bluuebunny/crossref_metadata_2025_split huggingface dataset:
Combined effects of an anticoagulant and a lipid‐lowering agent on the prevention of steroid‐induced osteonecrosis in rabbits
Authors: Motomura Goro , Yamamoto Takuaki , Miyanishi Keita , Jingushi Seiya , Iwamoto Yukihide 
Published: October 2004

AbstractObjectiveTo investigate the effects of combination treatment with an anticoagulant (warfarin) plus a lipid‐lowering agent (probucol) on the prevention of steroid‐induced osteonecrosis (ON) in rabbits.MethodsAdult male Japanese white rabbits were injected once intramuscularly with 20 mg/kg of methylprednisolone acetate into the right gluteus medius muscle. The rabbits were then divided into 4 groups and treated as follows: one group received warfarin plus probucol (WP; n = 25), one received probucol alone (PA; n = 30), one received warfarin alone (WA; n = 26), and one received no treatment (nonprophylactic [NP]; n = 20). Two weeks after the steroid injection, the femora and humeri were examined histopathologically for the presence of ON. The sizes of the bone marrow fat cells were examined morphologically. Hematologic examinations were performed before and after the steroid injection.ResultsThe incidence of ON in the WP group (5%) was significantly lower than that observed in the NP group (70%). While the incidence rates of ON in the PA (38%) and WA (33%) groups were also significantly lower than that in the NP group, they were significantly higher than that observed in the WP group. The sizes of the bone marrow fat cells in both the WP (53.5 ± 4.1 μm) and the PA (52.0 ± 5.0 μm) groups were significantly smaller than those in the NP group (60.0 ± 4.0 μm). We also observed a prolongation of the prothrombin time and a reduction in the plasma lipid levels in the WP group during the study.ConclusionThis study experimentally confirmed that the combined use of an anticoagulant and a lipid‐lowering agent helps prevent steroid‐induced ON in rabbits.
Reduction of synovial sublining layer inflammation and proinflammatory cytokine expression in psoriatic arthritis treated with methotrexate
Authors: Kane David , Gogarty Martina , O'Leary John , Silva Ivan , Bermingham Niamh , Bresnihan Barry , FitzGerald Oliver 
Published: October 2004

AbstractObjectiveMethotrexate is one of the most commonly used disease‐modifying antirheumatic drugs in the management of psoriatic arthritis (PsA). Despite the differences between the inflammation in PsA and rheumatoid arthritis (RA), the effects of methotrexate on the synovium have been described solely in RA. In this study, we sought to determine the effects of methotrexate on the inflammatory infiltrate and on cytokine and metalloproteinase gene expression in the synovium of PsA patients.MethodsTen patients with PsA (median duration 18 months) underwent arthroscopy and synovial biopsy of an inflamed knee before and after clinical improvement induced by methotrexate. Immunohistologic analysis was performed using antibodies to CD3, CD4, CD8, CD68, factor VIII, vascular cell adhesion molecule, E‐selectin, and intercellular adhesion molecule (ICAM). Matrix metalloproteinase 3 (MMP‐3) and tissue inhibitor of metalloproteinases 1 (TIMP‐1) messenger RNA (mRNA) were quantified by competitive reverse transcription–polymerase chain reaction (RT‐PCR). Interleukin‐1α (IL‐1α), IL‐1β, IL‐2, IL‐4, IL‐5, IL‐8, IL‐10, IL‐12p35, IL‐12p40, IL‐15, interferon‐γ (IFNγ), and tumor necrosis factor α (TNFα) mRNA expression was quantified by real‐time PCR.ResultsPatients received a median methotrexate dosage of 13.75 mg/week (range 7.5–15) for a median of 11.5 months (range 7–14 months). The Ritchie Articular Index, swollen joint count, and Disease Activity Score were significantly reduced. There was a decrease in all immunohistologic staining, although this was statistically significant only for CD3, CD4, CD8, CD68, E‐selectin, and ICAM. Despite clinical improvement in all patients, there was a residual T cell infiltrate in all synovial biopsy tissues. The synovial lining layer thickness, but not hypervascularity, was significantly reduced. There was also a significant reduction in MMP‐3, but not TIMP‐1, expression. Before treatment, PsA synovium was characterized by a predominant expression of the proinflammatory cytokines IL‐15, IFNγ, IL‐1β, and TNFα and the antiinflammatory cytokine IL‐10. Methotrexate reduced synovial IL‐1α, IL‐1β, IL‐8, IL‐10, IL‐15, IFNγ, and TNFα mRNA expression, but the effect was significant only for IL‐8.ConclusionMethotrexate produced a clinical response in PsA by reducing, but not abolishing, the inflammatory infiltrate, adhesion molecule expression, and MMP‐3 and proinflammatory cytokine gene expression, particularly IL‐8, in the synovium. Methotrexate did not reduce hypervascularity, which is a prominent differentiating feature of PsA synovium.
Involvement of inducible costimulator in the exaggerated memory B cell and plasma cell generation in systemic lupus erythematosus
Authors: Hutloff Andreas , Büchner Kerstin , Reiter Karin , Baelde Hans J. , Odendahl Marcus , Jacobi Annett , Dörner Thomas , Kroczek Richard A. 
Published: October 2004

