bluuebunny/crossref_metadata_2025_split huggingface dataset:
Acyl Homoserine Lactones Induce Early Response in the Airway
Authors: Sbarbati Andrea , Tizzano Marco , Merigo Flavia , Benati Donatella , Nicolato Elena , Boschi Federico , Cecchini Maria Paola , Scambi Ilaria , Osculati Francesco 
Published: February 2009

AbstractAcyl homoserine lactones (AHLs) are intercellular signaling molecules used in quorum sensing by Gram‐negative bacteria. We studied the early effects on the rat airway of in vivo intratracheal administration of AHLs (i.e., P. aeruginosa and B. cepacia) to test the hypothesis that AHLs also act on the airway cells, modifying secretory mechanisms which are important in mucosal defense. One hour after treatment, N‐butyryl‐homoserine lactone (C4‐HL) had caused dilated extracellular spaces, loss of cilia, reduction of secretory material, and the presence of prenecrotic elements in the epithelium, while N‐octanoyl‐homoserine lactone (C8‐HL) caused a mild lesion in the epithelium. After treatment with either C4‐ or C8‐HL, reduced immunoreactivity was found using CC10 antibody. At ultrastructural examination, dilatation of the mitochondria was evident in ciliate and secretory cells, while solitary chemosensory cells appeared better preserved, showing aspects of nucleocytoplasmic activation. Using microarray analysis, we found down‐regulation of early gene Fos and Egr1 in all AHL‐treated specimens. In vivo pharmacological magnetic resonance imaging after C4‐ or C8‐HL treatment showed a slight increase in tracheal secretion at a first evaluation 5 min after administration, with no increase in the following minutes. In conclusion, AHLs induce an early mucosal response, and the chondriomas of ciliate and secretory cells are the main cytological target of AHL action. Our results show that AHL action is not limited to activation of conspecific bacteria, but also modifies innate airway defense mechanisms. Anat Rec, 292:439–448, 2009. © 2009 Wiley‐Liss, Inc.
Evaluation of ankylosing spondylitis spinal mobility measurements in the assessment of spinal involvement in psoriatic arthritis
Authors: FerNández‐Sueiro José Luis , Willisch Alfredo , Díaz Sonia Pértega‐ , Tasende José Antonio Pinto , Fernández‐Lopez Carlos , Galdo Fausto , Blanco Francisco Javier 
Published: February 2009

AbstractObjectiveTo determine the clinical usefulness of spinal mobility measurements used for ankylosing spondylitis (AS) to assess spinal involvement in patients with psoriatic arthritis (PsA).MethodsWe assessed 100 patients with PsA and 103 patients with AS. Patients were classified as having axial PsA if they had grade 2 or higher unilateral sacroiliitis in the presence of spinal symptoms. All PsA patients, without taking the degree of joint involvement into consideration, were evaluated using several measurements for AS. Spinal measurements were compared with axial and peripheral forms of PsA, and the ability of the techniques to discriminate between the 2 forms of PsA was analyzed using the Mann‐Whitney U test and the area under the receiver operating characteristic (ROC) curve. A logistic regression model was used to determine the best measurements for evaluating axial PsA. Finally, the results of measurements for axial PsA were compared with those for AS.ResultsOf the 100 PsA patients, 46 met the classification criteria for axial PsA, which presented more severe spinal measurement assessments compared with peripheral PsA. Modified Schober test, lumbar side flexion, chest expansion, and cervical rotation measurements performed best under the ROC curve. Modified Schober test, lumbar side flexion, and cervical rotation were the more suitable measurements for assessing axial PsA. There were only minor differences between axial PsA and AS.ConclusionThe spinal measurements used to evaluate AS performed well to assess spinal involvement in PsA. These measurements, notably the modified Schober test, lumbar side flexion, and cervical rotation, should be used in daily clinical practice to assess PsA patients with spinal involvement.
Effect of hyaluronic acid in symptomatic hip osteoarthritis: A multicenter, randomized, placebo‐controlled trial
Authors: Richette Pascal , Ravaud Philippe , Conrozier Thierry , Euller‐Ziegler Liana , Mazières Bernard , Maugars Yves , Mulleman Denis , Clerson Pierre , Chevalier Xavier 
Published: February 2009

