bluuebunny/crossref_metadata_2025 huggingface dataset:
Crystallographic report: Triorganotin 2‐(p‐chlorophenyl)‐3‐methylbutyrates
Authors: Song Xueqing , Cahill Christopher , Eng George
Published: August 2003

The crystal structures of two triorganotin butyrates were determined. Tricyclohexyltin 2‐(p‐chlorophenyl)‐3‐methylbutyrate was determined to have a distorted tetrahedral geometry. Trimethyltin 2‐(p‐chlorophenyl)‐3‐methylbutyrate, on the other hand, was found to be polymeric in nature with a trigonal bipyramidal configuration. The three methyl groups are located in the equatorial positions with the axial positions occupied by oxygen atoms from two different carboxylate groups. Copyright © 2003 John Wiley & Sons, Ltd.
Dihalodimethyltin(IV) complexes of 2‐(pyrazol‐1‐ylmethyl)pyridine
Authors: Álvarez‐Boo Pedro , Sergio Casas José , Castiñeiras Alfonso , Delfina Couce María , Freijanes Eduardo , Novoa Eva , Sordo José
Published: August 2003

Reaction of dichloro‐ and dibromodimethyltin(IV) with 2‐(pyrazol‐1‐ylmethyl)pyridine (PMP) afforded [SnMe2Cl2(PMP)] and [SnMe2Br2(PMP)] respectively. The new complexes were characterized by elemental analysis and mass spectrometry and by IR, Raman and NMR (1H, 13C) spectroscopies. Structural studies by X‐ray diffraction techniques show that the compounds consist of discrete units with the tin atom octahedrally coordinated to the carbon atoms of the two methyl groups in a trans disposition (SnC = 2.097(5), 2.120(5) Å and 2.110(6), 2.121(6) Å in the chloro and in the bromo compounds respectively), two cis halogen atoms (SnCl = 2.4908(16), 2.5447(17) Å; SnBr = 2.6875(11), 2.7464(9) Å) and the two donor atoms of the ligand (SnN = 2.407(4), 2.471(4) Å and 2.360(5), 2.455(5) Å). In both cases, the SnN(pyridine) bond length is markedly longer than the SnN(pyrazole) distance. Copyright © 2003 John Wiley & Sons, Ltd.
Crystallographic report: The crystal structure of 2‐benzo[b]thienylgermatrane
Authors: Lukevics Edmunds , Ignatovich Luba , Shul'ga Tatyana , Belyakov Sergey
Published: August 2003

The germanium atom is penta‐coordinated and adopts trigonal bipyramidal geometry. The 2‐benzo[b]thienyl group and the nitrogen atom each occupy an apical position with the transannular N → Ge bond distance being 2.180(4) Å. Copyright © 2003 John Wiley & Sons, Ltd.
Morphological characterization of poly(phenylacetylene) nanospheres prepared by homogeneous and heterogeneous catalysis
Authors: Mastrorilli Piero , Nobile Cosimo Francesco , Suranna Gian Paolo , Corradi Anna , Leonelli Cristina , Veronesi Paolo
Published: August 2003

Scanning electron microscopy characterization of the materials obtained by homogeneous and heterogeneous catalytic polymerization of phenylacetylene is described. The catalysts used are β‐dioxygenato rhodium(I) complexes. The effects of the reaction medium, presence of a cocatalyst and the type of catalysis (homogeneous or heterogeneous) on the morphology of the polymers obtained have been studied and discussed. Using a supported complex at 0 °C, nanoparticles with a diameter distribution as narrow as 30 to 70 nm were obtained. Polymer nanopowders were found to be unaffected by ageing. Copyright © 2003 John Wiley & Sons, Ltd.
Biotransformation of arsenate to arsenosugars by Chlorella vulgaris
Authors: Murray Linda A. , Raab Andrea , Marr Iain L. , Feldmann Jörg
Published: August 2003

Chlorella vulgaris was cultivated in a growth medium containing arsenate concentration of <0.01, 10, 100 and 1000 mg l−1. Illumination was carried out in 12 h cycles for 5 days. The health status of the culture was monitored by continuous pH and dissolved oxygen (DO) readings. Destructive sampling was used for the determination of biomass, chlorophyll, total arsenic and arsenic species. The chlorophyll a content, the DO and pH cycles were not significantly different for the different arsenate concentrations in the culture. In contrast, biomass production was significantly (p < 0.05) increased for the arsenic(V) treatment at 1000 mg l−1 compared with 100 mg l−1.

The arsenic concentration in the algae increased with the arsenate concentration in the culture. However, the bioconcentration factor decreased a hundred‐fold with increase of arsenate from the background level to 1000 mg l−1. The arsenic species were identified by using strong anion‐exchange high‐performance liquid chromatography–inductively coupled plasma mass spectrometry analysis after methanol/water (1 : 1) extraction. The majority (87–100%) of the extractable arsenic was still arsenate; arsenite was found to be between 1 and 6% of total extractable arsenic in the algae. In addition to dimethylarsinic acid, one unknown arsenical (almost co‐eluting with methylarsonic acid) and three different arsenosugars have been identified for the first time in C. vulgaris growing in a culture containing a mixture of antibiotics and believed to be axenic. The transformation to arsenosugars in the algae is not dependent on the arsenate concentration in the culture and varies between 0.2 and 5% of total accumulated arsenic. Although no microbiological tests for bacterial contamination were made, this study supports the hypothesis that algae, and not associated bacteria, produce the arsenosugars. Copyright © 2003 John Wiley & Sons, Ltd.
Crystallographic report: Crystal structure of 1‐bromo‐1′‐[(2S)‐N‐(1‐hydroxy‐3‐methylbutane‐2‐yl)]‐ferroceneamide
Authors: Arion Vladimir B. , Nazarov Alexey A. , Hartinger Christian G. , Giester Gerald , Keppler Bernhard K.
Published: August 2003

