bluuebunny/crossref_metadata_2025_split huggingface dataset:
Atacicept in patients with rheumatoid arthritis: Results of a multicenter, phase ib, double‐blind, placebo‐controlled, dose‐escalating, single‐ and repeated‐dose study
Authors: Tak P. P. , Thurlings R. M. , Rossier C. , Nestorov I. , Dimic A. , Mircetic V. , Rischmueller M. , Nasonov E. , Shmidt E. , Emery P. , Munafo A. 
Published: December 2007

AbstractObjectiveAtacicept is a recombinant fusion protein that binds and neutralizes B lymphocyte stimulator and a proliferation‐inducing ligand. The purpose of this study was to investigate the tolerability, pharmacokinetics, and pharmacodynamics of atacicept treatment in patients with rheumatoid arthritis (RA) and to collect exploratory data on clinical outcomes.MethodsIn this multicenter, phase Ib, randomized, placebo‐controlled, dose‐escalating trial, 73 patients were enrolled into 6 escalating‐dose cohorts. Patients received atacicept or placebo as single doses (70, 210, or 630 mg) or as repeated doses given at 2‐week intervals (3 doses of 70 mg, 3 doses of 210 mg, or 7 doses of 420 mg), followed by 10 weeks of trial assessments, with a followup assessment at 3 months after the final dose.ResultsAtacicept was well tolerated, with few differences between treatment groups and no obvious safety concerns. The pharmacokinetics profile was nonlinear, but was consistent and predictable across all doses and regimens. Treatment‐related decreases in immunoglobulin (particularly IgM) and rheumatoid factor levels were evident, and a clear decrease in anti–citrullinated protein antibodies was observed in the cohort that received 7 doses of 420 mg. The B cell response was biphasic, with an initial transient increase (dominated by memory B cells) followed by a dose‐related decrease (dominated by mature B cells). Clinical assessments showed trends toward improvement with the 3‐month treatment. Little effect on the erythrocyte sedimentation rate or C‐reactive protein levels was seen.ConclusionAtacicept was well tolerated both systemically and locally. The results demonstrated that the biologic activity of atacicept was consistent with its mechanism of action.
Glomerular accumulation of plasmacytoid dendritic cells in active lupus nephritis: Role of interleukin‐18
Authors: Tucci Marco , Quatraro Cosima , Lombardi Lucia , Pellegrino Cecilia , Dammacco Franco , Silvestris Franco 
Published: December 2007

AbstractObjectiveDefective circulating dendritic cells (DCs) have been described in systemic lupus erythematosus (SLE) and correlated with high levels of interferon‐α (IFNα). DCs are differentiated as being either myeloid or plasmacytoid, according to chemokine expression and the tendency to migrate toward inflamed tissue. We investigated the potential role of interleukin‐18 (IL‐18) in driving the glomerular migration of DCs in lupus nephritis (LN) and in affecting the ability of DCs to induce an imbalance in the Th1:Th2 ratio.MethodsDC subsets were characterized by flow cytometry and defined as either myeloid or plasmacytoid according to the expression of CD11c/blood dendritic cell antigen 1 (BDCA‐1) and CD123/BDCA‐2, respectively. The serum Th1:Th2 profile was studied by enzyme‐linked immunosorbent assay. IL‐18 receptor (IL‐18R) and other chemokine receptors were analyzed by flow cytometry. Glomerular levels of IL‐18/IL‐18R and the presence of plasmacytoid DCs and myeloid DCs were investigated by immunohistochemical analysis.ResultsThe number of peripheral plasmacytoid DCs was decreased in patients with SLE compared with control subjects, and this defect in the number of DCs was correlated with LN. Patients with LN showed a prevalent Th1 response, with high production of IL‐18, IL‐12 and IFNγ. Only plasmacytoid DCs expressed IL‐18R. Patients with severe LN showed a high accumulation of IL‐18 within glomeruli in association with the presence of plasmacytoid DCs, whereas myeloid DCs were almost absent.ConclusionA deficient number of peripheral plasmacytoid DCs correlated with high levels of Th1 cytokines and was associated with LN. Both serum and glomerular IL‐18 were increased in LN. It is suggested that the high level of expression of IL‐18R by peripheral plasmacytoid DCs allows the DCs to relocate within glomeruli under IL‐18 stimulation and triggers the resident T cells, thus promoting renal damage.
High N‐terminal pro–brain natriuretic peptide levels and low diffusing capacity for carbon monoxide as independent predictors of the occurrence of precapillary pulmonary arterial hypertension in patients with systemic sclerosis
Authors: Allanore Y. , Borderie D. , Avouac J. , Zerkak D. , Meune C. , Hachulla E. , Mouthon L. , Guillevin L. , Meyer O. , Ekindjian O. G. , Weber S. , Kahan A. 
Published: December 2007

