bluuebunny/crossref_metadata_2025_split huggingface dataset:
Effects of teriparatide versus alendronate for treating glucocorticoid‐induced osteoporosis: Thirty‐six–month results of a randomized, double‐blind, controlled trial
Authors: Saag Kenneth G. , Zanchetta Jose R. , Devogelaer Jean‐Pierre , Adler Robert A. , Eastell Richard , See Kyoungah , Krege John H. , Krohn Kelly , Warner Margaret R. 
Published: October 2009

AbstractObjectiveTo compare the bone anabolic drug teriparatide (20 μg/day) with the antiresorptive drug alendronate (10 mg/day) for treating glucocorticoid‐induced osteoporosis (OP).MethodsThis was a 36‐month, randomized, double‐blind, controlled trial in 428 subjects with OP (ages 22–89 years) who had received ≥5 mg/day of prednisone equivalent for ≥3 months preceding screening. Measures included changes in lumbar spine and hip bone mineral density (BMD), changes in bone biomarkers, fracture incidence, and safety.ResultsIncreases in BMD from baseline were significantly greater in the teriparatide group than in the alendronate group, and at 36 months were 11.0% versus 5.3% for lumbar spine, 5.2% versus 2.7% for total hip, and 6.3% versus 3.4% for femoral neck (P < 0.001 for all). In the teriparatide group, median percent increases from baseline in N‐terminal type I procollagen propeptide (PINP) and osteocalcin (OC) levels were significant from 1 to 36 months (P < 0.01), and increases in levels of C‐terminal telopeptide of type I collagen (CTX) were significant from 1 to 6 months (P < 0.01). In the alendronate group, median percent decreases in PINP, OC, and CTX were significant by 6 months and remained below baseline through 36 months (P < 0.001). Fewer subjects had vertebral fractures in the teriparatide group than in the alendronate group (3 [1.7%] of 173 versus 13 [7.7%] of 169; P = 0.007), with most occurring during the first 18 months. There was no significant difference between groups in the incidence of nonvertebral fractures (16 [7.5%] of 214 subjects taking teriparatide versus 15 [7.0%] of 214 subjects taking alendronate; P = 0.843). More subjects in the teriparatide group (21%) versus the alendronate group (7%) had elevated predose serum calcium concentrations (P < 0.001).ConclusionOur findings indicate that subjects with glucocorticoid‐induced OP treated with teriparatide for 36 months had greater increases in BMD and fewer new vertebral fractures than subjects treated with alendronate.
Gadd45β deficiency in rheumatoid arthritis: Enhanced synovitis through JNK signaling
Authors: Svensson Camilla I. , Inoue Tomoyuki , Hammaker Deepa , Fukushima Akihisa , Papa Salvatore , Franzoso Guido , Schett Georg , Corr Maripat , Boyle David L. , Firestein Gary S. 
Published: October 2009

AbstractObjectiveJNK‐mediated cell signaling plays a critical role in matrix metalloproteinase (MMP) expression and joint destruction in rheumatoid arthritis (RA). Gadd45β, which is an NF‐κB–regulated gene, was recently identified as an endogenous negative regulator of the JNK pathway, since it could block the upstream kinase MKK‐7. This study was carried out to evaluate whether low Gadd45β expression in RA enhances JNK activation and overproduction of MMPs in RA, and whether Gadd45β deficiency increases arthritis severity in passive K/BxN murine arthritis.MethodsActivation of the NF‐κB and JNK pathways and Gadd45β expression were analyzed in human synovium and fibroblast‐like synoviocytes (FLS) using quantitative polymerase chain reaction, immunoblotting, immunohistochemistry, electrophoretic mobility shift assay, and luciferase reporter constructs. Gadd45β−/−and wild‐type mice were evaluated in the K/BxN serum transfer model of inflammatory arthritis, and clinical signs of arthritis, osteoclast formation, and bone erosion were assessed.ResultsExpression levels of the Gadd45β gene and protein were unexpectedly low in human RA synovium despite abundant NF‐κB activity. Forced Gadd45β expression in human FLS attenuated tumor necrosis factor–induced signaling through the JNK pathway, reduced the activation of activator protein 1, and decreased the expression of MMP genes. Furthermore, Gadd45β deficiency exacerbated K/BxN serum–induced arthritis in mice, dramatically increased signaling through the JNK pathway, elevatedMMP3andMMP13gene expression in the mouse joints, and increased the synovial inflammation and number of osteoclasts.ConclusionDeficient Gadd45β expression in RA can contribute to activation of JNK, exacerbate clinical arthritis, and augment joint destruction. This process can be mitigated by enhancing Gadd45β expression or by inhibiting the activity of JNK or its upstream regulator, MKK‐7.
Medical decision making in patients with knee pain, meniscal tear, and osteoarthritis
Authors: Suter Lisa G. , Fraenkel Liana , Losina Elena , Katz Jeffrey N. , Gomoll Andreas H. , Paltiel A. David 
Published: October 2009

