bluuebunny/crossref_metadata_2025_split huggingface dataset:
Is antibody clustering predictive of clinical subsets and damage in systemic lupus erythematosus?
Authors: To C. H. , Petri M. 
Published: December 2005

AbstractObjectiveTo examine autoantibody clusters and their associations with clinical features and organ damage accrual in patients with systemic lupus erythematosus (SLE).MethodsThe study group comprised 1,357 consecutive patients with SLE who were recruited to participate in a prospective longitudinal cohort study. In the cohort, 92.6% of the patients were women, the mean ± SD age of the patients was 41.3 ± 12.7 years, 55.9% were Caucasian, 39.1% were African American, and 5% were Asian. Seven autoantibodies (anti–double‐stranded DNA [anti‐dsDNA], anti‐Sm, anti‐Ro, anti‐La, anti‐RNP, lupus anticoagulant (LAC), and anticardiolipin antibody [aCL]) were selected for cluster analysis using the K‐means cluster analysis procedure.ResultsThree distinct autoantibody clusters were identified: cluster 1 (anti‐Sm and anti‐RNP), cluster 2 (anti‐dsDNA, anti‐Ro, and anti‐La), and cluster 3 (anti‐dsDNA, LAC, and aCL). Patients in cluster 1 (n = 451), when compared with patients in clusters 2 (n = 470) and 3 (n = 436), had the lowest incidence of proteinuria (39.7%), anemia (52.8%), lymphopenia (33.9%), and thrombocytopenia (13.7%). The incidence of nephrotic syndrome and leukopenia was also lower in cluster 1 than in cluster 2. Cluster 2 had the highest female‐to‐male ratio (22:1) and the greatest proportion of Asian patients. Among the 3 clusters, cluster 2 had significantly more patients presenting with secondary Sjögren's syndrome (15.7%). Cluster 3, when compared with the other 2 clusters, consisted of more Caucasian and fewer African American patients and was characterized by the highest incidence of arterial thrombosis (17.4%), venous thrombosis (25.7%), and livedo reticularis (31.4%). By using the Systemic Lupus International Collaborating Clinics/American College of Rheumatology Damage Index, the greatest frequency of nephrotic syndrome (8.9%) was observed in patients in cluster 2, whereas cluster 3 patients had the highest percentage of damage due to cerebrovascular accident (12.8%) and venous thrombosis (7.8%). Osteoporotic fracture (11.9%) was also more common in cluster 3 than in cluster 2.ConclusionAutoantibody clustering is a valuable tool to differentiate between various subsets of SLE, allowing prediction of subsequent clinical course and organ damage.
Amelioration of autoimmune nephritis by imatinib in MRL/lpr mice
Authors: Sadanaga Atsushi , Nakashima Hitoshi , Masutani Kohsuke , Miyake Katsuhisa , Shimizu Sakiko , Igawa Takashi , Sugiyama Naonobu , Niiro Hiroaki , Hirakata Hideki , Harada Mine 
Published: December 2005

AbstractObjectiveTo examine whether the platelet‐derived growth factor (PDGF) receptor antagonist imatinib ameliorates glomerulonephritis in MRL/lpr mice, a condition that is similar to severe lupus nephritis in humans.MethodsSixteen‐week‐old MRL/lpr female mice having an advanced stage of glomerulonephritis were divided into 3 groups according to treatment: 1) 50 mg/kg or 2) 10 mg/kg of imatinib (administered orally 4 times a week up to 24 weeks of age) or 3) vehicle solution (untreated group). The histopathologic condition of the kidneys and salivary glands of each mouse as well as the cumulative survival rates, extent of lymphadenopathy and splenomegaly, and serum chemistry and immunologic values were assessed.ResultsIn mice treated with 50 mg/kg imatinib, neither proliferation of glomerular cells nor crescent formation occurred. A drastic decrease in mesangial matrix was noted. Mice treated with 50 mg/kg imatinib had a prolonged life span compared with mice treated with 10 mg/kg imatinib and untreated mice. Expression of PDGF receptor and transforming growth factor β messenger RNA in the kidneys was significantly reduced in the 50 mg/kg imatinib–treated mice compared with that in the 10 mg/kg imatinib–treated mice (P < 0.05) and the untreated mice (P < 0.01). Intriguingly, lymphadenopathy and salivary gland inflammation were also attenuated in imatinib‐treated mice, in a dose‐dependent manner. Serum levels of IgG and anti–double‐stranded DNA antibodies were also reduced in the imatinib‐treated mice.ConclusionThese findings indicate that imatinib has a pleiotropic therapeutic effect, namely, the inhibition of PDGF signaling and immunosuppression, on the glomerulonephritis of MRL/lpr mice, which suggests a potential application of this drug in the treatment of human lupus nephritis.
Cyclooxygenase‐ and lipoxygenase‐derived eicosanoids in bronchoalveolar lavage fluid from patients with scleroderma lung disease: An imbalance between proinflammatory and antiinflammatory lipid mediators
Authors: Kowal‐Bielecka Otylia , Kowal Krzysztof , Distler Oliver , Rojewska Joanna , Bodzenta‐Lukaszyk Anna , Michel Beat A. , Gay Renate E. , Gay Steffen , Sierakowski Stanislaw 
Published: December 2005