AbstractObjectiveTo evaluate predictors of pulmonary arterial hypertension (PAH) in a prospective cohort of patients with systemic sclerosis (SSc).MethodsRoutine clinical assessments as well as measurements of the diffusing capacity for carbon monoxide/alveolar volume (DLCO/VA) ratio and N‐terminal pro–brain natriuretic peptide (NT‐proBNP) level were performed in a prospective cohort of 101 SSc patients who did not have PAH or severe comorbidities. After a planned 36‐month followup, we evaluated the predictive value of these parameters for the development of precapillary PAH, as demonstrated by cardiac catheterization, disease progression, and death. Criteria for cardiac catheterization were a systolic pulmonary artery pressure (PAP) of >40 mm Hg on echocardiography, a DLCO value of <50% without pulmonary fibrosis, and unexplained dyspnea.ResultsEight patients developed PAH, 29 had disease progression, and 10 died during a median followup of 29 months. Kaplan‐Meier analysis identified the following baseline parameters as being predictors of PAH: DLCO/VA ratio <70% or <60% (P < 0.01 for each comparison), elevated plasma NT‐proBNP level (>97th percentile of normal; P = 0.005), echocardiographically estimated systolic PAP >40 mm Hg (P = 0.08), and erythrocyte sedimentation rate >28 mm/hour (P = 0.015). In multivariate analyses, an elevated baseline NT‐proBNP level (hazard ratio [HR] 9.97 [95% confidence interval (95% CI) 1.69–62.42]) and a DLCO/VA ratio <60% (HR 36.66 [95% CI 3.45–387.6]) were predictors of the occurrence of PAH during followup. An increased NT‐proBNP level together with a decreased DLCO/VA ratio of <70% was highly predictive of the occurrence of PAH during followup (HR 47.20 [95% CI 4.90–450.33]).ConclusionThis prospective study identified a decreased DLCO/VA ratio and an increased NT‐proBNP as predictors of PAH in SSc. Use of these markers should result in improved PAH risk stratification and allow earlier initiation of therapy.
Antibodies against citrullinated vimentin in rheumatoid arthritis: Higher sensitivity and extended prognostic value concerning future radiographic progression as compared with antibodies against cyclic citrullinated peptides
Authors: Mathsson Linda , Mullazehi Mohammed , Wick Marius C. , Sjöberg Olof , van Vollenhoven Ronald , Klareskog Lars , Rönnelid Johan 
Published: December 2007

AbstractObjectiveThe Sa autoantigen can be found in inflamed synovium of patients with rheumatoid arthritis (RA), and at least part of the humoral RA‐specific anti‐Sa response is directed against citrullinated vimentin. This study was undertaken to evaluate the sensitivity, specificity, and prognostic value of determination of levels of antibodies against modified citrullinated vimentin (anti‐MCV) as compared with antibodies against cyclic citrullinated peptides (anti‐CCP) in an inception cohort of patients with early RA.MethodsClinical data, radiographs, and measurements of levels of anti‐MCV and anti‐CCP antibodies were obtained in 273 patients with early RA at baseline, after 3 months, and after 1, 2, 3, and 5 years. Autoantibodies were also analyzed in 100 healthy controls.ResultsOf the 273 patients, 193 (70.7%) were anti‐MCV positive and 158 (57.9%) were anti‐CCP positive at the time of diagnosis, with nearly equal specificities (95% and 96%, respectively). Forty (14.7%) were anti‐MCV positive only, and 5 (1.8%) were anti‐CCP positive only. Anti‐MCV–positive and anti‐MCV–negative patients had similar disease activity at baseline, but presence of anti‐MCV was predictive of subsequent high disease activity and continued radiographic progression. Changes in anti‐MCV level showed stronger correlation with changes in clinical parameters than did changes in anti‐CCP level. The subgroup of patients who were anti‐MCV positive and anti‐CCP negative showed a higher rate of radiographic destruction than did patients who were negative for both anti‐MCV and anti‐CCP.ConclusionThese findings show that when patients with early RA are compared with healthy controls, analysis of anti‐MCV yields greater sensitivity and unchanged specificity as compared with analysis of anti‐CCP. Anti‐MCV also appears to perform better than anti‐CCP in identifying poor radiographic prognosis in patients with early RA.
Amphipathic weak acid glucocorticoid prodrugs remote‐loaded into sterically stabilized nanoliposomes evaluated in arthritic rats and in a Beagle dog: A novel approach to treating autoimmune arthritis
Authors: Avnir Yuval , Ulmansky Rina , Wasserman Veronica , Even‐Chen Simcha , Broyer Maya , Barenholz Yechezkel , Naparstek Yaakov 
Published: December 2007

