bluuebunny/crossref_metadata_2025 huggingface dataset:
Influence of electric and mechanical forces on the oxidation kinetics and electroconductive polyisoprene composition properties
Authors: Gul' V. E. , Kirsh I. A. , Kvasnikova E. V. , Zabulonov D. U. , Soina M. V. , Zaikov G. E.
Published: July 2007

The investigation results of the simultaneous effect of electric current and tensile deformation on the oxidation processes and electroconductive polyisoprene composition (EPIC) properties are presented in the study. The effects of the EPIC oxidation process under the conditions of complex factor action, consisting of the gaseous product emission and decrease of the oxidation rate at the final stage of the experiment, were disclosed. It was found out that the change in the electric resistance of EPIC aging with time was characterized by three sections: decrease, constant value area, and increase of the electric resistance. It was demonstrated that the values of the electric resistance and duration of the above sections depended on the deformation temperature and extent. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 2007
Crystallization behavior of carbon nanofiber/linear low density polyethylene nanocomposites
Authors: Lee Sungho , Kim Myung‐Soo , Ogale Amod A.
Published: July 2007

Crystallization behavior of LLDPE nanocomposites is reported in the presence of three types of carbon nanofibers (CNFs) (MJ, PR‐19, and PR‐24). During nonisothermal crystallization studies, all three crystalline melting peaks for LLDPE matrix were observed in the presence of PR‐19 nanofibers (up to 15 wt % content), but only the high‐ and low‐temperature peaks were observed in the presence MJ nanofibers. The broad melting peak at low‐temperature became bigger, suggesting an increase in the relative content of thinner lamellae in the presence of MJ nanofibers. TEM results of nanocomposites revealed transcrystallinity of LLDPE on the surface of CNFs, and a slightly broader distribution of lamellar thickness. STEM studies revealed a rougher surface morphology of the MJ nanofibers relative to that of PR nanofibers. Also, BET studies confirmed a larger specific surface area of MJ nanofibers relative to that of PR nanofibers, suggesting that the larger and the rougher surface of MJ nanofibers contributes toward the different crystallization behavior of MJ/LLDPE nanocomposites. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2007
Studies on the electrical diffusivities of mono‐carboxylates through heterogeneous anion exchange membranes
Authors: Balaji V. , Adhikary S. K. , Ray P.
Published: July 2007

Heterogeneous anion exchange membranes have been prepared by solution casting technique with poly (vinyl chloride) (PVC) as inert binder and anion exchange resin (−300 + 400 mesh) by varying their blend ratio from 60 : 40 to 30 : 70. The membranes were characterized with respect to their physical, mechanical, and electrochemical behavior. The transport behavior of such membranes was studied in the solutions of different homologous monocarboxylate salts starting from formate to butyrate. Membrane conductance values, in conjunction with the solution conductance, were used to determine the isoconductance points following the microheterogeneous model developed by Zabolotsky and Nikonenko, J Membr Sci 1993, 79, 181. From the electro conductivity (κ) and exchange capacity (Q) of the joint gel phase, the diffusion coefficients of different carboxylate anions have been determined. The specific conductivities of the joint gel phase decreases in the order κ formate > κ acetate > κ propionate > κ butyrate. For any specific carboxylate counter ion, the κ70 > κ60 > κ50 > κ40. For any particular resin loading the diffusion coefficient in membrane for formate > acetate > propionate > butyrate. The membranes studied here (varying in their blend ratios) may be synchronized by nearly same heterogeneity factor β of value 0.38 ± 0.04. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2007
Filmogen organic–inorganic hybrids obtained by sol–gel in the presence of cationic polymer
Authors: Donescu Dan , Serban Sever , Uricanu Violeta , Duits Michel , Perichaud Alain , Olteanu Mihaela , Spiroiu Manuela , Vasilescu Marilena
Published: July 2007

Self‐standing and coated‐on‐glass films were prepared from polymer–inorganic ormosils, using the cationic polymer poly(methacrylamide propyl quaternarydimethyldodecyl bromide). The inorganic compound was grown in sol–gel reactions based on methyltriethoxysilane (MeTES), with or without addition of the titanium‐precursor: tetraisopropyl orthotitanate. As evidenced by thermogravimetric analysis and differential scanning calorimetry data, the thermal properties of the films are highly dependent on the internal morphology. Inorganic granules with a TiO2 rich shell have a more polar surface, which stimulates stronger electrostatic interactions with the polymer, hence, a reduced mobility for the amino end and a smaller probability to have amino ends engaged in interactions at the surface of the granules. Coated‐on‐glass films drawn from pure cationic polymer suffer from partial dewetting. Topographic and force‐versus‐distance recordings using atomic force microscopy showed a change in the energy balance and no dewetting regions were encountered for polymer/MeTES based composites. However, because of nongrafted polymer, these films are not immune at washing with water/ acetone. Explorations of antibacterial activity against the gram‐negative bacteria, Pseudomonas aeruginosa, were done using ormosil films with alkoxysilanes combinations. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2007
Antimicrobial finishing of cellulose with incorporation of aminopyridinium salts to reactive and direct dyed fabrics
Authors: Zhao Tao , Sun Gang
Published: July 2007

Three quaternary ammonium salts namely 4‐amino‐laurylpyridinium chloride, 4‐benzoylamino‐1‐dodecylpyridinium bromide, and 4‐(1‐naphthoyl) amino‐1‐dodecylpyridinium bromide were employed in antimicrobial finishing of dyed and undyed cotton fabrics. The intermolecular interactions between the dyes and the aminopyridinium salts, and their impact on the exhaustions of salts on the dyed fabrics were discussed. The quaternary ammonium salts could form ionic interactions with sulfonate groups on the dyed cotton fibers, which contribute to higher exhaustion uptakes of the salts and better antimicrobial activities against Escherichia coli of the dyed cotton fabrics compared with that of the undyed sample. However, the washing durability of the antimicrobial functions on the finished cotton fabrics was still low because of easy dissociation of the ionic interactions in water. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2007
Morphological features and melting behavior of nanocomposites based on isotactic polypropylene and multiwalled carbon nanotubes
Authors: Avila‐Orta Carlos A. , Medellín‐Rodríguez Francisco J. , Dávila‐Rodríguez Mario V. , Aguirre‐Figueroa Yrayda A. , Yoon Kyunghwan , Hsiao Benjamin S.
Published: July 2007

