bluuebunny/crossref_metadata_2025_split huggingface dataset:
Interleukin‐12 induces salivary gland dysfunction in transgenic mice, providing a new model of Sjögren's syndrome
Authors: Vosters Jelle L. , Landek‐Salgado Melissa A. , Yin Hongen , Swaim William D. , Kimura Hiroaki , Tak Paul P. , Caturegli Patrizio , Chiorini John A. 
Published: November 2009

AbstractObjectiveInterleukin‐12 (IL‐12) is a pleiotropic cytokine that is elevated in the affected organs of patients with Sjögren's syndrome (SS). We have previously reported that overexpression of IL‐12 in CBA mice leads to mononuclear infiltration of salivary and lacrimal glands, as well as to expansion of bronchial lymphoid tissue and decreased mucociliary clearance. Because xerostomia is one of the most important clinical features in SS patients, our main objective in the current study was to evaluate salivary gland function in IL‐12–transgenic mice. Our secondary objective was to further characterize this animal model and to determine if the changes observed in these mice are representative of those observed in patients with SS overall.MethodsPilocarpine‐stimulated salivary flow was used to address salivary gland function in a large group of IL‐12–transgenic mice bred onto the autoimmune‐prone SJL background. Furthermore, salivary glands were removed to assess the formation of infiltrates in the glands and gland morphology. Serum was also collected from these animals to investigate the formation of autoantibodies.ResultsPilocarpine‐stimulated salivary flow was significantly lower in IL‐12–transgenic mice than in wild‐type controls. Salivary glands from transgenic mice exhibited an increase in both the number and the size of lymphocytic foci, versus glands from age‐matched controls. Furthermore, the acini in transgenic mice were fewer in number and larger in size compared with acini in controls. An age‐dependent increase in anti‐SSB/La antibodies was observed in IL‐12–transgenic mice and was accompanied by an increase in antinuclear antibodies.ConclusionOur findings indicate that a number of conditions associated with SS are exhibited by IL‐12–transgenic SJL mice and that this model might be useful in researching multiple aspects of the disease.
HLA–DPB1 and DPB2 are genetic loci for systemic sclerosis: A genome‐wide association study in Koreans with replication in North Americans
Authors: Zhou Xiaodong , Lee Jong Eun , Arnett Frank C. , Xiong Momiao , Park Min Young , Yoo Yeon Kyeong , Shin Eun Soon , Reveille John D. , Mayes Maureen D. , Kim Jin Hyun , Song Ran , Choi Ji Yong , Park Ji Ah , Lee Yun Jong , Lee Eun Young , Song Yeong Wook , Lee Eun Bong 
Published: November 2009

AbstractObjectiveTo identify systemic sclerosis (SSc) susceptibility loci via a genome‐wide association study.MethodsA genome‐wide association study was performed in 137 patients with SSc and 564 controls from Korea using the Affymetrix Human SNP Array 5.0. After fine‐mapping studies, the results were replicated in 1,107 SSc patients and 2,747 controls from a US Caucasian population.ResultsThe single‐nucleotide polymorphisms (SNPs) (rs3128930, rs7763822, rs7764491, rs3117230, and rs3128965) of HLA–DPB1 and DPB2 on chromosome 6 formed a distinctive peak with log P values for association with SSc susceptibility (P = 8.16 × 10−13). Subtyping analysis of HLA–DPB1 showed that DPB1*1301 (P = 7.61 × 10−8) and DPB1*0901 (P = 2.55 × 10−5) were the subtypes most susceptible to SSc in Korean subjects. In US Caucasians, 2 pairs of SNPs, rs7763822/rs7764491 and rs3117230/rs3128965, showed strong association with SSc patients who had either circulating anti–DNA topoisomerase I (P = 7.58 × 10−17/4.84 × 10−16) or anticentromere autoantibodies (P = 1.12 × 10−3/3.2 × 10−5), respectively.ConclusionThe results of our genome‐wide association study in Korean subjects indicate that the region of HLA–DPB1 and DPB2 contains the loci most susceptible to SSc in a Korean population. The confirmatory studies in US Caucasians indicate that specific SNPs of HLA–DPB1 and/or DPB2 are strongly associated with US Caucasian patients with SSc who are positive for anti–DNA topoisomerase I or anticentromere autoantibodies.
Rapamycin versus methotrexate in early diffuse systemic sclerosis: Results from a randomized, single‐blind pilot study
Authors: Su Tien‐I Karleen , Khanna Dinesh , Furst Daniel E. , Danovitch Gabriel , Burger Christina , Maranian Paul , Clements Philip J. 
Published: November 2009

