bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dynamic levels of glutamate within the insula are associated with improvements in multiple pain domains in fibromyalgia
Authors: Harris Richard E. , Sundgren Pia C. , Pang Yuxi , Hsu Michael , Petrou Myria , Kim Seong‐Ho , McLean Samuel A. , Gracely Richard H. , Clauw Daniel J. 
Published: March 2008

AbstractObjectiveFibromyalgia (FM) is a chronic widespread pain condition that is thought to arise from augmentation of central neural activity. Glutamate (Glu) is an excitatory neurotransmitter that functions in pain‐processing pathways. This study was carried out to investigate the relationship between changing levels of Glu within the insula and changes in multiple pain domains in patients with FM.MethodsTen patients with FM underwent 2 sessions of proton magnetic resonance spectroscopy (H‐MRS) and 2 sessions of functional magnetic resonance imaging (FMRI), each conducted before and after a nonpharmacologic intervention to reduce pain. During H‐MRS, the anterior and posterior insular regions were examined separately using single‐voxel spectroscopy. The levels of Glu and other metabolites were estimated relative to levels of creatine (Cr) (e.g., the Glu/Cr ratio). During FMRI, painful pressures were applied to the thumbnail to elicit neuronal activation. Experimental pressure‐evoked pain thresholds and clinical pain ratings (on the Short Form of the McGill Pain Questionnaire [SF‐MPQ]) were also assessed prior to each imaging sessionResultsBoth experimental pain (P = 0.047 versus pretreatment) and SF‐MPQ–rated clinical pain (P = 0.043 versus pretreatment) were reduced following treatment. Changes from pre‐ to posttreatment in Glu/Cr were negatively correlated with changes in experimental pain thresholds (r = −0.95, P < 0.001) and positively correlated with changes in clinical pain (r = 0.85, P = 0.002). Changes in the FMRI‐determined blood oxygenation level–dependent effect (a measure of neural activation) were positively correlated with changes in Glu/Cr within the contralateral insula (r = 0.81, P = 0.002).ConclusionChanges in Glu levels within the insula are associated with changes in multiple pain domains in patients with FM. Thus, H‐MRS data may serve as a useful biomarker and surrogate end point for clinical trials of FM.
Mediation of the proinflammatory cytokine response in rheumatoid arthritis and spondylarthritis by interactions between fibroblast‐like synoviocytes and natural killer cells
Authors: Chan Antoni , Filer Andrew , Parsonage Greg , Kollnberger Simon , Gundle Roger , Buckley Christopher D. , Bowness Paul 
Published: March 2008

AbstractObjectiveFibroblast‐like synoviocytes (FLS) are potentially directly involved in the propagation of inflammation. We have previously shown evidence of an expanded activated population of natural killer (NK) cells in spondylarthritis (SpA) patients. In the present study, we sought to determine whether the interaction between NK cells and FLS from SpA patients results in a proinflammatory response.MethodsAutologous NK cells and FLS were obtained from 6 patients with SpA, 4 patients with rheumatoid arthritis (RA), and 8 patients with osteoarthritis (OA). Physical interactions between NK cells and FLS were studied by time‐lapse phase‐contrast microscopy. Fluorescence‐activated cell sorting was used to study the activation, proliferation, and survival of NK cells in contact with FLS. Cytokine and stromal factor production were measured by a multiple cytokine bead assay.ResultsNK cells both adhered to and migrated beneath the FLS monolayer (pseudoemperipolesis). FLS from SpA and RA patients supported increased pseudoemperipolesis, activation, cytokine production, and survival of NK cells. The production of proinflammatory cytokines, including interleukin‐6 (IL‐6), IL‐8, IL‐1β, and IL‐15, was increased in cocultures of NK cells and FLS, particularly in those from RA and SpA patients. Production of interferon‐γ, RANTES, and matrix metalloproteinase 3 (MMP‐3) by NK cell and FLS coculture was greatest in SpA patients. Surface expression of IL‐15 on FLS was significantly increased in SpA and RA patients, but not OA patients. Blockade with an IL‐15 monoclonal antibody resulted in increased apoptosis of NK cells.ConclusionFLS promote the migration, activation, and survival of NK cells. The interaction of NK cells with FLS results in increased IL‐15 expression by FLS and the production of proinflammatory chemokines, cytokines, and MMPs, which may contribute to joint inflammation. This response was much more marked in SpA and RA patients as compared with OA patients.
Health economic consequences related to the diagnosis of fibromyalgia syndrome
Authors: Annemans L. , Wessely S. , Spaepen E. , Caekelbergh K. , Caubère J. P. , Lay K. Le , Taïeb C. 
Published: March 2008