Nanocomposites based on low molar mass isotactic polypropylene (iPP) and a low concentrations (1–2 wt %) of multiwalled carbon nanotubes (MWCNTs) were studied using thermal analysis, optical and electronic microscopy, and X‐ray diffraction/scattering techniques. It was first determined that MWCNT decrease induction time and act as nucleating agents of the iPP crystals during nonisothermal crystallization. One of the consequences of the nucleation effect was that the original spherulitic morphology of iPP was transformed into a fibrillar‐like. The corresponding long period of the original well‐defined lamellar structure slightly increased suggesting the formation of thicker crystals in samples containing MWCNT. The nature of the α‐iPP crystalline structure was not affected by MWCNT. After nonisothermal crystallization, two melting endotherms were present during thermal scanning of the iPP/MWCNT nanocomposites their proportion changing with the heating rate. After resolving the total DSC signal in its components using MDSC, the overall evolution of such behavior could be explained in terms of the melting/recrystallization mechanism. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2007
Toughening and compatibilization of polyphenylene sulfide/nylon 66 blends with SEBS and maleic anhydride grafted SEBS triblock copolymers
Authors: Tang Weihua , Hu Xiaoyi , Tang Jian , Jin Riguang
Published: July 2007

In this study, styrene‐b‐ethylene/butylene‐b‐styrene triblock copolymer (SEBS) and maleic anhydride grafted SEBS (SEBS‐g‐MA) were used as compatibilizers for the blends of polyphenylene sulfide/nylon 66 (PPS/PA66). The mechanical properties, including impact and tensile properties and morphology of the blends, were investigated by mechanical properties measurements and scanning electron microscopy. Impact measurements indicated that the impact strength of the blends increases slowly with elastomer (SEBS and SEBS‐g‐MA) content upto 20 wt %; thereafter, it increases sharply with increasing elastomer content. The impact energy of the elastomer‐compatibilized PPS/PA66 blends exceeded that of pure nylon 66, implying that the nylon 66 can be further toughened by the incorporation of brittle PPS minor phase in the presence of SEBS or SEBS‐g‐MA. The compatibilization efficiency of SEBS‐g‐MA for nylon‐rich PPS/PA66 was found to be higher than SEBS due to the in situ forming SEBS interphase between PPS and nylon 66. The correlation between the impact property and morphology of the SEBS‐g‐MA compatibilized PPS/PA66 blends is discussed. The excellent impact strength of the nylon‐rich blends resulted from shield yielding of the matrix. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci, 2007
Preparation and characterization of soluble polyaniline
Authors: Dan Ananya , Sengupta P. K.
Published: July 2007

Polyaniline, which is soluble in common organic solvents, has been synthesized through the oxidative chemical polymerization of aniline in the presence of benzene diazonium chloride salt in an aqueous HCl acid medium. The blue‐black polyaniline thus prepared exists in a lower oxidation state than emeraldine. An X‐ray photoelectron spectroscopy study has shown that the intrinsic oxidation state of the polymer is 0.38. An elemental analysis has shown that the fractional doping level or degree of oxidation of the blue‐black polyaniline is 0.26. The product is believed to consist of a lower number of imine nitrogens in comparison with the polyemeraldine base. This fact is also corroborated by the lower electrical conductivity of the polymer. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 2007
Convenient and efficient synthesis of a lanthanide3+‐coordinated, diethylene triamine pentaacetic acid labeled biopolymer as an assay for the cholecystokinin B receptor
Authors: Gao F. , Handl H. , Vagner J. , Hruby V. , Gillies R.
Published: July 2007

To develop an assay for the cholecystokinin B receptor with an Eu3+‐labeled cholecystokinin peptide via a diethylene triamine pentaacetic acid chelating linker, a commercial dianhydride diethylene triamine pentaacetic acid precursor was directly attached to the N‐terminus of cholecystokinin peptides by a solid‐phase synthesis method with a satisfactory yield and purity after reverse‐phase high‐performance liquid chromatography separation. Lanthanide was then coordinated to the peptide via a diethylene triamine pentaacetic acid bifunctional agent. This method is a useful approach to the large‐scale synthesis of lanthanide3+‐coordinated, diethylene triamine pentaacetic acid labeled biopolymers. This research provides not only a simple and convenient method for the preparation of lanthanide‐based peptide ligand libraries but also possible lanthanide‐based high‐throughput screening of peptide receptors with a time‐resolved fluorescence assay system. Five biopolymers were synthesized and characterized with high‐resolution electrospray ionization in this study. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 2007
Mutant tumor necrosis factor receptor associated with tumor necrosis factor receptor–associated periodic syndrome is altered antigenically and is retained within patients' leukocytes
Authors: Todd Ian , Radford Paul M. , Daffa Noura , Bainbridge Susan E. , Powell Richard J. , Tighe Patrick J.
Published: July 2007

Objective

To investigate the effect of mutations in tumor necrosis factor receptor superfamily member 1A (TNFRSF1A) in TNFR‐associated periodic syndrome (TRAPS) on the binding of anti‐TNFRSF1A monoclonal antibodies (mAb), and to investigate the subcellular distribution of mutant versus wild‐type (WT) TNFRSF1A in patients with TRAPS.