AbstractObjectiveTo evaluate the efficacy and tolerability of a single intraarticular (IA) injection of hyaluronic acid (HA) for the treatment of hip osteoarthritis (OA).MethodsA multicenter, randomized, parallel‐group, placebo‐controlled trial was conducted over 3 months. Patients (older than 30 years) with symptomatic hip OA (pain score of >40 mm on a visual analog scale [VAS]) and a Kellgren/Lawrence grade of 2 or 3 were randomly assigned to receive 1 fluoroscopically guided IA injection of HA (2.5 ml) or placebo (2.5 ml). Patients were followed up for 3 months. The main outcome measure was pain score on a VAS (100 mm) at month 3 compared with baseline. Secondary outcome measures were the proportion of responders defined by Osteoarthritis Research Society International criteria; Western Ontario and McMaster Universities Osteoarthritis Index subscores for pain, stiffness, and disability; and patient and physician global assessment. Randomization was computer generated. HA and placebo preparations were placed in numbered identical containers, and syringes were covered with masking tape. Physicians assessing outcomes were blinded with regard to group assignment.ResultsEighty‐five patients were randomized to the HA group (n = 42) or placebo group (n = 43). Baseline characteristics were similar between the 2 groups. At 3 months, the decrease in pain score did not differ between the HA and placebo groups in the intent‐to‐treat analysis (mean ± SD decrease 7.8 ± 24.9 mm with HA versus 9.1 ± 27.4 mm with placebo; P = 0.98). The responder rates were 33.3% and 32.6% in the HA and placebo groups, respectively (P = 0.94). Other secondary end points did not differ between the groups, nor did use of rescue medication or frequency of adverse events.ConclusionOur findings indicate that a single IA injection of HA is no more effective than placebo in treating the symptoms of hip OA.
Chondroitin sulfate increases hyaluronan production by human synoviocytes through differential regulation of hyaluronan synthases: Role of p38 and Akt
Authors: David‐Raoudi Maha , Deschrevel Brigitte , Leclercq Sylvain , Galéra Philippe , Boumediene Karim , Pujol Jean‐Pierre 
Published: February 2009

AbstractObjectiveTo uncover the mechanism by which chondroitin sulfate (CS) enhances hyaluronan (HA) production by human osteoarthritic (OA) fibroblast‐like synoviocytes (FLS).MethodsThe production of HA was investigated by exposing human OA FLS to CS in the presence or absence of interleukin‐1β (IL‐1β). HA levels were determined by enzyme‐linked immunosorbent assay, and levels of messenger RNA (mRNA) for HA synthase 1 (HAS‐1), HAS‐2, and HAS‐3 were determined by real‐time polymerase chain reaction analysis. The effect of CS and IL‐1β on signaling pathways was assessed by Western blotting. Specific inhibitors were used to determine their effects on both HA production and HAS expression. The molecular size of HA was analyzed by high‐pressure liquid chromatography.ResultsCS increased HA production by FLS through up‐regulation of the expression of HAS1 and HAS2. This was associated with activation of ERK‐1/2, p38, and Akt, although to a lesser extent. Both p38 and Akt were involved in CS‐induced HA accumulation. IL‐1β increased HA production and levels of mRNA for HAS1, HAS2, and HAS3. CS enhanced the IL‐1β–induced level of HAS2 mRNA and reduced the level of HAS3 mRNA. IL‐1β–induced activation of p38 and JNK was slightly decreased by CS, whereas that of ERK‐1/2 and Akt was enhanced. More high molecular weight HA was found in CS plus IL‐1β–treated FLS than in FLS treated with IL‐1β alone.ConclusionCS stimulates the synthesis of high molecular weight HA in OA FLS through up‐regulation of HAS1 and HAS2. It reduces the IL‐1β–enhanced transcription of HAS3 and increases the production of HA of large molecular sizes. These effects may be beneficial for maintaining viscosity and antiinflammatory properties in the joint.
Early targets of nuclear RNP humoral autoimmunity in human systemic lupus erythematosus
Authors: Poole Brian D. , Schneider Rebecca I. , Guthridge Joel M. , Velte Cathy A. , Reichlin Morris , Harley John B. , James Judith A. 
Published: February 2009