AbstractObjectiveTo evaluate the use and costs of medical resources before and after a diagnosis of fibromyalgia syndrome (FMS) in a large primary care population in the UK.MethodsWe applied an existing data set for medical resource use among patients with a coded diagnosis of FMS. The observed quantities of 157 types of medical resource use before and after the diagnosis of FMS were multiplied by unit costs in order to calculate the cost of care (general practitioner [GP] visits, drugs, referrals, and diagnostics) within the National Health Service, excluding hospital costs. Costs before diagnosis were used in a trend analysis to predict later costs, assuming the diagnosis had never been made, and these predicted costs were compared with the observed costs after diagnosis.ResultsFollowing a diagnosis of FMS, a decrease in costs as compared with the predicted trend was observed. In the 4 years after diagnosis, the average difference between the predicted and observed cost was £66.21 per 6 months per patient. This suggests that making the diagnosis leads to savings and a decrease in resource use. The main effect was observed for tests and imaging (£24.02 per 6 months), followed by pharmaceuticals (£22.27), referrals (£15.56), and GP visits (£4.36).ConclusionFailure to diagnose a true case of FMS has its own costs, largely in excess GP visits, investigations, and prescriptions.
Spondylarthritis in the absence of B lymphocytes
Authors: Baeten Dominique , Kruithof Elli , Breban Maxime , Tak Paul P. 
Published: March 2008

AbstractThe highly effective treatment of rheumatoid arthritis by B cell depletion and the presence of B cells in the peripheral and axial lesions of patients with spondylarthritis (SpA) raise the question as to whether B lymphocytes could also be an appropriate therapeutic target in the latter disease. We describe 2 male HLA–B27–positive patients who had active SpA despite absence of B cells. One patient developed SpA with sacroiliitis and asymmetric oligoarthritis after having been diagnosed as having severe Bruton agammaglobulinemia. Since extensive investigations excluded an infectious origin of the SpA, this case illustrates that functional B cells and/or gamma globulins are not strictly required for SpA pathogenesis. The second patient had severe axial and peripheral SpA that was treated successfully with etanercept. After discontinuation of etanercept treatment because of non‐Hodgkin's B cell lymphoma, both axial and peripheral SpA symptoms relapsed rapidly, and this exacerbation of articular disease activity was not modulated by successful B cell depletion therapy for the lymphoma. Although case reports have obvious limitations, our clinical observations provide evidence that active SpA can occur in the absence of functional mature B cells and thus emphasize the need for systematic studies of the exact role and function of B lymphocytes in this disease.
Autoimmune disease in individuals and close family members and susceptibility to non‐Hodgkin's lymphoma
Authors: Mellemkjaer Lene , Pfeiffer Ruth M. , Engels Eric A. , Gridley Gloria , Wheeler William , Hemminki Kari , Olsen Jørgen H. , Dreyer Lene , Linet Martha S. , Goldin Lynn R. , Landgren Ola 
Published: March 2008

AbstractObjectiveRheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and Sjögren's syndrome have been consistently associated with an increased risk of non‐Hodgkin's lymphoma (NHL). This study was initiated to evaluate the risks of NHL associated with a personal or family history of a wide range of autoimmune diseases.MethodsA population‐based case–control study was conducted that included 24,728 NHL patients in Denmark (years 1977–1997) and Sweden (years 1964–1998) and 55,632 controls. Using univariate logistic and hierarchical regression models, we determined odds ratios (ORs) of NHL associated with a personal history of hospital‐diagnosed autoimmune conditions. Risks of NHL associated with a family history of the same autoimmune conditions were assessed by similar regression analyses that included 25,941 NHL patients and 58,551 controls.ResultsA personal history of systemic autoimmune diseases (RA, SLE, Sjögren's syndrome, systemic sclerosis) was clearly linked with NHL risk, both for individual conditions (hierarchical odds ratios [ORh] ranged from 1.6 to 5.4) and as a group (ORh 2.64 [95% confidence interval (95% CI) 1.72–4.07]). In contrast, a family history of systemic autoimmune diseases was modestly and nonsignificantly associated with NHL (ORh 1.31 [95% CI 0.85–2.03]). An increased risk of NHL was found for a personal history of 5 nonsystemic autoimmune conditions (autoimmune hemolytic anemia, Hashimoto thyroiditis, Crohn's disease, psoriasis, and sarcoidosis) (ORh ranged from 1.5 to 2.6) of 27 conditions examined.ConclusionOverall, our results demonstrate a strong relationship of personal history of systemic autoimmune diseases with NHL risk and suggest that shared susceptibility may explain a very small fraction of this increase, at best. Positive associations were found for a personal history of some, though far from all, nonsystemic autoimmune conditions.
Genetic loci contributing to hemophagocytic lymphohistiocytosis do not confer susceptibility to systemic‐onset juvenile idiopathic arthritis
Authors: Donn Rachelle , Ellison Stuart , Lamb Rebecca , Day Thomas , Baildam Eileen , Ramanan Athimalaipet V. 
Published: March 2008

AbstractObjectiveTo investigate whether single‐nucleotide polymorphisms (SNPs) within the genes PRF1, GZMB, UNC13D, and Rab27a, which are involved in natural killer cell dysfunction and known to contribute to the risk of hemophagocytic lymphohistiocytosis (HLH), confer an increased risk of susceptibility to systemic‐onset juvenile idiopathic arthritis (JIA).MethodsFour SNPs across the PRF1 gene locus, 5 for GZMB, 7 for UNC13D, and 11 for Rab27a were investigated using MassArray genotyping in 133 UK Caucasian patients with systemic‐onset JIA and 384 ethnically matched unrelated control subjects. Additional control genotypes were accessed from the data generated by the Wellcome Trust Case Control Consortium.ResultsNo significant association was found between any SNP within the 4 selected loci and systemic‐onset JIA, by either single‐point or haplotype analysis.ConclusionThe results of this study demonstrate that genes involved in HLH do not confer a significant risk of association with systemic‐onset JIA.
Reduced fragmentation of apoptotic chromatin is associated with nephritis in lupus‐prone (NZB × NZW)F1 mice
Authors: Zykova Svetlana N. , Seredkina Natalya , Benjaminsen Jørgen , Rekvig Ole Petter 
Published: March 2008