Methods

HEK 293 cells transfected with WT and/or mutant TNFRSF1A were used to investigate the interaction of anti‐TNFRSF1A mAb with the WT and mutant proteins. Monoclonal antibodies that differentially bound to C33Y TNFRSF1A were used to investigate the distribution of WT and mutant TNFRSF1A in TRAPS patients with the C33Y mutation.

Results

We identified a mAb whose binding to TNFRSF1A was completely abolished by the C33Y or C52F TRAPS‐associated mutations, whereas other mutations (T50M, C88Y, R92Q) had lesser effects on the binding of this mAb. A different mAb was found to bind efficiently to all of the mutant forms of TNFRSF1A examined as well as to the WT receptor. Exploitation of the differential binding properties of these mAb indicated that mutant (as distinct from WT) TNFRSF1A showed abnormal intracellular retention in the neutrophils of TRAPS patients with the C33Y mutation, with little if any expression of mutant TNFRSF1A on the cell surface or as soluble receptor in plasma.

Conclusion

TRAPS‐associated mutant TNFRSF1A has an antigenically altered structure and shows abnormal retention in the leukocytes of patients with TRAPS, which is consistent with previous findings from in vitro and transgenic model systems. This is consistent with a misfolded protein response contributing to the pathophysiology of TRAPS.
Evidence that the p38 MAP kinase pathway is dysregulated in HLA–B27–expressing human monocytic cells: Correlation with HLA–B27 misfolding
Authors: Sahlberg Anna S. , Penttinen Markus A. , Heiskanen Kaisa M. , Colbert Robert A. , Sistonen Lea , Granfors Kaisa
Published: July 2007

Objective

To investigate the cause of the enhanced intracellular replication of Salmonella enteritidis in HLA–B27–transfected U937 human monocytic cells and the contribution of HLA–B27 heavy chain (HC) misfolding.

Methods

U937 monocytic cell transfectants stably expressing pSV2neo resistant vector (mock), wild‐type HLA–B27, or mutated HLA–B27 HCs with amino acid substitutions in the B pocket were differentiated, infected with S enteritidis, and treated with signaling pathway inhibitors or specific p38 small interfering RNA (siRNA). The numbers of living intracellular bacteria were determined with the colony‐forming unit method. To visualize S enteritidis, the bacteria were transformed with green fluorescent protein, and studied by microscopy.

Results

Treatment with the p38 MAPK inhibitors or with p38 siRNA enhanced the replication of S enteritidis in U937 transfectants, whereas the other inhibitors had no effect. In mock‐transfected cells and in cells expressing the mutated B27 HCs in which the misfolding had been corrected, p38 inhibitors impaired their ability to resist the replication of bacteria (mock, B27.A2B, B27.E45M, and B27.C67A). In contrast, the number of intracellular bacteria was not significantly increased in p38 inhibitor‐treated cells expressing misfolded B27 HCs (B27g, B27cDNA, and B27.H9F).

Conclusion

Our results show that p38 activity plays a crucial role in controlling intracellular S enteritidis in U937 cells. Enhanced replication of bacteria in B27‐expressing cells requires that the HCs contain glutamic acid at position 45 and cysteine at position 67. Furthermore, in transfectants expressing misfolded B27 HCs, p38 inhibition had no significant effect on bacterial replication, suggesting that in these cells, the p38 pathway may not function properly.
Clinical subsets, skin thickness progression rate, and serum antibody levels in systemic sclerosis patients with anti–topoisomerase I antibody
Authors: Perera Achini , Fertig Noreen , Lucas Mary , Rodriguez‐Reyna Tatiana S. , Hu Paul , Steen Virginia D. , Medsger Thomas A.
Published: July 2007

Objective

To describe the clinical and laboratory features and natural history of the disease in systemic sclerosis (SSc; scleroderma) patients with anti–topoisomerase I (anti–topo I) antibody who have different skin thickness progression rates (STPRs).

Methods

SSc patients (n = 212) who were anti–topo I antibody positive were divided into 5 subgroups based on STPRs. Skin thickness was measured using the modified Rodnan skin thickness score (MRSS). Anti–topo I IgG antibody levels were determined.

Results

Sixty patients who were anti–topo I antibody positive had diffuse cutaneous SSc (dcSSc) with rapid progression, 82 had dcSSC with intermediate progression, and 29 had dcSSc with slow progression, 14 had limited cutaneous SSc (lcSSc) that became dcSSc, and 27 had lcSSc that did not change throughout. Patients beginning with lcSSc were younger at disease onset and had longer disease duration when diagnosed as having SSc. Interstitial lung disease was common and was equally distributed across the subgroups. Renal crisis occurred most often in patients with rapid progression (22%) and was absent in lcSSc patients. Cardiac involvement was most frequent in the dcSSc subgroups. Both kidney and heart disease occurred most often within 3 years after the onset of skin thickening. The 10‐year cumulative survival rate was <40% for patients with rapid and intermediate progression. Renal and cardiac causes of death were disproportionately frequent in these 2 subgroups. Anti–topo I antibody levels correlated with the STPR and the MRSS.

Conclusion

Anti–topo I antibody–positive patients with SSc with a rapid STPR have reduced survival rates, primarily due to early and often fatal renal and cardiac involvement. Anti–topo I antibody levels parallel the MRSS at the first visit and the STPR. This information is important for managing physicians and researchers planning clinical trials involving patients with early dcSSc.
Inflammation and ectopic lymphoid structures in rheumatoid arthritis synovial tissues dissected by genomics technology: Identification of the interleukin‐7 signaling pathway in tissues with lymphoid neogenesis
Authors: Timmer Trieneke C. G. , Baltus Belinda , Vondenhoff Mark , Huizinga Tom W. J. , Tak Paul P. , Verweij Cornelis L. , Mebius Reina E. , van der Pouw Kraan Tineke C. T. M.
Published: July 2007

Objective

In ∼25% of synovial tissues from rheumatoid arthritis (RA) patients, infiltrates of T cells, B cells, and follicular dendritic cells (FDCs) are spatially organized into structures resembling lymph nodes with germinal centers. The remainder of the tissues lack FDCs and show either a diffuse or an aggregated T cell and B cell infiltrate. To gain more insight into this specific disease process, we sought to identify the genes expressed in RA tissues with ectopic lymphoid structures.