AbstractObjectiveMeniscal tears and osteoarthritis (OA) frequently coexist, but to our knowledge, no data exist to identify who will benefit from arthroscopic partial meniscectomy (APM) versus nonoperative management. Our objective was to evaluate the capability of preoperative information to predict APM outcomes in OA.MethodsUsing a mathematical model and published data, we combined 2 clinical (mechanical symptoms and pain pattern) and 2 magnetic resonance imaging (tear type and bone marrow lesions) indicators into 36 possible combinations and ranked each combination according to the likelihood of having primarily tear‐ versus OA‐related pain in individuals ages 45–65 years with knee pain, OA, and meniscal tears. By considering alternative thresholds for performing APM, we identified the cutoff rank that maximized the overall population International Knee Documentation Committee (IKDC) score (0–100 scale).ResultsRank 1 (e.g., displaced tear, locking, increased pain, no bone marrow lesions) represented the highest likelihood of APM benefit; rank 36 (e.g., oblique tear, no mechanical symptoms, static pain, severe bone marrow lesions) represented the lowest likelihood of APM benefit. Indeterminate middle ranks included individuals with mixed findings (i.e., 2 findings consistent with high and 2 with low likelihood of APM benefit). APM thresholds between ranks 17 and 23 resulted in >82% of the population receiving treatment producing the greatest possible IKDC improvement, with mean incremental gains in IKDC score of >24 points. Findings were robust across a broad range of indicator assumptions, but were sensitive to outcome assumptions.ConclusionAmong individuals with degenerative meniscal tears and OA, easily obtainable clinical information can differentiate those who are more likely to benefit from APM.
Progressive multifocal leukoencephalopathy following rituximab treatment in a patient with rheumatoid arthritis
Authors: Fleischmann R. M. 
Published: October 2009

AbstractProgressive multifocal leukoencephalopathy (PML) is a rare brain disease caused by reactivation of the JC virus. Herein, a case of PML in association with rituximab treatment in a patient with chronic rheumatoid arthritis (RA) and Sjögren's syndrome is described. The patient received 4 courses of rituximab (2 1,000‐mg infusions administered 2 weeks apart) over a period of ∼40 months, during a phase III trial and safety extension study. PML was diagnosed ∼18 months after the last rituximab course, and the patient died 1 month later. Determination of the cause of PML was confounded by the fact that the patient had developed oropharyngeal cancer, which was treated with chemoradiotherapy, 9 months prior to the development of PML. Although there was no direct evidence that linked rituximab to the development of PML, this case highlights the need to consider a diagnosis of PML in patients with RA who have been treated with rituximab and who subsequently develop new neurologic symptoms.
Impaired myofibrillar function in the soleus muscle of mice with collagen‐induced arthritis
Authors: Yamada Takashi , Place Nicolas , Kosterina Natalia , Östberg Therese , Zhang Shi‐Jin , Grundtman Cecilia , Erlandsson‐Harris Helena , Lundberg Ingrid E. , Glenmark Birgitta , Bruton Joseph D. , Westerblad Håkan 
Published: October 2009