For the unsymmetrical title compound, 1‐bromo‐1′‐[(2S)‐N‐(1‐hydroxy‐3‐methylbutane‐2‐yl)]‐ferroceneamide, two independent molecules were found in the asymmetric unit. Copyright © 2003 John Wiley & Sons, Ltd.
Direct evidence for co‐binding of cisplatin and cadmium to a native zinc‐ and cadmium‐containing metallothionein
Authors: Mandal Rupasri , Jiang Guifeng , Li Xing‐Fang
Published: August 2003

Cisplatin is widely used to treat a number of cancers, and its covalent binding to DNA is believed to cause cell death; however, the roles of cisplatin–protein interactions in the mechanisms of action, toxicity, and resistance of the drug largely remain to be elucidated. Here, we investigate the interactions of cisplatin and a native rabbit metallothionein (MT), containing 1.4% zinc and 7.9% cadmium, using nanospray tandem quadrupole time‐of‐flight mass spectrometry (MS) and size‐exclusion high‐performance liquid chromatography with inductively coupled plasma MS. At near‐neutral pH conditions, reactions between cisplatin and MT resulted in the formation of complexes that contained Cd4–Ptn–MT (n = 1–7). While zinc was displaced by cisplatin, both platinum and cadmium were bound to the same MT molecule. This is the first report to provide direct evidence for the co‐binding of cadmium and platinum to MT, which suggests that the mechanism of the binding of cisplatin to the native MT may not be through the displacement of cadmium as previously proposed. A tandem MS investigation into the binding sites of the platinum and cadmium to MT showed platinum‐ and cadmium‐related fragments, such as (PtS2C2H7N)+ and (CdS3C5H17N2)+, demonstrating the platinum–cysteine and cadmium–cysteine binding. In addition, detection of Cd4–Pt7–MT demonstrated more than ten metals bound to a single MT molecule. This finding was extended to the binding of MT with a five‐fold excess of CdCl2. As many as 14 metal atoms (13 cadmium and one zinc) were detected bound to a single MT molecule, the complexes being Cdx–Zn–MT (x = 5–13). The high binding capacity of MT for cadmium and platinum is consistent with the role of MT in reduction of metal toxicity and its involvement in drug resistance. Copyright © 2003 John Wiley & Sons, Ltd.
Prevalence, incidence, survival, and disease characteristics of systemic sclerosis in a large US population
Authors: Mayes Maureen D. , Lacey James V. , Beebe‐Dimmer Jennifer , Gillespie Brenda W. , Cooper Brenda , Laing Timothy J. , Schottenfeld David
Published: August 2003

Objective

To estimate the prevalence, incidence, survival, and disease characteristics of systemic sclerosis (SSc) in the Detroit tricounty area.

Methods

A census of SSc cases for the period 1989–1991 was conducted in the Detroit area, using multiple sources for case identification. Diagnoses were verified by medical record review. Capture‐recapture analysis was used to estimate the total SSc population. Cases of localized scleroderma (morphea and linear disease) were excluded.

Results

Based on 706 verified cases of SSc, prevalence was initially estimated to be 242.0 cases per million adults (95% confidence interval [95% CI] 213–274), with an annual incidence of 19.3 new cases per million adults per year (95% CI 12.4–30.2). Capture‐recapture analysis, based on the degree of overlap of verified cases among multiple sources, resulted in a revised prevalence estimate of 276 cases per million adults (95% CI 245–310). Sex‐ and race‐specific prevalence estimates were significantly higher for women than for men, and for blacks than for whites. The average age at diagnosis was significantly younger for blacks than for whites. Compared with white patients, black patients were almost twice as likely to have diffuse disease (prevalence proportion ratio 1.86, 95% CI 1.48–2.35). Median survival was ∼11 years. Factors negatively affecting survival included male sex (hazard ratio 1.81, 95% CI 1.29–2.55) and older age at diagnosis (hazard ratio 1.04, 95% CI 1.03–1.05).

Conclusion

This study establishes baseline estimates of SSc occurrence and characteristics in a large US cohort consisting primarily of black adults and white adults. These data should facilitate research regarding the role of geographic, ethnic, racial, and environmental factors for this disease in comparison populations.
Limited versus severe Wegener's granulomatosis: Baseline data on patients in the Wegener's granulomatosis etanercept trial
Authors: Stone John H.
Published: August 2003

Objective

To report baseline data on 180 patients with Wegener's granulomatosis (WG) enrolled in the WG Etanercept Trial (WGET), and to examine demographic and clinical differences between patients with limited disease and those with severe disease.

Methods

Definitions of limited and severe disease were agreed upon by consensus of the investigators at a pretrial meeting and were incorporated into the protocol as a stratification criterion. These data were applied prospectively to the WGET patient cohort, based on clinical features and the intention to treat patients according to disease activity. Data related to disease onset, date of diagnosis, clinical features, antineutrophil cytoplasmic antibody assays, tissue biopsy findings, and other medical history were collected on a baseline medical history form. Physician‐investigators from each center participated in the development of this form, and all were certified in its use prior to the start of the trial. Selected data on patients who were screened for the trial but were not enrolled were also collected.

Results

Several significant differences between the limited and severe disease subsets were observed. Patients with limited disease were nearly a decade younger at disease onset compared with patients with severe disease. Thirty‐three percent of patients with severe disease were women, compared with 58% of those with limited disease. Despite their younger age at symptom onset, patients with limited disease tended to have longer disease duration, a greater likelihood of experiencing exacerbation of previous disease following a period of remission, and a higher prevalence of destructive upper respiratory tract disorders at the time of enrollment (e.g., saddle‐nose deformity). Patients with limited WG were less likely than those with severe disease to have antibodies to either proteinase 3 or myeloperoxidase. Patients with severe disease had a higher likelihood of previous thyroid disease, particularly either Graves' disease or Hashimoto thyroiditis, suggesting the possibility of different pathogenetic factors within these disease subsets. Other observed differences between these subsets, such as the greater frequency of alveolar hemorrhage in the severe disease group, were related to the a priori definitions of limited and severe disease.

