bluuebunny/crossref_metadata_2025_split huggingface dataset:
Overexpression of CD70 and overstimulation of IgG synthesis by lupus T cells and T cells treated with DNA methylation inhibitors
Authors: Oelke Kurt , Lu Qianjin , Richardson Derek , Wu Ailing , Deng Chun , Hanash Samir , Richardson Bruce 
Published: June 2004

AbstractObjectiveGeneralized DNA hypomethylation contributes to altered T cell function and gene expression in systemic lupus erythematosus (SLE). Some of the overexpressed genes participate in the disease process, but the full repertoire of genes affected is unknown. Methylation‐sensitive T cell genes were identified by treating T cells with the DNA methyltransferase inhibitor 5‐azacytidine and comparing gene expression with oligonucleotide arrays. CD70, a costimulatory ligand for B cell CD27, was one gene that reproducibly increased. We then determined whether CD70 is overexpressed on T cells treated with other DNA methylation inhibitors and on SLE T cells, and determined its functional significance.MethodsOligonucleotide arrays, real‐time reverse transcription–polymerase chain reaction, and flow cytometry were used to compare CD70 expression in T cells treated with 2 DNA methyltransferase inhibitors (5‐azacytidine and procainamide) and 3 ERK pathway inhibitors known to decrease DNA methyltransferase expression (U0126, PD98059, and hydralazine). The consequences of CD70 overexpression were tested by coculture of autologous T and B cells with and without anti‐CD70 and measuring IgG production by enzyme‐linked immunosorbent assay. The results were compared with those of T cells from lupus patients.ResultsSLE T cells and T cells treated with DNA methylation inhibitors overexpressed CD70 and overstimulated B cell IgG production. The increase in IgG synthesis was abrogated by anti‐CD70.ConclusionSLE T cells and T cells treated with DNA methyltransferase inhibitors and ERK pathway inhibitors overexpress CD70. This increased B cell costimulation and subsequent immunoglobulin overproduction may contribute to drug‐induced and idiopathic lupus.
Quadriceps weakness and its relationship to tibiofemoral and patellofemoral knee osteoarthritis in Chinese: The Beijing osteoarthritis study
Authors: Baker Kristin R. , Xu Ling , Zhang Yuqing , Nevitt Michael , Niu Jingbo , Aliabadi Piran , Yu Wei , Felson David 
Published: June 2004

AbstractObjectiveWeakness has been documented as a feature of tibiofemoral knee osteoarthritis (OA) and may cause disease in this compartment by shock absorption during impulse loading at heel strike, when the patellofemoral joint is not engaged. Our objective was to determine the association of muscle weakness with compartment‐specific knee OA, to evaluate sex‐specific differences in this relationship, and to determine, by evaluating asymptomatic individuals with OA, whether symptoms may produce the weakness seen in OA.MethodsThis cross‐sectional study involved 2,472 subjects (1,475 women and 997 men) ages 60 years or older from 4 central districts of Beijing, China. For all subjects, a skyline view of each knee and an anteroposterior (AP) or posteroanterior (PA) radiograph of both knees were obtained during weight bearing. Radiographs were read by one reader for Kellgren/Lawrence (K/L) grade, joint space narrowing (JSN), and osteophytes. We defined a subject as having tibiofemoral OA when the K/L grade was ≥2 on AP/PA view, patellofemoral OA on skyline view when the osteophyte score was ≥2 (or when the JSN score was ≥2 and the osteophyte score was ≥1), and mixed OA when the knee had both patellofemoral and tibiofemoral radiographic OA. Strength was measured isometrically for each leg separately, and knee pain was evaluated by questionnaire.ResultsIn women, quadriceps weakness was associated with tibiofemoral OA (odds ratio [OR] 0.7, 95% confidence interval [95% CI] 0.4–1.0), patellofemoral OA (OR 0.6, 95% CI 0.4–0.9), and mixed OA (OR 0.4, 95% CI 0.3–0.6). In men, weakness was associated with mixed OA (OR 0.5, 95% CI 0.3–0.8), and the ORs suggesting an association of patellofemoral OA with weakness were the same as those in women, although in men this trend did not reach statistical significance (P= 0.12). In men, isolated tibiofemoral disease was not associated with weakness; however, the sample size in this analysis was limited. When subjects with knee symptoms were excluded, the relationship of quadriceps weakness to OA was attenuated, with only the relationship between muscle weakness and mixed OA remaining significant.ConclusionThere is a relationship between quadriceps weakness and knee OA in all compartments, with the strongest association in mixed disease. Pain may contribute to some of this weakness.
Molecular analysis of the MVK and TNFRSF1A genes in patients with a clinical presentation typical of the hyperimmunoglobulinemia D with periodic fever syndrome: A low‐penetrance TNFRSF1A variant in a heterozygous MVK carrier possibly influences the phenotype of hyperimmunoglobulinemia D with periodic fever syndrome or vice versa
Authors: Stojanov Silvia , Lohse Peter , Lohse Pia , Hoffmann Florian , Renner Ellen D. , Zellerer Stephanie , Kéry Anja , Shin Yoon S. , Haas Dorothea , Hoffmann Georg F. , Belohradsky Bernd H. 
Published: June 2004

