bluuebunny/crossref_metadata_2025 huggingface dataset:
Causative factors and epidemiology of bilateral vestibulopathy in 255 patients
Authors: Zingler Vera C. , Cnyrim Christian , Jahn Klaus , Weintz Eva , Fernbacher Julia , Frenzel Claudia , Brandt Thomas , Strupp Michael
Published: March 2007

Objective

To determine the causative factors and epidemiology of bilateral vestibulopathy (BV).

Methods

This is a retrospective review of 255 patients (mean age, 62 ± 16 years) with BV diagnosed in our dizziness unit between 1988 and 2005. All patients had undergone a standardized neurophthalmological and neurootological examination, electronystagmography with caloric irrigation, cranial magnetic resonance imaging or computed tomography (n = 214), and laboratory tests.

Results

Sixty‐two percent of the study population were male subjects. Previous vertigo attacks had occurred in 36%, indicating a sequential manifestation. The definite cause of BV was determined in 24% and the probable cause in 25%: The most common causes were ototoxic aminoglycosides (13%), Menière's disease (7%), and meningitis (5%). Strikingly, 25% exhibited cerebellar signs. Cerebellar dysfunction was associated with peripheral polyneuropathy in 32% compared with 18% in BV patients without cerebellar signs. Hypoacusis occurred bilaterally in 25% and unilaterally in 6% of all patients. It appeared most often in patients with BV caused by Cogan's syndrome, meningitis, or Menière's disease.

Interpretation

The cause of BV remains unclear in about half of all patients despite intensive examinations. A large subgroup of these patients have associated cerebellar dysfunction and peripheral polyneuropathy. This suggests a new syndrome that may be caused by neurodegenerative or autoimmune processes. Ann Neurol 2007
Development of light‐induced functionalized asymmetric polysulfone membranes
Authors: Yogesh  , Paul P. , Basu S. , Bhattacharya A.
Published: March 2007

The introduction of functionality into asymmetric polysulfone membranes has widened their applicability. They are modified with acrylic acid with a light‐induced technique. Fourier transform infrared, contact‐angle, porometry, and atomic force microscopy studies have been carried out to characterize the membranes. The performance of the modified membranes has been investigated with permeation measurements. The salt rejection (NaCl and Na2SO4) performance of the modified membranes shows evidence of functionalization on them. The modification of the membranes also develops the retention of small organic molecules (glucose and 2,4‐dichlorophenol). © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 2007
Crystallization behavior of poly(ϵ‐caprolactone) in poly(ϵ‐caprolactone) and poly(vinyl methyl ether) mixtures
Authors: Meng Yanfeng , Li Hongfei , Huo Hong , Jiang Shichun , An Lijia
Published: March 2007

The morphological development and crystallization behavior of poly(ϵ‐caprolactone) (PCL) in miscible mixtures of PCL and poly(vinyl methyl ether) (PVME) were investigated by optical microscopy as a function of the mixture composition and crystallization temperature. The results indicated that the degree of crystallinity of PCL was independent of the mixture composition upon melt crystallization because the glass‐transition temperatures of the mixtures were much lower than the crystallization temperature of PCL. The radii of the PCL spherulites increased linearly with time at crystallization temperatures ranging from 42 to 49°C. The isothermal growth rates of PCL spherulites decreased with the amount of the amorphous PVME components in the mixtures. Accounting for the miscibility of PCL/PVME mixtures, the radial growth rates of PCL spherulites were well described by a kinetic equation involving the Flory–Huggins interaction parameter and the free energy for the nuclei formation in such a way that the theoretical calculations were in good agreement with the experimental data. From the analysis of the equilibrium melting point depression, the interaction energy density of the PVME/PCL system was calculated to be −3.95 J/cm3. © 2007 Wiley Periodicals, Inc. J Appl Polym Sci 2007
Gross anatomical study of the sympathetic cardiac nerves in the house musk shrew (Suncus murinus)
Authors: Tanaka Ai , Tanaka Shigenori , Miyamoto Kensaku , Yi Shuang‐Qin , Nakatani Toshio
Published: March 2007

