bluuebunny/crossref_metadata_2025_split huggingface dataset:
Association of serum nitrate and nitrite levels with longitudinal assessments of disease activity and damage in systemic lupus erythematosus and lupus nephritis
Authors: Oates Jim C. , Shaftman Stephanie R. , Self Sally E. , Gilkeson Gary S. 
Published: December 2007

AbstractObjectiveReactive intermediate production is an essential component of the innate immune response that is induced during disease activity in murine lupus. This study was undertaken to determine whether a marker of systemic nitric oxide (NO) production correlates with prospectively studied disease activity in human systemic lupus erythematosus (SLE) and lupus nephritis patients.MethodsEighty‐three SLE patients and 40 control subjects were studied longitudinally. The SLE group included 23 patients with lupus nephritis documented by renal biopsy and 26 with a history of lupus nephritis. During each visit, following a 24‐hour low‐nitrate diet, traditional markers of disease activity and damage were determined. Serum nitrate plus nitrite (NOx) levels were determined by chemiluminescence detection.ResultsNOx levels were higher in SLE patients than in controls during the first visit. In univariate longitudinal analyses, NOx levels were associated with SLE Disease Activity Index scores. In multivariate analyses, NOx levels were associated with serum levels of C3 and creatinine and the urinary protein:creatinine ratio. Among patients with lupus nephritis, those with proliferative lesions had higher NOx levels, and higher NOx levels were associated with accumulation of renal damage and lack of response to therapy.ConclusionThis is the first study to prospectively demonstrate longitudinal associations between serum NOx levels and markers of SLE and lupus nephritis disease activity. The more pronounced association with proliferative lupus nephritis and with longitudinal response to lupus nephritis therapy provides a rationale for the study of reactive intermediates as biomarkers of disease activity and therapeutic targets in proliferative lupus nephritis.
Interleukin‐1β up‐regulation of Smad7 via NF‐κB activation in human chondrocytes
Authors: Baugé C. , Attia J. , Leclercq S. , Pujol J.‐P. , Galéra P. , Boumédiene K. 
Published: December 2007

AbstractObjectiveWe have previously shown that interleukin‐1β (IL‐1β) impairs transforming growth factor β (TGFβ) signaling through TGFβ receptor type II (TGFβRII) down‐regulation and Smad7 up‐regulation. This mechanism could account for the reduced responsiveness of osteoarthritic chondrocytes to TGFβ and the cartilage breakdown linked to this disease. The aim of this study was to investigate the molecular mechanism underlying the IL‐1β–induced stimulation of Smad7 in human articular chondrocytes.MethodsHuman articular chondrocytes were treated with IL‐1β in the presence of TGFβ1, pyrrolidine dithiocarbamate (a repressor of the NF‐κB pathway), or cycloheximide. Then, steady‐state messenger RNA and protein levels were estimated by real‐time reverse transcription–polymerase chain reaction and immunocytology. In addition, transient transfections of p65 expression vector or p65‐targeted short hairpin RNA were performed to define the effect of NF‐κB on Smad7 expression.ResultsTGFβRII overexpression restored the TGFβ response of human articular chondrocytes. However, this effect was transient, implying that a secondary mechanism was responsible for the alteration of the TGFβ response with long‐term exposure to IL‐1β. Moreover, IL‐1β caused a late induction of the inhibitory Smad7. This effect was direct, since it did not require de novo synthesis. In addition, we established, by experiments with gain/loss of function, that the up‐regulation of Smad7 by IL‐1β is mediated through the NF‐κB pathway, especially the p65 subunit.ConclusionThese findings clarify the regulatory process of IL‐1β on Smad7 expression. Understanding the molecular basis of IL‐1β induction of Smad7 and the reduction of chondrocyte responsiveness to TGFβ provides new insights into the molecular mechanisms of osteoarthritis and may facilitate the identification of novel approaches for its treatment.
Cannabinoid‐mediated antinociception is enhanced in rat osteoarthritic knees
Authors: Schuelert Niklas , McDougall Jason J. 
Published: December 2007

