bluuebunny/crossref_metadata_2025 huggingface dataset:
Regulation of the expression of 5‐lipoxygenase–activating protein/5‐lipoxygenase and the synthesis of leukotriene B4 in osteoarthritic chondrocytes: Role of transforming growth factor β and eicosanoids
Authors: Martel‐Pelletier Johanne , Mineau François , Fahmi Hassan , Laufer Stefan , Reboul Pascal , Boileau Christelle , Lavigne Martin , Pelletier Jean‐Pierre
Published: December 2004

Objective

To explore the modulation of 5‐lipoxygenase–activating protein (FLAP) and 5‐lipoxygenase (5‐LOX) expression in human osteoarthritic (OA) chondrocytes, their relative implications in leukotriene B4 (LTB4) production, the effect of different factors on this system, and the influence of increased LTB4 production on the synthesis of catabolic factors of cartilage.

Methods

FLAP and 5‐LOX expression and LTB4 production were monitored following treatment with transforming growth factor β1 (TGFβ1; 5 ng/ml) and 1,25‐dihydroxyvitamin D3 (1,25[OH]2D3; 50 nM) alone or in combination with selective or nonselective cyclooxygenase (COX) inhibitors, naproxen (90 μg/ml), NS‐398 (10 μM), or FR122047 (5 μM), or a dual inhibitor of COX/5‐LOX activity, licofelone (2.6 μM). LTB4, prostaglandin E2 (PGE2), and matrix metalloprotease 1 (MMP‐1) production were measured by specific enzyme‐linked immunosorbent assays, nitric oxide by the Griess reaction, and FLAP and 5‐LOX expression by quantitative polymerase chain reaction.

Results

Human OA chondrocytes expressed both FLAP and 5‐LOX. TGFβ1 and/or 1,25(OH)2D3 induced a rapid and marked enhancement (∼4–13‐fold) in FLAP messenger RNA (mRNA) levels, which was associated with a subsequent and late increase in LTB4 production and PGE2 synthesis. Treatment with COX inhibitors in the absence or presence of TGFβ1 and 1,25(OH)2D3 induced a rapid increase in LTB4 production; this response was mediated by the sustained and significant (P < 0.01) up‐regulation (∼1.5‐fold) of 5‐LOX mRNA levels. Conversely, treatment with licofelone showed no effect on 5‐LOX but significantly reduced FLAP expression levels. Coincubation of licofelone with TGFβ1 plus 1,25(OH)2D3 did not affect FLAP or 5‐LOX levels. In the presence of TGFβ1 plus 1,25(OH)2D3, naproxen, but not licofelone, induced MMP‐1 production and both drugs decreased nitric oxide levels.

Conclusion

Both the eicosanoids PGE2 and LTB4 are important cofactors in regulating FLAP/5‐LOX expression; the inhibition of PGE2 up‐regulates 5‐LOX while down‐regulating FLAP gene expression, and LTB4 appears to be an up‐regulating factor on the 5‐LOX gene. Importantly, nonsteroidal antiinflammatory drugs up‐regulate the synthesis of LTB4, supporting the shunt hypothesis from COX to 5‐LOX. We also demonstrated that LTB4 likely contributes to the up‐regulation of important catabolic factors involved in the pathophysiology of OA, such as MMP.
Clinical and genetic heterogeneity among Spanish patients with recurrent autoinflammatory syndromes associated with the CIAS1/PYPAF1/NALP3 gene
Authors: Aróstegui Juan I. , Aldea Anna , Modesto Consuelo , Rua Maria Jesús , Argüelles Federico , González‐Enseñat Maria Antonia , Ramos Eduardo , Rius Josefa , Plaza Susana , Vives Jordi , Yagüe Jordi
Published: December 2004

Objective

To investigate the involvement of the CIAS1/PYPAF1/NALP3 gene in 7 unrelated Spanish families with recurrent autoinflammatory diseases characterized by early onset, recurrent fever, and a chronic urticarial rash, in whom a clinical diagnosis of cryopyrin‐associated periodic syndromes (CAPS) is suspected.

Methods

Clinical symptoms, results of laboratory analyses, and data on previous treatments in members of the 7 families were recorded on a questionnaire specific for hereditary autoinflammatory diseases. All coding regions and intronic flanking boundaries of the CIAS1/PYPAF1/NALP3 gene were amplified by polymerase chain reaction and sequenced.

Results

Five different missense mutations, including 2 de novo and 1 previously unreported mutation (R488K), were identified in exon 3 of the CIAS1/PYPAF1/NALP3 gene in 5 of the 7 affected families. Expanded genetic analysis among the healthy individuals identified incomplete penetrance in 2 families. No mutations were found in 2 of the 3 patients with chronic infantile neurologic, cutaneous, articular (CINCA) syndrome/neonatal‐onset multisystem inflammatory disease (NOMID).

Conclusion

The clinical data suggested a diagnosis of familial cold‐induced autoinflammatory syndrome in 3 families, CINCA/NOMID syndrome in 3 others, and a possible Muckle‐Wells syndrome, whereas mutational analysis showed different CIAS1/PYPAF1/NALP3 missense mutations in 5 families. These data are consistent with a common molecular basis of these diseases and highlights the phenotypic heterogeneity among CIAS1/PYPAF1/NALP3 gene–associated syndromes. The previously unreported mutation and the incomplete penetrance found in 2 families expand the genetic basis underlying these autoinflammatory syndromes. These findings should alert clinicians to the possible genetic basis of these conditions, even in the absence of a family history, in their attempts to establish an accurate diagnosis and the optimal therapeutic approach.
Microsatellite association mapping of a primary osteoarthritis susceptibility locus on chromosome 6p12.3–q13
Authors: Southam Lorraine , Dowling Barbara , Ferreira Athena , Marcelline Lucy , Mustafa Zehra , Chapman Kay , Bentham Graham , Carr Andrew , Loughlin John
Published: December 2004

Objective

To test a high density of microsatellite markers from within a primary osteoarthritis (OA) locus on chromosome 6 for association with OA as a means of narrowing and focusing our search for the susceptibility gene.

