data in patients with or without antibodies to β2GPI and with the clinical manifestations of APS.

Methods

We studied 39 patients with primary APS and compared them with 106 clinically healthy subjects. Polymorphism was determined by polymerase chain reaction–restriction fragment length polymorphism. The presence of “true” anticardiolipin (aCL) antibodies, β2GPI‐dependent aCL antibodies (IgG and IgM), and phospholipid‐free anti‐β2GPI antibodies (IgG isotype) were detected by enzyme‐linked immunosorbent assay (ELISA) utilizing nonirradiated ELISA plates. Clinical manifestations associated with antiphospholipid antibodies were also evaluated.

Results

We found no significant differences in the genotype expression between the control group and the primary APS patients (13% with VV, 52% with VL, and 35% with LL versus 23% with VV, 51% with VL, and 26% with LL, respectively). In contrast, anti‐β2GPI–positive patients had significantly higher frequencies of the VV genotype and V allele expression than the control subjects and the anti‐β2GPI–negative patients. These genotype and allele frequencies were also significantly higher in patients with arterial thrombosis than in patients without it. Anti‐β2GPI–negative patients without arterial thrombosis did not express the VV genotype. We found no differences in the Val/Leu247 polymorphism of the β2GPI gene in primary APS patients with or without “true” aCL antibodies or in primary APS patients with or without β2GPI‐dependent aCL antibodies.

Conclusion

Our results suggest that the VV genotype at position 247 of the β2GPI gene may play a role in the generation of anti‐β2GPI antibodies and perhaps in the expression of arterial thrombosis in primary APS.
Binding of outer surface protein A and human lymphocyte function–associated antigen 1 peptides to HLA–DR molecules associated with antibiotic treatment–resistant Lyme arthritis
Authors: Steere Allen C. , Falk Ben , Drouin Elise E. , Baxter‐Lowe Lee Ann , Hammer Juergen , Nepom Gerald T.
Published: February 2003

Objective

To assess the binding of outer surface protein A (OspA) and human lymphocyte function–associated antigen 1 (hLFA‐1) peptides to 5 major histocompatibility complex (MHC) molecules.

Methods

Peptide binding to the MHC molecules was determined by in vitro binding assays, and binding was correlated with the frequencies of the 5 MHC molecules in patients with treatment‐resistant Lyme arthritis.

Results

The HLA–DRB1*0401 molecule bound both OspA163–175 and hLFA‐1αL330–342 well. Although the magnitude of the binding was less, the DRB1*0404 molecule also showed binding of both peptides. The DRB1*0101 molecule bound OspA163–175 well, but hLFA‐1αL330–342 only weakly; the DRB1*0801 or *1101 molecule bound both peptides weakly, if at all. The magnitude of OspA163–175 binding correlated well with the frequencies of the DRB1 alleles in patients with treatment‐resistant arthritis, but the binding of hLFA‐1αL330–342 showed only an association with the DRB*04 alleles.

Conclusion

These correlations support the hypothesis that OspA163–175 is the critical epitope in triggering antibiotic treatment–resistant Lyme arthritis. However, the inability of the DRB*0101 molecule to bind hLFA‐1αL330–342 suggests that this peptide may not be a relevant autoantigen, at least in DRB1*0101‐positive patients.
Measurement of radiographic joint space width in the tibiofemoral compartment of the osteoarthritic knee: Comparison of standing anteroposterior and Lyon Schuss views
Authors: Vignon Eric , Piperno Muriel , Le Graverand Marie‐Pierre Hellio , Mazzuca Steven A. , Brandt Kenneth D. , Mathieu Pierre , Favret Huguett , Vignon Martine , Merle‐Vincent Florence , Conrozier Thierry
Published: February 2003

Objective

To evaluate progression of joint space narrowing in radiographs of osteoarthritic (OA) knees imaged in both the standing anteroposterior (AP) and the Lyon schuss positions, using alternative methods to measure joint space width (JSW).