AbstractObjectiveTo determine whether local administration of the cannabinoid 1 (CB1) receptor agonist arachidonyl‐2‐chloroethylamide (ACEA) can modulate joint nociception in control rat knee joints and in experimental osteoarthritis (OA).MethodsOA was induced in male Wistar rats by intraarticular injection of 3 mg of sodium mono‐iodoacetate, with a recovery period of 14 days. Electrophysiologic recordings were made of knee joint primary afferent nerve fibers in response to normal rotation and noxious hyperrotation of the joint both before and after close intraarterial injection of different doses of ACEA.ResultsLocal application of the CB1agonist significantly reduced the firing rate of afferent nerve fibers by up to 50% in control knee joints (n = 19) and up to 62% in OA knee joints (n = 29;P< 0.01). Coadministration of the CB1receptor antagonist AM251 or the transient receptor potential vanilloid 1 (TRPV‐1) ion channel antagonist SB366791 significantly reduced the desensitizing effect of ACEA. The CB1receptor antagonist AM251 by itself had no effect in the control joint but significantly increased the firing rate of afferent nerve fibers in the OA joint.ConclusionThese findings indicate that activation of peripheral CB1receptors reduces the mechanosensitivity of afferent nerve fibers in control and OA knee joints. Blockade of either the CB1receptor or the TRPV‐1 channel significantly reduced the efficacy of ACEA, which suggests that both receptors are involved in cannabinoid‐mediated antinociception. The increased nerve activity observed following CB1receptor antagonism suggests a tonic release of endocannabinoids during OA. As such, peripheral CB1receptors may be important targets in controlling OA pain.
Risks and relative risks of Wegener's granulomatosis among close relatives of patients with the disease
Authors: Knight Ann , Sandin Sven , Askling Johan 
Published: December 2007

AbstractObjectiveThe etiology of Wegener's granulomatosis (WG) supposedly involves interplay between genetic susceptibility and environmental triggers. However, little is known about whether WG actually clusters in families. Information on the degree of familial aggregation in WG is of clinical relevance, because patients with WG often want to know whether their diagnosis puts their closest relatives at increased risk of the disease. The aim of this study was to investigate the risk of WG in relatives of patients with WG.MethodsUsing Swedish nationwide registers on morbidity, family structure, and vital status, we compared the occurrence of WG (register‐based plus chart review) among 6,670 first‐degree relatives and 428 spouses of 1,944 Swedish patients with WG with the occurrence among 68,994 first‐degree relatives and 4,812 spouses of 19,655 control subjects from the general population. Relative risks were estimated using the Cox proportional hazards regression model.ResultsTwo of the 6,670 first‐degree relatives of patients with WG and 13 of the 68,994 first‐degree relatives of their population controls had WG, resulting in a relative risk of 1.56 (95% confidence interval 0.35–6.90). None of the 428 spouses of patients had WG.ConclusionIn absolute terms, the occurrence of WG among close biologic and nonbiologic relatives of patients with WG is low. In terms of relative risk, our results provide strong evidence against a pronounced increase in familial risk such as that noted for systemic lupus erythematosus, irritable bowel disease, and multiple sclerosis but are compatible with familial aggregation of a magnitude similar to that for rheumatoid arthritis.
Association of microsomal prostaglandin E synthase 1 deficiency with impaired fracture healing, but not with bone loss or osteoarthritis, in mouse models of skeletal disorders
Authors: Yamakawa Kiyofumi , Kamekura Satoru , Kawamura Naohiro , Saegusa Masatomo , Kamei Daisuke , Murakami Makoto , Kudo Ichiro , Uematsu Satoshi , Akira Shizuo , Chung Ung‐il , Nakamura Kozo , Kawaguchi Hiroshi 
Published: December 2007