Conclusion

There are significant differences between patients with limited WG and those with severe WG with regard to sex, age, the likelihood of recurrent disease, the risk of damage in certain organ systems, and, possibly, etiologic factors. These differences (and perhaps other differences that are currently unrecognized) in patient subsets may have implications for mechanisms of pathogenesis, prognosis, response to treatment, and the design of future clinical investigations.
New radiographic bone erosions in the wrists of patients with rheumatoid arthritis are detectable with magnetic resonance imaging a median of two years earlier
Authors: Østergaard Mikkel , Hansen Michael , Stoltenberg Michael , Jensen Karl Erik , Szkudlarek Marcin , Pedersen‐Zbinden Brigitta , Lorenzen Ib
Published: August 2003

Objective

In a 5‐year followup study, we investigated the temporal relationship between development of wrist joint erosions as visualized by magnetic resonance imaging (MRI) versus conventional radiography (CR), in patients with rheumatoid arthritis. We also evaluated the risk of erosive progression on CR associated with the presence of MRI erosions.

Methods

In 10 patients with rheumatoid arthritis, MRI and CR of the dominant wrist were performed annually for 5 years. In each image set, each wrist bone (metacarpal bases, carpal bones, radius, and ulna) was assessed for the absence or presence of bone erosions.

Results

Nine bones showed radiographic erosions at baseline. Twenty‐seven new radiographic erosions developed during the 5‐year followup period. Of these 27 new erosions, 21 were detected 1–5 years earlier by MRI than by CR, 3 were simultaneously detected by both methods, 2 were detected 1–2 years later by MRI than by CR, and 1 erosion (radiographically detected at 5‐year followup) was not visualized with MRI. MRI detection of new radiographic erosions preceded CR detection by a median of 2 years. In bones with MRI erosions at baseline, the relative risk of radiographic erosions at 5‐year followup was 4.5 (95% confidence interval [95% CI] 2.6–7.6), compared with bones without baseline MRI erosions. If bones with baseline radiographic erosions were excluded from the analysis, the relative risk was 4.1 (95% CI 2.2–7.5).

Conclusion

Most new radiographic bone erosions (78%) were visualized at least 1 year earlier by MRI than by CR. This illustrates that the information on joint destruction provided by CR is considerably delayed compared with that provided by MRI. A significantly increased risk of progression of radiographic erosion in bones with baseline MRI erosions was observed, demonstrating a prognostic value of MRI with respect to long‐term radiographic outcome.
Role of S100A8 and S100A9 in neutrophil recruitment in response to monosodium urate monohydrate crystals in the air‐pouch model of acute gouty arthritis
Authors: Ryckman Carle , McColl Shaun R. , Vandal Karen , de Médicis Rinaldo , Lussier André , Poubelle Patrice E. , Tessier Philippe A.
Published: August 2003

Objective

To examine the role of chemokines, S100A8, and S100A9 in neutrophil accumulation induced by the causative agent of gout, monosodium urate monohydrate (MSU) crystals.

Methods

MSU crystal–induced neutrophil migration was studied in the murine air‐pouch model. Release of chemokines, S100A8, S100A9, and S100A8/A9 in response to MSU crystals was quantified by enzyme‐linked immunosorbent assays. Recruited cells were counted following acetic blue staining, and the subpopulations were characterized by Wright‐Giemsa staining of cytospins.

Results

MSU crystals induced the accumulation of neutrophils following injection in the air pouch, which correlated with the release of the chemokines CXCL1, CXCL2, CCL2, and CCL3. However, none of these was found to play an important role in neutrophil migration induced by MSU crystals by passive immunization with antibodies directed against each chemokine. S100A8, S100A9, and S100A8/A9 were also found at high levels in the pouch exudates following injection of MSU crystals. In addition, injection of S100A8, S100A9, or S100A8/A9 led to the accumulation of neutrophils in the murine air pouch, demonstrating their proinflammatory activities in vivo. Passive immunization with anti‐S100A8 and anti‐S100A9 led to a total inhibition of the accumulation of neutrophils. Finally, S100A8/A9 was found at high concentrations in the synovial fluid of patients with gout.

Conclusion

S100A8 and S100A8/A9 are essential to neutrophil migration induced by MSU crystals. These results suggest that they might be involved in the pathogenesis of gout.
Occurrence of an activated, profibrotic pattern of gene expression in lung CD8+ T cells from scleroderma patients
Authors: Luzina Irina G. , Atamas Sergei P. , Wise Robert , Wigley Fredrick M. , Choi Jung , Xiao Hui Qing , White Barbara
Published: August 2003

Objective

Pulmonary fibrosis is a major cause of death in scleroderma patients. Previous studies have shown an increase in CD8+ T cells in the lungs of scleroderma patients. In the present study, we sought to determine whether activated CD8+ T cells contribute to pulmonary fibrosis in scleroderma patients through the production and activation of profibrotic mediators.

Methods

CD8+ cells were isolated from bronchoalveolar lavage fluid obtained from 19 scleroderma patients and 7 healthy subjects. The phenotype of these cells was determined using DNA array technology. Expression of selected genes was confirmed in real‐time polymerase chain reaction and enzyme‐linked immunosorbent assay experiments.

