bluuebunny/crossref_metadata_2025_split huggingface dataset:
Heterogeneity of collagen synthesis in normal and systemic sclerosis skin fibroblasts. Increased proportion of high collagen‐producing cells in systemic sclerosis fibroblasts
Authors: Jelaska Ante , Arakawa Masami , Broketa Goran , Korn Joseph H. 
Published: February 2007

AbstractObjective. The goal of this study was to quantitatively analyze the distribution of collagen synthesis in normal and systemic sclerosis (SSc) fibroblast populations in order to determine the extent of activation in SSc populations.Methods. We used quantitative in situ hybridization to assess the population distribution of type I collagen synthesis. Fibroblast cultures were derived from both clinically involved and uninvolved skin regions of patients with SSc, and from healthy adults, and assessed for levels of α1(I) procollagen messenger RNA (mRNA).Results. Dermal fibroblasts from both patients with SSc and normal adults were heterogeneous for distribution of α1(I) procollagen mRNA when assessed by in situ hybridization, with a wide range of grains per cell. In contrast, clones of neonatal fibroblasts showed a relatively homogeneous distribution of grain counts. Involved SSc skin fibroblasts had a larger proportion of cells in the high collagen‐producing mRNA subpopulation (mean ± SEM 28.4 ± 6.85%), compared with normal fibroblasts (1.75 ± 1.44%) and uninvolved fibroblasts (9.6 ± 6.73%). Conversely, within the low collagen‐producing mRNA subpopulation, involved fibroblasts had a smaller proportion of cells (mean ± SEM 14.0 ± 5.63%) than did uninvolved fibroblasts (37.8 ± 13.69%), while normal fibroblasts had a majority of the cells in this subpopulation (53.5 ± 8.68%).Conclusion. These results suggest that only a specific subset of fibroblasts are activated in SSc, as evidenced by an increased proportion of cells with high levels of α1(I) procollagen mRNA. Differences between the SSc and normal fibroblast populations appeared to be quantitative rather than qualitative. This may be a result of either clonal selection or selective activation in the pathogenesis of SSc.
Transcriptional activation of the α1(1) procollagen gene in systemic sclerosis dermal fibroblasts. Role of intronic sequences
Authors: Hitraya Elena G. , Jiménez Sergio A. 
Published: February 2007

AbstractObjective. To investigate the transcriptional regulation of the α(1) procollagen gene (COL1A1) in cultured dermal fibroblasts from patients with diffuse systemic sclerosis (SSc) of recent onset and to evaluate the role that intronic sequences may play in the upregulated expression of COL1A1 in SSc dermal fibroblasts.Methods. Dermal fibroblasts from 6 patients with diffuse SSc of recent onset and from 3 healthy individuals were studied. The steady‐state levels of α1(I) procollagen messenger RNA were evaluated by Northern hybridization analysis, and the transcriptional regulation of COL1A1 was examined by transient transfection experiments with deletion constructs containing portions of COL1A1 promoter (with 5′ end points at ‐5.3 kb, ‐2.3 kb, and ‐804 bp and 3′ end point at +42 bp) ligated to the chloramphenicol acetyltransferase (CAT) reporter gene. To examine the role of intronic sequences, constructs containing, in addition to the COL1A1 promoter, a portion of the first intron (+380 bp to +1,440 bp) cloned in front of the CAT gene were transfected. The efficiency of transfections was normalized relative to the net amount of CAT plasmid actually transfected into recipient cells, determined by a modified Southern hybridization procedure.Results. Maximal CAT activity was observed with constructs extending from ‐804 bp to +42 bp in both normal and SSc fibroblasts. However, the activity driven by this construct was 80–110% higher in SSc fibroblasts. The CAT activity driven by a construct with a 5′ end point at ‐5.3 kb was only 15–20% higher in SSc cells, and the CAT activity driven by a construct with a 5′ end point ‐5.3 kb was only 15–20% higher in SSc cells, and the CAT activity driven by a construct with a 5′ end point ‐2.3 kb was 35‐45% higher in SSc fibroblasts. The CAT activity driven by the ‐804‐bp promoter construct was increased up to 4‐fold in SSc fibroblasts in comparison with normal cells when the intronic segment spanning +380 bp to +1,440 bp was included in the transfected construct.Conclusion. The results directly demonstrate the transcriptional activation of COL1A1 in dermal fibroblasts from SSc patients. The data also indicate that first‐intron sequences of COL1A1 are required for maximal transcriptional activity of the collagen gene and may play an important role in the up‐regulation of its expression in SSc fibroblasts.
Development of complete heart block in an adult patient with Sjögren's syndrome and anti‐Ro/SS‐A autoantibodies
Authors: Lee Lela A. , Pickrell Michael B. , Reichlin Morris 
Published: February 2007