AbstractObjectiveProgressive muscle weakness is a common feature in patients with rheumatoid arthritis (RA). However, little is known about whether the intrinsic contractile properties of muscle fibers are affected in RA. This study was undertaken to investigate muscle contractility and the myoplasmic free Ca2+ concentration ([Ca2+]i) in the soleus, a major postural muscle, in mice with collagen‐induced arthritis (CIA).MethodsMuscle contractility and [Ca2+]i were assessed in whole muscle and intact single‐fiber preparations, respectively. The underlying mechanisms of contractile dysfunction were assessed by investigating redox modifications using Western blotting and antibodies against nitric oxide synthase (NOS), superoxide dismutase (SOD), 3‐nitrotyrosine (3‐NT), carbonyl, malondialdehyde (MDA), and S‐nitrosocysteine (SNO‐Cys).ResultsThe tetanic force per cross‐sectional area was markedly decreased in the soleus muscle of mice with CIA, and the change was not due to a decrease in the amplitude of [Ca2+]i transients. The reduction in force production was accompanied by slowing of the twitch contraction and relaxation and a decrease in the maximum shortening velocity. Immunoblot analyses showed a marked increase in neuronal NOS expression but not in inducible or endothelial NOS expression, which, together with the observed decrease in SOD2 expression, favors peroxynitrite formation. These changes were accompanied by increased 3‐NT, carbonyl, and MDA adducts content in myofibrillar proteins from the muscles of mice with CIA. Moreover, there was a significant increase in SNO‐Cys content in myosin heavy‐chain and troponin I myofibrillar proteins from the soleus muscle of mice with CIA.ConclusionThese findings show impaired contractile function in the soleus muscle of mice with CIA and suggest that this abnormality is due to peroxynitrite‐induced modifications in myofibrillar proteins.
Association of higher rheumatoid arthritis disease activity during pregnancy with lower birth weight: Results of a national prospective study
Authors: de Man Yaël A. , Hazes Johanna M. W. , van der Heide Hugo , Willemsen Sten P. , de Groot Christianne J. M. , Steegers Eric A. P. , Dolhain Radboud J. E. M. 
Published: October 2009

AbstractObjectiveTo determine the outcome of pregnancy in women with rheumatoid arthritis (RA) in relation to disease activity and medication use during the pregnancy.MethodsIn a prospective study, pregnant women with RA were evaluated before conception (when possible), during each trimester of the pregnancy, and postpartum. Clinical characteristics, disease activity, medication use, and pregnancy outcome were analyzed. To examine the independent influence of prednisone use and disease activity on birth weight, regression analyses were performed, with adjustments for gestational age of the child at delivery, the sex of the newborn, and the mother's smoking status, education level, parity, and use of an assisted reproduction technique. Kaplan‐Meier curve analyses were performed to examine the association between medication use and gestational age at delivery.ResultsData from 152 Caucasian RA patients with singleton pregnancies were available. Both the mean ± SD birth weight (3,379 ± 564 gm) and the mean ± SD birth weight standard deviation score (SDS; +0.1 ± 1.1), which is the birth weight adjusted for the gestational age and sex of the newborn, were comparable with those in the general population. On multiple linear regression analyses of birth weight and birth weight SDS, both of which were adjusted for covariates, only disease activity was associated with lower birth weight (P = 0.025). The gestational age at delivery was significantly lower in women who were taking prednisone (38.8 versus 39.9 weeks; P = 0.001), and their delivery was more often premature (<37 weeks; P = 0.004).ConclusionPregnancy outcome in women with well‐controlled RA is comparable with that in the general population. The effect of prednisone on birth weight is mediated by a lower gestational age at delivery, whereas a higher level of disease activity independently influences birth weight negatively, suggesting an immune‐mediated mechanism.
A novel inhibitor of Smad‐dependent transcriptional activation suppresses tissue fibrosis in mouse models of systemic sclerosis
Authors: Hasegawa Minoru , Matsushita Yukiyo , Horikawa Mayuka , Higashi Kiyoshi , Tomigahara Yoshitaka , Kaneko Hideo , Shirasaki Fumiaki , Fujimoto Manabu , Takehara Kazuhiko , Sato Shinichi 
Published: October 2009