Methods

One hundred forty‐six families, each with 2 or more women concordant for primary OA (ascertained by total hip replacement), were genotyped for 36 microsatellite markers from within a narrow interval at 6p12.3–q13 which we had previously shown to be linked to OA. Each marker was tested for linkage and for association, the latter by means of the transmission disequilibrium test and by a case–control analysis.

Results

The highest 2‐point logarithm of odds (LOD) score was 4.8, with 11 markers having LOD scores ≥2.0. Several markers demonstrated evidence of association, in particular, a cluster of markers positioned within or near the functional candidate gene BMP5.

Conclusion

Our linkage data reinforce the evidence of a major susceptibility locus on chromosome 6. We had previously failed to detect an association with BMP5 using gene‐based single‐nucleotide polymorphisms. The association data reported here prompt us to speculate that the chromosome 6 susceptibility may be coded for by cis‐acting polymorphism in the regulatory elements of this gene, rather than by variation in its protein coding sequence.
Effects of disease‐modifying antirheumatic drugs and antiinflammatory cytokines on human osteoclastogenesis through interaction with receptor activator of nuclear factor κB, osteoprotegerin, and receptor activator of nuclear factor κB ligand
Authors: Lee Chang‐Keun , Lee Eun Young , Chung Son Mi , Mun Se Hwan , Yoo Bin , Moon Hee‐Bom
Published: December 2004

Objective

To demonstrate the effects of disease‐modifying antirheumatic drugs and antiinflammatory cytokines on human osteoclastogenesis through their effects on receptor activator of nuclear factor κB (RANK), osteoprotegerin (OPG), and RANK ligand (RANKL).

Methods

Peripheral blood mononuclear cells (PBMCs) and rheumatoid arthritis (RA) fibroblast‐like synoviocytes (FLS) were cocultured in the presence of macrophage colony‐stimulating factor, 1,25‐dihydroxyvitamin D3, and various concentrations of methotrexate (MTX), sulfasalazine (SSZ), hydroxychloroquine (HCQ), anti–tumor necrosis factor α monoclonal antibody (infliximab), interleukin‐4 (IL‐4), and IL‐10. Osteoclast formation was assayed by counting cells after staining for tartrate‐resistant acid phosphatase. RANKL expression in RA FLS and RANK expression in PBMCs were assayed by Western blotting, reverse transcription–polymerase chain reaction (RT‐PCR), and real‐time PCR. OPG expression was measured by enzyme‐linked immunosorbent assay, RT‐PCR, and real‐time PCR in cultures of RA FLS.

Results

MTX, SSZ, infliximab, and IL‐4, but not IL‐10 and HCQ, each inhibited osteoclast formation in a dose‐dependent manner. We observed no evidence of synergistic inhibition of osteoclast formation by IL‐4 and IL‐10. High doses of infliximab suppressed the expression of RANK in PBMCs. MTX, SSZ, infliximab, and IL‐4 each inhibited the expression of RANKL in RA FLS in a dose‐dependent manner, and also increased the secretion of OPG in RA FLS supernatants.

Conclusion

MTX, SSZ, infliximab, and IL‐4 inhibit human osteoclastogenesis by modulating the interaction of RANKL, RANK, and OPG. These results are indicative of the underlying mechanisms of the antiresorptive effects of these 4 agents.
Thrust during ambulation and the progression of knee osteoarthritis
Authors: Chang Alison , Hayes Karen , Dunlop Dorothy , Hurwitz Debra , Song Jing , Cahue September , Genge Ronuk , Sharma Leena
Published: December 2004

Objective

To determine whether the presence of varus thrust at baseline increases the risk of progression of medial tibiofemoral osteoarthritis (OA), whether knees with thrust have a greater adduction moment, whether thrust has any additional impact on top of static varus, and whether thrust is associated with poor physical function outcome.

Methods

Two hundred thirty‐seven patients with knee OA (definite osteophytes and symptoms) underwent baseline gait observation to assess varus thrust and full‐limb radiography to assess alignment. Sixty‐four of these 237 patients also underwent quantitative gait analysis to determine the maximum knee adduction moment. Two hundred thirty patients (97%) returned for followup at 18 months. At baseline and 18 months, the 230 participants had semiflexed, fluoroscopically confirmed knee radiographs (with progression defined as worsening of medial joint space grade); self‐reported and performance‐based measures of function were also assessed. Logistic regression with generalized estimating equations was used to estimate odds ratios (ORs) for medial OA progression, after excluding knees that were not at risk for progression.

Results

Varus thrust was present in 67 of 401 knees. Thrust increased 4‐fold (age‐, sex‐, body mass index–, and pain‐adjusted OR 3.96, 95% confidence interval [95% CI] 2.11–7.43) the odds of medial progression, with some reduction after further adjustment for varus alignment severity. In varus‐aligned knees, thrust increased the odds of OA progression 3‐fold (adjusted OR 3.17, 95% CI 1.60–6.31). In the gait substudy, the adduction moment was greater in knees with a thrust compared with knees without a thrust. Having a thrust in both knees versus neither knee was associated with a 2‐fold increase in the OR for poor physical function outcome (P not significant).