Methods

Standing AP (extended view) and Lyon schuss (posteroanterior [PA] view, with 20–30° of flexion) radiographic images of 58 OA knees were obtained twice (at baseline and 2 years later). With both methods, fluoroscopy was used to align the anterior and posterior margins of the medial or lateral tibial plateau with the central x‐ray beam. Minimum JSW, mean JSW, and joint space area (JSA) of the medial or lateral femorotibial joint space were measured using a new digital image analysis system. The effects of knee flexion versus extension and parallel versus nonparallel tibial plateau alignment were evaluated with respect to the reproducibility of JSW in repeated examinations (intraclass correlation coefficient [ICC]), the mean of within‐knee standard deviations of repeated measurements (SDm), and the sensitivity to changes in JSW in serial radiographs (standardized response mean [SRM]).

Results

The performance of the new software, as assessed by the reproducibility of repeated measurements of minimum JSW on the same image, was excellent in both the standing AP (ICC = 0.98) and Lyon schuss radiographs (2 SDm = 0.5 mm, ICC = 0.98). The reproducibility in different radiographs of the same knee was not evaluated. However, over 2 years, the mean (± SD) decrease in the minimum JSW of OA knees was 0.17 ± 0.75 mm in standing AP radiographs (P not significant) and 0.24 ± 0.50 mm in Lyon schuss views (P = 0.007), with SRMs of 0.23 and 0.48, respectively. The quality of alignment of the tibial plateau was satisfactory (<1 mm between anterior and posterior margins of the medial tibial plateau) in 66% of the pairs of Lyon schuss radiographs and in 57% of the pairs of standing AP radiographs. In the Lyon schuss radiographs, SRM was highly dependent on tibial plateau alignment. Minimum JSW was more sensitive to change than was mean JSW or JSA, in paired Lyon schuss radiographs that exhibited satisfactory alignment.

Conclusion

Compared with the standing AP radiograph, PA imaging of the knee in 20–30° flexion (the schuss position) increases the reproducibility of radiographic JSW measurements in OA knees and the sensitivity to change in JSW in serial radiographs. Sensitivity to change in minimum JSW is notably increased by aligning the medial tibial plateau with the central x‐ray beam in the Lyon schuss radiograph.
Transcription factor early growth response 1 activity up‐regulates expression of tissue inhibitor of metalloproteinases 1 in human synovial fibroblasts
Authors: Aicher Wilhelm K. , Alexander Dorothea , Haas Christian , Kuchen Stefan , Pagenstecher Axel , Gay Steffen , Peter Hans‐Hartmut , Eibel Hermann
Published: February 2003

Objective

To investigate the regulatory potential of early growth response 1 (Egr‐1) on tissue inhibitor of metalloproteinases 1 (TIMP‐1) expression in synovial fibroblasts.

Methods

Egr‐1 and TIMP‐1 transcripts were detected by in situ hybridization in synovial tissue. Egr‐1–regulated TIMP expression was studied in immortalized fibroblast lines using gel retardation assays, RNase protection analysis, reporter gene studies using the human TIMP‐1 promoter, and by enzyme‐linked immunosorbent assay.

Results

TIMP‐1 and Egr‐1 were coexpressed in synovial fibroblasts of inflamed joints, and Egr‐1 activated the expression of TIMP‐1. Egr‐1 binding to a recognition sequence in the TIMP‐1 promoter was demonstrated in gel retardation and reporter gene assays. Since the same DNA sequence was also recognized by the transcription factor Sp‐1, our results suggest that the expression of TIMP‐1 in synovial fibroblasts may be differentially regulated by Egr‐1 and Sp‐1. In addition, fibroblasts expressing Egr‐1 at high levels were found to express increased levels of TIMP‐2 and TIMP‐3 messenger RNA.

Conclusion

The enhanced expression of Egr‐1 may regulate the activity of matrix metalloproteinases in synovial fibroblasts by enhancing the expression of the TIMP‐1, ‐2, and ‐3 genes.
Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement
Authors: Steen Virginia , Medsger Thomas A.
Published: February 2003

Objective

To determine whether there are factors, such as the diffusing capacity for carbon monoxide (DLCO) or pulmonary artery pressure (PAP) on echocardiogram, that can predict the development of pulmonary hypertension (PHT) in patients with limited scleroderma.

