bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antileukoproteinase: Modulation of neutrophil function and therapeutic effects on anti–type II collagen antibody–induced arthritis
Authors: Sehnert Bettina , Cavcic Andrea , Böhm Beate , Kalden Joachim R. , Nandakumar Kutty Selva , Holmdahl Rikard , Burkhardt Harald 
Published: July 2004

AbstractObjectiveAntileukoproteinase (ALP) is a physiologic inhibitor of granulocytic serine proteases. The present study was undertaken to investigate its therapeutic benefit in an antibody‐transfer model of erosive polyarthritis and to elucidate its potential to interfere with immune complex–dependent inflammatory pathways.MethodsArthritis development was induced in male (BALB/c × B10.Q)F1 mice by intravenous injection of two monoclonal antibodies specific for type II collagen and was quantified by clinical scoring and histopathology. Arthritis severity was assessed in a cohort of mice under systemic treatment with recombinant human ALP (daily doses of 0.1 mg for 5 days starting immediately after disease induction) in comparison with untreated controls. Concomitantly, functional assays (phagocytosis, oxidative burst, fluorescence‐activated cell sorting analysis of integrin expression) were performed on neutrophils upon in vitro stimulation by IgG‐coated latex beads.ResultsALP treatment reduced arthritis incidence and severity and had a protective effect against cartilage and bone erosion. ALP inhibited the conversion of the leukocyte β2 integrins into an active conformation upon Fc receptor stimulation of granulocytes. ALP bound to the actin‐bundling protein L‐plastin and down‐modulated filamentous actin assembly in response to stimulation with IgG‐coated latex beads in granulocytes. ALP exerted additional inhibitory effects on neutrophil functions associated with cytoskeletal reorganization, such as phagocytosis and oxidative burst.ConclusionIn addition to its antiprotease activity, ALP exerts a variety of blocking effects on neutrophil functions, probably due to modulation of cytoskeletal changes, that may contribute to this inhibitor's antiarthritis potential and qualify it as a multifunctional regulator of inflammatory responses.
First‐degree heart block in the fetus of an anti‐SSA/Ro–positive mother: Reversal after a short course of dexamethasone treatment
Authors: Vesel Samo , Mazić Uroš , Blejec Tanja , Podnar Tomaž 
Published: July 2004

AbstractIsolated congenital heart block is almost invariably associated with the presence of antibodies to SSA/Ro and SSB/La antigens in the maternal circulation. Once established, third‐degree congenital heart block is permanent. However, a lesser degree of autoantibody‐associated heart block in a fetus can be reversed if it is recognized and treated early enough with fluorinated glucocorticosteroids. The only method available clinically for the recognition of first‐degree heart block in a fetus is measurement of the mechanical PR interval by pulsed Doppler echocardiography. This is the first report of a fetus in whom a diagnosis of first‐degree heart block and the consequent decision to intervene were based solely on this technique. In addition, the first‐degree heart block resolved completely after only 2 weeks of dexamethasone treatment, and the heart rhythm remained stable throughout the remainder of the pregnancy despite early discontinuation of therapy due to oligohydramnios.
Articular hypermobility is a protective factor for hand osteoarthritis
Authors: Kraus V. B. , Li Y.‐J. , Martin E. R. , Jordan J. M. , Renner J. B. , Doherty M. , Wilson A. G. , Moskowitz R. , Hochberg M. , Loeser R. , Hooper M. , Sundseth Scott 
Published: July 2004