AbstractObjectiveTissue fibrosis is a major cause of morbidity and mortality in systemic sclerosis (SSc), and an increasing number of promising molecular targets for antifibrotic therapies have been described recently. Transforming growth factor β (TGFβ) is well known to be the principal factor that leads to tissue fibrosis. The present study was undertaken to investigate the ability of HSc025, a novel small compound that antagonizes TGFβ/Smad signaling through the activation of nuclear translocation of Y‐box binding protein 1, to prevent tissue fibrosis in vitro or in mouse models of SSc.MethodsHuman dermal fibroblasts were exposed to HSc025 at various concentrations in the presence of TGFβ, and levels of collagen or fibronectin expression were determined. HSc025 (15 mg/kg/day for 14 days) was administered orally to tight skin mice and to mice with bleomycin‐induced pulmonary fibrosis. Improvement of tissue fibrosis was evaluated by histologic or biochemical examination in each model.ResultsPretreatment with HSc025 prevented Smad‐dependent promoter activation, in a dose‐dependent manner; however, HSc025 had no effect on TGFβ‐induced phosphorylation of Smad3. The inhibitory effects of HSc025 on TGFβ‐induced collagen or fibronectin expression were also confirmed in vitro. Orally administered HSc025 significantly reduced hypodermal thickness and hydroxyproline content in tight skin mice, and markedly decreased the histologic score and hydroxyproline content in the lungs of bleomycin‐treated mice.ConclusionThese results demonstrate that HSc025 is a novel inhibitor of TGFβ/Smad signaling, resulting in the improvement of skin and pulmonary fibrosis. Orally available HSc025 might therefore be useful in the treatment of SSc.
Dabigatran, a direct thrombin inhibitor, demonstrates antifibrotic effects on lung fibroblasts
Authors: Bogatkevich Galina S. , Ludwicka‐Bradley Anna , Silver Richard M. 
Published: October 2009

AbstractObjectiveMyofibroblasts are the principal mesenchymal cells responsible for tissue remodeling, collagen deposition, and the restrictive nature of lung parenchyma associated with pulmonary fibrosis. We previously reported that thrombin activates protease‐activated receptor 1 (PAR‐1) and induces a myofibroblast phenotype in normal lung fibroblasts resembling the phenotype of scleroderma lung myofibroblasts. We undertook this study to investigate whether a selective direct thrombin inhibitor, dabigatran, interferes with signal transduction in human lung fibroblasts induced by thrombin and mediated via PAR‐1.MethodsLung fibroblast proliferation was analyzed using the Quick Cell Proliferation Assay. Expression and organization of α‐smooth muscle actin (α‐SMA) was studied by immunofluorescence staining and immunoblotting. Contractile activity of lung fibroblasts was measured by a collagen gel contraction assay. Connective tissue growth factor (CTGF) and type I collagen expression was analyzed on Western blots.ResultsDabigatran, at concentrations of 50–1,000 ng/ml, inhibited thrombin‐induced cell proliferation, α‐SMA expression and organization, and the production of collagen and CTGF in normal lung fibroblasts. Moreover, when treated with dabigatran (1 μg/ml), scleroderma lung myofibroblasts produced 6‐fold less α‐SMA, 3‐fold less CTGF, and 2‐fold less type I collagen compared with untreated cells.ConclusionDabigatran restrains important profibrotic events in lung fibroblasts and warrants study as a potential antifibrotic drug for the treatment of fibrosing lung diseases such as scleroderma lung disease and idiopathic pulmonary fibrosis.
Distinct subtypes of myelitis in systemic lupus erythematosus
Authors: Birnbaum J. , Petri M. , Thompson R. , Izbudak I. , Kerr D. 
Published: October 2009

AbstractObjectiveMyelitis causes pain, weakness, and sphincteric deficits, and is 1,000‐fold more prevalent in patients with systemic lupus erythematosus (SLE) than in the general population. For the last century, descriptions of SLE myelitis have been primarily limited to case reports. In contrast, larger‐scale cohort studies have revealed that myelitis occurring in the idiopathic demyelinating diseases (i.e., multiple sclerosis versus neuromyelitis optica) represents distinct syndromes. This study was undertaken to determine whether SLE myelitis similarly encapsulates distinct syndromes.MethodsWe analyzed a cohort of 22 patients with SLE and myelitis. Patients were assessed for neurologic variables related to myelitis and for clinical and serologic features of SLE. Magnetic resonance images of the spine, cerebrospinal fluid profiles, and autoantibody profiles were obtained.ResultsEleven patients presented with signs of gray matter dysfunction (i.e., flaccidity and hyporeflexia), whereas 11 patients presented with signs of white matter dysfunction (i.e., spasticity and hyperreflexia). Patients with gray matter dysfunction were more likely to have irreversible paraplegia (P< 0.01), despite presenting with a monophasic versus polyphasic course (P= 0.01), higher levels of SLE activity (mean SLE Disease Activity Index 9.8 versus 2.0;P= 0.01), and a cerebrospinal fluid profile indistinguishable from bacterial meningitis. Prior to irreversible paraplegia, these patients presented with prodromes of fever and urinary retention, but were misdiagnosed by physicians of different specialties as having urinary tract infections. Patients with white matter dysfunction were more likely to meet criteria for neuromyelitis optica (P= 0.04) and were also more likely to have antiphospholipid antibodies (lupus anticoagulant) (P= 0.01).ConclusionOur findings indicate that SLE myelitis encapsulates 2 distinct and previously unrecognized syndromes that can be distinguished clinically by gray matter versus white matter findings. Recognition of fever and urinary retention as prodromes of irreversible paraplegia may allow earlier diagnosis and treatment in SLE patients presenting with gray matter findings.
Role of the urate transporter SLC2A9 gene in susceptibility to gout in New Zealand Māori, Pacific Island, and Caucasian case–control sample sets
Authors: Hollis‐Moffatt Jade E. , Xu Xin , Dalbeth Nicola , Merriman Marilyn E. , Topless Ruth , Waddell Chloe , Gow Peter J. , Harrison Andrew A. , Highton John , Jones Peter B. B. , Stamp Lisa K. , Merriman Tony R. 
Published: October 2009