Methods

Using the large Pittsburgh Scleroderma Databank, 106 patients who had the diagnosis of PHT after January 1, 1982, were matched with 106 controls by scleroderma subtype, age, sex, race, disease duration, and the mean time to the diagnosis of PHT after the initial Pittsburgh visit. Autoantibodies, vascular features, use of calcium channel blockers, extent of pulmonary function, and echocardiogram findings were determined at any time prior to the diagnosis of PHT (or prior to the matched time in controls).

Results

Patients with PHT had a mean DLCO of 52% of predicted at an average of 4.5 years prior to the diagnosis of PHT. This was markedly decreased compared with the values in controls, whose mean DLCO was 81% of predicted (P < 0.0001). The estimated mean PAP on echocardiogram was only slightly higher in the PHT patients compared with controls (34 mm Hg versus 29 mm Hg; P not significant). Nineteen PHT patients had 4 serial measurements of the DLCO during the 15 years prior to the diagnosis of PHT. The initial mean DLCO was 80% of predicted, which decreased in a linear manner to a mean of 35% of predicted at the time of diagnosis of PHT, whereas the value in controls remained at ∼80% of predicted (P < 0.0001). PHT patients had more severe Raynaud's phenomenon and more severe digital tip ulcers, but they used calcium channel blockers significantly less frequently (37% versus 61% of controls; P < 0.01). The predominance of nucleolar autoantibodies and the absence of anti–Scl 70 antibody were associated with PHT.

Conclusion

A decreasing DLCO is an excellent predictor of the subsequent development of isolated PHT in limited scleroderma. The DLCO may be significantly decreased for many years prior to the diagnosis of PHT. The presence of autoantibodies and the PAP may also be helpful predictors. The long‐term use of calcium channel blockers may be protective, but newer agents that are more effective in treating PHT may also be helpful in altering the natural history of this serious complication in limited scleroderma.
Cytokine profile of the rheumatoid nodule suggests that it is a Th1 granuloma
Authors: Hessian Paul A. , Highton John , Kean Annabel , Sun Cheuk Kwan , Chin Michael
Published: February 2003

Objective

To define the cytokine profile within rheumatoid subcutaneous nodules, and to determine whether the destructive inflammatory process in this lesion displays features of a lymphocyte‐driven Th1 or Th2 granuloma.

Methods

Subcutaneous nodules excised from 10 patients with rheumatoid arthritis were examined. Transcripts for interleukin 1β (IL‐1β) IL‐2, IL‐4, IL‐5, IL‐10, IL‐12, IL‐13, IL‐15, IL‐18, and for tumor necrosis factor α (TNFα) and interferon‐γ (IFNγ) were detected by reverse transcription–polymerase chain reaction of extracted RNA.

Results

Nine of 10 nodules contained transcripts for IFNγ. We observed no evidence for the expression of IL‐2, IL‐4, or IL‐5 among the lymphokine genes analyzed. Transcripts for TNFα, IL‐1β, IL‐10, IL‐15, and IL‐18 were present in all 10 nodules. Transcripts for IL‐12 were present in all but one nodule. Expression of IL‐13 messenger RNA was observed in only 5 nodules.

Conclusion

The cytokine profile within the rheumatoid nodule (i.e., presence of IFNγ but not IL‐2, and prominent expression of IL‐1β and TNFα together with IL‐12, IL‐18, IL‐15, and IL‐10) is similar to the profile of cytokines in the synovial lesion of rheumatoid arthritis, which is generally accepted as being attributable to a Th1‐mediated inflammatory mechanism. Our results suggest that damage to affected synovial membrane or subcutaneous tissue is caused by the same inflammatory mechanisms, and that the nodule is a Th1 granuloma.
Safety and efficacy of long‐term intraarticular steroid injections in osteoarthritis of the knee: A randomized, double‐blind, placebo‐controlled trial
Authors: Raynauld Jean‐Pierre , Buckland‐Wright Chris , Ward Rupert , Choquette Denis , Haraoui Boulos , Martel‐Pelletier Johanne , Uthman Imad , Khy Visithan , Tremblay Jean‐Luc , Bertrand Carole , Pelletier Jean‐Pierre
Published: February 2003

Objective

To evaluate the safety and efficacy of long‐term intraarticular (IA) steroid injections for knee pain related to osteoarthritis (OA).