AbstractObjectiveVery few studies have evaluated the association of articular hypermobility and radiographic osteoarthritis (OA) in humans. We assessed hypermobility and its relationship to radiographic hand OA in a family‐based study.MethodsA total of 1,043 individuals were enrolled in the multicenter Genetics of Generalized Osteoarthritis study, in which families were required to have 2 siblings with radiographic OA involving ≥3 joints (distributed bilaterally) of the distal interphalangeal (DIP), proximal interphalangeal (PIP), or carpometacarpal (CMC) joint groups, and OA in at least one DIP joint. Radiographic OA was defined as a score of ≥2 on the Kellgren/Lawrence scale in one or more joints within the group. The Beighton criteria for assessment of hypermobility were recorded on a 0–9‐point scale. Hypermobility was defined as a Beighton score of ≥4, a threshold generally used to establish a clinical diagnosis of joint laxity. A threshold of ≥2 was also evaluated to assess lesser degrees of hypermobility. The Beighton score for the present was calculated based on clinical examination, and that for the past was based on recall of childhood hypermobility in the first 2 decades of life. The association of hypermobility and radiographic OA of the PIP, CMC, and metacarpophalangeal joints was evaluated in all participants and in men and women separately. Multiple logistic regression was used to examine the relationship of hypermobility with radiographic OA in each joint group, after adjusting for age and sex. The association of hypermobility and DIP OA was not evaluated, because evidence of DIP OA was required for study inclusion.ResultsUsing a threshold Beighton score of 4, 3.7% of individuals were classified as hypermobile based on the present examination, and 7.4% were classified as hypermobile based on the past assessment. A significant negative association between present hypermobility and age was observed. In persons with hypermobility, the odds of OA in PIP joints was lower (for present, odds ratio [OR] 0.34, 95% confidence interval [95% CI] 0.16–0.71; for past, OR 0.43, 95% CI 0.24–0.78). Similar results were obtained using a threshold Beighton score of 2. The lower odds of PIP OA with hypermobility were significant after adjusting for sex and age (for present, OR 0.44, 95% CI 0.20–0.94; for past, OR 0.48, 95% CI 0.26–0.87).ConclusionThis study demonstrated a joint‐protective effect of hypermobility for radiographic OA of PIP joints. In contrast to previous studies showing an association of hypermobility and CMC OA, in this cohort there was no evidence for increased odds of OA in any joint group of the hand in association with articular hypermobility.
Absence of antibodies to cyclic citrullinated peptide in sera of patients with hepatitis C virus infection and cryoglobulinemia
Authors: Wener Mark H. , Hutchinson Kathleen , Morishima Chihiro , Gretch David R. 
Published: July 2004

AbstractObjectiveTo determine if antibodies to cyclic citrullinated peptide (anti‐CCP) are found in chronic hepatitis C virus (HCV) infection.MethodsRheumatoid factor (RF) and anti‐CCP were measured in sera from 50 patients with HCV infection but without cryoglobulinemia, sera from 29 patients with mixed cryoglobulinemia (including 13 with rheumatic symptoms and 5 with arthritis), and sera from 20 normal blood donors. Anti‐CCP was measured by second‐generation enzyme‐linked immunosorbent assay (ELISA).ResultsNo sera with elevated anti‐CCP were found in patients with HCV infection without cryoglobulinemia, and in that population, the maximum anti‐CCP was 10 units, well below the positive cutoff of 20 units. Positive findings on RF testing >13 IU/ml were present in 22 (44%) of the HCV patients, with RF >50 IU/ml in 8 (16%) and a maximum RF of 526 IU/ml. Of the cryoglobulinemia patients, 22 (76%) had positive results on tests for RF, including 18 (62%) with RF >50 IU/ml and a maximum RF of 5,540 IU/ml. Two (6.9%) of the cryoglobulinemia patients had borderline‐positive findings on tests for anti‐CCP (25 units and 37 units), which were false‐positive results caused by nonspecific binding in the ELISA. No association between the RF and the anti‐CCP concentrations was found.ConclusionWhereas RF was frequent in patients with HCV infection with and without cryoglobulinemia, anti‐CCP was not observed in patients with uncomplicated HCV infection. Borderline‐positive anti‐CCP results were observed infrequently in patients with mixed cryoglobulinemia and were caused by nonspecific binding to plastic. Measurement of anti‐CCP may help in diagnosing RA in patients with chronic HCV infection.
Targeting osteoclasts with zoledronic acid prevents bone destruction in collagen‐induced arthritis
Authors: Sims Natalie A. , Green Jonathan R. , Glatt Markus , Schlict Stephen , Martin T. John , Gillespie Matthew T. , Romas Evan 
Published: July 2004