Results

Hierarchical clustering of gene expression profiles revealed 2 groups of subjects. Group 1 consisted of 11 patients (8 with and 3 without lung inflammation). Group 2 consisted of 15 subjects (7 healthy controls and 2 patients with and 6 without lung inflammation). Gene expression in group 1 indicated T cell activation, a type 2 phenotype, production of profibrotic factors and matrix metalloproteinases, and reduced activation‐induced cell death. Increased expression of β6 integrin messenger RNA by CD8+ T cells in group 1 suggested the possibility that these T cells might induce cell‐contact–dependent activation of latent transforming growth factor β (TGFβ).

Conclusion

A subset of scleroderma patients at higher risk of progressive lung disease have activated, long‐lived CD8+ T cells in their lungs that could promote fibrosis directly, through production of profibrotic factors such as interleukin‐4 and oncostatin M, as well as indirectly, through activation of TGFβ.
Effects of oral cyclophosphamide and prednisolone therapy on the endothelial functions and clinical findings in patients with early diffuse systemic sclerosis
Authors: Apras Sule , Ertenli Ihsan , Ozbalkan Zeynep , Kiraz Sedat , Ozturk M. Akif , Haznedaroglu Ibrahim C. , Çobankara Veli , Pay Salih , Calguneri Meral
Published: August 2003

Objective

The endothelial damage of microvascular structures in systemic sclerosis (SSc; scleroderma) is associated with increased levels of endothelial adhesion molecules and endothelium‐associated cytokines, including E‐selectin and thrombomodulin. Although there is still no ideal specific pharmacologic therapy for SSc, cyclophosphamide has resulted in clinical improvement in patients with SSc‐related active alveolitis. This study was designed to assess the expression of E‐selectin and thrombomodulin in patients with early diffuse SSc, and to investigate the effects of oral cyclophosphamide combined with prednisolone therapy on the levels of these endothelium‐associated cytokines and on the patients' clinical outcomes.

Methods

Thirteen patients with early diffuse SSc were treated with oral cyclophosphamide (2–2.5 mg/kg/day) and methylprednisolone (30 mg/every other day) for 1 year. The outcomes were determined as clinical (skin score) and laboratory parameters (including the erythrocyte sedimentation rate, complete blood cell count, levels of C‐reactive protein, antinuclear antibody, anti–double‐stranded DNA, rate of creatinine clearance, and findings on pulmonary function tests, esophageal manometry, and echocardiography). The concentrations of E‐selectin and thrombomodulin were measured in the pretreatment and posttreatment serum samples from the SSc patients and from 12 healthy adults as controls.

Results

In the patients with early diffuse SSc, pretreatment and posttreatment mean levels of E‐selectin were 51 ng/ml (range 34.2–135.5) and 33.4 ng/ml (range 23–62.5), respectively (P = 0.01), and those of thrombomodulin were 82 ng/ml (range 35.8–120.5) and 74.6 ng/ml (range 23.3–91.3), respectively (P = 0.016). Clinical and laboratory parameters (the skin score and measures of pulmonary function [forced vital capacity and diffusing capacity for carbon monoxide]) were also improved (P < 0.05 for each) at the end of the followup period.

Conclusion

Combination therapy with cylophosphamide plus prednisolone is effective in the treatment of early diffuse SSc. Circulating levels of E‐selectin and thrombomodulin not only demonstrate the extent of endothelial injury and/or activation, but also could be a useful marker to monitor the disease activity in SSc.
Molecular mechanisms of interleukin‐4–induced up‐regulation of type I collagen gene expression in murine fibroblasts
Authors: McGaha Tracy L. , Le Maithao , Kodera Takao , Stoica Cristina , Zhu Jinfang , Paul William E. , Bona Constantin A.
Published: August 2003

Objective

There is evidence that interleukin‐4 (IL‐4) plays a major role in the induction of extracellular matrix protein synthesis in fibrotic disease. We therefore examined the effect of IL‐4 on collagen synthesis in primary fibroblasts isolated from normal and TSK/+ mice, which spontaneously develop a scleroderma‐like syndrome characterized by diffuse cutaneous hyperplasia.

Methods

Expression of the IL‐4 receptor was determined by flow cytometry and Western blotting. The IL‐4 signal transduction cascade was analyzed by Western blotting. We assessed the role of signal transducer and activator of transcription 6 (STAT‐6) in IL‐4 induction of α2(I) collagen promoter activity and message levels via luciferase reporter assay and real‐time polymerase chain reaction. The activation status of the transcription factors activator protein 1 (AP‐1) and Sp‐1 upon stimulation with IL‐4 in normal and TSK/+ fibroblasts was examined by electrophoretic mobility shift assay.

Results

Flow cytometry and Western blotting showed that IL‐4 receptor α expression was elevated in TSK/+ fibroblasts compared with normal fibroblasts. After IL‐4 stimulation, janus‐activated kinase 1 (JAK‐1) and JAK‐2 were phosphorylated to a greater degree in TSK/+ fibroblasts than in C57BL/6 fibroblasts. TSK/+ fibroblasts appeared to be hyperresponsive to IL‐4, displaying increased synthesis of α1(I) collagen messenger RNA (mRNA), collagen protein, and activity of a luciferase reporter construct containing the −300 to +54 murine α2(I) collagen promoter. Overexpression of STAT‐6 enhanced this effect, whereas expression of a dominant‐negative STAT‐6 abrogated the ability of IL‐4 to induce α1(I) collagen mRNA in TSK/+ fibroblasts. Moreover, IL‐4 induced increased DNA binding activity of transcription factors that are important for collagen synthesis.