The sympathetic cardiac nerves originating from the cervical and upper thoracic sympathetic ganglia in the house musk shrew (Suncus murinus) were examined using macroscopic and whole‐mount immunohistochemical methods. Based on the results, the nerves were macroscopically classified into the following three groups: nerves innervating the cervical sympathetic ganglia mainly to the arterial porta of the heart; nerves supplying the stellate and thoracic sympathetic ganglia at the level of T2–T5 or T6 for both the arterial and venous portae of the heart; and nerves innervating the thoracic sympathetic ganglia at the level of T4–T9 to the esophagus and lung and then the heart via the blood vessels within the mediastinal pleura. These findings in the house musk shrew suggest a possible primitive morphological pattern of the cervical and thoracic sympathetic nervous system that may be related to those in other mammals, including humans. Anat Rec, 2007. © 2007 Wiley‐Liss, Inc.
Amelogenin expression in long bone and cartilage cells and in bone marrow progenitor cells
Authors: Haze Amir , Taylor Angela L. , Blumenfeld Anat , Rosenfeld Eli , Leiser Yoav , Dafni Leah , Shay Boaz , Gruenbaum‐Cohen Yael , Fermon Eran , Haegewald Stefan , Bernimoulin Jean‐Pierre , Deutsch Dan
Published: March 2007

The amelogenin protein is considered as the major molecular marker of developing ectodermal enamel. Recent data suggest other roles for amelogenin beyond structural regulation of enamel mineral crystal growth. Here we describe our novel discovery of amelogenin expression in long bone cells, in cartilage cells, in cells of the epiphyseal growth plate, and in bone marrow stromal cells. Anat Rec, 2007. © 2007 Wiley‐Liss, Inc.
Up‐regulation of stromal cell–derived factor 1 (CXCL12) production in rheumatoid synovial fibroblasts through interactions with T lymphocytes: Role of interleukin‐17 and CD40L–CD40 interaction
Authors: Kim Kyoung‐Woon , Cho Mi‐La , Kim Hae‐Rim , Ju Ji‐Hyeon , Park Mi‐Kyung , Oh Hye‐Jwa , Kim Joon‐Seok , Park Sung‐Hwan , Lee Sang‐Heon , Kim Ho‐Youn
Published: March 2007

Objective

Stromal cell–derived factor 1 (SDF‐1) is a potent chemoattractant for memory T cells in inflamed rheumatoid arthritis (RA) synovium. This study was undertaken to investigate the effect of interleukin‐17 (IL‐17) and CD40–CD40L interaction on SDF‐1 production in RA fibroblast‐like synoviocytes (FLS).

Methods

Synovial fluid (SF) and serum levels of SDF‐1 in RA patients were measured by enzyme‐linked immunosorbent assay (ELISA). The SDF‐1 produced by cultured RA FLS was evaluated by real‐time polymerase chain reaction and ELISA after FLS were treated with IL‐17 and inhibitors of intracellular signal molecules. The SDF‐1 level was also determined after FLS were cocultured with T cells in the presence and absence of IL‐17.

Results

Concentrations of SDF‐1 in the sera and SF were higher in RA patients than in osteoarthritis patients, although the increase in the serum levels did not reach statistical significance. The production of SDF‐1 in RA FLS was enhanced by IL‐17 stimulation. This effect of IL‐17 was blocked by inhibitors of phosphatidylinositol 3‐kinase (PI 3‐kinase), NF‐κB, and activator protein 1 (AP‐1). When FLS were cocultured with T cells, SDF‐1 production was up‐regulated, especially in the presence of IL‐17, but FLS were inhibited by neutralizing anti–IL‐17 and anti‐CD40L antibodies. Addition of RA SF to cultured RA FLS significantly up‐regulated SDF‐1 messenger RNA expression, which was hampered by pretreatment with anti–IL‐17 antibody.

Conclusion

SDF‐1 is overproduced in RA FLS, and IL‐17 could up‐regulate the expression of SDF‐1 in RA FLS via pathways mediated by PI 3‐kinase, NF‐κB, and AP‐1. Our findings suggest that inhibition of the interaction between IL‐17 from T cells and SDF‐1 in FLS may provide a new therapeutic approach in RA.
Positive association of SLC26A2 gene polymorphisms with susceptibility to systemic‐onset juvenile idiopathic arthritis
Authors: Lamb Rebecca , Thomson Wendy ,   British Society of Paediatric and Adolescent Rheumatology, Ogilvie Emma M. , Donn Rachelle
Published: March 2007

Objective

To investigate SLC26A2, the gene that causes diastrophic dysplasia, in juvenile idiopathic arthritis (JIA).