Conclusion

Varus thrust is a potent risk factor, identifiable by simple gait observation, for disease progression in the medial compartment, the most common site of OA involvement at the knee. Varus thrust may also predict poor physical function outcome. Varus thrust increased the odds of progression among varus‐aligned knees considered separately, suggesting that knees with a thrust are a subset of varus‐aligned knees at particularly high risk for progression of OA.
Selective inhibition of activin receptor–like kinase 5 signaling blocks profibrotic transforming growth factor β responses in skin fibroblasts
Authors: Mori Yasuji , Ishida Wataru , Bhattacharyya Swati , Li Yongzhong , Platanias Leonidas C. , Varga John
Published: December 2004

Objective

Members of the transforming growth factor β (TGFβ) cytokine superfamily play critical roles in both homeostasis and disease. In light of their profibrotic effects, these molecules are implicated in the pathogenesis of fibrosis. In fibroblasts, TGFβ signals through the activin receptor–like kinase 5 (ALK‐5) type I TGFβ and triggers Smad and MAP kinase signaling pathways. Because targeting of TGFβ signaling represents a potential approach to the treatment of systemic sclerosis (SSc) and other fibrotic disorders, we investigated the modulation of intracellular TGFβ signal transduction by SB431542, the first small‐molecule inhibitor of ALK‐5 to be described.

Methods

Ligand‐induced activation of the Smad signaling pathway in human dermal fibroblasts was examined by Western blot analysis and confocal immunocytochemistry. Modulation of profibrotic gene expression was investigated using Northern blot analysis, transient transfection assays, and confocal microscopy. Induction of TGFβ production was evaluated by enzyme‐linked immunosorbent assay.

Results

SB431542 abrogated TGFβ‐induced phosphorylation and nuclear importation of endogenous Smad2/3 and Smad4, and inhibited Smad3‐ and Smad2‐dependent gene transcription. Treatment with SB431542 prevented TGFβ‐induced stimulation of collagen, fibronectin, plasminogen activator inhibitor 1, and connective tissue growth factor gene expression, TGFβ autoinduction, and myofibroblast transdifferentiation, and it could reverse stimulation even when added to the cultures after TGFβ. In contrast, STAT‐6–mediated stimulation of collagen gene expression induced by interleukin‐13 was not prevented by SB431542, indicating the specificity of blockade for ALK‐5–dependent signaling. Furthermore, in contrast to its effects on receptor‐activated Smad activation, SB431542 failed to prevent TGFβ‐induced activation of MAP kinases.

Conclusion

The results indicate that SB431542 is a potent inhibitor of intracellular TGFβ signaling in normal fibroblasts through selective interference with ALK‐5–mediated Smad activation and Smad‐dependent transcriptional responses. Therefore, SB431542 is useful as a novel experimental tool for gaining a detailed understanding of normal and aberrant TGFβ signaling in SSc. Furthermore, as an anti‐TGFβ agent, SB431542 may represent a potential new approach to the treatment of fibrosis.
Effect of glucocorticoids on the arteries in rheumatoid arthritis
Authors: del Rincón Inmaculada , O'Leary Daniel H. , Haas Roy W. , Escalante Agustín
Published: December 2004

Objective

Glucocorticoids are suspected to cause atherosclerosis. Because of the possibility that their antiinflammatory effect may be antiatherogenic, this study investigated the effect of glucocorticoids on the arteries of patients with rheumatoid arthritis (RA).

Methods

We assessed the arteries of 647 patients with RA. Central atherosclerosis was measured using high‐resolution carotid ultrasound for the presence of plaque and for the extent of carotid artery intima‐media thickness (CaIMT). Peripheral atherosclerosis was assessed using the systolic pressures of the dorsal pedal, posterior tibial, and brachial arteries to obtain the ankle‐brachial index (ABI). Cumulative glucocorticoid dose was determined using pharmacy records, supplemented by self‐report. Cardiovascular (CV) risk factors and RA clinical manifestations were ascertained using clinical and laboratory methods.

Results

Among the RA patients studied, 427 (66%) had received glucocorticoids. Of those who had never received glucocorticoids, 100 (47%) of 215 had carotid plaque and 17 (8%) of 219 had ≥1 incompressible lower‐limb artery (ABI >1.3). Among patients in the highest tertile of lifetime glucocorticoid exposure (>16.24 gm prednisone), the frequency of carotid plaque increased to 85 (62%) of 138 (P = 0.006) and that of lower‐limb arterial incompressibility increased to 24 (17%) of 140 (P = 0.008), with differences remaining significant after adjustment for age at onset, disease duration, sex, CV risk factors, and RA clinical manifestations (tender, swollen, and deformed joint counts, subcutaneous nodules, rheumatoid factor seropositivity, and erythrocyte sedimentation rate). The CaIMT also displayed an increase with higher glucocorticoid exposure, but the differences did not reach significance. Lower‐limb artery obstruction (ABI ≤0.9) was not associated with glucocorticoid exposure.

Conclusion

In this RA sample, glucocorticoid exposure was associated with carotid plaque and arterial incompressibility, independent of CV risk factors and RA clinical manifestations. This supports a role for glucocorticoids in the CV complications that occur in RA.
Effects of oral prednisolone on biomarkers in synovial tissue and clinical improvement in rheumatoid arthritis
Authors: Gerlag Danielle M. , Haringman Jasper J. , Smeets Tom J. M. , Zwinderman A. H. , Kraan Maarten C. , Laud Peter J. , Morgan Shethah , Nash Anthony F. P. , Tak Paul P.
Published: December 2004

Objective

To create greater understanding of the changes in synovial tissue parameters that occur in conjunction with clinical response by using an effective therapy, in order to facilitate the planning of future studies with therapeutic agents for rheumatoid arthritis (RA).