AbstractObjectiveIn systemic lupus erythematosus (SLE), the increased generation of memory B cells and plasma cells leads to autoimmune hypergammaglobulinemia and destructive immunoglobulin deposits in the kidneys. We undertook this study to determine the biologic mechanism driving this overactivation of the B cell compartment, which is the central issue in SLE.MethodsWe used flow cytometry to analyze expression of the T cell–specific inducible costimulator (ICOS) and its ligand (ICOS‐L) on B cells obtained from the peripheral blood of SLE patients. We correlated ICOS‐L expression with the differentiation status of the B cells using a large panel of surface antigens. In addition, SLE kidneys were analyzed by immunohistology.ResultsWe found an increased expression of ICOS on CD4+ as well as CD8+ T cells in SLE. At the same time, we documented a down‐regulation of ICOS‐L on a high proportion of peripheral blood memory B cells. Based on in vitro experiments, we inferred that this ICOS‐L down‐regulation on B cells was a signature of recent interaction with ICOS+ T cells in vivo. In the kidneys of SLE patients, we found clusters of B cells and plasma cells in close contact with ICOS+ T cells.ConclusionDetailed analysis of B cells with down‐regulated ICOS‐L suggests that ICOS is one of the forces driving the formation of memory B cells and plasma cells in SLE. Furthermore, our identification of plasma cells in areas of T cell–B cell interaction in kidneys suggests that components of a T cell–driven B cell activation process may take place in peripheral tissues in SLE.
Thrombotic thrombocytopenic purpura with severe ADAMTS‐13 deficiency in two patients with primary antiphospholipid syndrome
Authors: Amoura Zahir , Costedoat‐Chalumeau Nathalie , Veyradier Agnès , Wolf Martine , Ghillani‐Dalbin Pascale , Cacoub Patrice , Meyer Dominique , Piette Jean‐Charles 
Published: October 2004

AbstractArterial thrombotic events, thrombocytopenia, and hemolytic anemia with schistocytes may be encountered in the setting of both thrombotic thrombocytopenic purpura (TTP) and primary antiphospholipid syndrome (APS). We report 2 cases of TTP occurring in patients with definite primary APS. We also describe the results of tests for ADAMTS‐13 activity in 20 consecutive patients with primary APS, as well as tests for antiphospholipid antibodies in 26 patients who had TTP, severe ADAMTS‐13 deficiency, and ADAMTS‐13–inhibiting antibodies. In both of the patients with primary APS and TTP, ADAMTS‐13 activity was undetectable, and ADAMTS‐13–inhibiting antibodies were present. None of the 26 patients with TTP and severe ADAMTS‐13 deficiency was positive for the lupus anticoagulant. One of these patients had a low level of anticardiolipin antibodies (22 IgG phospholipid units). In the 20 patients with primary APS, mean ADAMTS‐13 activity was 116% (range 44–250%), and no severe deficiency (<5%) was observed. Our findings suggest that primary APS must be added to the list of autoimmune disorders that can be complicated by TTP.
A human COL2A1 gene with an Arg519Cys mutation causes osteochondrodysplasia in transgenic mice
Authors: Sahlman Janne , Pitkänen Marja T. , Prockop Darwin J. , Arita Machiko , Li Shi‐Wu , Helminen Heikki J. , Långsjö Teemu K. , Puustjärvi Kaija , Lammi Mikko J. 
Published: October 2004