Conclusion

Our observations indicate that IL‐4 has a profound effect on several factors that have been identified as playing major roles in the regulation of collagen synthesis and suggest that IL‐4 increases the expression of type I collagen through a mechanism involving the activation of transcription factors that bind to and activate collagen promoter.
Synovial fluid exoglycosidases are predictors of rheumatoid arthritis and are effective in cartilage glycosaminoglycan depletion
Authors: Ortutay Zsuzsanna , Polgár Anna , Gömör Béla , Géher Pál , Lakatos Tamás , Glant Tibor T. , Gay Renate E. , Gay Steffen , Pállinger Éva , Farkas Csaba , Farkas Éva , Tóthfalusi László , Kocsis Katalin , Falus András , Buzás Edit I.
Published: August 2003

Objective

To analyze enzymes involved in joint damage by simultaneous investigation of glycosidases and matrix metalloproteinases (MMPs) in patients with various joint diseases.

Methods

Activities of glycosidases (β‐D‐glucuronidase, β‐D‐N‐acetyl‐glucosaminidase, β‐D‐N‐acetyl‐galactosaminidase, β‐D‐galactosidase, and α‐D‐mannosidase) were tested at an acidic pH as well as at the original pH of the synovial fluid (SF) samples in parallel with activities of MMP‐1 and MMP‐9.

Results

Patients with rheumatoid arthritis (RA) were characterized by significantly elevated activities of β‐D‐glucuronidase and β‐D‐N‐acetyl‐glucosaminidase in SF compared with patients with osteoarthritis, seronegative spondylarthritis, or acute sports injury. To select the best predictor for distinguishing among patient groups, a stepwise logistic regression analysis was performed; the strongest association was found to be between RA and β‐D‐glucuronidase/β‐D‐N‐acetyl‐glucosaminidase activities (measured at the pH of the SF). Further, a significant correlation was observed between the activity of SF β‐D‐N‐acetyl‐glucosaminidase and the level of rheumatoid factor. In vitro digestion of human hyaline cartilage samples revealed that the dominant glycosidases, alone or in combination with MMPs, proved to be effective in depleting glycosaminoglycans (GAGs) from cartilage.

Conclusion

These results suggest that exoglycosidases, which are present in the SF of RA patients, may contribute to the depletion of GAGs from cartilage and thereby facilitate the invasion of synovial cells and their attachment to cartilage in RA.
A comparative genetic analysis between collagen‐induced arthritis and pristane‐induced arthritis
Authors: Olofsson Peter , Lu Shemin , Holmberg Jens , Song Tusheng , Wernhoff Patrik , Pettersson Ulf , Holmdahl Rikard
Published: August 2003

Objective

To compare the genetic regulation of collagen‐induced arthritis (CIA) with that of pristane‐induced arthritis (PIA) in rats.

Methods

A genome‐wide linkage analysis of an (E3 × DA)DA backcross of rats with CIA (n = 364 male rats; the same strain combinations as previously used to determine the genetic control of PIA) was performed. The strongest loci in both CIA and PIA (i.e., Cia12/Pia4 and Cia13/Pia7) were isolated in congenic strains. Susceptibility in both congenic strains was tested in rats with CIA and in rats with PIA.

Results

We found a striking, although not complete, similarity of the arthritis‐controlling loci in CIA and in PIA, as well as the previously defined loci associated with cartilage destruction, antibody production, and the acute‐phase response. All major PIA quantitative trait loci (QTLs) identified in early severe arthritis were also strong regulators of CIA. The 2 strongest QTLs, Cia12/Pia4 on chromosome 12 and Cia13/Pia7 on chromosome 4, were also analyzed in congenic strains with DA or E3 as the background genome. Consistent with the results of linkage analysis, the congenic strain experiments showed that the chromosome 4 locus was more penetrant in CIA than in PIA, while the chromosome 12 locus almost completely dominated the control of PIA severity.

Conclusion

The underlying genetic control of CIA was found to have many, but not all, pathogenic mechanisms in common with PIA, despite the use of a cartilage‐specific antigen (type II collagen) to induce CIA but not PIA.
Familial Mediterranean fever among patients from Karabakh and the diagnostic value of MEFV gene analysis in all classically affected populations
Authors: Cazeneuve Cécile , Hovannesyan Zaruhi , Geneviève David , Hayrapetyan Hasmik , Papin Stéphanie , Girodon‐Boulandet Emmanuelle , Boissier Brigitte , Feingold Josué , Atayan Karine , Sarkisian Tamara , Amselem Serge
Published: August 2003

Objective

Familial Mediterranean fever (FMF) is an autosomal‐recessive disorder that is common in Armenian, Turkish, Arab, and Sephardic Jewish populations. Its clinical diagnosis is one of exclusion, with the patients displaying nonspecific symptoms related to serosal inflammation. MEFV gene analysis has provided the first objective diagnostic criterion for FMF. However, in the absence of an identified mutation (NI/NI genotype), both the sensitivity of the molecular analyses and the involvement of the MEFV gene in FMF are called into question. The present study was designed to further evaluate the diagnostic value of MEFV analysis in another population of Mediterranean extraction.

Methods

The MEFV gene was screened for mutations in 50 patients living in Karabakh (near Armenia) who fulfilled the established criteria for FMF. In addition, we analyzed published series of patients from the above‐mentioned at‐risk populations.

Results

The mutation spectrum in Karabakhian patients, which consisted of only 6 mutations (with 26% of NI alleles), differed from that reported in Armenian patients. Strikingly, among patients from Karabakh and among all classically affected populations, the distribution of genotypes differed dramatically from Hardy‐Weinberg equilibrium (P = 0.0016 and P < 0.00001, respectively). These results, combined with other population genetics–based data, revealed the existence of an FMF‐like condition that, depending on the patients' ancestry, was shown to affect 85–99% of those with the NI/NI genotype.