Methods

Nine polymorphisms across the SLC26A2 gene locus were investigated using MassArray genotyping in 826 UK Caucasian JIA cases and 617 ethnically matched healthy controls.

Results

Significant associations between multiple single‐nucleotide polymorphisms (SNPs) across SLC26A2 and systemic‐onset JIA were found. In each case, homozygosity for the minor allele conferred the increased risk of disease susceptibility: rs1541915 (odds ratio [OR] 2.3, 95% confidence interval [95% CI] 1.4–3.7, P = 0.0003), rs245056 (OR 2.8, 95% CI 1.7–4.6, P = 0.00002), rs245055 (OR 2.5, 95% CI 1.2–5.0, P = 0.004), rs245051 (OR 2.3, 95% CI 1.4–3.7, P = 0.0005), rs245076 (OR 2.7, 95% CI 1.3–5.4, P = 0.0015), and rs8073 (OR 2.3, 95% CI 0.9–5.6, P = 0.04).

Conclusion

These findings show the value of using monogenic disease loci as candidates for investigation in JIA. We identified a subgroup‐specific association between SNPs within the SLC26A2 gene and systemic‐onset JIA. Our findings also highlight systemic‐onset JIA as being a distinctly different disease from that in the other JIA subgroups.
Analysis of vascular gene expression in arthritic synovium by laser‐mediated microdissection
Authors: Hashimoto Atsushi , Tarner Ingo H. , Bohle Rainer M. , Gaumann Andreas , Manetti Mirko , Distler Oliver , Steinmeyer Jürgen , Ulfgren Ann‐Kristin , Schulz Andreas , Gay Steffen , Müller‐Ladner Ulf , Neumann Elena
Published: March 2007

Objective

In rheumatoid arthritis (RA), formation of new blood vessels is necessary to meet the nutritional and oxygen requirements of actively proliferating synovial tissue. The aim of this study was to analyze the specific synovial vascular expression profiles of several angiogenesis‐related genes as well as CD82 in RA compared with osteoarthritis (OA), using laser‐mediated microdissection (LMM).

Methods

LMM and subsequent real‐time polymerase chain reaction were used in combination with immunohistochemical analysis for area‐specific analysis of messenger RNA (mRNA) and protein expression of vascular endothelial growth factor (VEGF), VEGF receptor 1 (VEGFR‐1), VEGFR‐2, hypoxia‐inducible factor 1α (HIF‐1α), HIF‐2α, platelet‐derived growth factor receptor α (PDGFRα), PDGFRβ, inhibitor of DNA binding/differentiation 2 (Id2), and CD82 in RA and OA synovial microvasculature and synovial lining.

Results

Expression of Id2 mRNA was significantly lower in RA synovial vessels compared with OA synovial vessels (P = 0.0011), whereas expression of VEGFR‐1 was significantly higher in RA (P = 0.0433). No differences were observed for the other parameters. At the protein level, no statistically significant differences were observed for any parameter, although Id2 levels were 2.5‐fold lower in RA (P = 0.0952). However, the number of synovial blood vessels and the number of VEGFR‐2–expressing blood vessels were significantly higher in RA compared with OA.

Conclusion

Our results underscore the importance of area‐specific gene expression analysis in studying the pathogenesis of RA and support LMM as a robust tool for this purpose. Of note, our results indicate that previously described differences between RA and OA in the expression of angiogenic molecules are attributable to higher total numbers of synovial and vascular cells expressing these molecules in RA rather than higher expression levels in the individual cells.
Interleukin‐6 and chemokines in the neuropsychiatric manifestations of systemic lupus erythematosus
Authors: Fragoso‐Loyo H. , Richaud‐Patin Y. , Orozco‐Narváez A. , Dávila‐Maldonado L. , Atisha‐Fregoso Y. , Llorente L. , Sánchez‐Guerrero J.
Published: March 2007

Objective

To define the cytokine and chemokine profile in cerebrospinal fluid (CSF) from patients with neuropsychiatric systemic lupus erythematosus (NPSLE).