Methods

In a randomized, double‐blind trial, 68 patients with OA of the knee received IA injections of triamcinolone acetonide 40 mg (34 patients) or saline (34 patients) into the study knee every 3 months for up to 2 years. The primary outcome variable was radiologic progression of joint space narrowing of the injected knee after 2 years. Measurements of minimum joint space width were performed by an automated computerized method on standardized fluoroscopically guided radiographs taken with the patient standing and with the knee in a semiflexed position. The clinical efficacy measure of primary interest was the pain subscale from the Western Ontario and McMaster Universities OA Index (WOMAC). Efficacy measures of secondary interest were the total score on the WOMAC, physician's global assessment, patient's global assessment, patient's assessment of pain, range of motion (ROM) of the affected knee, and 50‐foot walking time. Clinical symptoms were assessed just before each injection.

Results

At the 1‐year and 2‐year followup evaluations, no difference was noted between the two treatment groups with respect to loss of joint space over time. The steroid‐injected knees showed a trend toward greater symptom improvement, especially at 1 year, for the WOMAC pain subscale, night pain, and ROM values (P = 0.05) compared with the saline‐injected knees. Using area under the curve analyses, knee pain and stiffness were significantly improved throughout the 2‐year study by repeated injections of triamcinolone acetonide, but not saline (P < 0.05).

Conclusion

Our findings support the long‐term safety of IA steroid injections for patients with symptomatic knee OA. No deleterious effects of the long‐term administration of IA steroids on the anatomical structure of the knee were noted. Moreover, long‐term treatment of knee OA with repeated steroid injections appears to be clinically effective for the relief of symptoms of the disease.
Geldanamycin inhibits the production of inflammatory cytokines in activated macrophages by reducing the stability and translation of cytokine transcripts
Authors: Wax Stephen , Piecyk Monica , Maritim Beatrice , Anderson Paul
Published: February 2003

Objective

Heat‐shock protein 90 (Hsp90) is critical in the intracellular signaling pathways that promote inflammatory cytokine production. Geldanamycin (GD) is a benzoquinone ansamycin that inhibits the function of Hsp90. GD inhibits the production of tumor necrosis factor α (TNFα) in activated macrophages and suppresses the progression of adjuvant‐induced arthritis and experimental allergic encephalomyelitis in rodents. GD has been used to investigate the mechanisms by which Hsp90 regulates inflammatory cytokine production.

Methods

The macrophage cell line RAW264.7 (or primary peritoneal macrophages) was activated with lipopolysaccharide in the absence or presence of GD. The effect of GD on the transcription, stability, and translation of inflammatory cytokine messenger RNA (mRNA) was determined using nuclear run‐on assays, mRNA decay assays, and sucrose gradient polysome profiles, respectively.

Results

Our data revealed that GD potently inhibits the production of TNFα, interleukin‐6 (IL‐6), and IL‐1β in activated macrophages. Although GD did not significantly reduce the transcription of inflammatory cytokine mRNA, it significantly decreased the stability of these transcripts. Polysome profiles indicated that GD also inhibited the translation of TNFα and IL‐6 transcripts. These effects may be due, in part, to inhibition of p38 mitogen‐activated protein kinase, a kinase known to regulate the stability and translation of inflammatory cytokine transcripts.

Conclusion

These results indicate that the function of Hsp90 is important in the posttranscriptional control of inflammatory cytokine production.
Mapping and functional characterization of rat chromosome 4 regions that regulate arthritis models and phenotypes in congenic strains
Authors: Bäckdahl Liselotte , Ribbhammar Ulrica , Lorentzen Johnny C.
Published: February 2003

Objective

DA rats are highly susceptible to experimental models of rheumatoid arthritis (RA). Linkage analyses in different models have identified several quantitative trait loci (QTLs) within a 70‐cM region of DA rat chromosome 4 (C4). We produced congenic strains for these QTLs in order to map and characterize their impact on arthritis development.