Conclusion

These data illuminate the meaning of negative results of MEFV analyses and show that in all populations evaluated, most patients with the NI/NI genotype had disease that mimicked FMF and was unrelated to the MEFV gene. Our findings also demonstrate the high sensitivity of a search for very few mutations in order to perform a molecular diagnosis of MEFV‐related FMF.
In primary Sjögren's syndrome, HLA class II is associated exclusively with autoantibody production and spreading of the autoimmune response
Authors: Gottenberg Jacques‐Eric , Busson Marc , Loiseau Pascale , Cohen‐Solal Julien , Lepage Virginia , Charron Dominique , Sibilia Jean , Mariette Xavier
Published: August 2003

Objective

To reevaluate, in a large series of patients with Sjögren's syndrome (SS) recruited from 2 French centers, the question of whether HLA is associated with SS itself or with a pattern of secretion of autoantibodies.

Methods

One hundred forty‐nine white patients fulfilling the American‐European Consensus Group criteria for SS were divided into 3 subgroups, according to their anti‐Ro/SSA and anti‐La/SSB status, as follows: group 1 (n = 53), no antibody; group 2 (n = 46), anti‐SSA only; group 3 (n = 50), both anti‐SSA and anti‐SSB. Patients were compared with 222 unrelated healthy subjects representative of the white population in France.

Results

Comparisons between the 149 SS patients and 222 controls confirmed the association of SS with DRB1*03 (the frequency was 25% in patients versus 10% in controls) and DQB1*02 (32% versus 22%). The association between HLA and SS was restricted to patients with anti‐SSA and/or anti‐SSB; no association with HLA was observed in patients in group 1 (no antibody). The frequency of HLA–DRB1*15 was highest in group 2 (24%), compared with 11% in group 1 and 11% in controls, whereas the frequency of HLA–DRB1*03 was highest in group 3 (44%), compared with 12% in group 1, 19% in group 2, and 10% in controls. Group 2 and group 3 had more clinical and biologic markers of activity than did group 1 but were not clinically different. HLA alleles were not associated with clinical features of the disease, and were associated with only some biologic features: rheumatoid factor positivity, increased serum IgG, and thrombocytopenia were associated with HLA–DRB1*03, and neutropenia was associated with DQB1*01.

Conclusion

HLA class II markers confer genetic susceptibility to Sjögren's syndrome. The association between HLA and SS is restricted to patients with anti‐SSA and/or anti‐SSB antibodies; HLA is not associated with SS in patients without these autoantibodies. The absence of a difference in disease severity between groups 2 and 3, as well as the restricted association of HLA–DRB1*03 in group 3, strongly suggest that HLA alleles predispose to autoantibody secretion, without being associated with clinical outcome. HLA class II phenotype might support epitope spreading: HLA–DR15 favors anti‐SSA synthesis, whereas HLA–DR3 is associated with both anti‐SSA and anti‐SSB production.
Long‐term efficacy and safety of infliximab in the treatment of ankylosing spondylitis: An open, observational, extension study of a three‐month, randomized, placebo‐controlled trial
Authors: Braun J. , Brandt J. , Listing J. , Zink A. , Alten R. , Burmester G. , Golder W. , Gromnica‐Ihle E. , Kellner H. , Schneider M. , Sörensen H. , Zeidler H. , Reddig J. , Sieper J.
Published: August 2003

Objective

Treatment of ankylosing spondylitis (AS) with infliximab, an anti–tumor necrosis factor α monoclonal antibody, was shown to be efficacious in patients with active disease during a 3‐month treatment period. The purpose of this study was to evaluate the efficacy and safety of infliximab treatment of AS for a 1‐year period.

Methods

This study was an open, observational, extension study of a 3‐month, randomized, placebo‐controlled trial. All patients who had tolerated infliximab (infliximab/infliximab group) or placebo (placebo/infliximab 12‐week crossover group) therapy for 3 months entered the open extension trial (n = 65). Infliximab was administered at a dosage of 5 mg/kg every 6 weeks after the induction phase (weeks 0, 2, and 6). The primary end point was a 50% improvement in the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI).

Results

At week 54, a total of 54 of the 69 patients (78%) continued to take infliximab. The intent‐to‐treat primary efficacy analysis at week 54 showed that 47% of patients in the infliximab/infliximab group (95% confidence interval 31–63) and 51% of the patients in the placebo/infliximab group (95% confidence interval 36–67) achieved 50% improvement in BASDAI scores. In the analysis of those who completed the study, the mean BASDAI scores improved between weeks 0 and 54 in both treatment groups: from 6.6 to 2.4 in the infliximab/infliximab group and from 6.3 to 2.6 in the placebo/infliximab group. The dosage of nonsteroidal antiinflammatory drugs was reduced in ∼70% of the patients. There were significant improvements in measures of functioning, metrologic parameters, and quality of life. Between weeks 12 and 54, a total of 4 patients had serious adverse events that were possibly related to infliximab and resulted in their discontinuing the study.

Conclusion

Infliximab therapy in AS patients resulted in a rapid and significant improvement in BASDAI scores (>50% improvement) and a durable response for 1 year. The safety profile of infliximab in AS was comparable to that observed in the postmarketing experience for the approved indications.
Identification of major loci controlling clinical manifestations of ankylosing spondylitis
Authors: Brown Matthew A. , Brophy Sinead , Bradbury Linda , Hamersma Jasmin , Timms Andrew , Laval Steven , Cardon Lon , Calin Andrei , Wordsworth B. Paul
Published: August 2003

Objective

To identify genomic regions linked with determinants of age at symptom onset, disease activity, and functional impairment in ankylosing spondylitis (AS).

Methods

A whole genome linkage scan was performed in 188 affected sibling pair families with 454 affected individuals. Traits assessed were age at symptom onset, disease activity assessed by the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), and functional impairment assessed by the Bath Ankylosing Spondylitis Functional Index (BASFI). Parametric and nonparametric quantitative linkage analysis was performed using parameters defined in a previous segregation study.