AbstractObjectiveEicosanoids play a key role in the regulation of inflammation and fibrosis. Recently we showed that levels of 5‐lipoxygenase (5‐LOX)–derived proinflammatory/profibrotic leukotrienes are elevated in bronchoalveolar lavage (BAL) fluid from patients with scleroderma lung disease (SLD). The present study was undertaken to investigate whether increased levels of leukotrienes are balanced by the antiinflammatory/antifibrotic cyclooxygenase (COX)– and 15‐LOX–derived eicosanoids in the lungs of patients with SLD.MethodsLevels of 5‐LOX–derived leukotriene B4 (LTB4), COX‐derived prostaglandin E2 (PGE2), and 15‐LOX–derived 15‐hydroxyeicosatetraenoic acid (15‐HETE) and lipoxin A4 (LXA4) in BAL fluid from systemic sclerosis (SSc) patients with SLD (n = 32) and without SLD (n = 16) and from healthy individuals (n = 12) were measured by enzyme‐linked immunosorbent assay.ResultsLevels of LTB4 (mean ± SEM 248 ± 29 pg/ml) and PGE2 (51 ± 10 pg/ml) in SSc patients with SLD were significantly higher compared with patients without SLD (LTB4 119 ± 35 pg/ml, PGE2 17 ± 3 pg/ml; P < 0.05 for both) and with healthy controls (85 ± 12 pg/ml and 19 ± 2 pg/ml, respectively; P < 0.05 for both). Accordingly, the mean ± SEM PGE2:LTB4 ratio was similar in SSc patients with SLD (0.30 ± 0.05), SSc patients without SLD (0.29 ± 0.07), and controls (0.31 ± 0.07). In contrast, levels of 15‐HETE and LXA4 in patients with SLD did not differ significantly from levels in patients without SLD or in controls. The ratio of LXA4:LTB4 in SLD patients (0.16 ± 0.03) was significantly lower (P < 0.05) than that in patients without SLD (0.40 ± 0.10) or controls (0.34 ± 0.08).ConclusionIncreased production of LTB4 in the lungs of patients with SLD is not balanced by an up‐regulation of 15‐LOX–derived antiinflammatory/antifibrotic eicosanoids such as 15‐HETE or LXA4. Targeting the 5‐LOX/15‐LOX balance may be of practical value in the treatment of SLD.
Early detection of pulmonary arterial hypertension in systemic sclerosis: A French nationwide prospective multicenter study
Authors: Hachulla Eric , Gressin Virginie , Guillevin Loïc , Carpentier Patrick , Diot Elisabeth , Sibilia Jean , Kahan André , Cabane Jean , Francès Camille , Launay David , Mouthon Luc , Allanore Yannick , Tiev Kiet Phong , Clerson Pierre , Groote Pascal de , Humbert Marc 
Published: December 2005

AbstractObjectiveScreening allows for early management of pulmonary arterial hypertension (PAH), a severe complication of systemic sclerosis (SSc). Since no consensus has been reached on the method and criteria for optimal screening, we sought to develop an algorithm based on symptoms, Doppler echocardiography, and right heart catheterization (RHC) for application to a nationwide multicenter SSc population in France.MethodsThis prospective study was conducted from September 2002 to July 2003 by experts at 21 SSc centers. At each center, SSc patients without severe pulmonary function abnormalities underwent Doppler echocardiography by an experienced cardiologist. Patients with a peak velocity of tricuspid regurgitation (VTR) of >3 meters/second or 2.5–3 meters/second with unexplained dyspnea were asked to undergo RHC to confirm PAH according to international guidelines.ResultsOf the 599 patients analyzed, 29 had known PAH and 33 had suspected PAH, based on Doppler echocardiography, and underwent RHC. Of these 33, 18 were found to have PAH, 3 had left ventricular dysfunction, and 12 had no PAH. Newly diagnosed cases of PAH were of mild severity (mean ± SD pulmonary artery pressure [mPAP] 30 ± 9 mm Hg, mean ± SD total pulmonary resistance [TPR] 524 ± 382 dynes × second/cm5). Hemodynamic findings in patients with known PAH were mPAP 49 ± 17 mm Hg and TPR 1,007 ± 615 dynes × second/cm5. The estimate of PAH prevalence was 7.85% (95% confidence interval 5.70–10.00).ConclusionThis screening algorithm, based on dyspnea, Doppler echocardiographic evaluation of VTR, and RHC, enabled early detection of PAH at a mild stage. Whether mild PAH will evolve to severe PAH in reported cases and whether this early diagnosis translates into improved prognosis for patients with mild PAH will be evaluated in the ongoing 3‐year followup of this cohort.
Synergistic interaction between methotrexate and a superoxide dismutase mimetic: Pharmacologic and potential clinical significance
Authors: Cuzzocrea Salvatore , Mazzon Emanuela , di Paola Rosanna , Genovese Tiziana , Muià Carmelo , Caputi Achille P. , Salvemini Daniela 
Published: December 2005