Methods

Twenty‐one patients with active RA were randomized to receive either oral prednisolone (n = 10) or placebo (n = 11) for 2 weeks. In all patients, synovial tissue biopsy specimens were obtained by arthroscopy directly before treatment and after 14 days of treatment. Immunohistochemical analysis was performed to characterize the cell infiltrate and vascularity. Stained tissue sections were analyzed by digital imaging. Statistical analysis was performed using an analysis of covariance model.

Results

After treatment, the mean Disease Activity Score in 28 joints (DAS28) was 2.0 units lower (95% confidence interval [95% CI] 1.0–3.0) in patients who received prednisolone than in those who received placebo. In the prednisolone group, the mean (±SD) DAS28 decreased from 6.27 ± 0.95 to 4.11 ± 1.43 after therapy; minimal change was observed in the placebo group. For macrophages, the estimated effect of prednisolone was large. Patients receiving active treatment had fewer (mean 628 cells/mm2 [95% CI 328–927]) macrophages after therapy compared with those receiving placebo. A reduction in the total number of CD68+ macrophages, from 1,038 ± 283 cells/mm2 before treatment to 533 ± 248 cells/mm2 after treatment, was observed in the prednisolone group. There were clear trends toward decreased infiltration by T cells, plasma cells, and fibroblast‐like synoviocytes after active treatment. We observed a trend toward a reduction in αvβ3+ newly formed blood vessels and expression of vascular growth factors after prednisolone therapy.

Conclusion

Prednisolone therapy in RA is associated with a marked reduction in macrophage infiltration in synovial tissue, suggesting that synovial macrophage numbers could be used as a biomarker for clinical efficacy.
Factors influencing the oxygen concentration gradient from the synovial surface of articular cartilage to the cartilage–bone interface: A modeling study
Authors: Zhou Shengda , Cui Zhanfeng , Urban Jill P. G.
Published: December 2004

Objective

There is very little information on the gradients of oxygen concentration from the synovial surface to the subchondral bone in articular cartilage. Cartilage is usually regarded as hypoxic, even though cellular metabolism is inhibited at low oxygen concentrations. We therefore measured rates of cellular consumption of oxygen and used these rates to calculate oxygen tension profiles across articular cartilage.

Methods

The rate of oxygen consumption by bovine articular chondrocytes was measured in vitro, either in intact cartilage slices or in isolated chondrocytes. The oxygen tension profile across articular cartilage was predicted by solving a 1‐dimensional reaction–diffusion equation. The effect of synovial fluid oxygen concentration, cell density, cartilage thickness, and influx of oxygen from the subchondral bone on the oxygen profile in the tissue was examined.

Results

Oxygen consumption rates were relatively independent of oxygen tension at high oxygen tensions (5–21%), where they were ∼10 nmoles/106 cells/hour for both isolated chondrocytes and for cartilage slices. Below 5% oxygen, the rate fell in an oxygen tension–dependent manner. Analysis showed that the oxygen profile across cartilage fell steeply in all but the thinnest cartilage samples but only fell to ∼1% for low oxygen tensions in synovial fluid, with no supply from the subchondral bone.

Conclusion

The oxygen tension in normal cartilage is not likely to fall to 1% except under abnormal conditions. Oxygen tensions within cartilage are strongly affected by a number of factors, including oxygen concentrations in synovial fluid, cartilage thickness, cell density, and cellular oxygen consumption rates. Supply from the subchondral bone may be of particular importance.
Familial aggregation of juvenile idiopathic arthritis
Authors: Prahalad Sampath , O'Brien Elizabeth , Fraser Alison M. , Kerber Richard A. , Mineau Geraldine P. , Pratt David , Donaldson David , Bamshad Michael J. , Bohnsack John
Published: December 2004

Objective

To estimate the degree of familial aggregation of juvenile idiopathic arthritis (JIA), determine whether the aggregation of JIA and the aggregation of type 1 diabetes mellitus (type 1 DM) overlap, and identify multiplex JIA pedigrees.

Methods

Records of individuals with JIA or type 1 DM were probabilistically linked with records in the Utah Population Database (UPDB), a large computerized family history database. For each case of JIA or type 1 DM, 10 matched controls or 5 matched controls, respectively, were selected. All familial relationships among cases of JIA or type 1 DM were established. A familial risk score was calculated for each subject. For various levels of familial exposure to JIA or type 1 DM, one's risk (odds ratio [OR]) of developing JIA or type 1 DM was established (cases compared with controls). Recurrence risks for JIA were computed for relatives of JIA cases compared with relatives of controls. Extended JIA families were identified from a list of common ancestors.

Results

Records of a total of 443 patients were linked with the UPDB. Of these, 381 (86.0%) met criteria for JIA. An increased risk for JIA was observed among relatives of probands with JIA. The prevalence of type 1 DM among JIA cases was higher than the US prevalence of type 1 DM (P < 0.003). The recurrence risk for JIA was significantly elevated among first‐degree relatives of cases with JIA (OR 30.4). The overall prevalence of JIA was 28/100,000. Four extended JIA pedigrees were identified.

Conclusion

There is familial aggregation of JIA in the Intermountain West region of the US. We have demonstrated that multiplex JIA pedigrees can be identified using a genealogic database.
Segment‐specific but pathologic laminin isoform profiles in human labial salivary glands of patients with Sjögren's syndrome
Authors: Laine Mikael , Virtanen Ismo , Salo Tuula , Konttinen Yrjö T.
Published: December 2004

Objective

To assess the laminins in basement membrane of the labial salivary glands of patients with Sjögren's syndrome (SS) and healthy controls.