AbstractObjectiveAn arginine‐to‐cysteine substitution at position 519 of the COL2A1 gene causes early generalized osteoarthritis with mild chondrodysplasia in humans. In this study, a human COL2A1 gene with the same mutation was introduced into a murine genome having 1 or no alleles of the murine Col2a1 gene, and the skeletal phenotypes of the transgenic mice were compared with those of control mice.MethodsMice with 1 allele of the normal murine Col2a1 gene and 1 allele of the mutated human COL2A1 gene (n = 10), those with no murine Col2a1 gene and 2 alleles of the mutated human COL2A1 gene (n = 13), those with no murine Col2a1 gene and only 1 allele of the mutated COL2A1 gene (n = 9), and normal control mice (n = 11) were studied for skeletal abnormalities, using radiographic imaging and light microscopic analyses of histologic sections. The collagen network of cartilage was also investigated with transmission electron microscopy.ResultsAt 2 months of age, all transgenic mice had dysplastic changes in their long bones, flattened vertebral bodies, and osteoarthritic changes in their joints. The intervertebral discs of the transgenic animals were degenerated, and their histologic structure was disturbed. The changes were more severe in mice with no murine Col2a1 allele.ConclusionThe human COL2A1 gene with the Arg519Cys mutation causes osteochondrodysplasia in mice, as it does in humans.
Outcome of pregnancies in patients with anti‐SSA/Ro antibodies: A study of 165 pregnancies, with special focus on electrocardiographic variations in the children and comparison with a control group
Authors: Costedoat‐Chalumeau Nathalie , Amoura Zahir , Lupoglazoff Jean‐Marc , Thi Huong Du Le , Denjoy Isabelle , Vauthier Danièle , Sebbouh Djamel , Fain Olivier , Georgin‐Lavialle Sophie , Ghillani Pascale , Musset Lucile , Wechsler Bertrand , Duhaut Pierre , Piette Jean‐Charles 
Published: October 2004

AbstractObjectiveAside from congenital heart block (CHB), sinus bradycardia and prolongation of the corrected QT (QTc) interval have been reported in infants born to mothers with anti‐SSA antibodies. To assess the pathologic nature of these manifestations, this study focused on electrocardiographic (EKG) variations in these children, comparing them with findings in a control group.MethodsWe studied 165 consecutive pregnancies in 106 anti‐SSA–positive women with connective tissue diseases (CTDs). EKGs obtained on 58 children of this group were compared with those obtained on 85 infants born to mothers with CTD who were negative for both anti‐SSA and anti‐SSB.ResultsNo statistically significant difference was seen between the 2 study groups with regard to gestational age, prematurity, birth weight, age of the children at the time of EKG, age of the mothers, or treatments received by the mothers during their pregnancies. Seven of 137 children developed cutaneous neonatal lupus syndrome; 1 child developed CHB (CHB risk of 1 in 99 [1%] if only the first prospectively observed pregnancy in women without a history of CHB is included in the analysis). For EKGs recorded during the first 2 months of life, the mean ± SD PR interval was 96 ± 16 msec in the anti‐SSA–positive group and 96 ± 13 msec in the anti‐SSA–negative group (P = 0.84), with mean QTc values of 397 ± 27 and 395 ± 25 msec (P = 0.57) and mean heart rates of 141 ± 23 and 137 ± 21 beats per minute (P = 0.20), respectively. No difference in the PR interval, QTc interval, or heart rate was observed for EKGs obtained between 2 and 4 months of life. When EKGs obtained at 0–2 months were compared with those obtained at 2–4 months, a physiologic prolongation of the QTc interval was observed in both study groups. No sudden infant death or symptomatic arrhythmia occurred during the first year of life.ConclusionThe EKG findings in children of anti‐SSA–positive and anti‐SSA–negative mothers were not significantly different. Our results suggest that the prolongation of the QTc interval and sinus bradycardia that have recently been reported in children of mothers with anti‐SSA antibodies occur independently of the anti‐SSA antibodies. The pathologic nature of these EKG variations was not confirmed by our controlled study.
Interaction between RANKL and HLA–DRB1 genotypes may contribute to younger age at onset of seropositive rheumatoid arthritis in an inception cohort
Authors: Wu Hui , Khanna Dinesh , Park Grace , Gersuk Vivian , Nepom Gerald T. , Wong Weng Kee , Paulus Harold E. , Tsao Betty P. 
Published: October 2004