AbstractObjectiveTo investigate the effects of combination therapy with M40403 and methotrexate (MTX) on collagen‐induced arthritis (CIA) in rats.MethodsCIA was elicited in Lewis rats that had been assigned to different experimental groups, and the rats were treated daily, starting at the onset of arthritis (day 26), with M40403 2 mg/kg intraperitoneally, MTX 0.15 mg/kg orally, or combination therapy (M40403 2 mg/kg plus MTX 0.015 mg/kg).ResultsThe histopathologic features of CIA in type II collagen–challenged rats included erosion of the articular cartilage and bone resorption. Treatment of rats with MTX 0.15 mg/kg orally delayed the development of clinical signs (days 26–35) and improved histologic status in the knee and paw, as clearly demonstrated by a significant reduction in erosion of the articular cartilage at the joint margins and subchondral bone resorption. Furthermore, radiographic evidence of protection against bone resorption and soft tissue swelling was apparent in the tibiotarsal joints of rats treated with MTX 0.15 mg/kg daily. Furthermore, combination therapy with M40403 2 mg/kg plus MTX 0.015 mg/kg exerted significant protection against the development of arthritis, similar to that observed with MTX alone at a dose of 0.15 mg/kg. In contrast, no significant protection was observed in animals treated with M40403 2 mg/kg alone or with MTX 0.015 mg/kg alone.ConclusionThis study provides the first evidence that M40403, a potent superoxide dismutase mimetic, exerts a significant synergistic effect with MTX in rats with CIA.
Arthritis in mice that are deficient in interleukin‐1 receptor antagonist is dependent on genetic background
Authors: Zhou Fang , He Xiaowen , Iwakura Yoichiro , Horai Reiko , Stuart John M. 
Published: December 2005

AbstractObjectiveTo determine the effect of deletion of interleukin‐1 receptor antagonist (IL‐1Ra) protein in an animal model of rheumatoid arthritis.MethodsBALB/c mice deficient in IL‐1Ra (IL‐1Ra−/−) were bred with collagen‐induced arthritis (CIA)–susceptible DBA/1 mice and B10 mice transgenic for HLA–DRB1*0101 (B10.DR1). After generation of IL‐1Ra−/− mice on the DBA/1 and B10.DR1 backgrounds, the mice were observed for the development of spontaneous arthritis and immunized for induction of CIA.ResultsWe found that although BALB/c mice deficient in IL‐1Ra (BALB/c−/−) spontaneously developed chronic inflammatory arthritis, DBA/1 IL‐1Ra–deficient (DBA/1−/−) and B10.DR1 IL‐1Ra–deficient (B10.DR1−/−) mice did not. Splenocytes from BALB/c−/− mice produced elevated levels of IL‐2, IL‐4, IL‐6, IL‐10, IL‐17, and granulocyte–macrophage colony‐stimulating factor in response to anti‐CD3 stimulation. After immunization with type II collagen (CII), DBA/1−/− and B10.DR1−/− mice had a significantly earlier onset of CIA, and with increased severity compared with IL‐1Ra+/+ mice. Immunization of BALB/c−/− mice with CII did not aggravate spontaneous arthritis. All of the immunized mice developed antibodies to CII that correlated with arthritis severity. Levels of antibody to CII in the BALB/c−/− strain were relatively low.ConclusionThese data indicate that the spontaneous arthritis of IL‐1Ra deficiency is highly dependent on non–major histocompatibility complex genes and that autoimmunity to CII is not the major disease‐inducing event. Class II immune response genes are more important for the regulation of CIA, and although these 2 models of arthritis share many pathogenic mechanisms, they also have significant differences.
Antiferritin antibodies discovered by phage display expression cloning are associated with radiographic damage in rheumatoid arthritis
Authors: Mewar D. , Moore D. J. , Young‐Min S. , Bertolaccini M. L. , Khamashta M. A. , Watson P. F. , Wilson A. G. 
Published: December 2005