Methods

Labeling of laminin α1–α5, β1, β2, γ1, and γ2 chains was performed using immunohistochemistry with chain‐specific monoclonal antibodies and pattern recognition analysis of the labeled specimens.

Results

Laminin α1, α2, and α4 chains were detected exclusively in the acinar basement membranes, whereas laminin α3, α5, β1, γ1, and γ2 chains were also detected in ductal basement membranes. Laminin β2 chain was not found. In patients with SS, laminin α1 and α2 chains were weakly labeled, but laminin α4 labeling was also intense in areas not infiltrated by lymphocytes. Pattern recognition analysis suggested that laminin α1, α2, and α4 chains were associated with acinar cells, myoepithelial cells, and tissue damage/repair, respectively.

Conclusion

All salivary gland basement membranes signal through laminin 5, laminin 6, and laminin 10 trimers, but acinar basement membranes also signal through laminin 1, laminin 2, and laminin 8 trimers. Laminin α1 chain/laminin 1 may play a central role in the maintenance of acinar cells in healthy glands. This possibility was supported by the finding of variable expression of laminin α1 chain/laminin 1 in acinar basement membrane and its weak expression in SS with acinar cell atrophy. The impairment of myoepithelial laminin α2 chain/laminin 2 in patients with SS indicates a double defect in the acinar compartment and pathologic extracellular matrix–to‐cell signaling, which may contribute to structural deterioration and functional abnormality of the exocrine glands.
Coordinate overexpression of interferon‐α–induced genes in systemic lupus erythematosus
Authors: Kirou Kyriakos A. , Lee Christina , George Sandhya , Louca Kyriakos , Papagiannis Ioannis G. , Peterson Margaret G. E. , Ly Ngoc , Woodward Robert N. , Fry Kirk E. , Lau Anna Yin‐Har , Prentice James G. , Wohlgemuth Jay G. , Crow Mary K.
Published: December 2004

Objective

To study the contribution of interferon‐α (IFNα) and IFNγ to the IFN gene expression signature that has been observed in microarray screens of peripheral blood mononuclear cells (PBMCs) from patients with systemic lupus erythematosus (SLE).

Methods

Quantitative real‐time polymerase chain reaction analysis of healthy control PBMCs was used to determine the relative induction of a panel of IFN‐inducible genes (IFIGs) by IFNα and IFNγ. PBMCs from 77 SLE patients were compared with those from 22 disease controls and 28 healthy donors for expression of IFIGs.

Results

Expression of IFNα‐inducible genes was significantly higher in SLE PBMCs than in those from disease controls or healthy donors. The level of expression of all IFIGs in PBMCs from SLE patients with IFNα pathway activation correlated highly with the inherent responsiveness of those genes to IFNα, suggesting coordinate activation of that cytokine pathway. Expression of genes preferentially induced by IFNγ was not significantly increased in SLE PBMCs compared with control PBMCs. IFNα‐regulated gene‐inducing activity was detected in some SLE plasma samples.

Conclusion

The coordinate activation of IFNα‐induced genes is a characteristic of PBMCs from many SLE patients, supporting the hypothesis that IFNα is the predominant stimulus for IFIG expression in lupus.
Silver Ring Splints improve dexterity in patients with rheumatoid arthritis
Authors: Zijlstra Theo R. , Heijnsdijk‐Rouwenhorst Linda , Rasker Johannes J.
Published: December 2004

Objective

To study the effect of Silver Ring Splints (SRSs) on hand function in patients with rheumatoid arthritis (RA).

Methods

RA patients with stable disease and finger deformities eligible for splinting received 1 or more SRSs. Primary outcome was dexterity, which was measured with the Sequential Occupational Dexterity Assessment (SODA). Secondary outcome measures were self‐reported hand function (Dutch Arthritis Impact Measurement Scales 2), hand pain, grip and pinch strength, Disease Activity Score in 28 joints (DAS28), and patient satisfaction.

Results

Seventeen patients (median age 65 years; median disease duration 21 years) received a total of 72 SRSs. After 1 year, 48 SRSs were regularly used. Two patients dropped out because of adverse events related to SRSs. In the remaining 15 patients, SODA dexterity scores increased significantly (median 71 at baseline, 81 at 3 months, and 85 at 12 months), Wilcoxon signed ranks test P = 0.005 and P = 0.026. DAS28 scores did not change at 3 months and improved slightly after 12 months (–0.5; P = 0.019). Grip strength, self‐reported hand function, and hand pain showed no significant changes. Eleven patients stated they would continue using their splints.

Conclusion

SRSs can improve dexterity in selected patients with rheumatoid hand deformities. For a satisfactory result, careful patient preassessment and optimal adjustment of SRSs are essential.
Reports of joint instability in knee osteoarthritis: Its prevalence and relationship to physical function
Authors: Fitzgerald G. Kelley , Piva Sara R. , Irrgang James J.
Published: December 2004

Objective

To report the prevalence and relationship of self‐reported knee instability to physical function in a sample of subjects with knee osteoarthritis (OA), and to discuss the implications of these observations for rehabilitation.

Methods

Subjects were 105 individuals (80 females) with knee OA who rated their knee instability severity on a 6‐point numeric scale in response to the query “To what degree does giving way, buckling, or shifting of the knee affect your level of daily activity?” A principal component analysis was used to combine The Western Ontario and McMaster Universities pain, stiffness, and physical function subscale scores, and the Timed Get Up and Go Test score into a principal component score for physical function (PCPF). Other variables that could affect the PCPF such as age, sex, years with knee OA, radiographic severity of knee OA, knee pain, knee motion, and quadriceps strength were also recorded. The prevalence of self‐reported knee instability was determined by calculating the proportion of subjects who reported each severity level of knee instability. Hierarchical regression analysis was performed to determine if the level of self‐reported knee instability could predict the PCPF, even after accounting for the effects of the other variables.