AbstractWe describe the occurrence of complete heart block in a patient with Sjögren's syndrome. The patient's serum contained antibodies to both the 60‐kd and 52‐kd Ro proteins. This case indicates that although the adult atrioventricular node may be relatively resistant to the development of anti‐Ro–associated heart block, it can nevertheless be affected.
Increased responsiveness of rheumatoid factor–producing B cells in seronegative and seropositive rheumatoid arthritis
Authors: He Xiaowen , Zhong Wanyun , McCarthy Timothy G. , Weyand Cornelia M. , Goronzy Jörg J. 
Published: February 2007

AbstractObjective. To compare the frequencies and responsiveness of rheumatoid factor (RF)–producing B cells in the peripheral blood of patients with seronegative and seropositive rheumatoid arthritis (RA).Methods. Frequencies of IgM+, IgG+, and RF+ B cells were determined by limiting‐dilution analysis of purified peripheral blood B cells from 6 patients with seropositive RA, 8 patients with seronegative RA, and 7 normal controls. B cell help was provided by cloned T helper cells, which were stimulated by either anti‐CD3 or the bacterial superantigen staphylococcal enterotoxin D (SED). IgM and IgG antibodies and RF in culture supernatants were detected by enzyme‐linked immunosorbent assay.Results. In the presence of anti‐CD3–stimulated T helper cells, 2–10% of B cells from normal individuals secreted IgM and IgG antibodies. The frequency of RF+ B cells was low and ranged from 1:182 to 1:885 (RF+: IgM+) B cells. In patients with seropositive RA, the numbers of Ig‐producing B cells were reduced by a factor of 2, while the fraction of RF+ B cell precursors was expanded by more than 50‐fold (7–20% of IgM+ B cells; P = 0.004). Patients with seronegative RA had higher frequencies of RF‐producing B cells (1.5–6% of IgM+ B cells) than normal individuals (P = 0.002), but not to the same extent as seropositive patients (P = 0.002). Stimulation of B cells using SED preferentially induced RF+ B cells in normal controls and in patients with seronegative and seropositive RA.Conclusion. B cell precursors with the potential to secrete RF were detectable in high frequencies in normal individuals and in patients with seropositive and seronegative RA. In all donors, these B cells could be stimulated with the bacterial superantigen SED. In normal individuals, RF+ B cells remained nonresponsive to help provided by anti‐CD3–activated T cells, but were responsive in RA patients. Seronegative and seropositive RA form a continuous spectrum of disease, with a higher number of RF‐secreting B cells in the seropositive patients.
Chondroprotective effect of intraarticular injections of interleukin‐1 receptor antagonist in experimental osteoarthritis. Suppression of collagenase‐1 expression
Authors: Caron John P. , Fernandes Julio C. , Martel‐Pelletier Johanne , Tardif Ginette , Mineau François , Geng Changshan , Pelletier Jean‐Pierre 
Published: February 2007