AbstractObjectiveSeveral autoantibodies have been described in individuals with rheumatoid arthritis (RA), leading to interest in the use of such antibodies as diagnostic or prognostic markers in RA as well as in their relevance to disease pathology. The objective of this study was to use a phage display expression cloning system to identify novel autoantibody targets in RA.MethodsWe used immunoscreening of a phage‐displayed complementary DNA (cDNA) library to isolate a cDNA clone encoding the ferritin heavy chain polypeptide. Antiferritin antibody levels in patients with early and established RA, healthy controls, and disease controls were measured by enzyme‐linked immunosorbent assay. Antibody‐positive and antibody‐negative individuals were compared with respect to disease severity as measured by the modified Larsen score, demographic variables, rheumatoid factor status, and carriage of HLA–DRB1 shared epitope alleles.ResultsAntiferritin antibodies were present in 60 (16%) of 366 patients with established RA, 23 (19%) of 118 patients with early RA, 2 (2.7%) of 73 healthy blood donors, 2 (2.1%) of 94 individuals with osteoarthritis, and 2 (2.1%) of 97 patients with systemic lupus erythematosus (P < 0.01, RA patients versus healthy and disease controls). Antiferritin antibodies were more common in men than in women (28.4% versus 12.2%; P < 0.001), and antiferritin levels were associated with the severity of joint damage (P = 0.01).ConclusionAntiferritin antibodies are observed in a subset of patients with RA, are present early in the disease course, and are associated with the severity of radiographic damage. Further studies are required to explore their potential as diagnostic and prognostic markers in RA.
The mannose‐binding lectin gene polymorphisms and systemic lupus erythematosus: Two case–control studies and a meta‐analysis
Authors: Ho Lee Young , Witte Torsten , Momot Tanja , Schmidt Reinhold E. , Kaufman Kenneth M. , Harley John B. , Sestak Andrea L. 
Published: December 2005

AbstractObjectiveMannose‐binding lectin (MBL) enhances opsonization and activates complement. Dysfunctional alleles of MBL have been associated with low plasma concentrations of MBL and increased risk of systemic lupus erythematosus (SLE), but genotyping studies have shown inconsistent results. We performed case–control studies of the MBL polymorphisms in 2 Caucasian cohorts and a meta‐analysis incorporating all published results of MBL genotyping in SLE to explore whether the MBL functional variants are associated with SLE.MethodsMBL genotypes at 7 single‐nucleotide polymorphisms were sequenced in 96 European American patients with SLE and 96 age‐, race‐, and sex‐matched controls. MBL codons 52, 54, and 57 were genotyped in 285 German patients with SLE and 200 race‐matched controls. Allele frequencies of all known variants were tallied for meta‐analysis.ResultsAlthough there was a trend toward association with MBL polymorphisms in both patient cohorts evaluated, none of them was significantly associated with SLE on its own. Seventeen comparisons from 15 studies were included in the meta‐analysis. Publication bias was excluded by Egger's regression test (P = 0.14). The overall odds ratio for MBL codon 54 variant B was 1.406 (95% confidence interval 1.221–1.608; P < 0.001). Stratification by ethnicity showed significantly increased odds ratios for association of the MBL codon 54B variant with SLE in African, Asian, and Caucasian cohorts.ConclusionMeta‐analysis of all available studies on MBL polymorphisms and SLE shows that MBL variant alleles such as MBL exon 1 codon 54 B, promoter –550 L, and promoter –221 X are SLE risk factors. This association is robust and persists after incorporation of data from our 2 cohorts in which the association failed to reach significance.
The Disease Activity Score is not suitable as the sole criterion for initiation and evaluation of anti–tumor necrosis factor therapy in the clinic: Discordance between assessment measures and limitations in questionnaire use for regulatory purposes
Authors: Wolfe Frederick , Michaud Kaleb , Pincus Theodore , Furst Daniel , Keystone Edward 
Published: December 2005