AbstractObjectiveThe use of glucocorticoids (GCs) in rheumatoid arthritis is limited by side effects related to unfavorable pharmacokinetics and biodistribution. Liposomal GC formulations have been studied since the 1970s in an attempt to overcome this obstacle, but none has entered clinical use. We undertook this study to determine whether a novel approach could overcome the limitations that have thus far prevented the clinical use of these formulations: low drug:lipid ratio, low encapsulation efficiency, and lack of controlled release.MethodsWe used ∼80‐nm sterically stabilized (pegylated) nanoliposomes (NSSLs), which were remote‐loaded with an amphipathic weak acid GC (such as methyl prednisolone hemisuccinate) utilizing an intraliposome (aqueous compartment)–high/extraliposome (bulk medium)–low transmembrane calcium acetate gradient. This unique method actually “traps” the GC in the liposomal aqueous phase as a calcium–GC precipitate.ResultsOur liposome formulation exhibited high encapsulation efficiency (94%) and a high drug:lipid mole ratio (0.41) and demonstrated controlled release of the encapsulated GC during systemic circulation and in inflamed paws in rats with adjuvant‐induced arthritis. In addition, both in arthritic rats and in a Beagle dog, we showed the pharmacokinetic advantage of using liposomes as GC carriers. Finally, we demonstrated the superior therapeutic efficacy of our liposome formulation over that of free GCs in arthritic rats, both in early and in peak disease stages.ConclusionAmphipathic weak acid GCs remote‐loaded into ∼80‐nm NSSLs overcome past limitations of liposomal GC formulations. The unique loading method, which also leads to controlled release, improves the therapeutic effect both systemically and locally. Such a development has great potential for improving GC therapy.
Early‐onset degeneration of the intervertebral disc and vertebral end plate in mice deficient in type IX collagen
Authors: Boyd Lawrence M. , Richardson William J. , Allen Kyle D. , Flahiff Charlene , Jing Liufang , Li Yefu , Chen Jun , Setton Lori A. 
Published: December 2007

AbstractObjectiveType IX collagen is an important component of the intervertebral disc extracellular matrix. Mutations in type IX collagen are associated with premature disc degeneration in mice and a predisposition to disc disorders in humans. The aim of this study was to assess the prevalence and timeline of intervertebral disc degeneration in mice homozygous for an inactivated Col9a1 gene.MethodsIntact spine segments were harvested from wild‐type (WT) and type IX collagen–knockout (Col9a1−/−) mice at 3, 6, and 12 months of age. Sagittal spine sections were evaluated for evidence of histologic changes, by 2 blinded graders, using a semiquantitative grading method.ResultsThere was evidence of more degeneration of the disc and end plate in the spines of Col9a1−/− mice compared with those of WT controls, at most time points. These findings were significant for the disc region at 3 and 6 months (P < 0.01) and at 12 months (P < 0.10) and for the end plate region only at 6 months (P < 0.10). Degenerative changes in the disc consisted of cellular changes and mucous degeneration. Degeneration in the end plates was associated with more cell proliferation, cartilage disorganization, and new bone formation.ConclusionA deletion mutation for type IX collagen is associated with connective tissue changes characteristic of musculoskeletal degeneration in bony and cartilaginous tissue regions. Some of the observed changes were similar to cartilage changes in osteoarthritis, while others were more similar to disc degenerative changes in humans. The finding of premature onset of intervertebral disc degeneration in this mouse model may be useful in studies of the pathology and treatment of human disc degeneration.
Uridine supplementation antagonizes zidovudine‐induced mitochondrial myopathy and hyperlactatemia in mice
Authors: Lebrecht Dirk , Deveaud Catherine , Beauvoit Bertrand , Bonnet Jacques , Kirschner Janbernd , Walker Ulrich A. 
Published: December 2007