Results

Heritabilities of the traits studied in this data set were as follows: BASDAI 0.49 (P = 0.0001, 95% confidence interval [95% CI] 0.23–0.75), BASFI 0.76 (P = 10−7, 95% CI 0.49–1.0), and age at symptom onset 0.33 (P = 0.005, 95% CI 0.04–0.62). No linkage was observed between the major histocompatibility complex (MHC) and any of the traits studied (logarithm of odds [LOD] score <1.0). “Significant” linkage (LOD score 4.0) was observed between a region on chromosome 18p and the BASDAI. Age at symptom onset showed “suggestive” linkage to chromosome 11p (LOD score 3.3). Maximum linkage with the BASFI was seen at chromosome 2q (LOD score 2.9).

Conclusion

In contrast to the genetic determinants of susceptibility to AS, clinical manifestations of the disease measured by the BASDAI, BASFI, and age at symptom onset are largely determined by a small number of genes not encoded within the MHC.
Defects in the regulation of B cell apoptosis are required for the production of citrullinated peptide autoantibodies in mice
Authors: López‐Hoyos Marcos , Marquina Regina , Tamayo Esther , González‐Rojas Jovanna , Izui Shozo , Merino Ramón , Merino Jesús
Published: August 2003

Objective

Protein deimination, a process to modify arginine residues to citrulline by the addition of a neutral oxygen group, is associated with apoptosis. The presence of autoantibodies recognizing citrullinated peptides is highly specific to rheumatoid arthritis (RA) and is therefore a useful marker for the early diagnosis of RA. In this study, we explored whether anti–cyclic citrullinated peptide (anti‐CCP) autoantibodies are produced in several experimental models of autoimmune diseases in mice.

Methods

The levels of anti‐CCP autoantibodies were analyzed by enzyme‐linked immunosorbent assay in several lupus‐prone strains of mice, in animals with type II collagen (CII)–induced arthritis, and after induction of neonatal tolerance to alloantigens.

Results

We observed the production of these autoantibodies in 2 different lupus‐prone mice, MRL‐lpr/lpr and (NZW × B6)F1‐hbcl‐2 transgenic mice, characterized by the presence of abnormalities in the regulation of B cell apoptosis. Other genetic defects, determining autoimmune susceptibility, present in MRL and NZW mice were additionally required for anti‐CCP autoantibody production. The induction of autoantibodies in normal BALB/c mice injected at birth with semiallogeneic spleen cells from (BALB/c × B6)F1‐hbcl‐2 transgenic mice suggested that these additional autoimmune defects may be related, at least in part, to the establishment of abnormal interactions between T cells and B cells. In addition, anti‐CCP autoantibodies were not produced in the course of CII‐induced arthritis, an experimental model of RA in mice.

Conclusion

Our study provides evidence for the association between defects in the regulatory cell death machinery of B lymphocytes and the production of certain autoantibody specificities.
Dendritic cell uptake of human apoptotic and necrotic neutrophils inhibits CD40, CD80, and CD86 expression and reduces allogeneic T cell responses: Relevance to systemic vasculitis
Authors: Clayton Abigail R. , Prue Rebecca L. , Harper Lorraine , Drayson Mark T. , Savage Caroline O. S.
Published: August 2003

Objective

There is a breakdown of tolerance to neutrophil components during systemic vasculitis, which is marked by autoantibodies and T cells with specificity for proteinase 3 or myeloperoxidase, expressed on the surface of apoptotic neutrophils. This study was undertaken to investigate the effects of human apoptotic and necrotic neutrophils on human dendritic cell (DC) phenotype and ability to stimulate allogeneic T cell proliferation.

Methods

DCs were generated from human peripheral blood mononuclear cells and allowed to interact with human apoptotic and necrotic neutrophils in the presence or absence of tumor necrosis factor α (TNFα). Effects on DC phenotype and ability to stimulate T cell proliferation were observed.

Results

Immature DCs engulfed apoptotic and necrotic neutrophils, resulting in up‐regulation of CD83 and class II major histocompatibility complex molecules, but down‐regulation of CD40, CD80, and CD86, and a decreased ability to stimulate T cell proliferation. When TNFα was added in combination with apoptotic neutrophils, the inhibitory effects were overcome to some extent.

Conclusion

Our results suggest that DC uptake of apoptotic or necrotic neutrophils alone does not shift the immune response from tolerance to autoimmunity in systemic vasculitis. However, cytokines found at sites of inflammation in vasculitis patients may act as maturation factors for DCs, and in combination with apoptotic neutrophils, may lead to an autoimmune phenotype.
Bisphosphonate resistance in Paget's disease of bone
Authors: Joshua Fred , Epstein Martin , Major Gabor
Published: August 2003

Objective

To determine whether resistance to one bisphosphonate predicts resistance to another bisphosphonate.

Methods

One hundred patients with Paget's disease were treated with intravenous (IV) pamidronate. The initial dose was 120 mg, followed by further doses of 240 mg, until either biochemical remission was achieved or a total dose of 1 gm was given. Biochemical remission was defined as an alkaline phosphatase level within the reference range. Patients whose disease failed to respond to pamidronate were then treated with alendronate for 6 months. Patients whose disease failed to respond to alendronate were given either tiludronate for 3 months, or clodronate for 6 months.

Results

Sixteen of the 100 patients treated with pamidronate failed to achieve a biochemical response despite a cumulative dose of 1 gm. Of the 16 nonresponders, 1 died of an unrelated cause, and the remaining 15 patients were treated with alendronate. In 2 of these patients, the treatment was changed to another bisphosphonate because of gastrointestinal intolerance to alendronate. Of the remaining 13 patients, 9 (69%) achieved full biochemical remission. In 4 other patients, both pamidronate and alendronate therapy were unsuccessful (1 patient responded to tiludronate, tiludronate therapy was unsuccessful in 1, clodronate was unsuccessful in 1, and 1 patient elected to receive no further treatment). Of the 2 patients who could not receive alendronate because of gastrointestinal intolerance, 1 achieved normalization with tiludronate, and a repeat course of pamidronate was unsuccessful in the other. In total, 73% of patients in whom initial treatment with IV pamidronate was unsuccessful responded to a change in bisphosphonate treatment.