AbstractObjectiveAntinucleosome autoantibodies are pathogenic factors in lupus nephritis. Defects in apoptotic pathways may result in increased levels of apoptotic nucleosomes. The objectives of this study were 1) to determine whether low molecular weight oligonucleosomes are present in the kidneys of autoimmune (NZB × NZW)F1 mice, 2) to analyze whether the presence of glomerular membrane–associated TUNEL‐positive electron‐dense structures reflect the existence of low molecular weight oligonucleosomes, and 3) to determine an eventual temporal relationship between glomerular electron‐dense structures, oligonucleosomes, and proteinuria in these mice.MethodsDNA was isolated from mouse 111s34 hybridoma cells and from the kidneys of normal BALB/c mice in which apoptosis was induced by camptothecin and from the kidneys of (NZB × NZW)F1 mice at ages 4 weeks, 8 weeks, 20 weeks, and ≥26 weeks (nephritic mice). The DNA fragmentation pattern was determined with an Agilent bioanalyzer. An electron microscopy–based TUNEL assay was performed to detect apoptotic chromatin in glomerular membranes, and immunoelectron microscopy was used to determine antibody binding. Transcription levels for nucleases associated with apoptosis and necrosis were determined by real‐time polymerase chain reaction.ResultsDNA from camptothecin‐treated cell lines and BALB/c mouse kidneys, but not that from untreated (NZB × NZW)F1 mouse kidneys, demonstrated DNA cleavage consistent with apoptotic fragmentation. DNA from (NZB × NZW)F1 mice was devoid of apoptotic fragmentation, irrespective of the age of the mice, whereas TUNEL‐positive chromatin particles were detected in glomerular membranes in nephritic mice. Renal DNase I transcription was reduced in nephritic mice. Nucleosomal DNA fragmentation in response to camptothecin exposure was highly reduced in (NZB × NZW)F1 mouse kidneys compared with that in their normal counterparts.ConclusionThe results of this study demonstrate that TUNEL‐positive chromatin particles are deposited in the glomeruli of nephritic (NZB × NZW)F1 mice, due to reduced fragmentation and clearance of chromatin.
Tumor‐induced osteomalacia: Lessons learned
Authors: Lewiecki E. Michael , Urig Edward J. , Williams Ralph C. 
Published: March 2008

AbstractTumor‐induced osteomalacia is a rare acquired metabolic disorder characterized by hypophosphatemia and inappropriately low serum levels of 1,25‐dihydroxyvitamin D. Symptoms include chronic muscle and bone pain, weakness, and fatigue in association with a high risk of fragility fractures due to osteomalacia. The diagnosis is commonly delayed for years due to the nonspecific nature of the presenting symptoms, failure to include determination of serum phosphorus levels in blood chemistry testing, and difficulty in identifying the responsible tumor. The pathogenesis of tumor‐induced osteomalacia involves tumor expression of fibroblast growth factor 23, a hormone that inhibits proximal renal tubular reabsorption of phosphate and down‐regulates renal conversion of 25‐hydroxyvitamin D to its active form, 1,25‐dihydroxyvitamin D. The metabolic abnormalities may be partially or completely corrected with phosphate supplementation and calcitriol. A definitive diagnosis and treatment require excision of the responsible tumor.
Gene polymorphisms in the NALP3 inflammasome are associated with interleukin‐1 production and severe inflammation: Relation to common inflammatory diseases?
Authors: Verma Deepti , Lerm Maria , Blomgran Julinder Robert , Eriksson Per , Söderkvist Peter , Särndahl Eva 
Published: March 2008

AbstractObjectiveNALP3, ASC, and TUCAN are components of the NALP3 inflammasome, which triggers caspase 1–mediated interleukin‐1β (IL‐1β) release. Activating mutations in the gene encoding NALP3 (NLRP3) have recently been linked to familial periodic fever syndromes. We undertook this study to determine whether a patient with arthritis and antibiotic‐resistant fever carried mutations in the genes encoding the NALP3 inflammasome.MethodsGenetic analysis of NLRP3 and the gene encoding TUCAN (CARD‐8) was performed on genomic DNA from the patient and from a population‐based collection of DNA (806 subjects). For in vitro studies of IL‐1β production and caspase 1 activity, blood was obtained from the patient at different time points after administration of anakinra, an IL‐1 receptor antagonist, as well as from 5 healthy age‐ and sex‐matched control subjects.ResultsMutation analysis of the patient's genes encoding NALP3, ASC, and TUCAN revealed variations in the NLRP3 (Q705K) and CARD‐8 (C10X) genes. The allele frequencies of these single‐nucleotide polymorphisms (SNPs) in the population were 6.5% and 34%, respectively. The elevated activity of caspase 1 and the high levels of IL‐1β measured in samples from the patient returned to normal levels after treatment with anakinra.ConclusionOur results indicate that the patient's symptoms were due to elevated levels of IL‐1β, since treatment with anakinra effectively abolished the symptoms. The compound SNPs may explain the increased IL‐1β levels and inflammatory symptoms observed, but further studies are needed to reveal a functional relationship. The prevalence of the polymorphisms (4% of the population carry both SNPs) in the general population may suggest a genetic predisposition for common inflammatory disorders.
The abundant synovial expression of the RANK/RANKL/Osteoprotegerin system in peripheral spondylarthritis is partially disconnected from inflammation
Authors: Vandooren Bernard , Cantaert Tineke , Noordenbos Troy , Tak Paul P. , Baeten Dominique 
Published: March 2008