AbstractObjectiveZidovudine is an antiretroviral nucleoside analog reverse transcriptase inhibitor that induces mitochondrial myopathy by interfering with the replication of mitochondrial DNA (mtDNA). Because zidovudine inhibits thymidine kinases, the mechanism of mtDNA depletion may be related to an impairment of the de novo synthesis of pyrimidine nucleotides, which are required building blocks of mtDNA. This study was undertaken to determine whether mitochondrial myopathy is a class effect of antiretroviral nucleoside analogs, and whether the muscle disease can be prevented by treatment with uridine as a pyrimidine nucleotide precursor.MethodsBALB/c mice were treated with zidovudine or zalcitabine. Some of the mice were cotreated with mitocnol, a dietary supplement with high uridine bioavailability. Mice hind limb muscles were examined after 10 weeks.ResultsZidovudine induced muscle fiber thinning, myocellular fat deposition, and abnormalities of mitochondrial ultrastructure. In mice treated with zidovudine, organelles contained low mtDNA copy numbers and reduced cytochrome c oxidase activity. The expression of the mtDNA‐encoded cytochrome c oxidase I subunit, but not of nucleus‐encoded mitochondrial proteins, was impaired. Zidovudine also increased the levels of myocellular reactive oxygen species and blood lactate. Uridine supplementation attenuated or normalized all pathologic abnormalities and had no intrinsic effects. Zalcitabine did not elicit muscle toxicity.ConclusionOur findings indicate that zidovudine, but not zalcitabine, induces mitochondrial myopathy, which is substantially antagonized by uridine supplementation. These results provide proof of the importance of pyrimidine pools in the pathogenesis of zidovudine myopathy. Since uridine supplementation is tolerated well by humans, this treatment strategy should be investigated in clinical trials.
Index to ring finger length ratio and the risk of osteoarthritis
Authors: Zhang W. , Robertson J. , Doherty S. , Liu J. J. , Maciewicz R. A. , Muir K. R. , Doherty M. 
Published: December 2007

AbstractObjectiveTo determine the relationship between the index to ring finger (2D:4D) length ratio and the risk of knee and hip osteoarthritis (OA).MethodsWe conducted a case–control study, in which cases with persistent symptoms and radiographic evidence of knee or hip OA were compared with controls with no symptoms and no radiographic evidence of knee or hip OA. Hand radiographs were visually classified as type 1 (index finger longer than the ring finger), type 2 (index finger equal to the ring finger), or type 3 (index finger shorter than the ring finger). The 2D:4D phalangeal and metacarpal length ratios were measured separately. The odds ratio (OR) and 95% confidence interval (95% CI) were calculated and adjusted for possible confounding factors using a logistic regression model.ResultsOf 2,049 cases, 1,013 had radiographic evidence of knee OA and 995 had hip OA. Of 1,123 controls, 836 had no knee OA and 1,050 had no hip OA. The type 3 finger pattern was associated with knee OA (OR 1.94, 95% CI 1.54–2.44), and the risk was greater in women (OR 3.05, 95% CI 2.08–4.47) than in men (OR 1.45, 95% CI 1.08–1.95). There was a dose‐response relationship between both 2D:4D phalangeal and metacarpal length ratios and the risk of knee OA. The risk of hip OA was inconsistent.ConclusionCompared with types 1 and 2, the type 3 “male” pattern 2D:4D length ratio is associated with OA, especially knee OA. The risk is independent of other major OA risk factors.
A randomized controlled trial of the people with arthritis can exercise program: Symptoms, function, physical activity, and psychosocial outcomes
Authors: Callahan Leigh F. , Mielenz Thelma , Freburger Janet , Shreffler Jack , Hootman Jennifer , Brady Teresa , Buysse Katherine , Schwartz Todd 
Published: December 2007