AbstractObjectiveProstaglandin E synthase (PGES) functions as the terminal enzyme in the biosynthesis of prostaglandin E2 (PGE2) and is a potent regulator of bone and cartilage metabolism. Among the 3 isozymes of PGES, microsomal PGES‐1 (mPGES‐1) is known to play the most critical role in the production of PGE2 in pathophysiologic events. This study investigated the roles of mPGES‐1 under normal physiologic and pathophysiologic conditions in the skeletons of mPGES‐1–deficient (mPGES‐1−/−) mice.MethodsSkeletons of mPGES‐1−/− mice and their wild‐type littermates were compared by radiologic and histologic analyses. Four models of skeletal disorders were created: bone loss induced by ovariectomy, bone loss induced by hind limb unloading, osteoarthritis (OA) induced by instability in the knee joint, and bone fracture by osteotomy at the tibial midshaft. Expression of the PGES enzymes was examined by immunohistochemistry and real‐time reverse transcription–polymerase chain reaction. The cellular mechanism of fracture healing was examined in ex vivo cultures of costal cartilage chondrocytes.ResultsMicrosomal PGES‐1−/− mice had unaffected skeletal phenotypes under normal physiologic conditions. In the bone fracture model, fracture healing was impaired by the mPGES‐1 deficiency, with half of the mice remaining in a non–bone union state even after 21 days; normal fracture healing was restored by adenoviral reintroduction of mPGES‐1. The other skeletal disorders were not affected by the mPGES‐1 deficiency. In vivo and ex vivo analyses revealed an impaired proliferation of chondrocytes in cartilage with the mPGES‐1 deficiency, at an early stage of fracture healing.ConclusionIn these mouse models of skeletal disorders, mPGES‐1 was indispensable for bone repair through chondrocyte proliferation, but was not essential for the skeleton under normal physiologic conditions, nor did it play a role in the pathophysiologic conditions of bone loss due to ovariectomy, bone loss due to unloading, or stress‐induced OA.
Maintenance of infliximab treatment in ankylosing spondylitis: Results of a one‐year randomized controlled trial comparing systematic versus on‐demand treatment
Authors: Breban Maxime , Ravaud Philippe , Claudepierre Pascal , Baron Gabriel , Henry Yves‐Dominique , Hudry Christophe , Euller‐Ziegler Liana , Pham Thao , Solau‐Gervais Elisabeth , Chary‐Valckenaere Isabelle , Marcelli Christian , Perdriger Aleth , Le Loët Xavier , Wendling Daniel , Fautrel Bruno , Fournié Bernard , Combe Bernard , Gaudin Philippe , Jousse Sandrine , Mariette Xavier , Baleydier Alain , Trape Gérard , Dougados Maxime ,   French Ankylosing Spondylitis Infliximab Network
Published: December 2007

AbstractObjectiveContinuous treatment with the anti–tumor necrosis factor α (anti‐TNFα) antibody infliximab is efficacious in ankylosing spondylitis (AS), whereas treatment discontinuation results in disease relapse, with variable delay. This study was undertaken to compare the efficacy of continuous treatment with infliximab with that of a treatment regimen adapted to symptom recurrence. Methotrexate (MTX) in combination with infliximab was also tested.MethodsPatients with active AS were randomly assigned at week 0 to receive infliximab every 6 weeks (continuous treatment) or upon symptom recurrence (on‐demand treatment), following infusions at weeks 4, 6, and 10. Patients in the on‐demand group were randomly assigned to receive either MTX in combination with infliximab or infliximab alone. Patients were monitored for 1 year. The primary end point was the proportion of patients who met the ASsessment in AS International Working Group criteria for 20% improvement (ASAS20) at week 58.ResultsOf 247 patients, 124 were assigned to receive infliximab every 6 weeks and 123 to receive on‐demand treatment. Among the latter, 62 received MTX, and 61 received infliximab alone. A greater proportion of patients receiving infliximab every 6 weeks fulfilled ASAS20 response criteria at week 58 than did patients receiving on‐demand treatment (75% versus 46%; P < 0.0001). Patients in the continuous treatment group received more infliximab infusions after week 10 than did those in the on‐demand group (mean ± SD 5.8 ± 2.2 versus 3.5 ± 2; P < 0.0001). Addition of MTX did not significantly affect the proportion of patients with an ASAS20 response at week 58, nor the number of infliximab infusions administered.ConclusionThese findings indicate that continuous treatment of AS with infliximab is more efficacious than on‐demand treatment, and that the addition of MTX to infliximab provides no significant benefit.
Investigation of sensory neurogenic components in a bleomycin‐induced scleroderma model using transient receptor potential vanilloid 1 receptor– and calcitonin gene‐related peptide–knockout mice
Authors: Szabó Árpád , Czirják László , Sándor Zoltán , Helyes Zsuzsanna , László Terézia , Elekes Krisztián , Czömpöly Tamás , Starr Anna , Brain Susan , Szolcsányi János , Pintér Erika 
Published: December 2007