AbstractObjectiveSpondylarthritis (SpA) and rheumatoid arthritis (RA) have different patterns of bone damage, with more pronounced bone erosions in RA. The RANK/RANKL/osteoprotegerin (OPG) system plays a central role in bone resorption by promoting the maturation and activation of osteoclasts. To assess the potential role of this system in the distinct bone phenotype, we studied the synovial expression of these mediators in SpA and RA peripheral synovitis.MethodsSynovial biopsy specimens were obtained from the actively inflamed peripheral joints of 35 patients with SpA and 19 patients with RA. Paired synovial biopsy samples were obtained from 24 patients with SpA after tumor necrosis factor α (TNFα) blockade. Synovial tissue sections were immunostained for RANKL, OPG, RANK, and TRAP and assessed by semiquantitative scoring and digital image analysis.ResultsAfter extensive validation of the reactivity and specificity of the antibodies, we demonstrated the abundant expression of RANKL and OPG in SpA synovitis. RANKL was expressed by both fibroblast‐like synoviocytes and sublining T lymphocytes. RANK‐positive osteoclast precursors but no mature TRAP‐positive osteoclasts were present in the inflamed tissue. The expression of these mediators was not different between patients with nonpsoriatic SpA, patients with psoriatic SpA, and patients with RA, was not related to the degree of systemic or local inflammation, and was not significantly modulated by highly effective treatment with TNFα blockers. Only the subset of patients with the best systemic response to TNFα blockade had decreased RANKL expression in the intimal lining layer.ConclusionThe relative protection against bone erosions in SpA cannot be explained by qualitative or quantitative differences in the synovial expression of RANKL, OPG, and RANK. The abundant expression of these factors in SpA peripheral synovitis is largely disconnected from systemic and local inflammation.
Interleukin‐17–producing T cells are enriched in the joints of children with arthritis, but have a reciprocal relationship to regulatory T cell numbers
Authors: Nistala Kiran , Moncrieffe Halima , Newton Katy R. , Varsani Hemlata , Hunter Patricia , Wedderburn Lucy R. 
Published: March 2008

AbstractObjectiveTo identify interleukin‐17 (IL‐17)–producing T cells from patients with juvenile idiopathic arthritis (JIA), and investigate their cytokine production, migratory capacity, and relationship to Treg cells at sites of inflammation, as well as to test the hypothesis that IL‐17+ T cell numbers correlate with clinical phenotype in childhood arthritis.MethodsFlow cytometry was used to analyze the phenotype, cytokine production, and chemokine receptor expression of IL‐17–producing T cells in peripheral blood and synovial fluid mononuclear cells from 36 children with JIA, in parallel with analysis of forkhead box P3 (FoxP3)–positive Treg cells. Migration of IL‐17+ T cells toward CCL20 was assessed by a Transwell assay. Synovial tissue was analyzed by immunohistochemistry for IL‐17 and IL‐22.ResultsIL‐17+ T cells were enriched in the joints of children with JIA as compared with the blood of JIA patients (P = 0.0001) and controls (P = 0.018) and were demonstrated in synovial tissue. IL‐17+ T cell numbers were higher in patients with extended oligoarthritis, the more severe subtype of JIA, as compared with patients with persistent oligoarthritis, the milder subtype (P = 0.046). Within the joint, there was an inverse relationship between IL‐17+ T cells and FoxP3+ Treg cells (r = 0.61, P = 0.016). IL‐17+,CD4+ T cells were uniformly CCR6+ and migrated toward CCL20, but synovial IL‐17+ T cells had variable CCR4 expression. A proportion of IL‐17+ synovial T cells produced IL‐22 and interferon‐γ.ConclusionThis study is the first to define the frequency and characteristics of “Th17” cells in JIA. We suggest that these highly proinflammatory cells contribute to joint pathology, as indicated by relationships with clinical phenotypes, and that the balance between IL‐17+ T cells and Treg cells may be critical to outcome.
H‐2g, a glucose analog of blood group H antigen, mediates mononuclear cell recruitment via Src and phosphatidylinositol 3‐kinase pathways
Authors: Amin M. Asif , Ruth Jeffrey H. , Haas Christian S. , Pakozdi Angela , Mansfield Pamela J. , Haghshenas Jafar , Koch Alisa E. 
Published: March 2008