AbstractObjectiveTo determine whether the RANKL and HLA–DRB1 “shared epitope” (SE) genotypes contribute to the development of rheumatoid arthritis (RA).MethodsWe studied 237 patients with early RA (within 15 months of symptom onset) who were seropositive for rheumatoid factor. HLA–DRB1 genotyping was performed using the polymerase chain reaction (PCR)–based oligonucleotide probe assay. RANKL polymorphisms were analyzed using PCR pyrosequencing for SNP1 and fluorescence‐based PCR for the presence or absence of the TAAA insertion.ResultsThe presence of SE‐containing DRB1*04 alleles was associated with an earlier age at RA onset (mean ± SD 47 ± 12.7 years versus 53 ± 12.5 years in SE– patients; P = 0.0004). The 2 novel RANKL polymorphisms were in strong linkage disequilibrium (P < 0.0001) and were associated with earlier ages at disease onset (e.g., for the CC versus CT/TT genotypes, 44 ± 13.5 years versus 51 ± 12.7 years; P = 0.0080). The mean age at disease onset in SE+ patients with the RANKL‐CC genotype (35 ± 7.2 years) was a mean of 18 years younger than in SE– patients with RANKL‐CT/TT (53 ± 12.5 years; P < 0.0001) and was 17 years younger than in SE– patients with RANKL‐CC (52 ± 13.2 years; P = 0.0005). The proportion of patients with both the SE and RANKL risk alleles was highest (23%) in those who developed RA during their third decade of life (ages 20–30 years), with a declining trend among those who developed RA during their fourth (16%), fifth (5%), and sixth or later (0%) decades. Interestingly, 92% of the patients diagnosed as having RA between ages 20 and 30 years carried at least 1 of the RA‐associated DRB1*04 alleles, suggesting a strong influence of the SE in the early onset of RA. The majority of patients who developed RA symptoms in their third to fifth decades (74 of 119 [62%]) carried at least 1 copy of the DRB1*04 alleles; in contrast, fewer than half of the patients who developed RA in their sixth decade or later (50 of 118 [42%]) had DRB1*04 alleles. RANKL genotypes were not associated with erosive disease at baseline or with the yearly progression rate of radiographic joint damage.ConclusionThis study provides the first evidence that novel RANKL polymorphisms were associated with an earlier age at RA onset in SE+, but not SE–, patients and that an interaction between SE‐containing HLA–DRB1 and RANKL polymorphisms increased the disease penetrance, resulting in a mean age at RA onset that was 18–20 years younger. Our results also suggested genetic differences between patients with early‐onset and those with late‐onset RA.
Quantification of cortical bone loss and repair for therapeutic evaluation in collagen‐induced arthritis, by micro–computed tomography and automated image analysis
Authors: Barck Kai H. , Lee Wyne P. , Diehl Lauri J. , Ross Jed , Gribling Peter , Zhang Yifan , Nguyen Kathy , van Bruggen Nicholas , Hurst Stephen , Carano Richard A. D. 
Published: October 2004