AbstractObjective. To investigate the in vivo effect of recombinant human interleukin‐1 receptor antagonist (rHuIL‐1Ra) on the development of lesions and the expression of metalloproteases in the canine experimental osteoarthritis (OA) model.Methods. The right anterior cruciate ligament was sectioned percutaneously in 3 groups of dogs. The control group (n = 5) received an intraarticular injection of sterile physiologic saline (1 ml) twice weekly for 4 weeks starting on the day of surgery. The remaining 2 groups received intraarticular injections of either 2 mg (n = 6) or 4 mg (n = 5) rHuIL‐1Ra in 1 ml of physiologic saline according to the same schedule as the first group. All dogs were killed 4 weeks after surgery. The macroscopic appearance of femoral condyle osteophytes and the size and severity of cartilage lesions on femoral condyles and tibial plateaus were evaluated, as were the histologic features of cartilage and synovial membrane. Levels of collagenase‐1 and stromelysin‐1 messenger RNA expression in cartilage and synovium were determined by Northern blotting.Results. Recombinant human IL‐1Ra exerted a dose‐dependent protective effect on the development of osteophytes and cartilage lesions in vivo. Treatment with rHuIL‐1Ra reduced the incidence (saline‐treated group 70%, 2 mg rHuIL‐1Ra–treated group 42%, 4 mg rHuIL‐1Ra–treated group 20%) and size (saline‐treated group 2.3 ± 0.7 mm [mean ± SEM], 2 mg rHuIL‐1Ra–treated group 0.7 ± 0.3 mm, 4 mg rHuIL‐1Ra–treated group 0.5 ± 0.3 mm) of femoral condyle osteophytes. In addition, a dose‐dependent decrease in the size (saline‐treated group 24.40 ± 8.17 mm2, 2 mg rHuIL‐1Ra–treated group 20.90 ± 8.01 mm2, 4 mg rHuIL‐1Ra–treated group 7.70 ± 5.16 mm2) and the grade (0–4 scale; saline‐treated group 1.20 ± 0.29, 2 mg rHuIL‐1Ra–treated group 1.00 ± 0.26, 4 mg rHuIL‐1Ra–treated group 0.30 ± 0.21) of the tibial plateau cartilage lesions was found, with a significant difference (P < 0.04) reached only with 4 mg rHuIL‐1Ra. Similarly, the histologic lesions in dogs treated with 4 mg rHuIL‐1Ra (Mankin scale; mean ± SEM 2.95 ± 0.53) were significantly less severe (P < 0.002) compared with those in the saline‐treated group (4.95 ± 0.54). Importantly, rHuIL‐1Ra treatment led to a significant reduction (P < 0.005) of collagenase‐1 expression in OA cartilage.Conclusion. This study demonstrated that intraarticular injections of rHuIL‐1Ra can protect against the development of experimentally induced OA lesions. This effect could result, at least in part, from a reduction of collagenase‐1 expression. However, other catabolic processes involved in the degradation of OA cartilage may also be affected.
Local disruption of the insulin‐like growth factor system in the arthritic joint
Authors: Fernihough J. K. , Billingham M. E. J. , Cwyfan‐Hughes S. , Holly J. M. P. 
Published: February 2007