AbstractObjectiveAlong with their classic afferent function (nociception), capsaicin‐sensitive transient receptor potential vanilloid 1 (TRPV1) receptor–expressing sensory nerve terminals exert local and systemic efferent activities. Activation of TRPV1 causes sensory neuropeptide release, which modulates the inflammation process. The aim of the present study was to examine the role of this modulatory role of TRPV1 receptor and that of calcitonin gene‐related peptide (CGRP) in bleomycin‐induced scleroderma, using transgenic mice.MethodsCutaneous sclerosis was induced with daily subcutaneous injections of bleomycin for 30 days. Control groups were treated with phosphate buffered saline (PBS). TRPV1 receptor gene–deficient (TRPV1−/−) mice and CGRP‐knockout (CGRP−/−) mice and their wild‐type (WT) counterparts were investigated. A composite sclerosis score was calculated on the basis of thickening, leukocyte infiltration, and the amount/orientation of collagen bundles. Dermal thickness and the number of α‐smooth muscle actin (α‐SMA)–positive cells were also determined. The quantity of the collagen‐specific amino acid hydroxyproline was measured by spectrophotometry.ResultsBleomycin treatment induced marked cutaneous thickening and fibrosis compared with that observed in control mice treated with PBS. The composite sclerosis score was 18% higher, dermal thickness was 19% higher, the number of α‐SMA–positive cells was 47% higher, and the amount of hydroxyproline was 57% higher in TRPV1−/− mice than in their WT counterparts. Similarly, the composite sclerosis score was 47% higher, dermal thickness was 29% higher, the number of α‐SMA–positive cells was 76% higher, and the amount of hydroxyproline was 30% higher in CGRP−/− mice than in the respective WT groups.ConclusionThese results suggest that activation of the TRPV1 receptor by mediators of inflammation induces sensory neuropeptide release, which might exert protective action against fibrosis. We confirmed the protective role of CGRP in the development of cutaneous sclerosis.
Sphingomyelinase decreases type II collagen expression in bovine articular cartilage chondrocytes via the ERK signaling pathway
Authors: Gilbert S. J. , Blain E. J. , Duance V. C. , Mason D. J. 
Published: December 2007

AbstractObjectiveCeramide, a mediator of proinflammatory cytokine signaling, induces cartilage degradation and reduces type II collagen synthesis in articular cartilage. The accumulation of ceramide is associated with arthritis in Farber's disease. The aim of this study was to investigate the mechanism of ceramide‐induced down‐regulation of type II collagen.MethodsBovine articular chondrocytes were stimulated with sphingomyelinase (SMase) to increase levels of endogenous ceramide. Components of the ERK pathway were inhibited by Raf‐1 kinase inhibitor and the MEK inhibitor, PD98059. Cell extracts were analyzed by Western blotting for ERK‐1/2, SOX9, c‐Fos, and type II collagen, and the level of c‐fos messenger RNA (mRNA) was analyzed by quantitative polymerase chain reaction. Localization of ERK‐1/2, SOX9, and c‐Fos was assessed by immunocytochemistry and confocal microscopy.ResultsSMase treatment of chondrocytes caused sustained phosphorylation of ERK‐1/2 throughout the cytoplasm and nucleus that was reduced by inhibitors of Raf‐1 kinase and MEK‐1/2. SMase treatment of chondrocytes also induced translocation of c‐Fos to the nucleus and phospho‐SOX9 to the cytoplasm and increased expression of c‐fos mRNA. Type II collagen expression, which was down‐regulated by SMase treatment, was restored by the MEK‐1/2 inhibitor, PD98059.ConclusionSMase down‐regulates type II collagen in articular chondrocytes via activation of the ERK signaling cascade, redistribution of SOX9, and recruitment of c‐Fos. This new mechanism for cartilage degradation provides potential targets for future treatment of arthritic disease.
Central bone marrow lesions in symptomatic knee osteoarthritis and their relationship to anterior cruciate ligament tears and cartilage loss
Authors: Hernández‐Molina Gabriela , Guermazi Ali , Niu Jingbo , Gale Daniel , Goggins Joyce , Amin Shreyasee , Felson David T. 
Published: December 2007

AbstractObjectiveMedial and lateral compartment bone marrow lesions (BMLs) have been tied to cartilage loss. We undertook this study to assess 2 types of BMLs in the central region of the knee (type 1 BMLs, which are related anatomically to anterior cruciate ligament [ACL]/posterior cruciate ligament [PCL] insertions, and type 2 BMLs, which encompass both the central region and either the medial or the lateral compartment) and determine their relationship to cartilage loss and ACL tears.MethodsMagnetic resonance imaging (MRI) of the knee was performed at baseline and at followup (15 and/or 30 months) in 258 subjects with symptomatic osteoarthritis (OA). At baseline, we assessed ACL tears and central BMLs located at or between the tibial spines or adjacent to the femoral notch. Cartilage loss was present if the score in any region of the tibiofemoral joint increased by ≥1 units at the last available followup, using a modified Whole‐Organ MRI Score. We used logistic regression adjusted for alignment, body mass index, Kellgren/Lawrence score, sex, and age.ResultsOne hundred thirty‐nine knees (53.8%) had central BMLs, of which 129 had type 1 BMLs (96 abutted the ACL and had no coexistent type 2 features) and 25 had type 2 BMLs (often overlapped with type 1). Type 1 lesions were associated with ACL tears (odds ratio [OR] 5.9, 95% confidence interval [95% CI] 2.2–16.2) but not with cartilage loss (OR 1.6, 95% CI 0.8–3.1), while medial type 2 BMLs were related to medial cartilage loss (OR 6.1, 95% CI 1.0–35.2).ConclusionCentral BMLs that abutted the ACL were highly prevalent and strongly related to ACL pathology, suggesting a role of enthesopathy in OA. Only BMLs with medial extension were related to ipsilateral cartilage loss.
Expression of mucin 3 and mucin 5AC in arthritic synovial tissue
Authors: Volin Michael V. , Shahrara Shiva , Haines G. Kenneth , Woods James M. , Koch Alisa E. 
Published: December 2007