AbstractObjectiveTo assess the safety and efficacy of rapamycin in the treatment of diffuse systemic sclerosis (SSc; scleroderma).MethodsEighteen patients with diffuse SSc of ≤5 years duration were randomized to receive rapamycin or methotrexate (MTX) in a single‐blind, 48‐week study. Abnormalities in clinical and laboratory parameters were compared between the 2 treatment groups. The potential efficacy of the study drugs was evaluated by comparing results of the baseline and 48‐week assessments, including the modified Rodnan skin thickness score (MRSS) and the Health Assessment Questionnaire disability index.ResultsThe baseline characteristics of the patients were similar in both groups (n = 9 in each). One patient in the rapamycin group who never received the study drug was excluded from the analysis. Three patients in each group withdrew from the study; 2 of the withdrawals were treatment‐related (severe hypertriglyceridemia associated with rapamycin, and pancytopenia associated with MTX), and 4 were SSc‐related. Hypertriglyceridemia was the most notable side effect associated with rapamycin, but it was generally well tolerated and treatable. The incidence and severity of other adverse drug reactions were comparable between the 2 groups. Within each group, the MRSS improved significantly from baseline. In the rapamycin group, the patient's global assessment showed a significant improvement from baseline, while forced vital capacity values declined from baseline. The disease activity scores at 48 weeks and the changes in these scores from baseline were not significantly different between the 2 groups.ConclusionRapamycin has a reasonable safety profile in a select group of patients with scleroderma. Larger trials are needed to assess the efficacy of rapamycin in patients with early diffuse SSc.
Depletion of functionally active CD20+ T cells by rituximab treatment
Authors: Wilk Esther , Witte Torsten , Marquardt Nicole , Horvath Tibor , Kalippke Katy , Scholz Kirsten , Wilke Nadine , Schmidt Reinhold E. , Jacobs Roland 
Published: November 2009

AbstractObjectiveRituximab is a therapeutic anti‐CD20 antibody used for in vivo depletion of B cells in proliferative and autoimmune diseases. However, the mechanisms of action are not fully understood, since not all of the therapy‐mediated effects can be explained by the depletion of antibody‐secreting cells. In addition to B cells, there is also a small population of T cells coexpressing CD20 in all individuals. This study was conducted to examine the phenotype and function of CD3+CD20+ T cells in patients with rheumatoid arthritis (RA) and healthy controls.MethodsThe phenotype and apoptosis of peripheral blood mononuclear cells from healthy donors and RA patients were examined by 4‐color fluorescence‐activated cell sorting analyses. Cytokine production was determined by intracellular staining and measurement of cytokines in the supernatants. Proliferation of sorted T cell populations was analyzed using 3H‐thymidine uptake assays.ResultsIn healthy individuals, 0.1–6.8% of peripheral blood T cells (mean 1.6%; n = 142) coexpressed CD20, which was not significantly different from that in the peripheral blood of RA patients, in whom 0.4–2.6% of T cells (mean 1.2%; n = 27) were CD20+. During rituximab therapy, the CD20+ T cells along with the B cells were eliminated from the RA peripheral blood. Among the CD20+ T cells, 45% coexpressed CD8 and 55% coexpressed CD4. Polyclonal CD3+CD20+ cells were functionally characterized by constitutive cytokine production (i.e., interleukin‐1β and tumor necrosis factor α), a low proliferative capacity, a high activation state, and enhanced susceptibility to apoptosis.ConclusionThese findings suggest that CD20+ T cells represent a terminally differentiated cell type with immune‐regulatory and proinflammatory capacities. Depletion of CD20+ T cells may be an additional mechanism by which anti‐CD20 therapy functions in patients with RA.
A critical role of Cyr61 in interleukin‐17–dependent proliferation of fibroblast‐like synoviocytes in rheumatoid arthritis
Authors: Zhang Qiuyu , Wu Juanjuan , Cao Qi , Xiao Lianbo , Wang Li , He Dongyi , Ouyang Guilin , Lin Jinpiao , Shen Baihua , Shi Yuan , Zhang Yan , Li Dangsheng , Li Ningli 
Published: November 2009