AbstractObjectiveThe U1 small nuclear RNPs are common targets of autoantibodies in lupus and other autoimmune diseases. However, the etiology and progression of autoimmune responses directed against these antigens are not well understood. The aim of this study was to use a unique collection of serial samples obtained from patients before and after the development of nuclear RNP (nRNP) antibodies to investigate early humoral events in the development of anti‐nRNP autoimmunity.MethodsLupus patients with sera available from both before and after the development of nRNP antibody precipitin were identified from the Oklahoma Clinical Immunology Serum Repository. Antibodies in the serial samples were analyzed by enzyme‐linked immunosorbent assay, Western blotting, solid‐phase epitope mapping, and competition assays.ResultsThe first‐detected nRNP antibodies targeted 6 common initial epitopes in nRNP A, 2 in nRNP C, and 9 in nRNP 70K. The initial epitopes of nRNP A and nRNP C were significantly enriched for proline and shared up to 95% sequence homology. The initial nRNP 70K humoral epitopes differed from those of nRNP A and nRNP C. The initial antibodies to nRNP A and nRNP C were cross‐reactive with the SmB′‐derived peptide PPPGMRPP. Antibody binding against all 3 nRNP subunits diversified significantly over time.ConclusionAutoantibodies to nRNP A and nRNP C initially targeted restricted, proline‐rich motifs. Antibody binding subsequently spread to other epitopes. The similarity and cross‐reactivity between the initial targets of nRNP and Sm autoantibodies identifies a likely commonality in cause and a focal point for intermolecular epitope spreading.
GATA‐3 protects against severe joint inflammation and bone erosion and reduces differentiation of Th17 cells during experimental arthritis
Authors: van Hamburg Jan Piet , Mus Anne‐Marie , de Bruijn Marjolein J. W. , de Vogel Lisette , Boon Louis , Cornelissen Ferry , Asmawidjaja Patrick , Hendriks Rudi W. , Lubberts Erik 
Published: February 2009

AbstractObjectiveRheumatoid arthritis is associated with the infiltration of T helper cells into the joints. It is unclear whether interferon‐γ (IFNγ)–producing Th1 cells or the novel T helper subset, interleukin‐17 (IL‐17)–producing Th17 cells, are the pathogenic mediators of joint inflammation in chronic nonautoimmune arthritis. Therefore, this study was aimed at examining whether the Th2‐specific transcription factor GATA‐3 can regulate arthritis, in an experimental murine model, by modulating Th1 and/or Th17 cell polarization.MethodsArthritis was induced with methylated bovine serum albumin (mBSA) in both wild‐type and CD2 T cell–specific GATA‐3 (CD2–GATA‐3)–transgenic mice. At days 1 and 7 after the induction of arthritis, knee joints were scored macroscopically for arthritis severity and for histologic changes. Single‐cell suspensions were generated from the spleens, lymph nodes, and inflamed knee joints. Cytokine expression by CD4+ T cells was determined using flow cytometry, and IL‐17 expression in the inflamed knee joints was determined by enzyme‐linked immunosorbent assay. Analyses of gene expression were performed for Th17‐associated factors.ResultsWild‐type mice developed severe joint inflammation, including massive inflammatory cell infiltration and bone erosion that increased significantly over time, reaching maximal arthritis scores at day 7. In contrast, only mild joint inflammation was observed in CD2–GATA‐3–transgenic mice. This mild effect was further accompanied by systemic and local reductions in the numbers of IL‐17+IFNγ− and IL‐17+IFNγ+, but not IL‐17−IFNγ+, CD4+ T cells, and by induction of Th2 cytokine expression. Moreover, GATA‐3 overexpression resulted in reduced gene expression of the Th17‐associated transcription factor retinoic acid–related orphan receptor γt.ConclusionThese results indicate that enforced GATA‐3 expression protects against severe joint inflammation and bone erosion in mice, accompanied by reduced differentiation of Th17 cells, but not Th1 cells, during mBSA‐induced arthritis.
Membrane type 1 matrix metalloproteinase is a crucial promoter of synovial invasion in human rheumatoid arthritis
Authors: Miller Mary‐Clare , Manning Hugh B. , Jain Abhilash , Troeberg Linda , Dudhia Jayesh , Essex David , Sandison Ann , Seiki Motoharu , Nanchahal Jagdeep , Nagase Hideaki , Itoh Yoshifumi 
Published: February 2009