AbstractObjectiveTo describe biochemical findings and the spectrum of mevalonate kinase (MVK) gene mutations as well as an associated TNFRSF1A low‐penetrance variant in a series of patients with clinical features of the hyperimmunoglobulinemia D with periodic fever syndrome (HIDS).MethodsThe MVK gene was sequenced in 8 children and 1 adult (including 2 siblings) fulfilling the clinical criteria for HIDS. In addition, sequencing of exons 2, 3, 4, and 6 of the TNFRSF1A gene was performed in patients with only one or no MVK mutation. Mevalonate kinase (MK) enzyme activity in leukocytes and renal excretion of mevalonic acid were also measured.ResultsMutations in the coding region of the MVK gene were detected in 6 patients, and the most common mutation was V377I. Among these patients were 2 novel mutations, both of which were located in exon 6. These novel mutations resulted in the substitution of tryptophan (TGG) by a stop codon (TGA) at amino acid position 188 (W188X) and in the exchange of valine (GTG) for alanine (GCG) at amino acid position 203 (V203A). In 1 patient, a combination of one MVK (V377I) mutation and one TNFRSF1A (R92Q) mutation was present. The patient's clinical phenotype resembled a mixture of variant‐type HIDS and tumor necrosis factor receptor–associated periodic syndrome (TRAPS). Her IgD values varied between normal and slightly increased, and the MK activity was in the low‐normal range, while urinary mevalonate concentrations were always normal.ConclusionThe genotype findings indicate that a relatively small number of genes may be involved in the clinical manifestation of HIDS, with low‐penetrance TNFRSF1A variants possibly influencing the HIDS phenotype or MVK mutations contributing to TRAPS.
Regional differences in bronchoalveolar lavage and thoracic high‐resolution computed tomography results in dyspneic patients with systemic sclerosis
Authors: Clements Philip J. , Goldin Jonathan G. , Kleerup Eric C. , Furst Daniel E. , Elashoff Robert M. , Tashkin Donald P. , Roth Michael D. 
Published: June 2004

AbstractObjectiveInterstitial lung disease (ILD) is the leading cause of death in systemic sclerosis (SSc). Although early identification and treatment of alveolitis may prevent deterioration of lung function, the best approach for diagnosing active alveolitis remains controversial. This study was undertaken to investigate the utility of high‐resolution computed tomography (HRCT) of the chest, in comparison with bronchoalveolar lavage (BAL), in the diagnosis of alveolitis in these patients.MethodsEighteen patients with SSc and dyspnea were evaluated for ILD by pulmonary function testing and bronchoalveolar lavage (BAL), and 15 of these patients underwent chest HRCT. BAL was performed in either the middle lobe or the lingula, and also in a lower lung segment. Differential cell counts were determined by clinical cytopathology, with retrospective recounting in a blinded manner by a single technician. Active alveolitis was defined as the presence of ≥3.0% polymorphonuclear cells and/or ≥2% eosinophils in BAL fluid. BAL fluids were cultured for bacteria, mycobacteria, and fungi. HRCT scans were evaluated in a blinded manner for ground‐glass opacification and fibrosis in the lavaged lobes.ResultsNine of the 18 patients had active alveolitis recorded in both lavaged segments, while in 4 patients it was recorded in only 1 segment (lower lobe in 3). Following repeat differential cell counting, 3 patients were reclassified as having active alveolitis and 1 as having no alveolitis. Culture of BAL fluid identified clinically unsuspected infection in 3 patients. For the right middle lung lobe or lingula there was excellent agreement between ground‐glass opacification and the finding of alveolitis on BAL from segments in the same lung regions, but this was not observed for the lower lobes. The correlation between fibrosis on HRCT and the presence of alveolitis on BAL was significant for the lower lobes but not the middle lung fields.ConclusionBAL of the middle lobe or lingula may underestimate the presence of active alveolitis. Similarly, while ground‐glass opacification on HRCT accurately predicted alveolitis in the middle lung fields, HRCT did not detect all sites of inflammation and did not identify infectious etiologies. These data suggest that, in addition to HRCT, BAL with lavage, differential cell counting, and culture from at least 2 segments of lung be performed for diagnosing SSc alveolitis.
Strong association of a functional polymorphism in the monocyte chemoattractant protein 1 promoter gene with lupus nephritis
Authors: Tucci Marco , Barnes Elena V. , Sobel Eric S. , Croker Byron P. , Segal Mark S. , Reeves Westley H. , Richards Hanno B. 
Published: June 2004