Methods

Forty‐two SLE patients who had been hospitalized because of NP manifestations were studied. Patients were evaluated at hospitalization and 6 months later; a CSF sample was obtained at each evaluation. As controls, CSF from 6 SLE patients with septic meningitis, 16 SLE patients with no history of NP manifestations (non‐NPSLE), and 25 patients with nonautoimmune diseases were also studied. Soluble molecules, including cytokines (interleukin‐2 [IL‐2], IL‐4, IL‐6, IL‐10, tumor necrosis factor α [TNFα], and interferon‐γ [IFNγ]) and chemokines (monocyte chemotactic protein 1 [MCP‐1], RANTES, IL‐8, monokine induced by IFNγ [MIG], and interferon‐γ–inducible 10‐kd protein [IP‐10]), were measured with the use of cytometric bead array kits.

Results

CSF levels of the following molecules were significantly increased in NPSLE patients as compared with non‐NPSLE and nonautoimmune diseases control patients, respectively: IL‐6 (32.7 versus 3.0 and 2.96 pg/ml), IL‐8 (102.8 versus 29.97 and 19.7 pg/ml), IP‐10 (888.2 versus 329.7 [P not significant] and 133.6 pg/ml), RANTES (3.8 versus 2.5 and 2.2 pg/ml), MCP‐1 (401.7 versus 257.9 [P not significant] and 136.9 pg/ml), and MIG (35.4 versus 11.4 and 3.5 pg/ml). Low levels of IL‐2, IL‐4, IL‐10, TNFα, and IFNγ were found in all groups. All cytokines and chemokines, except TNFα, were significantly higher among the SLE patients with septic meningitis than among the NPSLE patients. Six months later and in the absence of NP manifestations, all elevated molecule levels, except RANTES, in patients with NPSLE had decreased significantly, and no differences were noted between the NPSLE and non‐NPSLE groups.

Conclusion

A central nervous system response composed of IL‐6 and chemokines, but not Th1/Th2 cytokines, is associated with NP manifestations in SLE patients.
Blockade of the interleukin‐21/interleukin‐21 receptor pathway ameliorates disease in animal models of rheumatoid arthritis
Authors: Young Deborah A. , Hegen Martin , Ma Hak Ling Margery , Whitters Matthew J. , Albert Leo M. , Lowe Leslie , Senices Mayra , Wu Paul W. , Sibley Barbara , Leathurby Yelena , Brown Tom P. , Nickerson‐Nutter Cheryl , Keith James C. , Collins Mary
Published: March 2007

Objective

Interleukin‐21 (IL‐21) is a T cell–derived cytokine that modulates T cell, B cell, and natural killer cell responses. In this study, the effects of blocking IL‐21 were examined in 2 rodent models of rheumatoid arthritis (RA) to determine whether IL‐21 contributes to their pathologic processes.

Methods

DBA/1 mice were immunized with bovine type II collagen and then treated with murine IL‐21 receptor Fc fusion protein (IL‐21R.Fc), which was initiated after the onset of arthritis symptoms in 10% of the cohort. The mice were assessed 3 times per week for signs of disease, including histologic features as well as serum cytokine, Ig, and cytokine messenger RNA (mRNA) levels in the paws. In a separate experiment, Lewis rats were immunized with Freund's complete adjuvant followed by administration of IL‐21R.Fc at the peak of inflammation in the joints. Rats were assessed daily for histologic features and for scoring of arthritis severity. In addition, the effects of IL‐21R.Fc on the production of interferon‐γ (IFNγ) by T cells were examined.

Results

Treatment of DBA/1 mice with IL‐21R.Fc reduced the clinical and histologic signs of collagen‐induced arthritis. Nonspecific IgG1 levels were decreased in response to treatment. The levels of IL‐6 mRNA in the paws and the serum IL‐6 levels were decreased after treatment with IL‐21R.Fc. IFNγ mRNA levels were increased in the paws, and the addition of IL‐21R.Fc to collagen‐activated lymph node cultures enhanced the levels of IFNγ. Collagen‐specific spleen cell responses in IL‐21R.Fc–treated mice were observed as reduced levels of IFNγ and increased levels of IL‐6. Treatment of Lewis rats with IL‐21R.Fc after induction of adjuvant‐induced arthritis resulted in reversal of disease signs and improvements in histologic parameters.