AbstractObjectiveFibroblast‐like synoviocytes (FLS) are a major component of the hyperplastic synovial pannus that aggressively invades cartilage and bone during the course of rheumatoid arthritis (RA). Cyr61 (CCN1) is a product of a growth factor–inducible immediate early gene and is involved in cell adhesion, proliferation, and differentiation. However, the role that Cyr61 plays in FLS proliferation has remained undetermined. The aim of this study was to identify the role of Cyr61 in regulating the proliferation of FLS derived from patients with RA.MethodsExpression of Cyr61 in synovial tissue (ST) and in FLS was determined simultaneously using immunohistochemistry, real‐time polymerase chain reaction, and Western blotting. Cyr61 levels in synovial fluid (SF) were determined by enzyme‐linked immunosorbent assay. FLS proliferation stimulated by SF, Cyr61, and interleukin‐17 (IL‐17) was measured by thymidine incorporation. Activation of signal transduction pathways was determined by Western blotting and confocal microscopy.ResultsCyr61 was overexpressed in ST, FLS, and SF samples from RA patients as compared with samples from normal controls. Elevated levels of Cyr61 in RA SF promoted the proliferation of FLS, an effect that was abrogated by a neutralizing monoclonal antibody against human Cyr61. Furthermore, in samples from RA patients, Cyr61 was found to protect FLS from apoptosis and to sustain the expression of Bcl‐2 in FLS. Most importantly, the expression of Cyr61 in FLS was regulated by IL‐17 mainly via the p38 MAPK and NF‐κB signaling pathways. Knockdown of expression of the Cyr61 gene inhibited IL‐17–stimulated FLS proliferation.ConclusionOur findings indicate that Cyr61 plays a critical role in IL‐17–mediated proliferation of FLS in RA and likely contributes to hyperplasia of synovial lining cells and eventually to joint destruction in patients with RA.
Rituximab may form a complex with iGmκ mixed cryoglobulin and induce severe systemic reactions in patients with hepatitis C virus–induced vasculitis
Authors: Sène Damien , Ghillani‐Dalbin Pascale , Amoura Zahir , Musset Lucile , Cacoub Patrice 
Published: November 2009

AbstractObjectiveTo report on 6 cases of hepatitis C virus (HCV)–induced mixed cryoglobulinemia (MC) vasculitis in patients who developed severe systemic reactions after rituximab infusion, and to report the results of the in vitro analysis of the underlying immunologic mechanisms.MethodsTwenty‐two HCV‐infected patients with MC vasculitis received rituximab infusions (a low‐dose protocol cycle with 375 mg/m2/week for 4 consecutive weeks in 18 patients and a high‐dose protocol cycle with 1,000 mg on days 1 and 15 in 4 patients). Systemic drug reactions following rituximab infusion were recorded and analyzed clinically and immunochemically.ResultsSix of 22 patients (27.3%) experienced systemic drug reactions after rituximab infusion. Four patients developed a severe flare of MC vasculitis 1 or 2 days after rituximab infusion. Two patients developed serum sickness syndrome 7 and 9 days after the first 1,000 mg rituximab infusion. Compared with patients without drug reactions, those with drug reactions had higher mixed cryoglobulin levels (mean ± SD 1.4 ± 0.82 gm/liter versus 0.71 ± 0.77 gm/liter; P = 0.0475) and lower C4 levels (mean ± SD 0.02 ± 0.006 gm/liter versus 0.07 ± 0.07 gm/liter; P = 0.02), and more of them received 1,000 mg high‐dose rituximab protocol (50% versus 6.25%; P = 0.046). In vitro immunochemical assays showed that rituximab formed a complex with the cryoprecipitating IgMκ that had rheumatoid factor (RF) activity. Moreover, the in vitro addition of rituximab to serum containing an RF‐positive IgMκ type II mixed cryoglobulin was associated with visibly accelerated cryoprecipitation.ConclusionIn HCV‐associated MC vasculitis, rituximab may form a complex with RF‐positive IgMκ, leading to accelerated cryoprecipitation and to severe systemic reactions. Rituximab should be administered with caution in MC vasculitis, with use of the 375 mg protocol and plasma exchanges prior to rituximab infusion in patients with high baseline levels of mixed cryoglobulin.
Matrix metalloproteinase 13–deficient mice are resistant to osteoarthritic cartilage erosion but not chondrocyte hypertrophy or osteophyte development
Authors: Little C. B. , Barai A. , Burkhardt D. , Smith S. M. , Fosang A. J. , Werb Z. , Shah M. , Thompson E. W. 
Published: November 2009