AbstractObjectiveTo study the effect of zoledronic acid (ZA) on synovial inflammation, structural joint damage, and bone metabolism in rats during the effector phase of collagen‐induced arthritis (CIA).MethodsCIA was induced in female dark agouti rats. At the clinical onset of CIA, rats were assigned to treatment with vehicle or single subcutaneous doses of ZA (1.0, 10, 50, or 100 μg/kg). Clinical signs in all 4 paws were scored on a daily basis. After 2 weeks, the joints in the hind paws were assessed using plain radiographs, microfocal computed tomography (micro‐CT), histologic scoring, and histomorphometry, and the serum levels of type I collagen crosslinks were measured by enzyme‐linked immunosorbent assay.ResultsAlthough ZA mildly exacerbated synovitis, it effectively suppressed structural joint damage. At doses of ≥10 μg/kg, ZA significantly reduced radiographic bone erosions, Larsen scores, and juxtaarticular trabecular bone loss as quantified by micro‐CT. ZA prevented increased type I collagen (bone) breakdown in CIA and diminished histologic scores of focal bone erosion by up to 80%. Increases in the percentage of eroded surface, osteoclast surface, and osteoclast numbers associated with CIA were prevented by ZA, even though synovitis scores were unchanged.ConclusionSingle doses (≥10 μg/kg) of ZA strikingly reduced focal bone erosions and juxtaarticular trabecular bone loss, although synovitis was mildly exacerbated. Targeting osteoclasts with ZA may therefore be an effective strategy for preventing structural joint damage in rheumatoid arthritis.
Zoledronic acid protects against local and systemic bone loss in tumor necrosis factor–mediated arthritis
Authors: Herrak Petra , Görtz Birgit , Hayer Silvia , Redlich Kurt , Reiter Erika , Gasser Jürg , Bergmeister Helga , Kollias Giorgos , Smolen Josef S. , Schett Georg 
Published: July 2004

AbstractObjectiveIncreased osteoclast activity is a key factor in bone loss in rheumatoid arthritis (RA). This suggests that osteoclast‐targeted therapies could effectively prevent skeletal damage in patients with RA. Zoledronic acid (ZA) is one of the most potent agents for blocking osteoclast function. We therefore investigated whether ZA can inhibit the bone loss associated with chronic inflammatory conditions.MethodsHuman tumor necrosis factor (TNF)–transgenic (hTNFtg) mice, which develop severe destructive arthritis as well as osteoporosis, were treated with phosphate buffered saline, single or repeated doses of ZA, calcitonin, or anti‐TNF, at the onset of arthritis.ResultsSynovial inflammation was not affected by ZA. In contrast, bone erosion was retarded by a single dose of ZA (−60%) and was almost completely blocked by repeated administration of ZA (−95%). Cartilage damage was partly inhibited, and synovial osteoclast counts were significantly reduced with ZA treatment. Systemic bone mass dramatically increased in hTNFtg mice after administration of ZA, which was attributable to an increase in trabecular number and connectivity. In addition, bone resorption parameters were significantly lowered after administration of ZA. Calcitonin had no effect on synovial inflammation, bone erosion, cartilage damage, or systemic bone mass. Anti‐TNF entirely blocked synovial inflammation, bone erosion, synovial osteoclast formation, and cartilage damage but had only minor effects on systemic bone mass.ConclusionZA appears to be an effective tool for protecting bone from arthritic damage. In addition to their role in antiinflammatory drug therapy, modern bisphosphonates are promising candidates for maintaining joint integrity and reversing systemic bone loss in patients with arthritis.
Endothelial precursor cells in the synovial tissue of patients with rheumatoid arthritis and osteoarthritis
Authors: Rüger Beate , Giurea Alexander , Wanivenhaus Axel H. , Zehetgruber Harald , Hollemann David , Yanagida Genya , Groger Marion , Petzelbauer Peter , Smolen Josef S. , Hoecker Paul , Fischer Michael B. 
Published: July 2004