Methods

Gene expression profiling of RA synovial tissues was determined by complementary DNA microarray analysis and quantitative real‐time polymerase chain reaction. The presence of lymphoid follicles and localization of interleukin‐7 (IL‐7) in synovial tissue sections was determined by immunofluorescence staining using specific antibodies.

Results

Findings of gene expression analysis confirmed previous reports that tissues with lymphoid structures showed elevated expression of CXCL13, CCL21, CCR7, and lymphotoxin α and β messenger RNA. In addition, the tissues also showed enhanced expression of the chemokines CXCL12 and CCL19 and the associated receptors CXCR4 and CXCR5, which are important for the attraction of T cells, B cells, and dendritic cells. Pathway analysis revealed increased expression of genes involved in JAK/STAT signaling, T cell– and B cell–specific pathways, Fcε receptor type I signaling in mast cells, and IL‐7 signal transduction in the tissues with ectopic lymphoid follicles, accompanied by increased expression of IL‐7 receptor α (IL‐7Rα)/IL‐2Rγ chains and IL‐7. Protein expression of IL‐7 in RA tissues was localized within fibroblast‐like synoviocytes, macrophages, and blood vessels and was colocalized with extracellular matrix structures around the B cell follicles.

Conclusion

Activation of the IL‐7 pathway may play an important role in lymphoid neogenesis, analogous to its role in the development of normal lymphoid tissue.
Pharmacologic induction of heme oxygenase 1 reduces acute inflammatory arthritis in mice
Authors: Benallaoua Mourad , François Mathias , Batteux Frédéric , Thelier Natacha , Shyy John Y.‐J. , Fitting Catherine , Tsagris Lydia , Boczkowski Jorge , Savouret Jean‐François , Corvol Marie‐Thérèse , Poiraudeau Serge , Rannou François
Published: July 2007

Objective

To determine the consequences of pharmacologic up‐regulation of heme oxygenase 1 (HO‐1), and inhibition of HO‐1 by injection of an anti–HO‐1 small interfering RNA (siRNA), in vivo in the acute phase of a mouse model of nonautoimmune arthritis.

Methods

In the K/BxN mouse serum transfer model, which mimics human inflammatory arthritis without lymphocyte influence, HO‐1 was up‐regulated by intraperitoneal injection of cobalt protoporphyrin IX (CoPP), a potent pharmacologic inducer, and was inhibited using a specific siRNA. The clinical progress of arthritis was monitored by measurement of paw thickness. Interleukin‐1β (IL‐1β), IL‐6, tumor necrosis factor α (TNFα), serum antioxidant, and nitric oxide (NO) levels, prostaglandin E2 (PGE2) production, and matrix metalloproteinase 9 (MMP‐9) activity were measured in serum. At the end of the experiments, joints were examined for immunohistopathologic changes.

Results

Intraperitoneal injection of CoPP alleviated disease symptoms, such as joint swelling, cartilage degradation, and proliferation of inflammatory tissue in joints, in the acute phase of inflammatory arthritis. The CoPP‐induced expression of HO‐1 in the joints and liver was associated with marked decreases in IL‐1β, IL‐6, and TNFα levels, PGE2 secretion, and MMP‐9 activity in serum, and with a marked increase in systemic antioxidant activity. In contrast, NO production in serum and inducible NO synthase expression in chondrocytes were not affected by HO‐1 induction. Specific inhibition of HO‐1 by in vivo delivery of anti–HO‐1 siRNA repressed the protective effects.

Conclusion

Our data provide the first evidence that pharmacologically induced up‐regulation of HO‐1 triggers a robust protective antiinflammatory response in a model of nonautoimmune arthritis in mice. This suggests that exogenously induced HO‐1 may have potential as therapy in the acute phase of inflammatory arthritis in humans.
Abatacept treatment does not exacerbate chronic Mycobacterium tuberculosis infection in mice
Authors: Bigbee Carolyn L. , Gonchoroff Daryl G. , Vratsanos George , Nadler Steven G. , Haggerty Helen G. , Flynn JoAnne L.
Published: July 2007

Objective

Treatment of rheumatoid arthritis and other autoimmune disorders with anti–tumor necrosis factor (anti‐TNF) agents is associated with an increased risk of reactivation of latent Mycobacterium tuberculosis. While the mechanism of action of abatacept is fundamentally different from that of anti‐TNF therapies, its effect on the protective response to latent tuberculosis is not known. We undertook this study to determine the effect of abatacept treatment in a murine model of chronic M tuberculosis infection.

Methods

Chronic M tuberculosis infection was established in C57BL/6 mice. Four months after infection, mice were treated for up to 16 weeks with abatacept, anti–murine TNF antibody, or vehicle. The primary end point was survival; body weight, bacterial load, histologic features, interferon‐γ (IFNγ) production by T cells, and cellular infiltration were also assessed.

Results

Abatacept‐ and vehicle‐treated groups both maintained control of M tuberculosis infection, with 100% survival after 16 weeks of treatment. These 2 groups had no significant differences in body weight, no clinically relevant differences in bacterial load in the lungs, lymph nodes, or spleen, and no differences in the mean percentage of total or activated T cells, macrophages, neutrophils, or B cells, or in IFNγ production in the lung or lymph nodes. In contrast, 100% mortality was seen in the anti‐TNF antibody–treated group by week 9, with significant body weight loss and increased bacterial load in the lungs, lymph nodes, and spleen. Furthermore, the anti‐TNF antibody–treated group had increased pathology consistent with the exacerbation of M tuberculosis infection.