AbstractObjectiveThe Disease Activity Score (DAS) is widely used in clinical trials. A DAS of 5.1 defines the level of severe rheumatoid arthritis (RA) and is the criterion for the initiation of anti–tumor necrosis factor therapy in the UK and The Netherlands. In North America, similar rules are sometimes imposed. However, it is not known how accurately the DAS characterizes RA activity. The present study was undertaken to determine the concordance between DAS scores and physicians' assessments of RA activity, to investigate factors relating to discrepancies, and to assess the suitability of using the DAS in individual patients.MethodsSix hundred sixty‐nine RA patients were assessed using the DAS and other clinical measures. A physician's global estimate of RA activity was performed using an 11‐point predefined scale and a standard definition of disease activity.ResultsThe DAS and physician global assessment had substantially different distributions of values. The level of agreement (Kendall's tau‐a) between DAS scores and physician global assessments was 49% (95% confidence interval 45–53%), Lin's coefficient of concordance was 0.62, and the Bland‐Altman 95% limits of agreement were −3.17 and 3.99. These results suggest poor‐to‐moderate concordance between the 2 measures of disease activity.ConclusionThe DAS and the physician's assessment of RA activity do not approach, value, and weight RA variables to the same extent, suggesting that RA activity is not evaluated similarly by North American physicians and with the DAS. The scales do not have acceptable levels of concordance. There is too much inherent variability in the DAS and other RA scales (e.g., the Health Assessment Questionnaire) to recommend them as sole determinants of RA activity for clinical or regulatory purposes.
Impact of [18F]fluorodeoxyglucose positron emission tomography on surgical management of melanoma patients
Authors: Bastiaannet E , Oyen W J G , Meijer S , Hoekstra O S , Wobbes T , Jager P L , Hoekstra H J 
Published: December 2005

Abstract

Background
Several studies have shown adequate sensitivity and specificity of [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) for the detection of metastases from melanoma, but few have addressed its impact on treatment. The aim of this retrospective study was to assess the impact of FDG-PET on treatment of melanoma in three Dutch university medical centres.

Methods
The medical records of 257 patients were reviewed. The indications for FDG-PET and findings were recorded. Unexpected findings of suspected (pre)malignant tumours other than melanoma were assessed. Treatment plans before and after FDG-PET were recorded and analysed to evaluate changes in disease management.

Results
Most scans (71·2 per cent) were requested for staging, mainly to detect distant metastases in patients with stage III disease. Overall, 56 patients (21·8 per cent) were upstaged as a result of PET. In 44 patients (17·1 per cent) treatment was changed, usually from surgery to systemic treatment in patients with stage III disease. Unexpected tumours were detected (mainly colorectal) in 11 patients (4·3 per cent).

Conclusion
FDG-PET is most valuable in patients with stage III melanoma for detection of distant metastases and identification of candidates for surgery and/or systemic treatment. Unexpected FDG-PET findings should not be disregarded, as (pre)malignant, clinically relevant, tumours may be identified.
Pathologic features of endometrial carcinoma associated with HNPCC
Authors: Broaddus Russell R. , Lynch Henry T. , Chen Lee‐may , Daniels Molly S. , Conrad Peggy , Munsell Mark F. , White Kristin G. , Luthra Rajyalakshmi , Lu Karen H. 
Published: December 2005

AbstractBACKGROUNDEndometrial carcinoma is a common malignancy in hereditary nonpolyposis colorectal carcinoma (HNPCC). Like colon carcinoma, endometrial carcinoma is diagnosed at an earlier age in women with HNPCC. In contrast to colon carcinoma, the pathologic features of endometrial carcinoma in HNPCC have not been studied in detail. It was the purpose of this study to pathologically characterize a series of HNPCC associated endometrial carcinomas.METHODSFifty women with HNPCC and endometrial carcinoma were analyzed from four different hereditary cancer registries. H&E stained slides and pathology reports were reviewed for clinically important pathologic features of endometrial carcinoma. These results were compared with those for two different groups of sporadic endometrial carcinoma – women younger than age 50 years (n = 42) and women of all ages with tumors demonstrating microsatellite instability (MSI‐high) secondary to methylation of MLH1 (n = 26).RESULTSNearly one‐fourth of HNPCC patients in this study had endometrial tumors with pathologic features that would require adjuvant therapy after hysterectomy. There was a trend toward the HNPCC patients having more nonendometrioid tumors; all of these patients were carriers of MSH2 mutations. Such nonendometrioid tumors were extremely rare in the MLH1 methylated group. A subset of MLH1 methylated sporadic tumors demonstrated a unique, ‘undifferentiated’ histology that was not observed in HNPCC or the young group.CONCLUSIONData suggest a genotype–phenotype relation in which microsatellite instability resulting from MLH1 methylation is almost exclusively associated with classical or ‘undifferentiated’ endometrioid tumors, whereas microsatellite instability secondary to MSH2 mutation can result in a more variable histologic spectrum of endometrial carcinoma. Cancer 2006. © 2005 American Cancer Society.