AbstractObjectiveTo find evidence for the presence of endothelial precursor cells, which can induce new vessel formation, in the synovial tissue of patients with rheumatoid arthritis (RA) and osteoarthritis (OA).MethodsPrecursor cells in the synovial tissue of 18 RA patients and 15 OA patients were identified by immunohistochemistry, morphometric analysis, and confocal laser scanning microscopy using the following phenotype markers: CD31, CD34, STRO‐1, CD133, vascular endothelial growth factor receptor 2 (VEGFR‐2), and CXCR4. The presence of CD31, CD34, CD133, VEGFR‐2, and CXCR4 messenger RNA in the synovial tissue was determined by reverse transcriptase–polymerase chain reaction, and the message for CXCR4 was quantified by an RNase protection assay.ResultsA population of cells that expressed CD34 on their surface but lacked the endothelial cell marker CD31 was found in the synovial tissue of RA and OA patients. CD34+,CD31− cells were detected in close proximity to STRO‐1+ and CD133+ cells, forming cell clusters in the sublining area of the synovial membrane. Within these cell clusters, CD34+,CD31− precursor cells were located on the inside surrounded by STRO‐1+ cells and with CD133+ cells on the outside. CD34+ precursor cells in the cell layer expressed high levels of the chemokine receptor CXCR4, while VEGFR‐2 was expressed on CD34+ and CD133+ cells, and α‐smooth muscle actin was expressed on STRO‐1+ cells.ConclusionThe presence of endothelial precursor cells in the synovial tissue of RA and OA patients provides evidence for vasculogenesis induced by precursor cells that arise in situ or from circulating progenitors.
Unknown Repeated Trials in the Unrelated Question Randomized Response Model
Authors: Singh Housila P. , Mathur N. 
Published: July 2004

AbstractThis paper proposes a modified randomization device for collecting information on sensitive issues. The estimator based on the suggested strategy is found to be unbiased for population proportion and is better than the Greenberg et. al.'s (1969) estimator. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Merits of Modelling Multivariate Survival Data Using Random Effects Proportional Odds Model
Authors: Lam K. F. , Lee Y. W. 
Published: July 2004

AbstractRecently, there has been a great deal of interest in the analysis of multivariate survival data. In most epidemiological studies, survival times of the same cluster are related because of some unobserved risk factors such as the environmental or genetic factors. Therefore, modelling of dependence between events of correlated individuals is required to ensure a correct inference on the effects of treatments or covariates on the survival times. In the past decades, extension of proportional hazards model has been widely considered for modelling multivariate survival data by incorporating a random effect which acts multiplicatively on the hazard function. In this article, we consider the proportional odds model, which is an alternative to the proportional hazards model at which the hazard ratio between individuals converges to unity eventually. This is a reasonable property particularly when the treatment effect fades out gradually and the homogeneity of the population increases over time. The objective of this paper is to assess the influence of the random effect on the within‐subject correlation and the population heterogeneity. We are particularly interested in the properties of the proportional odds model with univariate random effect and correlated random effect. The correlations between survival times are derived explicitly for both choices of mixing distributions and are shown to be independent of the covariates. The time path of the odds function among the survivors are also examined to study the effect of the choice of mixing distribution. Modelling multivariate survival data using a univariate mixing distribution may be inadequate as the random effect not only characterises the dependence of the survival times, but also the conditional heterogeneity among the survivors. A robust estimate for the correlation of the logarithm of the survival times within a cluster is obtained disregarding the choice of the mixing distributions. The sensitivity of the estimate of the regression parameter under a misspecification of the mixing distribution is studied through simulation. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Estimation from Censored Medical Cost Data
Authors: Başer Onur , Gardiner Joseph C. , Bradley Cathy J. , Given Charles W. 
Published: July 2004

AbstractThis paper applies the inverse probability weighted least‐squares method to predict total medical cost in the presence of censored data. Since survival time and medical costs may be subject to right censoring and therefore are not always observable, the ordinary least‐squares approach cannot be used to assess the effects of explanatory variables. We demonstrate how inverse probability weighted least‐squares estimation provides consistent asymptotic normal coefficients with easily computable standard errors. In addition, to assess the effect of censoring on coefficients, we develop a test comparing ordinary least‐squares and inverse probability weighted least‐squares estimators. We demonstrate the methods developed by applying them to the estimation of cancer costs using Medicare claims data. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Assessment of Optimal Selected Prognostic Factors
Authors: Lausen Berthold , Hothorn Torsten , Bretz Frank , Schumacher Martin 
Published: July 2004