Conclusion

Failure to achieve biochemical normalization is likely to be specific to the individual drug rather than indicative of bisphosphonate class resistance.
Treatment of rheumatoid arthritis with tumor necrosis factor inhibitors may predispose to significant increase in tuberculosis risk: A multicenter active‐surveillance report
Authors: Gómez‐Reino Juan J. , Carmona Loreto , Valverde Vicente Rodríguez , Mola Emilio Martín , Montero Maria Dolores
Published: August 2003

Objective

The long‐term safety of therapeutic agents that neutralize tumor necrosis factor (TNF) is uncertain. Recent evidence based on spontaneous reporting shows an association with active tuberculosis (TB). We undertook this study to determine and describe the long‐term safety of 2 of these agents, infliximab and etanercept, in rheumatic diseases based on a national active‐surveillance system following the commercialization of the drugs.

Methods

We analyzed the safety data actively collected in the BIOBADASER (Base de Datos de Productos Biológicos de la Sociedad Española de Reumatología) database, which was launched in February 2000 by the Spanish Society of Rheumatology. For the estimation of TB risk, the annual incidence rate in patients treated with these agents was compared with the background rate and with the rate in a cohort of patients with rheumatoid arthritis (RA) assembled before the era of anti‐TNF treatment.

Results

Seventy‐one participating centers sent data on 1,578 treatments with infliximab (86%) or etanercept (14%) in 1,540 patients. Drug survival rates (reported as the cumulative percentage of patients still receiving medication) for infliximab and etanercept pooled together were 85% and 81% at 1 year and 2 years, respectively. Instances of discontinuation were essentially due to adverse events. Seventeen cases of TB were found in patients treated with infliximab. The estimated incidence of TB associated with infliximab in RA patients was 1,893 per 100,000 in the year 2000 and 1,113 per 100,000 in the year 2001. These findings represent a significant increased risk compared with background rates. In the first 5 months of 2002, after official guidelines were established for TB prevention in patients treated with biologics, only 1 new TB case was registered (in January).

Conclusion

Therapy with infliximab is associated with an increased risk of active TB. Proper measures are needed to prevent and manage this adverse event.
sE‐selectin for stratifying outcome in rheumatoid arthritis
Authors: Egerer Karl , Hertzer Julia , Feist Eugen , Albrecht Anja , Rudolph Paul Eberhard , Dörner Thomas , Burmester Gerd‐Rüdiger
Published: August 2003

Objectives

To determine the usefulness of sE‐selectin as a marker for early diagnosis and stratification of rheumatoid arthritis.

Methods

We investigated several markers of disease activity, including circulating adhesion molecules and other standard laboratory tests, in a 2–3 year followup analysis of patients with rheumatoid arthritis.

Results

The mean ± SD levels of sE‐selectin (91.68 ± 31.8 ng/ml versus 49.83 ± 14.76 ng/ml) and rheumatoid factor (375.7 ± 394.4 U versus 44.66 ± 37.63 U) were strongly elevated in severe (n = 15) versus mild (n = 7) courses of disease. Statistical calculation of mean and standard deviation revealed that sE‐selectin represents a highly significant marker for the presence of persistent and aggressive disease over time, regardless of therapeutic intervention and observation time points (P = 0.0004). Notably, regression analysis identified constant values for all parameters analyzed and, therefore, a stable course of the disease could be predicted from the beginning.

Conclusion

sE‐selectin appears to be a powerful marker to predict the severity of rheumatoid arthritis.
Positive family history of psoriasis does not affect the clinical expression and course of juvenile idiopathic arthritis patients with oligoarthritis
Authors: Tsitsami Elena , Bozzola Elena , Magni‐Manzoni Silvia , Viola Stefania , Pistorio Angela , Ruperto Nicolino , Martini Alberto , Ravelli Angelo
Published: August 2003

Objective

In the 1997 revision of the International League of Associations for Rheumatology (ILAR) criteria for juvenile idiopathic arthritis (JIA), a family history of psoriasis is an exclusion for the oligoarthritis category. We investigated whether psoriasis in a first or second degree relative influences the clinical expression and course of JIA patients with oligoarthritis.

Methods

In a cross‐sectional study, consecutive oligoarticular‐onset JIA patients were investigated. Clinical evaluations included confirmation of a family history of psoriasis and assessment of nail abnormalities, dactylitis, psoriatic rash, variables of JIA activity, and laboratory indicators of inflammation. Retrospective assessments included sex, onset age, disease duration, antinuclear antibodies, HLA–B27, uveitis, ocular complications, second‐line therapies, intraarticular corticosteroid injections, radiographic joint lesions, joint involvement over time, and laboratory investigations at disease presentation and first observation.

Results

A total of 185 patients were included. Thirty‐three had a positive family history of psoriasis (group 2) and 139 did not (group 1). Thirteen patients fulfilled the ILAR criteria for juvenile psoriatic arthritis (group 3). Patients in groups 1 and 2 were comparable for all parameters, except for a higher frequency of females in group 1 (P = 0.04). As compared with group 2, patients in group 3 were less frequently antinuclear antibody positive and had a more severe arthritis and a different distribution of joint involvement.

Conclusion

We found close similarities in the clinical features and course among patients with oligoarthritis who had a positive family history for psoriasis and those who did not. These findings argue against the exclusion of the former patients from the oligoarthritis category of JIA.