Results

Sixty‐three percent of the subjects reported knee instability during activities of daily living, and 44% reported that instability affects their ability to function. The severity of self‐reported knee instability was associated with the PCPF (eta2 = 0.40, P < 0.001), and after controlling for all other independent variables, significantly increased the prediction of the PCPF (r2 = 0.56, r2 change = 0.05; P < 0.001).

Conclusion

The results indicate that a substantial proportion of individuals with knee OA report episodes of knee instability during activities of daily living, and instability affects physical function beyond that which can be explained by contributions from other impairments such as knee pain, range of motion, and quadriceps strength. Knee instability is a problem that should be specifically addressed in rehabilitation programs and may require interventions beyond those that address pain, joint motion, and muscular strength, to maximize the effectiveness of rehabilitation for individuals with knee OA.
Six‐month and one‐year followup of 23 weeks of aerobic exercise for individuals with fibromyalgia
Authors: Gowans S. E. , deHueck A. , Voss S. , Silaj A. , Abbey S. E.
Published: December 2004

Objective

To measure mood and physical function of individuals with fibromyalgia, 6 and 12 months following 23 weeks of supervised aerobic exercise.

Methods

This is a followup report of individuals who were previously enrolled in 23 weeks of land‐based and water‐based aerobic exercise classes. Outcomes included the 6‐minute walk test, Beck Depression Inventory (BDI), State‐Trait Anxiety Inventory, Arthritis Self‐Efficacy Scale (ASES), Fibromyalgia Impact Questionnaire (FIQ), tender point count, patient global assessment score, and exercise compliance. Outcomes were measured at the start and end of the exercise classes and 6 and 12 months later.

Results

Analyses were conducted on 29 (intent‐to‐treat) or 18 (efficacy) subjects. Six‐minute walk distances and BDI total scores were improved at followup (all analyses). BDI cognitive/affective scores were improved at the end of 23 weeks of exercise (both analyses) and at the 12‐month followup (efficacy analysis only). BDI somatic scores were improved at 6‐month (both analyses) and 12‐month followup (intent‐to‐treat only). FIQ and ASES function were improved at all followup points. ASES pain was improved in efficacy analyses only (all followup points). Tender points were unchanged after 23 weeks of exercise and at followup. Exercise duration at followup (total minutes of aerobic plus anaerobic exercise in the preceding week) was related to gains in physical function (6‐ and 12‐month followup) and mood (6‐month followup).

Conclusion

Exercise can improve physical function, mood, symptom severity, and aspects of self efficacy for at least 12 months. Exercising at followup was related to improvements in physical function and perhaps mood.
Physical self perceptions of women with rheumatoid arthritis
Authors: MacSween Alasdair , Brydson Gillian , Fox Kenneth R.
Published: December 2004

Objective

To assess the reliability and validity of the Physical Self‐Perception Profile (PSPP) and the Perceived Importance Profile (PIP) and to assess relationships between these scales and disease, function, and negative affect in rheumatoid arthritis (RA) patients.

Methods

Fifty‐two women (mean ± SD age 48.4 ± 10.4 years) completed the PSPP, PIP, and other measurements: the core measures of European League Against Rheumatism; the Hospital Anxiety and Depression Scale; distance walked; and peak and extrapolated maximal oxygen consumption during a 10‐meter shuttle walk test.

Results

PSPP subscales showed high internal consistency (Chronbach's alpha 0.73–0.81) and factor structure and strong relationships with physical self‐worth (PSW; r = 0.40–0.63). Multiple regression analysis showed that all subscales (except sport) significantly contributed to PSW variance (R2 = 59.1%). Very low PSPP scores, particularly for strength and sport competence, and PIP scores were observed in RA patients (significantly lower than US college‐aged and obese women), which were reflected in low PSW scores. Aspects of PSPP were related to depression and swollen joint count but not functional fitness. Discrepancy scores were associated with lower PSW scores (r = 0.48), substantiating that subjects were unable to meet their perceptual needs concerning their physical selves.

Conclusion

The PSPP and PIP are both reliable and valid and are sensitive to significant constructs in the mental health of women with RA. The PSPP appears to measure distinct mental properties not represented in other common RA measures; hence it may be useful in measuring an important aspect of RA patients' psychology.
Association of peripheral multifocal choroiditis with sarcoidosis: A study of thirty‐seven patients
Authors: Abad S. , Meyssonier V. , Allali J. , Gouya H. , Giraudet A. L. , Monnet D. , Parc C. , Tenenbaum f. , Alberini J. L. , Grabar S. , Pesce F. , Rollot F. , Sicard D. , Dhote R. , Blanche P. , Brézin A. P.
Published: December 2004

Objective

To assess the clinical spectrum of peripheral multifocal choroiditis (PMC) and its association with sarcoidosis.

Methods

Thirty‐seven patients examined between November 1997 and November 2001 who met all diagnostic criteria for PMC were included in this retrospective study. Patients were assessed for the following signs of sarcoidosis: typical changes on chest radiography or computed tomography; predominantly CD4 lymphocytosis in bronchoalveolar lavage fluid; elevated serum angiotensin‐converting enzyme levels; elevated gallium uptake; and noncaseating granuloma on biopsy.

