bluuebunny/crossref_metadata_2025_split huggingface dataset:
Synthesis and
Ru
(
II
)‐
BINAP
Reduction of a Ketoester Derived from Hydroxyproline: 2(
S
)‐(β‐
tert
‐Butoxycarbonyl‐α‐(
S
) and α‐(
R
)‐hydroxyethyl)‐4(
R
)‐hydroxypyrrolidine‐1‐carboxylic acid,
tert
‐Butyl Ester
Authors: King Steven A. , Armstrong Joseph , Keller Jennifer 
Published: December 2004

Abstract

2(
S)‐(
beta‐
tert‐
Butoxycarbonyl‐alpha‐(
S)‐
hydroxyethyl)‐4‐R‐hydroxypyrrolidine‐1‐carboxylic acid,
tert‐
butyl ester

(2
S‐
4
R)‐
2‐
tert‐
Butoxycarbonylacetyl‐4‐hydroxypyrrolidine‐1‐carboxylic acid,
tert‐
butyl ester

R‐BINAP

Lithium hexamethyldisilylamide

N‐Boc hydroxyproline methyl ester
A Convenient Preparation of an Orthogonally ProtectedCα,Cα‐Disubstituted Amino Acid Analog of Lysine: 1‐tert‐butyloxycarbonyl‐4‐((9‐fluorenylmethyloxycarbonyl)amino)‐piperidine‐4‐carboxylic Acid
Authors: Hammarström Lars G. J. , Fu Yanwen , Vail Sidney , Hammer Robert P. , McLaughlin Mark L. 
Published: December 2004

AbstractDMAP(4‐Dimethylamino)pyridine1‐tert‐Butoxycarbonylpiperidine‐4‐spiro‐5′‐(1′,3′‐bis(tert‐butoxycarbonyl)hydantoin4‐Amino1‐tert‐butoxycarbonylpiperidine‐4‐carboxylic acid1‐tert‐Butyloxycarbonyl‐4‐(9‐fluorenylmethyloxyamino)piperidine‐4‐carboxylic acid9‐Fluorenylmethyl chlorformate4‐Piperidone monohydrate hydrochloridePiperidine‐4‐spiro‐5′‐hydantoin
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

AbstractObjectiveTo 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.MethodsFLAP 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.ResultsHuman 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.ConclusionBoth 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

AbstractObjectiveTo 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.MethodsClinical 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.ResultsFive 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).ConclusionThe 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

AbstractObjectiveTo 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.MethodsOne 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.ResultsThe 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.ConclusionOur 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

AbstractObjectiveTo 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).MethodsPeripheral 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.ResultsMTX, 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.ConclusionMTX, 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

AbstractObjectiveTo 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.MethodsTwo 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.ResultsVarus 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).ConclusionVarus 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

AbstractObjectiveMembers 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.MethodsLigand‐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.ResultsSB431542 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.ConclusionThe 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

AbstractObjectiveGlucocorticoids 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).MethodsWe 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.ResultsAmong 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.ConclusionIn 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

AbstractObjectiveTo 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).MethodsTwenty‐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.ResultsAfter 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.ConclusionPrednisolone 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

AbstractObjectiveThere 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.MethodsThe 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.ResultsOxygen 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.ConclusionThe 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

AbstractObjectiveTo 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.MethodsRecords 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.ResultsRecords 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.ConclusionThere 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.