AbstractObjective. To identify differences in levels of insulin‐like growth factor (IGF) and IGF binding proteins (IG‐FBPs) between 30 patients with arthritis (14 with rheumatoid arthritis [RA], 16 with osteoarthritis [OA]) and 11 normal control subjects. IGF and IGFBP levels were correlated to the disease activity marker C‐reactive protein (CRP) to determine whether they were disease related. We also examined the degree of proteolytic modification of the IGFBPs.Methods. Radioimmunoassays were used for measuring IGF and IGFBP‐3 levels; CRP was measured by enzyme‐linked immunosorbent assay. Sodium dodecyl sulfate–polyacrylamide gel electrophoresis followed by Western blotting, chemiluminescence, and autoradiography were used for visualizing binding proteins.Results. There was a significant increase in synovial fluid levels of both IGF‐1 and IGFBP‐3 in both RA and OA. This resulted in an elevated IGFBP‐3 to IGF molar ratio of 1.49 in the OA group and 1.47 in the RA group, compared with 0.86 in the normal control group (P = 0.0002 for both). A significantly lower degree of IGFBP‐3 proteolysis was also seen in the synovial fluids from the patients compared with the controls. There were significant correlations between the CRP level and levels of IGF‐1, IGF‐2, and IGFBP‐3 in the RA patients (r = 0.62–0.898, P = 0.04–0.0007).Conclusion. There was significant local disruption of the IGF system in patients with arthritis. This may result in a lower amount of IGF that is able to bind to IGF receptors in the arthritic joint. Levels of IGF‐1, IGF‐2, and IGFBP‐3 all correlated with the CRP level in patients with RA, which indicates the possibility that the IGF system is involved in the disease process.
Hepatocyte growth factor. A cytokine mediating endothelial migration in inflammatory arthritis
Authors: Koch Alisa E. , Halloran Margaret M. , Hosaka Shigeru , Shah Manisha R. , Haskell Catherine J. , Baker Steven K. , Panos Ralph J. , Haines G. Kenneth , Bennett Gregory L. , Pope Richard M. , Ferrara Napoleone 
Published: February 2007

AbstractObjective. Angiogenesis is an integral component of the vasculoproliferative phase of rheumatoid arthritis (RA). Recently, a heparin‐binding cytokine termed hepatocyte growth factor (HGF), or scatter factor (due to its ability to disperse cohesive epithelial colonies), was described. We conducted this study to investigate the hypothesis that this cytokine was present in the milieu of the inflamed joint, and that it contributed to the chemotaxis of endothelial cells in the synovial tissue.Methods. We examined synovial fluid, synovial tissue, and peripheral blood from 91 patients with RA and other arthritides. We used 83 total samples in an enzyme‐linked immunosorbent assay to quantitate the HGF in synovial fluids and peripheral blood. To determine whether the HGF was biologically active, an epithelial scatter factor assay was performed. Immunohistochemical analysis was used to determine localization in synovial tissues. To define a function for synovial HGF, we preincubated rheumatoid synovial fluids with neutralizing anti‐HGF and measured the ability of these synovial fluids to induce endothelial chemotaxis.Results. Synovial fluid from patients with RA contained a mean ± SEM HGF concentration of 2.0 ± 0.3 ng/ml, while synovial fluid from patients with other arthritides (including inflammatory arthritis) contained 2.4 ± 0.7 ng/ml HGF. Osteoarthritis (OA) patient samples contained the smallest quantities of synovial fluid HGF at 0.9 ± 0.1 ng/ml. RA synovial fluid contained significantly more HGF than did RA peripheral blood (1.1 ± 0.2 ng/ml) (P < 0.05). Rheumatoid synovial fluids induced more scattering of cells than did OA synovial fluids, suggesting a role for this cytokine in rheumatoid joint destruction. Interleukin‐1β induced expression of rheumatoid synovial tissue fibroblast antigenic HGF and scatter factor activity. Immunohistochemically, HGF, as well as the HGF receptor (the met gene product), localized to significantly more rheumatoid synovial tissue lining cells than normal lining cells (P < 0.05). Both HGF and its receptor immunolocalized to subsynovial macrophages as well. Levels of synovial tissue immunoreactive HGF correlated positively with the number of synovial tissue blood vessels. Anti‐HGF neutralized a mean of 24% of the chemotactic activity for endothelial cells found in 10 rheumatoid synovial fluid samples.Conclusion. These results indicate that synovial HGF may contribute to the vasculoproliferative phase of inflammatory arthritides such as RA, by inducing HGF‐mediated synovial neovascularization. These findings point to a newly described role for HGF in the fibroproliferative phase of RA‐associated synovitis.
Expression of matrix metalloproteinase 9 (96‐kd gelatinase B) in human rheumatoid arthritis
Authors: Ahrens Diane , Koch Alisa E. , Pope Richard M. , Stein‐Picarella Monica , Niedbala Michael J. 
Published: February 2007