Results

Most of the patients were female (30 of 37; 81%) and white (30 of 37; 81%). Mean ± SD age at onset was 57.5 ± 18.7 years. Seven (19%) of the 37 patients had biopsy‐proven sarcoidosis and 18 patients (49%) with presumed sarcoidosis met at least 2 of the above‐mentioned criteria for sarcoidosis but had normal biopsy results. Twelve patients (32%) had an indeterminate diagnosis. Patients with presumed sarcoidosis did not differ from those with proven sarcoidosis as regards the above‐mentioned criteria, except for noncaseating granuloma, implying that more than two‐thirds of patients (predominantly whites) had underlying sarcoidosis. Most patients with positive gallium scintigraphy had increased mediastinal uptake, as described in sarcoidosis. Patients with underlying sarcoidosis had more severe visual impairment due to cystoid macular edema (CME). Weekly methotrexate (0.3 mg/kg) seemed to control CME.

Conclusion

White patients with PMC should be considered to have sarcoidosis. The identification of sarcoidosis in patients with severe ocular disease can help with therapeutic choices.
Mental health status and leisure‐time physical activity contribute to fatigue intensity in patients with spondylarthropathy
Authors: Da Costa Deborah , Dritsa Maria , Ring Angela , Fitzcharles Mary‐Ann
Published: December 2004

Objective

To examine the relationship between disease‐related variables, leisure‐time physical activity (LTPA), and mental health status with fatigue severity in patients with spondylarthropathy (SpA).

Methods

Sixty‐six SpA patients completed questionnaires assessing disease activity (Bath Ankylosing Spondylitis Disease Activity Index [BASDAI]), functional ability (Bath Ankylosing Spondylitis Functional Index), and health‐related quality of life (Short Form 36). LTPA patterns, demographics, and disease‐related data were obtained by interview. A clinical examination determined tender point count. Fatigue was assessed with the BASDAI fatigue item.

Results

The mean BASDAI fatigue score was 5.5 (SD = 2.7) with 59% of the sample obtaining a score ≥5. Disease activity, functional disability, and worse mental health contributed to greater fatigue (R2 = 0.56). The relationship between exercise duration and fatigue intensity was moderated by mental health status. For patients with poorer mental health scores, exercise did not influence fatigue severity. However, for patients reporting better mental health status, engaging in more LTPA decreased fatigue severity.

Conclusion

In addition to increased disease activity and functional disability, greater fatigue severity in SpA is associated with poorer mental health status. Integrating regular leisure physical activity into the comprehensive treatment of SpA may be useful for modulating fatigue.
Modeling the 5‐year cost effectiveness of treatment strategies including tumor necrosis factor‐blocking agents and leflunomide for treating rheumatoid arthritis in the Netherlands
Authors: Welsing Paco M. J. , Severens Johan L. , Hartman Margriet , van Riel Piet L. C. M. , Laan Roland F. J. M.
Published: December 2004

Objective

To determine the cost effectiveness of treatment strategies for rheumatoid arthritis patients satisfying the indication for tumor necrosis factor (TNF)‐blocking treatment.

Methods

A Markov model study was performed. The following treatment strategies were considered: 1) usual treatment; 2) treatment with leflunomide, in the case of nonresponse after 3 months, switch to usual treatment; 3) TNF‐blocking treatment, in the case of nonresponse after 3 months, switch to usual treatment; 4) treatment with leflunomide, in the case of nonresponse, switch to TNF‐blocking treatment, in the case of nonresponse to TNF‐blocking treatment, switch to usual treatment; 5) TNF‐blocking treatment, in the case of nonresponse, switch to leflunomide treatment, in the case of nonresponse to leflunomide, switch to usual treatment. Expected patient‐years in the different Markov states, costs, and quality‐adjusted life years (QALYs) were compared between the treatment strategies; incremental cost‐effectiveness ratios (ICERs) were calculated.

Results

Over the 5‐year period, the expected effect on disease activity and QALYs was better for treatment strategies that included TNF‐blocking treatment than for the other treatment strategies. The greater effectiveness of these treatment strategies reduced medical and nonmedical costs compared with usual treatment by about 16% and 33%, respectively, omitting the costs of medication. When the costs of medication were included, the costs of strategies that started with TNF‐blocking treatment were higher than those of the other treatment strategies. Treatment strategy 4 had the most favorable ICER of the treatment strategies that included TNF‐blocking treatment: €163,556/QALY compared with usual treatment.

Conclusion

Among strategies that include TNF‐blocking agents, one starting with leflunomide and, in the case of nonresponse, switching to TNF‐blocking treatment probably results in the most favorable ratio between incremental costs and effects.
The novel antifungal agent PLD‐118 is neither metabolized by liver microsomes nor inhibits cytochrome P450 in vitro
Authors: Parnham M.J. , Bogaards J.J.P. , Schrander F. , Schut M.W. , Orešković K. , Mildner B.
Published: December 2004

PLD‐118 is a novel, oral antifungal drug, under development for the treatment of Candida infections. Possible metabolism of PLD‐118 by rat, dog and human S9 liver homogenates and inhibition of human cytochrome P450 (CYP) enzymes were investigated. PLD‐118 (10 and 100 µM) incubated for 0–60 min with S9 fractions and NADPH was determined by HPLC, using the Waters AccQ.Tag method after derivatization of amino acids to stable, fluorescent derivatives. CYP assays were performed using pooled human liver microsomes with substrates, selective towards human CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP2E1 and CYP3A, incubated at concentrations around the Km. Incubation mixtures were preincubated with PLD‐118 (0.1–100 µM) or control inhibitor for 5 min. No metabolism of PLD‐118 was detected with rat and dog S9 fractions. A small (8%) decrease in PLD‐118 at 100 µM (not detected at 10 µM) with human microsomes was considered to be biologically irrelevant. PLD‐118 did not inhibit any of the tested CYPs. PLD‐118, at concentrations up to 100 µM, is not metabolized by rat, dog or human liver S9 homogenates and does not inhibit human CYPs in vitro, suggesting little likelihood for interaction of PLD‐118 with drugs metabolized by these enzymes. Copyright © 2004 John Wiley & Sons, Ltd.
Serum levels of folate, homocysteine, and vitamin B12 in head and neck squamous cell carcinoma and in laryngeal leukoplakia
Authors: Almadori Giovanni , Bussu Francesco , Galli Jacopo , Cadoni Gabriella , Zappacosta Bruno , Persichilli Silvia , Minucci Angelo , Giardina Bruno , Maurizi Maurizio
Published: December 2004