AbstractObjectiveTo examine the role of genetic variation in the renal urate transporter SLC2A9 in gout in New Zealand sample sets of Māori, Pacific Island, and Caucasian ancestry and to determine if the Māori and Pacific Island samples could be useful for fine‐mapping.MethodsPatients (n= 56 Māori, 69 Pacific Island, and 131 Caucasian) were recruited from rheumatology outpatient clinics and satisfied the American College of Rheumatology criteria for gout. The control samples comprised 125 Māori subjects, 41 Pacific Island subjects, and 568 Caucasian subjects without arthritis. SLC2A9 single‐nucleotide polymorphisms rs16890979 (V253I), rs5028843, rs11942223, and rs12510549 were genotyped (possible etiologic variants in Caucasians).ResultsAssociation of the major allele of rs16890979, rs11942223, and rs5028843 with gout was observed in all sample sets (P = 3.7 × 10−7, 1.6 × 10−6, and 7.6 × 10−5 for rs11942223 in the Māori, Pacific Island, and Caucasian samples, respectively). One 4‐marker haplotype (1/1/2/1; more prevalent in the Māori and Pacific Island control samples) was not observed in a single gout case.ConclusionOur data confirm a role of SLC2A9 in gout susceptibility in a New Zealand Caucasian sample set, with the effect on risk (odds ratio >2.0) greater than previous estimates. We also demonstrate association of SLC2A9 with gout in samples of Māori and Pacific Island ancestry and a consistent pattern of haplotype association. The presence of both alleles of rs16890979 on susceptibility and protective haplotypes in the Māori and Pacific Island sample is evidence against a role for this nonsynonymous variant as the sole etiologic agent. More extensive linkage disequilibrium in Māori and Pacific Island samples suggests that Caucasian samples may be more useful for fine‐mapping.
Increased frequency of extremely skewed X chromosome inactivation in juvenile idiopathic arthritis
Authors: Uz Elif , Mustafa Chigdem , Topaloglu Rezan , Bilginer Yelda , Dursun Ali , Kasapcopur Ozgur , Ozen Seza , Bakkaloglu Aysin , Ozcelik Tayfun 
Published: October 2009

AbstractObjectiveJuvenile idiopathic arthritis (JIA) is a childhood rheumatic disease of unknown etiology. Two subgroups of JIA, i.e., oligoarticular and polyarticular, are thought to have an autoimmune component, and show a higher female:male ratio. Skewed X chromosome inactivation (XCI) has previously been shown to be associated with scleroderma and autoimmune thyroiditis, 2 autoimmune disorders occurring predominantly in females. This study was undertaken to extend the analysis to the pediatric age group and to determine the XCI profiles of patients with JIA.MethodsA polymorphic repeat in the androgen receptor gene was genotyped to determine XCI status in 81 female patients with JIA (21 with polyarticular disease and 60 with oligoarticular disease) and 211 healthy female controls. DNA obtained from venous blood samples was used for this analysis.ResultsInformative data were obtained on 62 JIA patients and 155 controls. Skewed XCI was observed in 14 patients (22.6%) and 11 controls (7.1%) (P = 0.0036), and extreme skewing was apparent in 8 patients (12.9%) and 2 controls (1.3%) (P = 0.0008).ConclusionOur findings in the present study indicate that skewed XCI may be a risk factor for the occurrence of autoimmune disorders, including JIA.