Conclusion

These findings demonstrate a pathogenic role for IL‐21 in animal models of RA, and support consideration of IL‐21 as a therapeutic target in human RA.
Role of matrix metalloproteinases, proinflammatory cytokines, and oxidative stress–derived molecules in hepatitis C virus–associated mixed cryoglobulinemia vasculitis neuropathy
Authors: Saadoun David , Bieche Ivan , Authier François‐Jérome , Laurendeau Ingrid , Jambou Florence , Piette Jean Charles , Vidaud Michel , Maisonobe Thierry , Cacoub Patrice
Published: March 2007

Objective

Mixed cryoglobulinemia (MC) is a systemic vasculitis, usually associated with hepatitis C virus (HCV) infection. The molecular mechanisms responsible for HCV‐associated MC (HCV‐MC) vasculitis are largely unknown. This study was undertaken to assess the expression profile of selected genes involved in inflammatory vascular damage in patients with HCV‐MC vasculitis, patients with polyarteritis nodosa (PAN), and patients with noninflammatory idiopathic neuropathy.

Methods

The quantitative expression levels of 42 selected genes involved in inflammatory vascular damage were assessed in nerve lesions of patients with HCV‐MC vasculitis, PAN (rheumatic disease controls), and noninflammatory idiopathic neuropathy (noninflammatory neuropathy controls), using real‐time reverse transcriptase–polymerase chain reaction. Genes were considered to be differentially expressed when there was a >2‐fold difference in mean expression levels between groups and the P value was less than 0.05.

Results

Expression levels of 8 genes were significantly increased in HCV‐MC patients versus control patients with noninflammatory idiopathic neuropathy, with the highest increase for metallothionein 1 H (MT1H), a hypoxic and oxidative stress protein. Compared with PAN patients, HCV‐MC patients had higher expression levels of genes encoding oxidative stress–derived molecules (MT1H, endothelial cell nitric oxide synthase 3, Hsp70, and Hsp90) and tissue plasminogen activator and lower expression levels of matrix metalloproteinase 7 (MMP‐7). HCV‐MC neuropathies were classified according to their morphologic pattern and the presence or absence of necrotizing arteritis. MMP‐1, MMP‐7, MMP‐9, and interleukin‐1β were up‐regulated in patients with necrotizing arteritis.

Conclusion

This comprehensive molecular study of HCV‐MC vasculitis provides strong evidence that MMPs, proinflammatory cytokines, and oxidative stress–derived molecules have a role in the pathogenesis of HCV‐MC vasculitis neuropathy.
Gabapentin in the treatment of fibromyalgia: A randomized, double‐blind, placebo‐controlled, multicenter trial
Authors: Arnold Lesley M. , Goldenberg Don L. , Stanford Sharon B. , Lalonde Justine K. , Sandhu H. S. , Keck Paul E. , Welge Jeffrey A. , Bishop Fred , Stanford Kevin E. , Hess Evelyn V. , Hudson James I.
Published: March 2007

Objective

To assess the efficacy and safety of gabapentin in patients with fibromyalgia.

Methods

A 12‐week, randomized, double‐blind study was designed to compare gabapentin (1,200–2,400 mg/day) (n = 75 patients) with placebo (n = 75 patients) for efficacy and safety in treating pain associated with fibromyalgia. The primary outcome measure was the Brief Pain Inventory (BPI) average pain severity score (range 0–10, where 0 = no pain and 10 = pain as bad as you can imagine). Response to treatment was defined as a reduction of ≥30% in this score. The primary analysis of efficacy for continuous variables was a longitudinal analysis of the intent‐to‐treat sample, with treatment‐by‐time interaction as the measure of effect.

Results

Gabapentin‐treated patients displayed a significantly greater improvement in the BPI average pain severity score (P= 0.015; estimated difference between groups at week 12 = −0.92 [95% confidence interval −1.75, −0.71]). A significantly greater proportion of gabapentin‐treated patients compared with placebo‐treated patients achieved response at end point (51% versus 31%;P= 0.014). Gabapentin compared with placebo also significantly improved the BPI average pain interference score, the Fibromyalgia Impact Questionnaire total score, the Clinical Global Impression of Severity, the Patient Global Impression of Improvement, the Medical Outcomes Study (MOS) Sleep Problems Index, and the MOS Short Form 36 vitality score, but not the mean tender point pain threshold or the Montgomery Asberg Depression Rating Scale. Gabapentin was generally well tolerated.