AbstractObjectiveTo investigate the role of matrix metalloproteinase 13 (MMP‐13; collagenase 3) in osteoarthritis (OA).MethodsOA was surgically induced in the knees of MMP‐13–knockout mice and wild‐type mice, and mice were compared. Histologic scoring of femoral and tibial cartilage aggrecan loss (0–3 scale), erosion (0–7 scale), and chondrocyte hypertrophy (0–1 scale), as well as osteophyte size (0–3 scale) and maturity (0–3 scale) was performed. Serial sections were stained for type X collagen and the MMP‐generated aggrecan neoepitope DIPEN.ResultsFollowing surgery, aggrecan loss and cartilage erosion were more severe in the tibia than femur (P < 0.01) and tibial cartilage erosion increased with time (P < 0.05) in wild‐type mice. Cartilaginous osteophytes were present at 4 weeks and underwent ossification, with size and maturity increasing by 8 weeks (P < 0.01). There was no difference between genotypes in aggrecan loss or cartilage erosion at 4 weeks. There was less tibial cartilage erosion in knockout mice than in wild‐type mice at 8 weeks (P < 0.02). Cartilaginous osteophytes were larger in knockout mice at 4 weeks (P < 0.01), but by 8 weeks osteophyte maturity and size were no different from those in wild‐type mice. Articular chondrocyte hypertrophy with positive type X collagen and DIPEN staining occurred in both wild‐type and knockout mouse joints.ConclusionOur findings indicate that structural cartilage damage in a mouse model of OA is dependent on MMP‐13 activity. Chondrocyte hypertrophy is not regulated by MMP‐13 activity in this model and does not in itself lead to cartilage erosion. MMP‐13 deficiency can inhibit cartilage erosion in the presence of aggrecan depletion, supporting the potential for therapeutic intervention in established OA with MMP‐13 inhibitors.
Joint replacement surgeries among medicare beneficiaries in rural compared with urban areas
Authors: Francis Mark L. , Scaife Steven L. , Zahnd Whitney E. , Cook E. Francis , Schneeweiss Sebastian 
Published: November 2009

AbstractObjectivePeople in rural areas live farther away from hospitals than do people in urban areas. Thus, there is concern that people living in rural areas may be less willing or able to undergo elective surgical procedures. This study was undertaken to determine whether Medicare beneficiaries in rural areas were less likely to have elective total knee or hip replacement surgeries compared with their urban counterparts.MethodsWe performed a cross‐sectional study of Medicare beneficiaries, controlling for age, sex, race/ethnicity, and economic status. Beneficiaries were assigned to rural versus urban areas based on their zip code of residence and the 10‐point Rural‐Urban Commuting Area designation. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated.ResultsCompared with urban beneficiaries, rural beneficiaries were 27% more likely to have total knee or hip replacement surgeries (OR 1.27 [95% CI 1.26–1.28]). After adjusting for age, sex, race/ethnicity, median household income, average house value, mean poverty ratio, and state of residence, rural beneficiaries were still 14% more likely to have total joint replacement surgeries (OR 1.14 [95% CI 1.13–1.16]). Differential use of surgery before and after receiving Medicare eligibility did not explain the findings. While significant sex, racial, and ethnic disparities were present in both rural and urban areas, for the most part these disparities were ameliorated rather than accentuated in rural areas.ConclusionContrary to expectations, our findings indicate that Medicare beneficiaries living in rural areas are more likely to undergo total knee or hip replacement surgeries.
Inflammatory arthritis in caspase 1 gene–deficient mice: Contribution of proteinase 3 to caspase 1–independent production of bioactive interleukin‐1β
Authors: Joosten Leo A. B. , Netea Mihai G. , Fantuzzi Giamila , Koenders Marije I. , Helsen Monique M. A. , Sparrer Helmut , Pham Christine T. , van der Meer Jos W. M. , Dinarello Charles A. , van den Berg Wim B. 
Published: November 2009