AbstractObjectiveEx vivo and in vivo micro–computed tomography (micro‐CT) combined with a novel image analysis algorithm were used to quantify cortical bone loss and periosteal new bone formation for therapeutic evaluation in a murine model of collagen‐induced arthritis.MethodsAn automated algorithm was created to locate 5 metatarsophalangeal and 3 metacarpophalangeal joints in 3‐dimensional micro‐CT images of mouse paws for evaluation of joint cortical bone volume (JCBV) within close proximity of the joints as well as cortical bone mineral density and periosteal new bone formation within the paws. For validation, automated estimates of JCBV were compared with radiographic visual scores (RVS) in 4 treatment groups (n = 9 per group): rat anti‐mouse CD11a monoclonal antibody, methotrexate (MTX), anti‐CD11a plus MTX, and saline only. In a separate study, serial images of hind limbs were evaluated in 2 treatment groups: murine tumor necrosis factor receptor II–Fc fusion protein (mTNFRII; n = 10) and control antibody (n = 7).ResultsAutomated estimates of the JCBV were significantly correlated with the RVS (hind paws R = −0.94, front paws R = −0.81, combined R = −0.87). The anti‐CD11a group had significantly higher JCBV compared with controls. In the serial study, the automated estimate of JCBV detected significant treatment effects in the mTNFRII‐Fc group compared with controls. Cortical bone mineral density was significantly higher in all treatment groups compared with controls.ConclusionMicro‐CT combined with a novel image analysis technique (estimation of JCBV) provides a fully automated means to quantify bone destruction in a mouse model of rheumatoid arthritis.
Induction of endothelial cell apoptosis by heat‐shock protein 60–reactive antibodies from anti–endothelial cell autoantibody–positive systemic lupus erythematosus patients
Authors: Dieudé Mélanie , Senécal Jean‐Luc , Raymond Yves 
Published: October 2004

AbstractObjectiveTo determine whether anti–endothelial cell autoantibodies (AECAs) from systemic lupus erythematosus (SLE) patients with the antiphospholipid syndrome are involved in the initial endothelial cell (EC) membrane perturbation effect that is postulated to provide a target for antiphospholipid antibody (aPL) binding and, hence, to trigger the thrombotic cascade. To identify the AECA antigenic target on ECs and to determine the mechanism whereby the EC membrane is disrupted.MethodsAECAs from SLE patients were assayed for binding to ECs by flow cytometry. Positive AECAs were assayed by immunoblotting, and a consensus antigen was identified by mass spectrometry. This candidate antigen was tested in recombinant form for AECA recognition. AECAs were affinity‐purified on this antigen and incubated with ECs to determine their physiologic effects. Anti‐Hsp60 antibody titers were determined by enzyme‐linked immunosorbent assay. The relationship of anti‐Hsp60 status and lupus anticoagulant (LAC) status to thrombotic manifestations between disease onset and the last followup visit were analyzed.ResultsMost of the SLE sera (73%) possessed IgG that bound to the surface of ECs. These positive IgG shared reactivity against a 60‐kd EC surface polypeptide that was identified as human Hsp60. The presence of Hsp60 at the EC surface was established using anti‐Hsp60 antibodies from commercial sources or affinity‐purified from SLE sera that bound ECs. Incubation of ECs with these anti‐Hsp60 antibodies induced apoptosis in a time‐ and dose‐dependent manner, as determined by Hoechst 33342 dye staining of condensed nuclei and by annexin V binding to surface phosphatidylserine. Anti‐Hsp60 antibodies were not restricted to SLE patients, but were found in patients with other autoimmune diseases. However, anti‐Hsp60 antibodies were significantly associated with an increased frequency of thrombosis when present in combination with LAC in the SLE patients.ConclusionThe presence of Hsp60 at the surface of ECs serves as a target for the anti‐Hsp60 antibodies in SLE sera. These anti‐Hsp60 antibodies bind to ECs and induce apoptosis, particularly phosphatidylserine exposure, thus providing a target for the binding of aPL and inducing the subsequent thrombotic cascade.
The “enthesis organ” concept: Why enthesopathies may not present as focal insertional disorders
Authors: Benjamin M. , Moriggl B. , Brenner E. , Emery P. , McGonagle D. , Redman S. 
Published: October 2004