AbstractObjectiveLupus nephritis (LN) is a major contributor to morbidity and mortality in patients with systemic lupus erythematosus (SLE). There is evidence that polymorphisms in the genes of inflammatory mediators may predispose to the development of LN in patients with SLE. In this study, we examined the role of a functional monocyte chemoattractant protein 1 (MCP‐1) polymorphism in SLE and LN.MethodsDNA and paired urine and serum samples were obtained from 134 SLE patients (≥4 American College of Rheumatology criteria for SLE; 49 with and 85 without LN) and 118 controls. MCP‐1 genomic variants were detected by polymerase chain reaction followed by restriction enzyme–fragment analysis. Urinary and serum MCP‐1 levels and MCP‐1 production by peripheral blood macrophages were measured by enzyme‐linked immunosorbent assay.ResultsThe A/A genotype was more common in controls than in SLE patients (P = 0.0002), whereas both the A/G (P = 0.009) and G/G (P = 0.0212) genotypes were more frequent in SLE patients. The A/A genotype was observed in only 23% of the patients with LN compared with 58% of those without LN (P < 0.0001). MCP‐1 production by peripheral blood mononuclear cells from patients with the A/G and G/G phenotypes was markedly higher than the production by cells from patients with the A/A genotype. Urinary levels of MCP‐1 were significantly higher in patients with LN.ConclusionThese results suggest that an A/G or G/G genotype may predispose to the development of SLE and further indicate that SLE patients with these genotypes may be at higher risk of developing LN. Moreover, measurement of urinary levels of MCP‐1 may be a useful tool for the detection and management of LN.
Increased interleukin‐18 expression in bone marrow of a patient with systemic juvenile idiopathic arthritis and unrecognized macrophage‐activation syndrome
Authors: Maeno Nobuaki , Takei Syuji , Imanaka Hiroyuki , Yamamoto Kimie , Kuriwaki Kazumi , Kawano Yoshifumi , Oda Hiroshi 
Published: June 2004

AbstractThe aberrant induction of proinflammatory cytokines is considered to be crucial in the pathogenesis of systemic juvenile idiopathic arthritis and adult‐onset Still's disease. Interleukin‐18 (IL‐18) in particular has been reported to be a candidate for the key cytokine in both diseases; however, the origin of IL‐18 is unclear. To clarify the origin, we investigated specimens from various organs obtained during autopsy of a child with systemic JIA and macrophage activation syndrome, using immunohistochemical staining. Our results showed a high number of cells expressing IL‐18 in the bone marrow but not in the other organs. This finding suggests that bone marrow is the origin of increased serum IL‐18 and raises the possibility that other proinflammatory cytokines are also induced by IL‐18 in bone marrow in this disease. Bone marrow may be an essential organ in the pathogenesis of systemic JIA.
Initiation of degenerative joint damage by experimental bleeding combined with loading of the joint: A possible mechanism of hemophilic arthropathy
Authors: Hooiveld Michel J. J. , Roosendaal Goris , Jacobs Kim M. G. , Vianen Marieke E. , van den Berg H. Marijke , Bijlsma Johannes W. J. , Lafeber Floris P. J. G. 
Published: June 2004

AbstractObjectiveTo investigate the effect of a limited number of experimental joint bleedings, combined with loading of the affected joint, on the development of progressive degenerative joint damage.MethodsThe right knee of 8 mature beagle dogs was injected with freshly collected autologous blood 3 times per week for 4 weeks, to mimic a limited number of joint hemorrhages occurring over a short period. To ensure loading of the experimental joint, the contralateral control knee of the animals was fixed to the trunk 4 hours per day, 3 days per week. Ten weeks after the last injection, cartilage tissue and synovium were collected from both knees to analyze features of joint degeneration. Cartilage was prepared for analysis of proteoglycan turnover (synthesis, retention, release, and content) and histologic features. Synovium was prepared for histologic analysis.ResultsThe rate of proteoglycan synthesis was significantly increased, characteristic of degenerative cartilage damage as seen in osteoarthritis. Release of newly formed proteoglycans (as a measure of retention) and total loss of proteoglycans from the cartilage matrix were increased. Cartilage matrix integrity was adversely altered, as shown by histologic damage. Histologic analysis also revealed signs of synovial inflammation. These effects were not observed 10 weeks after the experimental bleedings in joints that did not undergo forced loading.ConclusionExperimental joint bleedings when combined with loading of the affected joint resulted in features of progressive degenerative joint damage, whereas similar joint hemorrhages without joint loading did not. This might reflect a possible mechanism of joint damage in hemophilia.
T cell receptors recognizing type II collagen in HLA–DR–transgenic mice characterized by highly restricted Vβ usage
Authors: He Xiaowen , Rosloniec Edward F. , Myers Linda K. , McColgan William Lewis , Gumanovskaya Marina , Kang Andrew H. , Stuart John M. 
Published: June 2004