AbstractObjectiveCaspase 1, a known cysteine protease, is a critical component of the inflammasome. Both caspase 1 and neutrophil serine proteases such as proteinase 3 (PR3) can process pro–interleukin‐1β (proIL‐1β), a crucial cytokine linked to the pathogenesis of rheumatoid arthritis. This study was undertaken to establish the relative importance of caspase 1 and serine proteases in mouse models of acute and chronic inflammatory arthritis.MethodsAcute and chronic arthritis were induced in caspase 1−/− mice, and the lack of caspase 1 was investigated for its effects on joint swelling, cartilage metabolism, and histopathologic features. In addition, caspase 1 activity was inhibited in mice lacking active cysteine proteases, and the effects of dual blockade of caspase 1 and serine proteases on arthritis severity and histopathologic features were evaluated.ResultsSurprisingly, caspase 1−/− mice, in a model of acute (neutrophil‐dominated) arthritis, developed joint swelling to an extent similar to that in wild‐type control mice. Joint fluid concentrations of bioactive IL‐1β were comparable in caspase 1−/− mice and controls. In contrast, induction of chronic arthritis (characterized by minimal numbers of neutrophils) in caspase 1−/− mice led to reduced joint inflammation and less cartilage damage, implying a caspase 1–dependent role in this process. In mice lacking neutrophil serine PR3, inhibition of caspase 1 activity resulted in decreased bioactive IL‐1β concentrations in the synovial tissue and less suppression of chondrocyte anabolic function. In addition, dual blockade of both PR3 and caspase 1 led to protection against cartilage and bone destruction.ConclusionCaspase 1 deficiency does not affect neutrophil‐dominated joint inflammation, whereas in chronic arthritis, the lack of caspase 1 results in reduced joint inflammation and cartilage destruction. These findings suggest that inhibitors of caspase 1 are not able to interfere with the whole spectrum of IL‐1β production, and therefore such inhibitors may be of therapeutic value only in inflammatory conditions in which limited numbers of neutrophils are present.
Do mothers and fathers hold similar views about their child's arthritis?
Authors: Mulligan Kathleen , Etheridge Angela , Kassoumeri Laura , Wedderburn Lucy R. , Newman Stanton 
Published: November 2009

AbstractObjectiveEvaluations of the well‐being of children with juvenile idiopathic arthritis (JIA) typically rely on parents as proxy respondents. An assumption of several studies appears to be that mothers' and fathers' ratings are interchangeable, as reports do not always specify which parent completed the assessments nor, in repeated measures, whether they were completed by the same parent. The aim of this study was to examine the level of agreement between mothers' and fathers' ratings of their child's quality of life (QOL) and to identify possible predictors of disagreement.MethodsMothers and fathers (n = 82) of children with JIA completed ratings of their child's symptoms, QOL, and measures of their mood and beliefs about their child's illness and treatment. The number of active and limited joints and the physician's global assessment were also recorded.ResultsIntraclass correlation coefficients between mothers' and fathers' ratings of physical and psychosocial QOL were high (0.824 and 0.755, respectively). However, calculation of difference scores revealed that 70.6% and 65.9%, respectively, were classified as discordant. Where parents differed, the direction of difference was not systematic. Discordance in parents' mood states and in their illness and treatment beliefs explained a small amount of the variance in discordance in QOL.ConclusionIt should not be assumed that proxy ratings of a child's well‐being can be generalized from one parent to the other. Studies that take repeated assessments should ensure that the same parent completes assessments at all time points. Other factors that may explain discordance between parents' ratings need to be explored.
Neurologic outcome of surgical and conservative treatment of rheumatoid cervical spine subluxation: A systematic review
Authors: Wolfs Jasper F. C. , Kloppenburg Margreet , Fehlings Michael G. , van Tulder Maurits W. , Boers Maarten , Peul Wilco C. 
Published: November 2009

AbstractObjectiveRheumatoid arthritis commonly involves the upper cervical spine and can cause significant neurologic morbidity and mortality. However, there is no consensus on the optimal timing for surgical intervention: whether surgery should be performed prophylactically or once neurologic deficits have become apparent.MethodsA systematic review of the literature was performed to analyze neurologic outcome (Ranawat) and survival time (Kaplan‐Meier) after surgical or conservative treatment using the MOOSE (Meta‐analysis Of Observational Studies in Epidemiology) and GRADE (Grading of Recommendations, Assessment, Development and Evaluation system) criteria.ResultsTwenty‐five observational studies were selected. No randomized controlled trials (RCTs) could be found. All of the studies had a high risk of bias. Twenty‐three studies reported the neurologic outcome after surgery for 752 patients. Neurologic deterioration rarely occurred in Ranawat I and II patients. Ranawat III patients did not fully recover. The 10‐year survival rates were 77%, 63%, 47%, and 30% for Ranawat I, II, IIIA, and IIIB, respectively. The Ranawat IIIB patients had a significantly worse outcome. Another 185 patients treated conservatively were described in 7 studies. Neurologic deterioration rarely occurred in Ranawat I patients, but was almost inevitable in Ranawat II, IIIA, and IIIB patients. The Kaplan‐Meier analysis showed a 10‐year overall survival rate of 40%.ConclusionThere are no RCTs that compared surgery with conservative treatment. In observational studies, surgical neurologic outcomes were better than conservative treatment in all patients with cervical spine involvement, and in asymptomatic patients with no neurologic impairment (Ranawat I) the outcomes were similar; however, the evidence is weak. Survival time of surgical and conservative treatment could not be compared.