Conclusion

Gabapentin (1,200–2,400 mg/day) is safe and efficacious for the treatment of pain and other symptoms associated with fibromyalgia.
Examining the role of CD1d and natural killer T cells in the development of nephritis in a genetically susceptible lupus model
Authors: Yang Jun‐Qi , Wen Xiangshu , Liu Hongzhu , Folayan Gbolahan , Dong Xin , Zhou Min , Van Kaer Luc , Singh Ram Raj
Published: March 2007

Objective

CD1d‐reactive invariant natural killer T (iNKT) cells secrete multiple cytokines upon T cell receptor (TCR) engagement and modulate many immune‐mediated conditions. The purpose of this study was to examine the role of these cells in the development of autoimmune disease in genetically lupus‐prone (NZB × NZW)F1 (BWF1) mice.

Methods

The CD1d1‐null genotype was crossed onto the NZB and NZW backgrounds to establish CD1d1‐knockout (CD1d0) BWF1 mice. CD1d0 mice and their wild‐type littermates were monitored for the development of nephritis and assessed for cytokine responses to CD1d‐restricted glycolipid α‐galactosylceramide (αGalCer), anti‐CD3 antibody, and concanavalin A (Con A). Thymus and spleen cells were stained with CD1d tetramers that had been loaded with αGalCer or its analog PBS‐57 to detect iNKT cells, and the cells were compared between BWF1 mice and class II major histocompatibility complex–matched nonautoimmune strains, including BALB/c, (BALB/c × NZW)F1 (CWF1), and NZW.

Results

CD1d0 BWF1 mice had more severe nephritis than did their wild‐type littermates. Although iNKT cells and iNKT cell responses were absent in CD1d0 BWF1 mice, the CD1d0 mice continued to have significant numbers of interferon‐γ–producing NKT‐like (CD1d‐independent TCRβ+,NK1.1+ and/or DX5+) cells. CD1d deficiency also influenced cytokine responses by conventional T cells: upon in vitro stimulation of splenocytes with Con A or anti‐CD3, type 2 cytokine levels were reduced, whereas type 1 cytokine levels were increased or unchanged in CD1d0 mice as compared with their wild‐type littermates. Additionally, numbers of thymic iNKT cells were lower in young wild‐type BWF1 mice than in nonautoimmune strains.

Conclusion

Germline deletion of CD1d exacerbates lupus in BWF1 mice. This finding, together with reduced thymic iNKT cells in young BWF1 mice as compared with nonautoimmune strains, implies a regulatory role of CD1d and iNKT cells during the development of lupus.
The clinical continuum of cryopyrinopathies: Novel CIAS1 mutations in North American patients and a new cryopyrin model
Authors: Aksentijevich Ivona , D. Putnam Christopher , Remmers Elaine F. , Mueller James L. , Le Julie , Kolodner Richard D. , Moak Zachary , Chuang Michael , Austin Frances , Goldbach‐Mansky Raphaela , Hoffman Hal M. , Kastner Daniel L.
Published: March 2007

Objective

The cryopyrinopathies are a group of rare autoinflammatory disorders that are caused by mutations in CIAS1, encoding the cryopyrin protein. However, cryopyrin mutations are found only in 50% of patients with clinically diagnosed cryopyrinopathies. This study was undertaken to investigate the structural effect of disease‐causing mutations on cryopyrin, in order to gain better understanding of the impact of disease‐associated mutations on protein function.

Methods

We tested for CIAS1 mutations in 22 patients with neonatal‐onset multisystem inflammatory disease/chronic infantile neurologic, cutaneous, articular syndrome, 12 with Muckle‐Wells syndrome (MWS), 18 with familial cold‐induced autoinflammatory syndrome (FCAS), and 3 probands with MWS/FCAS. In a subset of mutation‐negative patients, we screened for mutations in proteins that are either homologous to cryopyrin or involved in the caspase 1/interleukin‐1β signaling pathway. CIAS1 and other candidate genes were sequenced, models of cryopyrin domains were constructed using structurally homologous proteins as templates, and disease‐causing mutations were mapped.