AbstractObjectiveThe Achilles tendon insertion is associated with a complex of adjacent fibrocartilages, a bursa, and a fat‐pad, and is functionally much more than a focal insertion. This has important implications for a better understanding of the spondylarthropathies (SpA). However, the degree to which other insertions form comparable “enthesis organs” has not been established. The aim of this study was to demonstrate the applicability of the enthesis organ concept to other insertion sites.MethodsBoth joint‐related (articular) and extraarticular entheses were removed from 28 sites in the limbs of formalin‐fixed cadavers (age at death 70–101 years) that had been donated for anatomic study. The samples were prepared for paraffin histologic analysis and sectioned longitudinally. The presence and extent of enthesis organs was evaluated at each site in serial sections stained with Masson's trichrome and toluidine blue.ResultsArticular enthesis organs were found at 14 entheses, including the attachments of the digital extensor tendons and collateral ligaments, the cruciate ligaments, tibialis anterior, the lateral collateral ligament of the knee, and the popliteal tendon. Extraarticular enthesis organs were seen at 2 sites, the biceps brachii and patellar tendon insertions. In all enthesis organs, sesamoid and/or periosteal fibrocartilage was present in close association with synovium.ConclusionThe concept of an enthesis organ is of general significance in understanding attachment sites and may explain the diverse pathologic changes, including synovitis, bursitis, and extracapsular changes, seen adjacent to tendon/ligament entheses in SpA. These findings may provide insight into the reason the target tissues in SpA are apparently so diverse.
Association of increased expression of macrophage elastase (matrix metalloproteinase 12) with rheumatoid arthritis
Authors: Liu Mozhen , Sun Huijun , Wang Xiaofei , Koike Tomonari , Mishima Hajime , Ikeda Kotaro , Watanabe Teruo , Ochiai Naoyuki , Fan Jianglin 
Published: October 2004

AbstractObjectiveIncreased enzymatic activity of matrix metalloproteinases (MMPs) may promote the progression of rheumatoid arthritis (RA). We undertook this study to investigate the expression and localization of human macrophage elastase (MMP‐12) in synovial tissue from RA patients and to compare MMP‐12 levels in the synovial tissue and synovial fluid of RA patients with the corresponding levels in patients with osteoarthritis (OA).MethodsWe obtained synovial tissues from 23 RA patients and 29 OA patients and analyzed MMP‐12 expression using immunohistochemistry, Western and Northern blotting analyses, and zymography. Furthermore, we quantified MMP‐12 levels in synovial fluid by Western blotting and zymography.ResultsNorthern blotting analysis demonstrated that RA synovial tissue contained higher levels of MMP‐12 messenger RNA than did OA synovial tissue. Western blotting revealed that MMP‐12 proteins were consistently and markedly increased in RA synovial tissue compared with OA synovial tissue. A greater amount of immunoreactive proteins corresponding to catalytic forms of MMP‐12 was present in RA synovial tissue and synovial fluid, and the MMP‐12 proteins exhibited caseinolytic activity in vitro. Immunohistochemical staining showed that the major cells expressing MMP‐12 were synovial lining cells, many of which were inflammatory macrophages.ConclusionThese results establish a possible mechanism by which macrophage‐derived MMP‐12 may play an important role in the destructive process in RA. Inhibition of MMP‐12 may be a potential modality for the treatment of RA.