AbstractObjectiveA hallmark of rheumatoid arthritis (RA) is invasion of the synovial pannus into cartilage, and this process requires degradation of the collagen matrix. The aim of this study was to explore the role of one of the collagen‐degrading matrix metalloproteinases (MMPs), membrane type 1 MMP (MT1‐MMP), in synovial pannus invasiveness.MethodsThe expression and localization of MT1‐MMP in human RA pannus were investigated by Western blot analysis of primary synovial cells and immunohistochemical analysis of RA joint specimens. The functional role of MT1‐MMP was analyzed by 3‐dimensional (3‐D) collagen invasion assays and a cartilage invasion assay in the presence or absence of tissue inhibitor of metalloproteinases 1 (TIMP‐1), TIMP‐2, or GM6001. The effect of adenoviral expression of a dominant‐negative MT1‐MMP construct lacking a catalytic domain was also examined.ResultsMT1‐MMP was highly expressed at the pannus–cartilage junction in RA joints. Freshly isolated rheumatoid synovial tissue and isolated RA synovial fibroblasts invaded into a 3‐D collagen matrix in an MT1‐MMP–dependent manner. Invasion was blocked by TIMP‐2 and GM6001 but not by TIMP‐1. Invasion was also inhibited by the overexpression of a dominant‐negative MT1‐MMP, which inhibits collagenolytic activity and proMMP‐2 activation by MT1‐MMP on the cell surface. Synovial fibroblasts also invaded into cartilage in an MT1‐MMP–dependent manner. This process was further enhanced by removing aggrecan from the cartilage matrix.ConclusionMT1‐MMP serves as an essential collagen‐degrading proteinase during pannus invasion in human RA. Specific inhibition of MT1‐MMP–dependent invasion may represent a novel therapeutic strategy for RA.
CCAAT/ENHANCER binding protein β mediates expression of matrix metalloproteinase 13 in human articular chondrocytes in inflammatory arthritis
Authors: Hayashida Mitsumasa , Okazaki Ken , Fukushi Junichi , Sakamoto Akio , Iwamoto Yukihide 
Published: February 2009