Conclusion

Abatacept did not impair the ability of mice to control a chronic M tuberculosis infection. In contrast, mice treated with anti‐TNF therapy showed increased pathology and bacterial load, with 100% mortality by week 9. The clinical significance of these findings has not yet been determined.
Seasonal birth patterns in myositis subgroups suggest an etiologic role of early environmental exposures
Authors: Vegosen Leora J. , Weinberg Clarice R. , O'Hanlon Terrance P. , Targoff Ira N. , Miller Frederick W. , Rider Lisa G.
Published: July 2007

Objective

To evaluate whether seasonal early environmental exposures might influence later development of autoimmune disease, by assessing distributions of birth dates in groups of patients with idiopathic inflammatory myopathies (IIMs).

Methods

We assessed birth patterns in groups of patients with juvenile‐onset IIM (n = 307) and controls (n = 3,942) who were born between 1970 and 1999, and in groups of patients with adult‐onset IIM (n = 668) and controls (n = 6,991) who were born between 1903 and 1982. Birth dates were analyzed as circular data. Seasonal clustering was assessed by the Rayleigh test, and differences between groups by a rank‐based uniform scores test.

Results

The overall birth distributions among patients with juvenile IIM and among patients with adult IIM did not differ significantly from those among juvenile and adult controls, respectively. Some subgroups of patients with juvenile IIM had seasonal birth distributions. Hispanic patients with juvenile‐onset IIM had a seasonal birth pattern (mean birth date October 16) significantly different from that of Hispanic controls (P = 0.002), who had a uniform birth distribution, and from that of non‐Hispanic patients with juvenile‐onset IIM (P < 0.001), who had a mean birth date of May 2. Juvenile dermatomyositis patients with p155 autoantibody had a birth distribution that differed significantly from that of p155 antibody–negative juvenile dermatomyositis patients (P = 0.003). Juvenile IIM patients with the HLA risk factor allele DRB1*0301 had a birth distribution significantly different from those without the allele (P = 0.021). Similar results were observed for juvenile and adult IIM patients with the linked allele DQA1*0501, versus juvenile and adult IIM patients without DQA1*0501, respectively. No significant patterns in birth season were found in other subgroups.

Conclusion

Birth distributions appear to have stronger seasonality in juvenile than in adult IIM subgroups, suggesting greater influence of perinatal exposures on childhood‐onset illness. Seasonal early‐life exposures may influence the onset of some autoimmune diseases later in life.
Adjunctive methotrexate for treatment of giant cell arteritis: An individual patient data meta‐analysis
Authors: Mahr Alfred D. , Jover Juan A. , Spiera Robert F. , Hernández‐García César , Fernández‐Gutiérrez Benjamin , LaValley Michael P. , Merkel Peter A.
Published: July 2007

Objective

To reevaluate the efficacy and safety of adjunctive low‐dose methotrexate (MTX) in giant cell arteritis (GCA).

Methods

An individual patient data meta‐analysis of 3 randomized placebo‐controlled trials in patients with newly diagnosed GCA was performed. Treatment consisted of initial high‐dose corticosteroids and randomly assigned oral MTX therapy (7.5–15 mg/week) or placebo. Time‐to‐event outcomes were compared between groups using Cox proportional hazards models stratified by trial, and continuous outcomes were compared by calculating weighted mean differences.

Results

The combined data set comprised 161 patients, of whom 84 received MTX and 77 received placebo. The mean duration of followup was 54.7 weeks (SD 39.2 weeks). Hazard ratios (HRs) for a first and second relapse of GCA were 0.65 (P = 0.04) and 0.49 (P = 0.02), respectively, in patients receiving MTX as compared with patients receiving placebo. Accordingly, a predicted 3.6 individuals (95% confidence interval [95% CI] 2.2–56.8) and 4.7 individuals (95% CI 3.3–21.9) need to be treated with MTX to prevent the occurrence of one first or one second relapse, respectively, up to 48 weeks. Use of MTX resulted in a reduction in the corticosteroid cumulative dose by 842 mg within 48 weeks (P < 0.001). Moreover, MTX treatment was associated with a higher probability of achieving sustained discontinuation of corticosteroids for ≥24 weeks (HR 2.84, P = 0.001). Dropout rates and occurrence of adverse events did not differ between treatment groups.

Conclusion

In GCA, adjunctive treatment with MTX lowers the risk of relapse and reduces exposure to corticosteroids. These findings indicate that MTX could be considered as a therapeutic option in addition to standard‐of‐care treatment with corticosteroids for patients with GCA.
Trichostatin A prevents the accumulation of extracellular matrix in a mouse model of bleomycin‐induced skin fibrosis
Authors: Huber Lars C. , Distler Jörg H. W. , Moritz Falk , Hemmatazad Hossein , Hauser Thomas , Michel Beat A. , Gay Renate E. , Matucci‐Cerinic Marco , Gay Steffen , Distler Oliver , Jüngel Astrid
Published: July 2007

Objective

Tissue fibrosis is a hallmark compromising feature of many disorders. In this study, we investigated the antifibrogenic effects of the histone deacetylase inhibitor trichostatin A (TSA) on cytokine‐driven fibrotic responses in vitro and in vivo.

Methods

Skin fibroblasts from patients with systemic sclerosis (SSc) and normal healthy control subjects were stimulated with profibrotic cytokines in combination with TSA. Human Colα1(I) and fibronectin were measured using real‐time polymerase chain reaction, and levels of soluble collagen were estimated using the SirCol collagen assay. Electromobilty shift assay and confocal fluorescence microscopy were used to investigate the intracellular distribution of Smad transcription factors. For in vivo analysis, skin fibrosis was quantified by histologic assessment of mouse skin tissue in a model of bleomycin‐induced fibrosis.