Methods

Selective breeding was used to transfer C4 intervals from arthritis‐resistant PVG.1AV1 rats onto DA rats. These congenic strains were evaluated for susceptibility to arthritis induced by intradermal injection of rat type II collagen, pristane (a well‐defined synthetic adjuvant oil), mycobacteria, or squalene (an endogenous adjuvant oil used in human vaccine).

Results

Rats congenic for PVG.1AV1 genes in the 70‐cM region were less susceptible than DA rats to collagen‐induced arthritis (CIA), pristane‐induced arthritis, adjuvant‐induced arthritis, and squalene‐induced arthritis (SIA). Experiments in subcongenic strains indicated a gene regulating arthritis in males located in a 20‐cM interval overlapping the QTL Pia5. A second gene, located in a 10‐cM interval harboring the QTL Oia2, attenuated SIA and CIA. The latter caused a change in anticollagen antibody isotype levels toward a pattern similar to that seen in PVG.1AV1 rats.

Conclusion

The QTL Oia2 regulates arthritis induced both by the nonimmunogenic immunostimulant squalene and by cartilage collagen. In CIA, it also skews anticollagen isotype profiles, suggesting qualitative regulation of autoimmunity. Interestingly, the homologous human chromosome region 12p12–p13 has also been linked to RA, suggesting that genetic and functional dissection of this locus will provide clues to disease pathways that lead to joint inflammation.
Radiologic features in juvenile idiopathic arthritis: A first step in the development of a standardized assessment method
Authors: Van Rossum Marion A. J. , Zwinderman Aeilko H. , Boers Maarten , Dijkmans Ben A. C. , Van Soesbergen Renée M. , Fiselier Theo J. W. , Franssen Marcel J. A. M. , Cate Rebecca ten , Suijlekom‐Smit Lisette W. A. van , Wulffraat Nico M. , Kuis Wietse , Luijk Wilma H. J. van , Oostveen Johanna C. M. , Dijkstra Piet F. ,   on behalf of the Dutch Juvenile Idiopathic Arthritis Study Group
Published: February 2003

Objective

To describe radiologic features of patients with juvenile idiopathic arthritis (JIA) in a standardized manner, to test the reliability and feasibility of this description, and to correlate these features with clinical signs as a first step in the development of a standardized assessment method.

Methods

The placebo‐controlled study of sulfasalazine in patients with oligoarticular, extended oligoarticular, and polyarticular JIA performed by the Dutch Juvenile Idiopathic Arthritis Study Group yielded the data for this study. All trial entry radiographs (clinically involved joints and contralateral joints) were scored (in consensus by a skeletal radiologist and pediatric rheumatologist) for the presence of swelling, osteopenia, joint space narrowing, growth abnormalities, subchondral bone cysts, erosions, and malalignment.

Results

Data on 67 of 69 patients were analyzed. The mean age was 9.1 years (range 2.5–17.6 years), and the median disease duration was 24 months (range 5–176 months). Thirteen percent of the patients were IgM rheumatoid factor (IgM‐RF) positive, and 16% were HLA–B27 positive. All 68 clinically evaluated joints were included in the maximum of 19 radiographed joints (or joint groups) per patient. The mean number of radiographed joints per patient was 7 (range 2–15); knees, hands, ankles, and feet were most frequently affected. Fifty‐eight patients (87%) had radiologic abnormalities in at least one joint (soft‐tissue swelling in 63% of patients, growth disturbances in 48%, joint space narrowing in 28%, and erosions in 15%). In total, half of the radiographs of the clinically involved joints showed radiologic abnormalities, including two‐thirds of the radiographs of the clinically affected hands and knees. Univariate analysis revealed a good correlation between the overall articular (clinical) severity and the presence of radiologic abnormalities (odds ratio [OR] 1.38, P < 0.0001). Multivariate analysis showed increased ORs for the presence of radiologic abnormalities and IgM‐RF positivity (OR 4.6, P = 0.005) or HLA–B27 positivity (OR 3.0, P = 0.004). In general, reproducibility of the radiologic scoring method was good (mean kappa coefficient of 0.74 [range 0.40–0.86]), although there were scoring discrepancies for swelling, osteopenia, and growth disturbances. The scoring took 10–20 minutes per patient.