AbstractObjectiveTo determine the function of CCAAT/enhancer binding protein β (C/EBPβ) in the expression of matrix metalloproteinase 13 (MMP‐13) in chondrocytes in inflammatory arthritis.MethodsCartilage obtained from patients with rheumatoid arthritis and osteoarthritis was immunostained for expression of C/EBPβ or MMP‐13. Interleukin‐1β– or tumor necrosis factor α (TNFα)–stimulated chondrocytes were subjected to Western blotting and real‐time reverse transcriptase–polymerase chain reaction (RT‐PCR). MMP‐13 promoter assays were conducted, and the C/EBPβ response element was characterized by deletion and mutation analysis. C‐28/I2 cells were treated with TNFα and subjected to chromatin immunoprecipitation (ChIP) assays. Finally, C/EBPβ–liver‐enriched activator protein (LAP) was overexpressed in C‐28/I2 cells or cartilage tissues, and MMP‐13 expression was analyzed.ResultsC/EBPβ and MMP‐13 expression was colocalized in chondrocytes in arthritic cartilage. MMP‐13 promoter activity was stimulated by C/EBPβ overexpression in a dose‐dependent manner. Luciferase assays revealed that a –981‐bp promoter had the greatest activity, while deletion to –936 bp strongly diminished promoter activity. Luciferase activity was repressed to basal levels by mutations in potential C/EBP binding sites. The stimulatory effects of C/EBPβ overexpression were diminished by mutation. ChIP assays revealed that TNFα treatment enhanced the binding of C/EBPβ to the MMP‐13 promoter. When C/EBPβ‐LAP was overexpressed in C‐28/I2 cells, endogenous MMP‐13 expression was stimulated up to 32‐fold as detected by real‐time RT‐PCR. Furthermore, following adenoviral overexpression of C/EBPβ‐LAP in organ culture of articular cartilage, stimulation of MMP‐13 was also detected by immunohistochemistry.ConclusionC/EBPβ directly binds to the MMP‐13 promoter region and stimulates the expression of MMP‐13 in chondrocytes in inflammatory arthritis.
Lack of agreement between rheumatologists in defining digital ulceration in systemic sclerosis
Authors: Herrick Ariane L. , Roberts Christopher , Tracey Andrew , Silman Alan , Anderson Marina , Goodfield Mark , McHugh Neil , Muir Lindsay , Denton Christopher P. 
Published: February 2009

AbstractObjectiveTo test the intra‐ and interobserver variability, among clinicians with an interest in systemic sclerosis (SSc), in defining digital ulcers.MethodsThirty‐five images of finger lesions, incorporating a wide range of abnormalities at different sites, were duplicated, yielding a data set of 70 images. Physicians with an interest in SSc were invited to take part in the Web‐based study, which involved looking through the images in a random sequence. The sequence differed for individual participants and prevented cross‐checking with previous images. Participants were asked to grade each image as depicting “ulcer” or “no ulcer,” and if “ulcer,” then either “inactive” or “active.” Images of a range of exemplar lesions were available for reference purposes while participants viewed the test images. Intrarater reliability was assessed using a weighted kappa coefficient with quadratic weights. Interrater reliability was estimated using a multirater weighted kappa coefficient.ResultsFifty individuals (most of them rheumatologists) from 15 countries participated in the study. There was a high level of intrarater reliability, with a mean weighted kappa value of 0.81 (95% confidence interval [95% CI] 0.77, 0.84). Interrater reliability was poorer (weighted κ = 0.46 [95% CI 0.35, 0.57]).ConclusionThe poor interrater reliability suggests that if digital ulceration is to be used as an end point in multicenter clinical trials of SSc, then strict definitions must be developed. The present investigation also demonstrates the feasibility of Web‐based studies, for which large numbers of participants can be recruited over a short time frame.
The myeloid‐related proteins 8 and 14 complex, a novel ligand of toll‐like receptor 4, and interleukin‐1β form a positive feedback mechanism in systemic‐onset juvenile idiopathic arthritis
Authors: Frosch Michael , Ahlmann Martina , Vogl Thomas , Wittkowski Helmut , Wulffraat Nico , Foell Dirk , Roth Johannes 
Published: February 2009