AbstractObjective. To determine the expression of matrix metalloproteinase 9/gelatinase B (MMP‐9) in synovial fluid (SF), plasma, and synovial tissue from individuals with rheumatoid arthritis (RA), inflammatory arthritis (IA), and osteoarthritis (OA), using specific monoclonal antibody reagents.Methods. Gelatinolytic activity in the SF and plasma of patients with RA, IA, and OA was assessed by gelatin zymography. A mouse monoclonal antiserum, 277.13, which selectively recognizes soluble latent forms of human MMP‐9, was used to quantitate MMP‐9 levels in patient synovial effusions, plasma, and synovial tissue with a capture sandwich enzyme‐linked immunosorbent assay (ELISA). Fifty‐one SF samples (31 RA, 9 OA, 11 IA) were analyzed. Immunolocalization of MMP‐9 in RA, OA, and normal synovium was investigated using MMP‐9–specific antisera.Results. MMP‐9 antigen levels in synovial effusions were elevated 67‐fold in RA samples compared with OA samples. In addition, although MMP‐9 antigen levels in IA synovial effusions were 2.7‐fold less than the values in RA samples, they were elevated 34‐fold over the values in OA samples. These data indicate an association between increased MMP‐9 levels and inflammatory arthritis. A predominant 92‐kd gelatinolytic activity (specifically inhibited by EDTA) was evident in RA and IA samples, but no activity was observed in OA samples. Among 86 plasma samples (17 RA, 9 IA, 60 normal controls) analyzed for MMP‐9 antigen levels by immunocapture ELISA, MMP‐9 antigen levels were elevated 7‐fold in RA plasma compared with normal plasma. RA synovial tissue extracts demonstrated elevated levels of MMP‐9 antigen compared with OA synovial tissue. MMP‐9 immunolocalization studies demonstrated expression in infiltrating leukocytes (neutrophils and macrophages), endothelial cells, and synovial fibroblasts in RA synovium.Conclusion. Latent MMP‐9 and/or MMP‐9–tissue inhibitor of metalloproteinases 1 (TIMP‐1) complexes are elevated in RA and IA SF compared with OA SF. In addition, MMP‐9 is increased in RA plasma versus normal control plasma. Synovial tissue levels of MMP‐9 antigen are also elevated in RA versus OA. The tissue distribution of MMP‐9 within RA synovium is localized to sites of inflammation comprising surface synovial lining cells, endothelium, and leukocytes. Taken together, these observations suggest that connective tissue turnover occurs as a result of excessive MMP activity over TIMP action in the invading pannus, periarticular tissue, or SF. Further studies such as those used in the present investigation will help elucidate the role of a number of different enzymes and inhibitors in the destructive arthropathies.
Selective antibody reactivity with peptides from human endogenous retroviruses and nonviral poly(amino acids) in patients with systemic lupus erythematosus
Authors: Bengtsson Anders , Blomberg Jonas , Nived Ola , Pipkorn Rüdiger , Toth Lajos , Sturfel Gunnar 
Published: February 2007