Results

Reductions in the cytokine‐induced transcription of Colα1(I) and fibronectin were observed in both normal and SSc skin fibroblasts following the addition of TSA. Similarly, the expression of total collagen protein in TSA‐stimulated SSc skin fibroblasts was reduced to basal levels. The mechanism of action of TSA included inhibition of the nuclear translocation and DNA binding of profibrotic Smad transcription factors. Western blot analysis revealed an up‐regulation of the cell cycle inhibitor p21 by TSA, leading to reduced proliferation of fibroblasts. In addition, in bleomycin‐induced fibrosis in mice, TSA prevented dermal accumulation of extracellular matrix in vivo.

Conclusion

These findings provide novel insights into the epigenetic regulation of fibrosis. TSA and similar inhibitory compounds appear to represent early therapeutic strategies for achieving reversal of the cytokine‐driven induction of matrix synthesis that leads to fibrosis.
Increased expression of the collagen receptor discoidin domain receptor 2 in articular cartilage as a key event in the pathogenesis of osteoarthritis
Authors: Xu Lin , Peng Haibing , Glasson Sonya , Lee Peter L. , Hu Kenpan , Ijiri Kosei , Olsen Bjorn R. , Goldring Mary B. , Li Yefu
Published: July 2007

Objective

To investigate the role of the collagen receptor discoidin domain receptor 2 (DDR‐2) in the pathogenesis of osteoarthritis (OA).

Methods

Histologic and immunohistochemical analyses were performed to characterize femoral head cartilage from 7 patients with OA and 4 patients with fracture, as well as articular cartilage from the knee joints of mice with surgically induced OA. Gene constructs encoding human Raf kinase inhibitor protein (RKIP), DDR‐2 lacking the discoidin (DS) domain (ΔDS‐DDR‐2) or the protein tyrosine kinase (PTK) core (ΔPTK‐DDR‐2), DDR‐2 containing a substitution of tyrosine for alanine at position 740 (Y740A), and luciferase driven by the matrix metalloproteinase 13 (MMP‐13) promoter were transfected into human chondrocyte cell lines. Activated and neutralized α2β1 integrin polyclonal antibodies, interleukin‐1 receptor antagonist, and the chemical inhibitors SB203580, for p38, and SP600125, for JNKs, were used in cell cultures. Real‐time polymerase chain reaction was performed to examine MMP‐13 and DDR‐2 messenger RNA (mRNA).

Results

Increased immunostaining for DDR‐2, MMP‐13, and MMP‐derived type II collagen fragments was detected in cartilage from patients with OA and from mice with surgically induced OA. The discoidin domain and PTK core of DDR‐2 were essential for signal transmission and the resulting increased expression of MMP‐13 in chondrocytes. Y740A mutation of DDR‐2 reduced levels of mRNA for MMP‐13 and endogenous DDR‐2. The overexpression of RKIP or preincubation with the p38 inhibitor reduced MMP‐13 mRNA levels. DDR‐2 signaling was independent of the α2β1 integrin and the interleukin‐1–induced signaling pathways in chondrocytes.

Conclusion

These findings suggest that increased expression of DDR‐2, resulting in the elevated expression of MMP‐13, may be one of the common events in OA progression.
Novel conformation of histidyl–transfer RNA synthetase in the lung
Authors: Levine Stuart M. , Raben Nina , Xie Dan , Askin Frederic B. , Tuder Rubin , Mullins Marissa , Rosen Antony , Casciola‐Rosen Livia A.
Published: July 2007

Objective

We previously proposed that novel expression and/or conformation of autoantigens in the target tissue may play a role in generating phenotype‐specific immune responses. The strong association of autoantibodies to histidyl–transfer RNA synthetase (HisRS, Jo‐1) with interstitial lung disease in patients with myositis led us to study HisRS expression and conformation in the lung.

Methods

Normal human tissue specimens were probed with a novel anti‐HisRS antibody recognizing its granzyme B–cleavable conformation by immunoblotting and immunohistochemistry. The HisRS granzyme B site was mapped using site‐directed mutagenesis, and its relationship to the antibody recognition domain was evaluated in tandem immunoprecipitation/granzyme B cleavage studies.

Results

The HisRS α‐helical coiled‐coil N‐terminal domain recognized by autoantibodies is bounded by a granzyme B cleavage site. In immunoprecipitation studies with patient sera, HisRS was found to exist in 2 conformations, defined by sensitivity to cleavage by granzyme B and modification by autoantibody binding. Despite similar global expression of HisRS in different tissue, expression of its granzyme B–cleavable form was enriched in the lung and localized to the alveolar epithelium.

Conclusion

A proteolytically sensitive conformation of HisRS exists in the lung, the target tissue associated with this autoantibody response. We thus propose that autoimmunity to HisRS is initiated and propagated in the lung.
Freund's complete adjuvant induces arthritis in mice lacking a functional interferon‐γ receptor by triggering tumor necrosis factor α–driven osteoclastogenesis
Authors: Geboes Lies , Klerck Bert De , Balen Maarten Van , Kelchtermans Hilde , Mitera Tania , Boon Louis , Wolf‐Peeters Chris De , Matthys Patrick
Published: July 2007

Objective

To investigate the hypothesis that Freund's complete adjuvant (CFA) plays an essential role in the induction of collagen‐induced arthritis in mice, by testing whether CFA by itself is able to induce arthritis in interferon‐γ receptor–knockout (IFNγR‐KO) mice.