AbstractObjectiveFever of unknown origin is a diagnostic challenge in children, especially for differentiation of systemic‐onset juvenile idiopathic arthritis (systemic‐onset JIA) and infectious diseases. We undertook this study to analyze the relevance of myeloid‐related proteins (MRPs) 8 and 14, endogenous activators of Toll‐like receptor 4, in diagnosis and pathogenesis of systemic‐onset JIA.MethodsSerum concentrations of MRP‐8/MRP‐14 were analyzed in 60 patients with systemic‐onset JIA, 85 patients with systemic infections, 40 patients with acute lymphoblastic leukemia, 5 patients with acute myeloblastic leukemia, 18 patients with neonatal‐onset multisystem inflammatory disease (NOMID), and 50 healthy controls. In addition, we investigated the link between interleukin‐1β (IL‐1β) and MRP‐8/MRP‐14 in systemic‐onset JIA.ResultsSerum MRP‐8/MRP‐14 concentrations were significantly (P < 0.001) elevated in patients with active systemic‐onset JIA (mean ± 95% confidence interval 14,920 ± 4,030 ng/ml) compared with those in healthy controls (340 ± 70 ng/ml), patients with systemic infections (2,640 ± 720 ng/ml), patients with acute lymphoblastic leukemia (650 ± 280 ng/ml), patients with acute myeloblastic leukemia (840 ± 940 ng/ml), and patients with NOMID (2,830 ± 580 ng/ml). In contrast to C‐reactive protein levels, MRP‐8/MRP‐14 concentrations distinguished systemic‐onset JIA from infections, with a specificity of 95%. MRP‐14 in serum of patients with systemic‐onset JIA was a strong inducer of IL‐1β expression in phagocytes.ConclusionThe analysis of MRP‐8/MRP‐14 in serum is an excellent tool for the diagnosis of systemic‐onset JIA, allowing early differentiation between patients with systemic‐onset JIA and those with other inflammatory diseases. MRP‐8/MRP‐14 and IL‐1β represent a novel positive feedback mechanism activating phagocytes via 2 major signaling pathways of innate immunity during the pathogenesis of systemic‐onset JIA.
MQX‐503, a novel formulation of nitroglycerin, improves the severity of Raynaud's phenomenon: A randomized, controlled trial
Authors: Chung Lorinda , Shapiro Lee , Fiorentino David , Baron Murray , Shanahan Joseph , Sule Sangeeta , Hsu Vivien , Rothfield Naomi , Steen Virginia , Martin Richard W. , Smith Edwin , Mayes Maureen , Simms Robert , Pope Janet , Kahaleh Bashar , Csuka M. E. , Gruber Barry , Collier David , Sweiss Nadera , Gilbert Adam , Dechow Frederick J. , Gregory Jeffrey , Wigley Fredrick M. 
Published: February 2009

AbstractObjectiveRaynaud's phenomenon (RP) affects 3–9% of the general population and >90% of patients with systemic sclerosis. Nitrates are often prescribed for the treatment of RP, but currently available formulations are limited by side effects, particularly headaches, dizziness, and skin irritation. The purpose of this study was to evaluate the tolerability and efficacy of a novel formulation of topical nitroglycerin, MQX‐503, in the treatment of RP in an ambulatory setting.MethodsWe conducted a multicenter, randomized, placebo‐controlled study with a 2‐week single‐blind run‐in period to determine baseline severity, followed by a 4‐week double‐blind treatment phase. Two hundred nineteen adult patients with a clinical diagnosis of primary or secondary RP received 0.9% MQX‐503 gel or matching placebo during the treatment period. Gel was applied immediately before or within 5 minutes of the beginning of an episode of RP (maximum of 4 applications daily). End points included the change in the mean Raynaud's Condition Score (RCS; scale 0–10), the frequency and duration of episodes, and subjective assessments at the target week (the week during the treatment phase that most closely matched the run‐in period in terms of ambient temperature) compared with baseline.ResultsThe mean (%) change in the RCS at the target week compared with baseline was significantly greater in the MQX‐503 group (0.48 [14.3%]) than that in the placebo group (0.04 [1.3%]; P = 0.04). Changes in the frequency and duration of RP episodes and subjective assessments were not statistically different between the groups. MQX‐503 had a side effect profile similar to that of placebo.ConclusionMQX‐503 is well tolerated and more effective than placebo for the treatment of RP.