Results

Forty patients were mutation positive, and 7 novel mutations, V262A, C259W, L264F, V351L, F443L, F523C, and Y563N, were found in 9 patients. No mutations in any candidate genes were identified. Most mutations mapped to an inner surface of the hexameric ring in the cryopyrin model, consistent with the hypothesis that the mutations disrupt a closed form of cryopyrin, thus potentiating inflammasome assembly. Disease‐causing mutations correlated with disease severity only for a subset of known mutations.

Conclusion

Our modeling provides insight into potential molecular mechanisms by which cryopyrin mutations can inappropriately activate an inflammatory response. A significant number of patients who are clinically diagnosed as having cryopyrinopathies do not have identifiable disease‐associated mutations.
Decoy receptor 3 expressed in rheumatoid synovial fibroblasts protects the cells against fas‐induced apoptosis
Authors: Hayashi Shinya , Miura Yasushi , Nishiyama Takayuki , Mitani Makoto , Tateishi Koji , Sakai Yoshitada , Hashiramoto Akira , Kurosaka Masahiro , Shiozawa Shunichi , Doita Minoru
Published: March 2007

Objective

Decoy receptor 3 (DcR3), a newly identified member of the tumor necrosis factor receptor (TNFR) superfamily, is a soluble receptor that binds to members of the TNF family, including FasL, LIGHT, and TNF‐like molecule 1A. DcR3 is mostly expressed in tumor cells, and it competitively inhibits binding of TNF to TNFRs. The present study was undertaken to investigate DcR3 expression in fibroblast‐like synoviocytes (FLS) from patients with rheumatoid arthritis (RA) and osteoarthritis (OA), and to analyze the effects of DcR3 on Fas‐induced apoptosis in RA FLS.

Methods

Expression of DcR3 in FLS was measured by reverse transcriptase–polymerase chain reaction (RT‐PCR) and Western blotting. FLS were incubated with DcR3–Fc chimera protein or transfected with DcR3 small interfering RNA (siRNA) using the lipofection method, before induction of apoptosis. Apoptosis induced by Fas in FLS was detected with TUNEL staining and Western blotting of caspase 8 and poly(ADP‐ribose) polymerase. Finally, FLS were incubated with TNFα prior to Fas‐induced apoptosis, expression of DcR3 was analyzed by quantitative RT‐PCR, and apoptosis was measured.

Results

DcR3 was expressed in both RA FLS and OA FLS. DcR3–Fc protein inhibited Fas‐induced apoptosis in FLS. Down‐regulation of DcR3 in FLS by siRNA increased Fas‐induced apoptosis. TNFα increased DcR3 expression and inhibited Fas‐induced apoptosis in RA FLS, but not in OA FLS.

Conclusion

DcR3 expressed in RA FLS is increased by TNFα and protects the cells against Fas‐induced apoptosis. These findings indicate that DcR3 may be a possible therapeutic target in RA.
A tumor necrosis factor receptor loop peptide mimic inhibits bone destruction to the same extent as anti–tumor necrosis factor monoclonal antibody in murine collagen‐induced arthritis
Authors: Saito Hiroaki , Kojima Takefumi , Takahashi Mariko , Horne William C. , Baron Roland , Amagasa Teruo , Ohya Keiichi , Aoki Kazuhiro
Published: March 2007

Objective

The cyclic peptide WP9QY (YCWSQYLCY) was designed to mimic the most critical tumor necrosis factor α (TNFα) recognition loop on TNF receptor I, and it prevents interactions of TNFα with its receptor. We undertook this study to compare the effects of the WP9QY peptide on collagen‐induced arthritis (CIA) in mice with those of anti‐TNFα monoclonal antibody.

Methods

CIA was induced by primary and secondary immunizations. Osmotic minipumps were implanted in the backs of all mice on the day of the booster injection (day 21), and vehicle, anti‐TNF antibody (4 mg/kg/day), or WP9QY peptide (2 mg/kg/day or 4 mg/kg/day) was continuously infused until the mice were killed (day 40). Thereafter, clinical, radiographic, and histologic assessments were performed.