AbstractThe identification and assessment of prognostic factors is one of the major tasks in clinical research. The assessment of one single prognostic factor can be done by recently established methods for using optimal cutpoints. Here, we suggest a method to consider an optimal selected prognostic factor from a set of prognostic factors of interest. This can be viewed as a variable selection method and is the underlying decision problem at each node of various tree building algorithms.We propose to use maximally selected statistics where the selection is defined over the set of prognostic factors and over all cutpoints in each prognostic factor. We demonstrate that it is feasible to compute the approximate null distribution. We illustrate the new variable selection test with data of the German Breast Cancer Study Group and of a small study on patients with diffuse large B‐cell lymphoma. Using the null distribution for a p‐value adjusted regression trees algorithm, we adjust for the number of variables analysed at each node as well. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
An Extension of the Model Free Test to Test Synergy in Multiple Drug Combinations
Authors: Feng Ping , Kelly Colleen 
Published: July 2004

AbstractInteractions in a combination of drugs or chemicals are important in therapeutics, toxicology, environmental studies, and normal and abnormal physiology. It is important to be able to decide whether the observed effect of a combination is additive, synergistic or antagonistic. The traditional statistical approaches to the assessment of interactions of n drugs involve estimation of the (n + 1) dimensional response surface, the response surface method (RSM), or the estimation of n 2‐dimensional dose‐response curves, the marginal dose‐response curve method (MDRCM). Laska et al. (1994) proposed a unique approach to assessing synergy in two‐drug combinations that avoids the estimation of any dose‐response curve: their Model‐Free Test (MFT). This method enables the use of simple designs with only three dosages for two drugs: the combination dose of interest and a marginal dosage of each drug. The choice of the marginal dosages depends on the potency ratio of the two drugs at response e, ρ(e). Since ρ(e) is usually unknown, an estimate, r, is used instead. Laska et al. (1994) conclude that the power of the MFT depends heavily on the accuracy of the estimate r. We extend Laska's MFT to assess synergy in three or more drug combinations, and examine the effects of r, different combination dosages and different dose‐response functions on the power of the MFT. Additionally the power of the MFT is compared to the more traditional method, MDRCM. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
An Added Variable Goodness‐of‐fit Test for the Cox Proportional Hazards Model
Authors: May Susanne , Hosmer David W. 
Published: July 2004

AbstractWhile various goodness‐of‐fit tests have been developed to test the assumptions of the Cox proportional hazards model, this paper specifically examines the test proposed by Moreau, O'Quigley and Mesbah. We demonstrate that this test is algebraically identical to a test derived by adding group indicator variables to the model and testing the hypothesis that the coefficients of the group indicator variables are zero via the score test. Based on this result, the Moreau et al. test can be calculated using existing statistical software packages. However, considering that group indicator variables for time intervals need to be time‐dependent, the test needs to be implemented with care. We provide an example. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Asymptotical Tests on the Equivalence, Substantial Difference and Non‐inferiority Problems with Two Proportions
Authors: Martín Andrés A. , Herranz Tejedor I. 
Published: July 2004

AbstractLet d = p2 − p1 be the difference between two binomial proportions obtained from two independent trials. For parameter d, three pairs of hypothesis may be of interest: H1: d ≤ δ vs. K1: d > δ; H2: d ∉ (δ1, δ2) vs. K2: d ∈ (δ1, δ2); and H3: d ∈ [δ1, δ2] vs. K3: d ∉ [δ1, δ2], where Hi is the null hypothesis and Ki is the alternative hypothesis. These tests are useful in clinical trials, pharmacological and vaccine studies and in statistics generally. The three problems may be investigated by exact unconditional tests when the sample sizes are moderate. Otherwise, one should use approximate (or asymptotical) tests generally based on a Z‐statistics like those suggested in the paper. The article defines a new procedure for testing H2 or H3, demonstrates that this is more powerful than tests based on confidence intervals (the classic TOST – two one sided tests – test), defines two corrections for continuity which reduce the liberality of the three tests, and selects the one that behaves better. The programs for executing the unconditional exact and asymptotic tests described in the paper can be loaded at http://www.ugr.es/~bioest/software.htm. (© 2004 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)