AbstractObjective. To investigate antibody responses to a broad panel of peptides derived from human endogenous retroviruses (HERVs) among unselected patients with systemic lupus erythematosus (SLE).Methods. In sera obtained from 69 patients with SLE and healthy blood donors, immunoassay was used to measure levels of antibody against synthetic peptides derived from HERVs, exogenous retroviruses, and nonviral poly(amino acids).Results. Measurement by immunoassay revealed increased frequencies of antiretroviral antibodies against 2 peptides derived from the env gene of the type C—like class, which includes ERV‐9 and HERV‐H, and against 2 peptides from the gag region of human T lymphotropic virus type I—related endogenous sequence 1, in patients with SLE. Antibodies to 2 nonviral peptides, polyhistidine and polyproline, were also overrepresented in patient sera. In 1 patient, longitudinal data obtained over a period of 12 years indicated that the concentrations of certain antiretroviral antibodies varied according to disease activity.Conclusion. Reactivity to certain type C HERV—derived antigens was found among patients with SLE. This reactivity could be explained by increased exposure to cross‐reactive epitopes from essentially complete type C HERVs.
Development of the anti‐Ro autoantibody response in a patient with systemic lupus erythematosus
Authors: Scofield R. Hal , Zhang Fenchung , Kurien Biji T. , Anderson Camille J. , Reichlin Morris , Harley John B. , Stafford Haraldine A. 
Published: February 2007

AbstractObjective. To characterize the initial events in anti‐Ro production by a patient with systemic lupus erythematosus, in whom this autoantibody is developing.Methods. The immune response to the Ro ribonucleoprotein and other autoantigens were studied by enzyme‐linked immunosorbent assay for IgG and IgM, by isoelectric focusing, and by inhibition studies to determine apparent avidity.Results. The patient's sera showed an oligoclonal response to Ro that increased in complexity and affinity with time. IgM anti‐Ro appeared shortly before IgG anti‐Ro, and disappeared as IgG anti‐Ro increased in titer and affinity. IgG antiribosomal P autoantibodies also appeared during the patient's course, but in contrast to anti‐Ro, were not preceded by IgM antiribosomal P.Conclusion. These data are consistent with the Ro autoantigen being presented and processed in a manner similar to heterologous antigen, and with differences in the mechanisms that lead to the production of IgG anti‐Ro autoantibodies as opposed to antiribosomal P autoantibodies.
Rheumatoid arthritis lung disease. Determinants of radiographic and physiologic abnormalities
Authors: Saag Kenneth G. , Kolluri Sheela , Koehnke Rachelle K. , Georgou Thomas A. , Rachow John W. , Hunninghake Gary W. , Schwartz David A. 
Published: February 2007

AbstractObjective. To determine the prevalence and important clinical predictors of radiographic and physiologic abnormalities indicative of rheumatoid arthritis interstitial lung disease (RA‐ILD).Methods. An unselected cohort of patients with a confirmed diagnosis of RA and known lung disease were identified (n = 336) and evaluated for RA disease activity and severity. Outcomes included abnormalities determined by the pulmonary function tests of forced vital capacity (FVC) and diffusion capacity for carbon monoxide (DLco), and/or chest radiographic findings of interstitial infiltrates. We used multivariable statistical modeling to determine the independent significance of cigarette smoking and other RA‐specific factors on the pulmonary abnormalities of interest.Results. At least 1 of the 3 abnormal findings was identified by pulmonary tests in 32.4% of all patients. These abnormal findings included an FVC <80% of predicted in 42 patients, a DLco <80% of predicted in 64 patients, and evidence of radiographic interstitial infiltrates in 40 patients. After statistical adjustment for confounding factors, pack‐years of cigarette smoking remained a significant predictor of low DLco (β = −0.07, 95% confidence interval [95% CI] −0.09, −0.04), low FVC (β = −0.003, 95% CI −0.006, −0.0004), and interstitial abnormalities on chest radiograph (odds ratio for ⩾25 pack‐years = 3.76, 95% CI 1.59, 8.88). The Health Assessment Questionnaire (HAQ) Disability Index (DI) was also an important risk factor for the decline in both the DLco (β = −1.15, 95% CI −2.00, −0.30) and FVC (β = −0.23, 95% CI −0.32, −0.13).Conclusion. Although RA disease activity/severity (particularly as defined by the HAQ DI) was important, smoking was the most consistent independent predictor of radiographic and physiologic abnormalities suggestive of ILD in RA.