Conclusion

Our model of describing and scoring radiologic abnormalities of radiographed joints in JIA was feasible, mostly reproducible, correlated well with the overall articular severity score, and added substantial new information not available on clinical examination.
Diagnostic value of high‐resolution B‐mode and doppler sonography for imaging of hand and finger joints in rheumatoid arthritis
Authors: Weidekamm C. , Köller M. , Weber M. , Kainberger F.
Published: February 2003

Objective

High‐resolution sonography enables a detailed assessment of intraarticular and extraarticular soft tissue abnormalities of joints affected by rheumatoid arthritis (RA). This study was undertaken to evaluate the diagnostic value of B‐mode sonography and power Doppler compared with that of clinical examinations and conventional radiography.

Methods

The study group comprised 47 patients (14 men, 33 women) with different grades of RA; 31 patients were rheumatoid factor (RF) positive, and 16 were RF negative. The wrists, first through fifth metacarpophalangeal joints, and second through fifth proximal interphalangeal joints of these patients were scored with ultrasound in B‐mode and power Doppler application, using a standardized technique. Involvement and severity of inflammation, as well as vascularization, were scored according to a new 3‐point scale. The results were correlated with benchmarks of the clinical and radiologic investigations. Clinical status and conventional radiologic status were determined according to the Disease Activity Score and the Larsen score.

Results

After preliminary studies in 15 patients, 39% of 704 joints were found to be abnormal by clinical investigation. Erosions were detected by radiography and sonography in 23% and 43% of joints, respectively. Hypervascularization was observed in 34% of 704 joints by power Doppler application. There was a significant correlation (P < 0.001) between the different methods for the detection of the severity of lesions. Use of a modern, state‐of‐the‐art power Doppler program was necessary for semiquantification, and a standardized investigation technique and scoring system provided sufficient quality measures.

Conclusion

Sonography detects 20% more abnormalities than does radiography, and sonography has the potential to provide simple grading of disease activity. The rate of detection of abnormalities was slightly higher with clinical examination compared with sonography.
The inheritance of hand osteoarthritis in Iceland
Authors: Jonsson Helgi , Manolescu Ileana , Stefansson Stefan Einar , Ingvarsson Thorvaldur , Jonsson Hjortur H. , Manolescu Andrei , Gulcher Jeff , Stefansson Kari
Published: February 2003

Objective

To assess the contribution of genetics to hand osteoarthritis (HOA) and its subsets in the Icelandic population.

Methods

A list of 2,919 HOA patients, constituting 1% of the Icelandic population, was compiled through nationwide sources. This patient list was cross‐referenced with a comprehensive Icelandic genealogy database, enabling the use of algorithms to assess familiality of HOA. Two methods were used: the average pairwise kinship coefficient (KC) of the patients, and the relative risk (RR) of HOA in relatives of patients. In each case, the results were compared with 1,000 control sets of similar composition with regard to number, age, and sex, generated from the genealogy database.

Results

The KC for patients was significantly higher than for the control sets and was proportional to the degree of both interphalangeal (IP) and thumb base (first carpometacarpal [CMC] joint) involvement. The RR of HOA in sisters of women in the study was 2.0 (P < 0.001), while the RR in spouses was not significantly different from that in controls. The RR increased with the severity of the disease. Thus, sisters of women with severe IP HOA had an RR of 5.0 and sisters of those with severe first CMC involvement had an RR of 6.9. The increased risk also extended beyond the nuclear family, with significantly increased risk in cousins.

Conclusion

Patients seeking medical services for HOA are more related to each other than matched controls, supporting the role of a genetic component in the disease. The genetic influence in both IP and first CMC HOA appears to be similar and increases with increasing severity of the disease.