Methods

IFNγR‐KO and wild‐type mice were sensitized with a single intradermal injection of CFA containing heat‐killed Mycobacterium butyricum. Flow cytometric analysis and in vitro osteoclastogenesis assays were performed on blood, spleen, and bone marrow cells. Tumor necrosis factor (TNF) levels were measured in the serum, and levels of RANKL, osteoprotegerin (OPG), and TNFα in the synovium were determined by quantitative reverse transcriptase–polymerase chain reaction. Effects of treatment with the TNFα antagonist etanercept were assessed.

Results

Symptoms of arthritis appeared in IFNγR‐KO mice but not in wild‐type mice, and reached an incidence of 55%. The onset coincided with an expansion of CD11b+ splenocytes that spontaneously produced TNFα and with increased osteoclastogenesis in spleen and blood cells. Expansion of CD11b+ splenocytes and osteoclast precursor cells was more pronounced in arthritic than in nonarthritic mice. There was a >100‐fold increase in the RANKL:OPG ratio in the synovia of CFA‐sensitized mice compared with those of naive animals. Treatment with etanercept prevented the development of arthritis and mitigated the increased expansion of myeloid cells as well as the increase in osteoclast precursor numbers in the spleen and blood.

Conclusion

These results indicate that sensitization of mice with CFA creates a condition in which dysregulation of a single cytokine leads to arthritis by triggering TNFα‐driven osteoclastogenesis.
Prostaglandin E2 exacerbates collagen‐induced arthritis in mice through the inflammatory interleukin‐23/interleukin‐17 axis
Authors: Sheibanie Amir F. , Khayrullina Tanzilya , Safadi Fayez F. , Ganea Doina
Published: July 2007

Objective

Recently, Th17 cells, a new subset of CD4+ T cells, emerged as major players in inflammation/autoimmunity. Maintenance of the Th17 phenotype requires interleukin‐23 (IL‐23), whereas the Th1‐promoting cytokine IL‐12p70 exerts a negative effect on Th17 cell differentiation. The lipid mediator prostaglandin E2 (PGE2) acts primarily as a proinflammatory agent in autoimmune conditions, through mechanisms that remain to be elucidated. The aim of this study was to investigate whether PGE2 released in inflammatory foci activates resident dendritic cells (DCs) to express IL‐23 (at the expense of IL‐12) and IL‐6, resulting in a shift toward Th17 cell responses.

Methods

The effect of PGE2 on IL‐23 production by DCs and subsequent induction of T cell–derived IL‐17 was assessed in vitro and in vivo. The effect of the stable PGE analog misoprostol was evaluated in a murine model of rheumatoid arthritis, in conjunction with IL‐23 and IL‐17 expression in affected joints and draining lymph nodes.

Results

In vivo administration of PGE2 induced IL‐23–dependent IL‐17 production. Administration of misoprostol exacerbated collagen‐induced arthritis (CIA). CIA exacerbation was associated with increased levels of IL‐23p19/p40 messenger RNA and reduced expression of IL‐12p35, and with increased levels of the proinflammatory cytokines IL‐17, IL‐1β, IL‐6, and tumor necrosis factor in the affected joint. Following ex vivo restimulation, draining lymph node cells from misoprostol‐treated mice secreted higher levels of IL‐17 and lower levels of interferon‐γ.

Conclusion

Our results indicate that PGE2 enhances DC‐derived IL‐6 production and induces a shift in the IL‐23/IL‐12 balance in favor of IL‐23, resulting in increased IL‐17 production, presumably through the amplification of self‐reactive Th17 cells.
Late‐onset tumor necrosis factor receptor–associated periodic syndrome in multiple sclerosis patients carrying the TNFRSF1A R92Q mutation
Authors: Kümpfel Tania , Hoffmann Lisa‐Ann , Rübsamen Heike , Pöllmann Walter , Feneberg Wolfgang , Hohlfeld Reinhard , Lohse Peter
Published: July 2007

Objective

Tumor necrosis factor receptor–associated periodic syndrome (TRAPS) is an autosomal‐dominantly inherited autoinflammatory disorder caused by mutations in the TNFRSF1A gene. It is characterized by episodes of autoinflammation usually associated with fever, abdominal pain, myalgia, exanthema, arthralgia/arthritis, and ocular involvement. We undertook this study to investigate the prevalence of TRAPS in patients with multiple sclerosis (MS) who reported, in addition to their neurologic symptoms, at least 2 other symptoms compatible with TRAPS.

Methods

Twenty‐five unrelated MS patients were prospectively screened for TNFRSF1A mutations. In addition, blood samples from 365 unrelated MS patients and 407 unrelated Caucasian controls were analyzed to determine the R92Q carrier frequency.

Results

Six of 25 adult MS patients (24%) with symptoms suggestive of TRAPS were found to carry the identical arginine‐to‐glutamine substitution at amino acid position 92 (R92Q or p.Arg121Gln) encoded by exon 4 of the TNFRSF1A gene. All R92Q heterozygotes had similar symptoms, including arthralgias/arthritis, myalgias, urticarial rash, and severe fatigue, which began before the onset of MS. In 5 of the 6 patients, we could identify family members who had TRAPS symptoms and had inherited the identical mutation. The R92Q exchange was also detected in 17 of 365 unselected MS patients (4.66%) and in 12 of 407 controls (2.95%) (P = 0.112). Three patients were heterozygous carriers of MEFV variants, in 1 patient in combination with the R92Q mutation.

Conclusion

Autoinflammatory syndromes and especially late‐onset TRAPS should be considered in MS patients who report symptoms such as arthralgias/arthritis, myalgias, urticarial rash, and severe fatigue.
The effect of oral calcitonin on cartilage turnover and surface erosion in an ovariectomized rat model
Authors: Sondergaard Bodil‐Cecilie , Oestergaard Svetlana , Christiansen Claus , Tankó Laszló B. , Karsdal Morten Asser
Published: July 2007

Objective

To investigate whether oral calcitonin treatment influences the increases in type II collagen (CII) degradation and related surface erosions of articular cartilage in ovariectomized rats.