BACKGROUND

The authors evaluated serum levels of folate, homocysteine, and vitamin B12 in patients with head and neck squamous cell carcinoma (HNSCC) and in patients with laryngeal leukoplakia, a well known preneoplastic lesion.

METHODS

One hundred forty‐four consecutive, untreated patients with HNSCC and 40 consecutive, untreated patients with laryngeal leukoplakia were enrolled in the Department of Otolaryngology at the authors' institution. Data from those patients were compared with data from one control group, which included 90 smokers, and from another control group, which included 120 nonsmokers. Serum levels of homocysteine, folate, and vitamin B12 were measured by an automated immunoassay method based on fluorescence polarization immunoassay technology.

RESULTS

Comparing groups by Student–Newman–Keuls test, serum folate levels were significantly lower in patients with HNSCC and in patients with laryngeal leukoplakia compared with serum folate levels in both the smoker control group and the nonsmoker control group. Serum homocysteine levels in patients with HNSCC were significantly higher compared with homocysteine levels both in the smoker and nonsmoker control groups and in patients with laryngeal leukoplakia. There were no statistically significant differences between groups in serum vitamin B12 levels.

CONCLUSIONS

A role for folate deficiency as a risk factor in head and neck carcinogenesis is plausible. A chemoprevention protocol with folate is both feasible and ethically correct and is in progress at the authors' institution. Homocysteine levels in patients with HNSCC probably are affected largely by the HNSCC phenotype. An accumulation of homocysteine may reveal a genetic defect, which, theoretically, may be a target for pharmacologic therapy, for example, with antifolic drugs. Cancer 2005. © 2004 American Cancer Society.
Heterogeneity testing in meta‐analysis of genome searches
Authors: Zintzaras Elias , Ioannidis John P. A.
Published: December 2004

Genome searches for identifying susceptibility loci for the same complex disease often give inconclusive or inconsistent results. Genome Search Meta‐analysis (GSMA) is an established non‐parametric method to identify genetic regions that rank high on average in terms of linkage statistics (e.g., lod scores) across studies. Meta‐analysis typically aims not only to obtain average estimates, but also to quantify heterogeneity. However, heterogeneity testing between studies included in GSMA has not been developed yet. Heterogeneity may be produced by differences in study designs, study populations, and chance, and the extent of heterogeneity might influence the conclusions of a meta‐analysis. Here, we propose and explore metrics that indicate the extent of heterogeneity for specific loci in GSMA based on Monte Carlo permutation tests. We have also developed software that performs both the GSMA and the heterogeneity testing. To illustrate the concept, the proposed methodology was applied to published data from meta‐analyses of rheumatoid arthritis (4 scans) and schizophrenia (20 scans). In the first meta‐analysis, we identified 11 bins with statistically low heterogeneity and 8 with statistically high heterogeneity. The respective numbers were 9 and 6 for the schizophrenia meta‐analysis. For rheumatoid arthritis, bins 6.2 (the HLA region that is a well‐documented susceptibility locus for the disease) and 16.3 (16q12.2‐q23.1) had both high average ranks and low between‐study heterogeneity. For schizophrenia, this was seen for bin 3.2 (3p25.3‐p22.1) and heterogeneity was still significantly low after adjusting for its high average rank. Concordance was high between the proposed metrics and between weighted and unweighted analyses. Data from genome searches should be synthesized and interpreted considering both average ranks and heterogeneity between studies. Genet. Epidemiol. 28:123–137, 2005. © 2004 Wiley‐Liss, Inc.
Exploiting gene‐environment independence in family‐based case‐control studies: Increased power for detecting associations, interactions and joint effects
Authors: Chatterjee Nilanjan , Kalaylioglu Zeynep , Carroll Raymond J.
Published: December 2004

Family‐based case‐control studies are popularly used to study the effect of genes and gene‐environment interactions in the etiology of rare complex diseases. We consider methods for the analysis of such studies under the assumption that genetic susceptibility (G) and environmental exposures (E) are independently distributed of each other within families in the source population. Conditional logistic regression, the traditional method of analysis of the data, fails to exploit the independence assumption and hence can be inefficient. Alternatively, one can estimate the multiplicative interaction between G and E more efficiently using cases only, but the required population‐based G‐E independence assumption is very stringent. In this article, we propose a novel conditional likelihood framework for exploiting the within‐family G‐E independence assumption. This approach leads to a simple and yet highly efficient method of estimating interaction and various other risk parameters of scientific interest. Moreover, we show that the same paradigm also leads to a number of alternative and even more efficient methods for analysis of family‐based case‐control studies when parental genotype information is available on the case‐control study participants. Based on these methods, we evaluate different family‐based study designs by examining their relative efficiencies to each other and their efficiencies compared to a population‐based case‐control design of unrelated subjects. These comparisons reveal important design implications. Extensions of the methodologies for dealing with complex family studies are also discussed. Genet Epidemiol. 28:138–156, 2005. © 2004 Wiley‐Liss, Inc.