AbstractObjectiveTo evaluate the basic 8‐week People with Arthritis Can Exercise (PACE) program for improvements in primary (symptoms, functioning, level of physical activity) and secondary (psychosocial) outcomes.MethodsA total of 346 individuals with self‐reported arthritis from 18 sites participated in a randomized controlled trial of PACE. Outcomes were measured at baseline and 8 weeks. The intervention group completed self‐reported assessments at 3 and 6 months. Two‐level multiple linear regression models were estimated to calculate adjusted outcome means in the intervention and control groups. A mixed‐effects repeated‐measures model was used to calculate adjusted means in the intervention group at 3 and 6 months. Both intent‐to‐treat (ITT) and as‐treated (AT) analyses were conducted.ResultsAt 8 weeks, the intervention group had improvements in the following outcomes: 2 symptom outcomes (pain, fatigue) and 1 psychosocial outcome (self‐efficacy for managing arthritis) in the ITT analyses; 1 symptom outcome (pain), 1 function outcome (chair stands), and 1 psychosocial outcome (self‐efficacy for arthritis management) in the AT analyses. In addition, completers who attended ≥9 classes had improvements in 3 symptom outcomes (pain, fatigue, stiffness), 2 function outcomes (10‐pound lifts, chair stands), and 1 psychosocial outcome (self‐efficacy for arthritis management) at 8 weeks. Relative to baseline, PACE participants maintained significant improvements in symptoms at 6 months, but declined in function and self‐efficacy for exercise.ConclusionIf adults with arthritis attend a majority of PACE classes, they may expect improvements in symptoms, self‐efficacy for arthritis management, and upper and lower extremity function. Achieving sustained improvement in outcomes may require continued participation in PACE.
Reduced lower extremity vibratory perception in osteoarthritis of the knee
Authors: Shakoor Najia , Agrawal Alan , Block Joel A. 
Published: December 2007

AbstractObjectiveVibratory perception threshold (VPT) assesses a distinct yet related sensory pathway that has been associated with neuropathic arthropathy but has not been assessed in knee osteoarthritis (OA). The purpose of this study was to evaluate VPT in subjects with knee OA to determine whether the lower extremity afferent deficits observed in knee OA involve more than just proprioception.MethodsTwenty‐seven individuals with symptomatic and radiographic knee OA were compared with 14 age‐matched normal subjects. VPT was assessed using a biothesiometer. Five sites of the lower extremity were evaluated. VPT of OA subjects was compared with VPT of normal subjects.ResultsVPT of the OA subjects was significantly reduced at all 5 testing sites compared with normal subjects (P < 0.05 at all sites). VPT scores (mean ± SEM volts) for OA subjects and normal subjects were as follows: first metatarsophalangeal joint (15.0 ± 1.9 versus 6.4 ± 0.9), medial malleolus (22.0 ± 2.2 versus 12.3 ± 1.4), lateral malleolus (22.3 ± 2.0 versus 10.4 ± 0.8), medial femoral condyle (25.8 ± 1.8 versus 15.9 ± 1.9), and lateral femoral condyle (27 ± 1.9 versus 18.9 ± 2.4).ConclusionThis was the first study to evaluate VPT in OA and demonstrate that VPT is reduced at the lower extremity of subjects with knee OA. The noted deficits in VPT may have significant implications in the neuromechanical pathophysiology of OA. VPT is a simple and reliable technique to measure sensory deficits in subjects with OA of the knee.
Patellar taping and bracing for the treatment of chronic knee pain: A systematic review and meta‐analysis
Authors: Warden Stuart J. , Hinman Rana S. , Watson Mark A. , Avin Keith G. , Bialocerkowski Andrea E. , Crossley Kay M. 
Published: December 2007

AbstractObjectiveTo evaluate the evidence for patellar taping and bracing in the management of chronic knee pain.MethodsRandomized or quasi‐randomized studies assessing patellar taping or bracing effects on chronic knee pain were sourced from 7 electronic databases (to November 2006), and assessed using the Physiotherapy Evidence Database scale. Weighted mean differences were determined, and pooled estimates of taping and bracing effects were obtained using random‐effects models.ResultsOf 16 eligible trials, 13 investigated patellar taping or bracing effects in individuals with anterior knee pain, and 3 investigated taping effects in individuals with knee osteoarthritis (OA). The methodologic quality of the taping studies was significantly higher than the bracing studies (mean ± SD 4.8 ± 2.1 versus 2.8 ± 0.8; P < 0.05). On a 100‐mm scale, tape applied to exert a medially‐directed force on the patella decreased chronic knee pain compared with no tape by 16.1 mm (95% confidence interval [95% CI] −22.2, −10.0; P < 0.001) and sham tape by 10.9 mm (95% CI −18.4, −3.4; P < 0.001). For anterior knee pain and OA, medially‐directed tape decreased pain compared with no tape by 14.7 mm (95% CI −22.8, −6.9; P < 0.001) and 20.1 mm (95% CI −26.0, −14.3; P < 0.001), respectively. There was disputable evidence from low‐quality studies for patellar bracing benefits.ConclusionThere was evidence that tape applied to exert a medially‐directed force on the patella produces a clinically meaningful change in chronic knee pain. There was limited evidence to demonstrate the efficacy of patellar bracing. These outcomes were limited by the presence of high heterogeneity between study outcomes and significant publication bias.