Methods

Fifty rats were randomly allocated into 1 of the 5 following intervention groups: sham‐operated, ovariectomy, ovariectomy plus subcutaneously implanted 17β‐estradiol pellet, ovariectomy plus 2 mg/kg salmon calcitonin plus 50 mg/kg 5CNAC (carrier), or ovariectomy plus 50 mg/kg 5CNAC. Each treatment was administered for 9 weeks after the ovariectomy. Blood samples for biochemical marker analysis were collected from fasting animals at baseline, on day 3, and after 1, 2, 4, 6, and 9 weeks. CII degradation was quantified by specific immunoassay, and the changes in severity scores of articular cartilage erosions were visualized and scored in histologic sections of the knees.

Results

Ovariectomy resulted in a marked increase in serum levels of C‐telopeptide of type II collagen (CTX‐II) (P < 0.001), which could be effectively reversed by 17β‐estradiol supplementation. Oral administration of calcitonin elicited similar decreases in serum levels of CTX‐II (P < 0.001). Histologic scoring of cartilage erosion showed significantly less cartilage erosion in calcitonin‐treated ovariectomized rats versus control ovariectomized rats that were untreated or treated with 5CNAC alone. (P < 0.01).

Conclusion

The in vivo effects of calcitonin in rats suggest that calcitonin is able to counteract CII degradation and the accompanying structural disintegration of articular cartilage promoted by estrogen deficiency. Clinical assessment of the chondroprotective potential of calcitonin in postmenopausal women seems warranted.
Improved survival in psoriatic arthritis with calendar time
Authors: Ali Yaser , Tom Brian D. M. , Schentag Catherine T. , Farewell Vernon T. , Gladman Dafna D.
Published: July 2007

Objective

To determine whether there has been a change in mortality rates over the last 3 decades in patients with psoriatic arthritis (PsA) whose cases were followed prospectively.

Methods

Patients receiving followup care according to a standard protocol at the University of Toronto PsA Clinic between 1978 and 2004 were included. Information on patient deaths was collected prospectively. Mortality data for the general population of Ontario, Canada, stratified by 5‐year age bands, sex, and calendar year from 1978 to 2004, were used to calculate the reference rates. Standardized mortality ratios (SMRs) were calculated through use of Poisson regression models for the number of observed deaths. Time trend analyses were performed through the use of 10‐year “rolling‐average” SMRs and followup period–specific SMRs stratified by the period of entry into clinic.

Results

Of 680 patients with PsA, 106 (15.6%) (55 women and 51 men) have died. Major causes of death were disease of the circulatory system, neoplasms, diseases of the respiratory system, diseases of the gastrointestinal system, injuries/poisoning, and unknown. The overall SMR for the period 1978–2004 was 1.36 (95% confidence interval 1.12, 1.64). The estimated number of life‐years lost by the PsA patient cohort overall was 2.99 years (95% confidence interval 1.14, 4.77). For patients who entered the cohort during the years 1978–1986, the SMRs were 1.89, 1.83, and 1.21 for followup periods 1978–1986, 1987–1995, and 1996–2004, respectively. For patients who entered the cohort during the years 1987–1995, the SMRs were 0.55 and 0.82, while the SMR for those who entered during 1996–2004 was 0.56.

Conclusion

The drop in SMRs in this PsA clinic population suggests that the mortality risk has improved over time. This improved survival may reflect disease severity at presentation in the earlier cohort as well as earlier diagnosis and more aggressive treatment in the more recent followup period.
Reactivity of γ/δ T cells to human 60‐kd heat‐shock protein and their cytotoxicity to aortic endothelial cells in Takayasu arteritis
Authors: Chauhan Sunil Kumar , Singh Mahavir , Nityanand Soniya
Published: July 2007

Objective

Increased numbers of circulating γ/δ T cells with a restricted T cell receptor repertoire, as well as colocalization of the expression of heat‐shock protein Hsp60/65 and γ/δ T cells in the arterial lesions of patients with Takayasu arteritis (TA), indicate that γ/δ T cells may react to Hsp60 and cause damage to the arterial endothelium. In this study we investigated the proliferative responses of γ/δ T cells to human Hsp60 and their cytotoxicity to human aortic endothelial cells (ECs) in patients with TA.

Methods

Blood samples were obtained from 12 patients with TA, 8 patients with systemic lupus erythematosus (SLE) (as disease controls), and 10 healthy control subjects. Proliferative responses of circulating γ/δ T cells to human Hsp60 were detected by flow cytometry–based bromodeoxyuridine incorporation assay. Cytotoxicity of the γ/δ T cells to human aortic ECs was analyzed by colorimetric lactate dehydrogenase release assay.

Results

The γ/δ T cells of 11 of 12 patients with TA exhibited reactivity to Hsp60, whereas none of the γ/δ T cells from patients with SLE or healthy controls showed reactivity (both P < 0.001). The mean ± SD proliferative response of γ/δ T cells in patients with TA was 21.4 ± 11.3%, compared with 4.2 ± 1.2% in patients with SLE and 4.01 ± 1.82% in healthy controls (both P < 0.001). In addition, compared with the control groups, the γ/δ T cells of patients with TA had increased spontaneous cytotoxicity to aortic ECs (22.1 ± 15.0% versus 9.6 ± 2.13% in SLE patients and 8.1 ± 4.7% in healthy controls; both P < 0.005), which was further enhanced following stimulation of γ/δ T cells with Hsp60. The cytotoxicity of the γ/δ T cells was significantly inhibited by treatment of these cells with concanamycin A and anti–Fas ligand–blocking antibodies.

Conclusion

The results show that γ/δ T cells in patients with TA are reactive to Hsp60 and exhibit cytotoxicity to aortic ECs, suggesting a key role of Hsp60 and γ/δ T cells in the pathogenesis of TA.