AbstractObjectiveTo determine the T cell receptor (TCR) structure recognizing type II collagen (CII) in HLA–DR–transgenic mice, and to examine the role of T cells with certain Vβ‐chains in collagen‐induced arthritis (CIA).MethodsT cell hybridomas were established from DR1‐ and DR4‐transgenic mice and selected for their responses to CII and CII peptide containing the T cell determinants. RNA was extracted and reverse transcribed into complementary DNA, which was then amplified using appropriate Vβ‐ and Vα‐subfamily–specific primers. The polymerase chain reaction products were purified and directly sequenced. To determine the role of T cells with certain Vβ‐chains in CIA, Vβ‐subfamily–specific antibodies were administered and the development and characteristics of arthritis were determined.ResultsTCRs of 23 clonally distinct T cell hybridomas that were derived from DR1‐transgenic mice and that were reactive to the CII peptide containing the immunodominant determinant were analyzed. These hybridomas predominantly used the TCR Vβ14 and Vβ8 gene segments (70% and 30%, respectively). The same restriction in Vβ usage was also found in CII‐reactive T cell hybridomas from DR4‐transgenic mice. There was also restricted use of Vα genes, although this was less marked than that of Vβ. In contrast, the hybridomas expressed a diverse third complementarity‐determining region. Deletion of both Vβ14‐bearing and Vβ8‐bearing T cells significantly reduced the incidence and severity of CIA.ConclusionThese data demonstrate that DR1 and DR4 not only bind and present the same CII immunodominant peptide, but also stimulate a highly restricted subset of T cells.
Ascorbic acid increases the severity of spontaneous knee osteoarthritis in a guinea pig model
Authors: Kraus Virginia B. , Huebner Janet L. , Stabler Thomas , Flahiff Charlene M. , Setton Lori A. , Fink Christian , Vilim Vladimir , Clark Amy G. 
Published: June 2004

AbstractObjectiveTo determine whether ascorbic acid might be of benefit for the treatment of spontaneous osteoarthritis (OA) when administered over a long period of time.MethodsWe investigated the effects of 8 months' exposure to low, medium, and high doses of ascorbic acid on the in vivo development of histologic knee OA in the male Hartley guinea pig. The low dose represented the minimum amount needed to prevent scurvy. The medium dose was the amount present in standard laboratory guinea pig chow and resulted in plasma levels comparable with those achieved in a person consuming 200 mg/day (5 fruits and vegetables daily). The high dose was the amount shown in a previous study of the guinea pig to slow the progression of surgically induced OA.ResultsWe found an association between ascorbic acid supplementation and increased cartilage collagen content but, in contrast to findings in a previous study of surgically induced OA in the guinea pig, ascorbic acid worsened the severity of spontaneous OA. Active transforming growth factor β (TGFβ) was expressed in marginal osteophytes, whose size and number were significantly increased with increasing intake of ascorbic acid. Synovial fluid levels of cartilage oligomeric matrix protein, a biomarker of cartilage turnover, corroborated the histologic findings.ConclusionAscorbic acid has been shown to activate latent TGFβ. Prolonged intraarticular exposure to TGFβ has been shown to cause OA‐like changes. We found expression of active TGFβ in osteophytes, a prominent feature of the joint histology seen in association with ascorbic acid treatment. Thus, the deleterious effects of prolonged ascorbic acid exposure may be mediated in part by TGFβ. This worsening of OA with ascorbic acid supplementation suggests that ascorbic acid intake should not be supplemented above the currently recommended dietary allowance (90 mg/day for men and 75 mg/day for women).
Juvenile rheumatoid arthritis affected sibpairs: Extent of clinical phenotype concordance
Authors: Moroldo Marta B. , Chaudhari Minakshi , Shear Edith , Thompson Susan D. , Glass David N. , Giannini Edward H. 
Published: June 2004