AbstractObjectiveRheumatoid arthritis (RA) is a chronic inflammatory disease that is characterized by hypertrophy of the synovial tissue, leukocyte infiltration, angiogenesis, and ultimately joint destruction. Mucins (MUCs) are a family of heavily glycosylated proteins that protect epithelial membranes and are used as ligands for cell adhesion. MUC gene expression has been found to be altered in many cancers and inflammatory states. This study was undertaken to examine its expression in synovial tissue (ST) and role in arthritis.MethodsWe performed immunohistochemistry, Western blotting, and reverse transcriptase–polymerase chain reaction to determine expression patterns of MUC1, MUC2, MUC3, and MUC5AC in RA, osteoarthritic (OA), and normal human ST.ResultsMUC3 was expressed in synovial lining cells, macrophages, and fibroblasts. Significantly more RA (n = 12) and OA (n = 13) synovial lining cells expressed MUC3 than did normal synovial lining cells (n = 7) (22% and 24% versus 0.4%, respectively; P < 0.05). Additionally, macrophages in RA and OA ST expressed significantly more MUC3 than did macrophages in normal ST (50% and 51% versus 10%, respectively; P < 0.05). MUC5AC was expressed at low levels in synovial lining cells, macrophages, and endothelial cells in RA and OA ST, and was barely expressed in normal ST. MUC1 and MUC2 proteins were not detected in ST. Messenger RNA (mRNA) for MUC3 and MUC5AC was detected in ST, and mRNA for MUC3 was detected in cultured ST fibroblasts.ConclusionThese data demonstrate up‐regulated MUC expression by ST cells and suggest a novel role of MUC3 and MUC5AC in the pathogenesis of arthritis.
Estimates of the prevalence of arthritis and other rheumatic conditions in the United States: Part II
Authors: Lawrence Reva C. , Felson David T. , Helmick Charles G. , Arnold Lesley M. , Choi Hyon , Deyo Richard A. , Gabriel Sherine , Hirsch Rosemarie , Hochberg Marc C. , Hunder Gene G. , Jordan Joanne M. , Katz Jeffrey N. , Kremers Hilal Maradit , Wolfe Frederick ,   National Arthritis Data Workgroup
Published: December 2007

AbstractObjectiveTo provide a single source for the best available estimates of the US prevalence of and number of individuals affected by osteoarthritis, polymyalgia rheumatica and giant cell arteritis, gout, fibromyalgia, and carpal tunnel syndrome, as well as the symptoms of neck and back pain. A companion article (part I) addresses additional conditions.MethodsThe National Arthritis Data Workgroup reviewed published analyses from available national surveys, such as the National Health and Nutrition Examination Survey and the National Health Interview Survey. Because data based on national population samples are unavailable for most specific rheumatic conditions, we derived estimates from published studies of smaller, defined populations. For specific conditions, the best available prevalence estimates were applied to the corresponding 2005 US population estimates from the Census Bureau, to estimate the number affected with each condition.ResultsWe estimated that among US adults, nearly 27 million have clinical osteoarthritis (up from the estimate of 21 million for 1995), 711,000 have polymyalgia rheumatica, 228,000 have giant cell arteritis, up to 3.0 million have had self‐reported gout in the past year (up from the estimate of 2.1 million for 1995), 5.0 million have fibromyalgia, 4–10 million have carpal tunnel syndrome, 59 million have had low back pain in the past 3 months, and 30.1 million have had neck pain in the past 3 months.ConclusionEstimates for many specific rheumatic conditions rely on a few, small studies of uncertain generalizability to the US population. This report provides the best available prevalence estimates for the US, but for most specific conditions more studies generalizable to the US or addressing understudied populations are needed.