AbstractObjectiveMonocyte recruitment by proinflammatory cytokines is a hallmark of rheumatoid arthritis (RA). Lewisy‐6 and H (Ley/H) are blood group antigens up‐regulated on RA synovial endothelium. We have previously shown that both soluble Ley/H and a glucose analog of H, H‐2g, are angiogenic and mediateleukocyte–endothelial adhesion via induction of intercellular adhesion molecule 1. We hypothesized that soluble Ley/H plays an important role in monocyte recruitment in RA.MethodsWe examined the role of H‐2g in monocyte chemotaxis in vitro. We used an RA synovial tissue (ST)–SCID mouse chimera model to evaluate the role of H‐2g in monocyte recruitment in vivo. We used Western blots to examine signaling molecules activated by H‐2g in monocytes.ResultsH‐2g induced human monocyte migration in vitro, which was mediated by Src and phosphatidylinositol 3‐kinase (PI 3‐kinase), since inhibitors and antisense oligodeoxynucleotides (ODNs) of Src and PI 3‐kinase significantly decreased H‐2g–induced monocyte migration (P < 0.05). H‐2g significantly increased mononuclear cell (MNC) homing in vivo into an RA ST–SCID mouse chimera (P < 0.05). Transfection of MNCs with Src antisense ODNs blocked H‐2g–induced MNC recruitment into the RA ST–SCID mouse chimera. Additionally, H‐2g induced marked phosphorylation of protein kinase CαI/βII (PKCαI/βII), Src, IκBα, and Akt in monocytes. Src, Akt, and NF‐κB were shown to be downstream targets of PKCαI/βII, since an inhibitor of PKCαI/βII reduced H‐2g–mediated phosphorylation of Src, Akt, and NF‐κB in monocytes.ConclusionThese data suggest that H‐2g may be a novel mediator of monocyte recruitment in chronic inflammatory diseases like RA.
C2‐ceramide mediates cerebellar granule cells apoptosis by activation of caspases‐2, ‐9, and ‐3
Authors: Miñano Alfredo , Caballero‐Benítez Andrea , Lluch Mónica , Morán Julio , Rodríguez‐Alvarez José 
Published: March 2008

AbstractCeramide is able to induce the apoptotic death of cerebellar granule cells (CGC) in culture. However, previous reports did not agree on whether ceramide‐induced apoptosis of CGC requires caspase activation. Here we have shown that addition of C2‐ceramide is able to produce extensive death of cultured CGC, which is associated with chromatin condensation, ladder‐like DNA fragmentation, and activation of caspases. Our results show that C2‐ceramide activates caspases‐3, ‐9, and ‐2 but not caspases‐1 and ‐8. Caspase‐9 activation was associated with cytochrome c release from mitochondria toward the cytosol and was followed by activation of caspases‐2 and ‐3. PARP proteolysis was also observed after caspase‐3 and ‐2 activation. The involvement of caspases‐9, ‐3, and ‐2 in ceramide‐mediated apoptotic death of CGC was further supported by the use of specific inhibitors. © 2008 Wiley‐Liss, Inc.