AbstractObjectiveTo investigate the clinical phenotypes and demographic characteristics of 183 affected sibling pairs (ASPs) with juvenile rheumatoid arthritis (JRA) and to determine whether there are differences between the clinical phenotypes of the ASP cohort compared with patients with sporadic disease and whether there is greater sharing of specific clinical features within versus between sibpairs.MethodsDetails of the JRA Affected Sibpair Registry operations have been described previously. The frequencies of phenotypes in the 2 cohorts were tabulated, summary statistics were determined, and comparisons were made by chi‐square test or t‐test. Sibling risk, sibling risk ratios (λs), and odds ratios were calculated to assess familial aggregation of several different clinical manifestations.ResultsThe most common onset type among the 164 nontwin ASPs was pauciarticular (65% overall). Fifty‐three percent of the ASPs were concordant for pauciarticular‐onset JRA; 19% were concordant for a polyarticular disease onset. Among subjects with polyarticular‐onset disease, significantly more joints were involved at onset in simplex patients than in ASPs (P = 0.008). The difference in age at JRA onset within sibpairs (sibling 1 versus sibling 2) was not significantly different. ASPs developed disease at a mean real‐time difference of 5.1 years apart. Familial aggregation was found for tenosynovitis (λs 29.5), leukocytosis (λs 25), rheumatoid factor (λs 11.0), anemia (λs 1.7), and antinuclear antibodies (λs 1.3).ConclusionThis study confirms the findings of earlier studies showing that a high proportion of ASPs overall show concordance of disease‐onset type, except for the subset of patients with systemic disease, and that nontwin ASPs do not develop disease at the same point in real time. We conclude that JRA and its clinical manifestations do not differ substantially between ASPs and the simplex population. The exception is the number of affected joints at JRA onset among patients with polyarticular‐onset disease. Familial aggregation of clinical features among ASPs adds strong evidence for a genetic background in this disease.
Local expression of the serum amyloid A and formyl peptide receptor–like 1 genes in synovial tissue is associated with matrix metalloproteinase production in patients with inflammatory arthritis
Authors: O'Hara Rosemary , Murphy Evelyn P. , Whitehead Alexander S. , FitzGerald Oliver , Bresnihan Barry 
Published: June 2004

AbstractObjectiveTo evaluate the regulation of acute‐phase serum amyloid A (A‐SAA) production in inflamed synovial tissue, and to elucidate a possible pathophysiologic role in the induction of matrix metalloproteinase (MMP) release by fibroblast‐like synoviocytes (FLS).MethodsSynovial tissue samples were obtained by arthroscopic biopsy from the knee joints of patients with inflammatory arthritis. Primary cultures of FLS from patients with rheumatoid arthritis (RA), psoriatic arthritis, sarcoid arthritis, and undifferentiated arthritis were established. Total RNA was extracted from FLS and analyzed by reverse transcription–polymerase chain reaction (PCR) using specific primers for A‐SAA and formyl peptide receptor–like 1 (FPRL1), an A‐SAA receptor. Southern blot analysis confirmed the PCR products generated. Immunohistochemical analysis demonstrated the expression of A‐SAA protein production by several synovial cell populations, and immunofluorescence analysis confirmed A‐SAA colocalization with the macrophage marker CD68. Primary FLS cultures stimulated with recombinant human A‐SAA resulted in dose‐dependent MMP‐1 and MMP‐3 production, as measured by an enzyme‐linked immunosorbent assay.ResultsA‐SAA messenger RNA (mRNA) and FPRL1 mRNA were present in FLS, macrophages, and endothelial cells isolated from the synovial tissue of patients with RA and other categories of inflammatory arthritis. A‐SAA expression was regulated by proinflammatory cytokines and occurred in association with FPRL1 expression in FLS and endothelial cells, which is consistent with a biologic role at the sites of inflammation. Recombinant human A‐SAA induced both MMP‐1 and MMP‐3 secretion by FLS. The mean fold increases in A‐SAA–induced MMP‐1 and MMP‐3 production were 2.6 and 10.6, respectively, compared with 7.6‐fold and 41.9‐fold increases in interleukin‐1β–induced MMP‐1 and MMP‐3 production.ConclusionThe up‐regulation of the A‐SAA and FPRL1 genes in inflamed synovial tissue suggests an important role in the pathophysiology of inflammatory arthritis. A‐SAA induces the production of MMPs. Therapeutic targeting of A‐SAA, or FPRL1, may modulate pathophysiologic pathways that are associated with matrix degradation in patients with RA and other forms of progressive inflammatory arthritis.