Results

WP9QY treatment inhibited CIA‐induced increases in the arthritis score, but onset of disease was not delayed by the peptide. The inhibitory effect of WP9QY on inflammation was definitely weaker than that of anti‐TNF antibody. Microfocal computed tomography analyses, however, revealed that WP9QY blocked CIA‐induced bone destruction at the knee joints to the same extent as did anti‐TNF antibody. In addition, WP9QY inhibited synovial pannus infiltration and reduced osteoclast number. Furthermore, inhibition of CIA‐induced systemic bone loss by WP9QY was more apparent than that by anti‐TNF antibody.

Conclusion

The TNFα antagonist WP9QY would be a useful template for the development of small molecular inhibitors to prevent both inflammatory bone destruction and systemic bone loss in rheumatoid arthritis.
Histopathologic and clinical outcome of rituximab treatment in patients with cyclophosphamide‐resistant proliferative lupus nephritis
Authors: Gunnarsson Iva , Sundelin Birgitta , Jónsdóttir Thorunn , Jacobson Stefan H. , Henriksson Elisabet Welin , van Vollenhoven Ronald F.
Published: March 2007

Objective

Rituximab is a monoclonal antibody directed against the CD20 marker of B cells. Because of its ability to deplete B lymphocytes, it has been suggested that the drug could be of benefit in B cell–dependent diseases, including systemic lupus erythematosus (SLE). The purpose of this study was to investigate the histopathologic and clinical effects of combination treatment with rituximab and cyclophosphamide (CYC) in patients with CYC‐resistant proliferative lupus nephritis.

Methods

Seven female patients with proliferative lupus nephritis were treated with rituximab in combination with CYC. Renal biopsies were performed before treatment and during followup. SLE activity was evaluated by the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the British Isles Lupus Assessment Group index. In 6 of the 7 patients, immunostaining of lymphocyte subpopulations in the renal tissue was performed before treatment and during followup.

Results

At 6 months of followup, significant clinical improvement was noted, with a reduction in SLEDAI scores (from a mean of 15 to 3), anti–double‐stranded DNA antibody levels (from a mean of 174 IU/ml to 56 IU/ml), and anti‐C1q antibody levels (from a mean of 35 units/ml to 22 units/ml). On repeat renal biopsy, improvement in the histopathologic class of nephritis occurred in a majority of patients, and a decrease in the renal activity index was noted (from 6 to 3). A reduction in the number of CD3, CD4, and CD20 cells in the renal interstitium was noted in 50% of the patients on repeat biopsy.

Conclusion

At 6 months of followup, all patients had responded both clinically and histopathologically to combination therapy. For patients with proliferative lupus nephritis who fail to respond to conventional immunosuppressive therapy including CYC, combined treatment with rituximab and CYC may constitute a new treatment option.
Clinical and immunogenetic features of patients with autoantibodies to asparaginyl–transfer RNA synthetase
Authors: Hirakata Michito , Suwa Akira , Takada Tetsuya , Sato Shinji , Nagai Sonoko , Genth Ekkehard , Song Yeong W. , Mimori Tsuneyo , Targoff Ira N.
Published: March 2007

Objective

We have previously described anti‐KS autoantibodies and provided evidence that they are directed against asparaginyl–transfer RNA (tRNA) synthetase (AsnRS). The aim of the present study was to identify patients with anti‐AsnRS autoantibodies and elucidate the clinical significance of this sixth antisynthetase antibody. In particular, we studied whether it was associated with the syndrome of myositis (polymyositis or dermatomyositis [DM]), interstitial lung disease (ILD), arthritis, and other features that had been previously associated with the 5 other anti–aminoacyl–tRNA synthetase autoantibodies.

Methods

More than 2,500 sera from patients with connective tissue disease (including myositis and ILD) and controls were examined for anti‐AsnRS autoantibodies by immunoprecipitation (IP). Positive and control sera were tested for the ability to inhibit AsnRS by preincubation of the enzyme source with the serum. The HLA class II (DRB1, DQA1, DQB1, DPB1) alleles were identified from restriction fragment length polymorphism of polymerase chain reaction–amplified genomic DNA.

Results

Anti‐AsnRS antibodies were identified in the sera of 8 patients (5 Japanese, 1 American, 1 German, and 1 Korean) by IP of the same distinctive set of tRNA and protein that differed from those precipitated by the other 5 antisynthetases, and these antibodies showed specific inhibition of AsnRS activity. Two of these patients had DM, but 7 of 8 (88%) had ILD. Four patients (50%) had arthritis, and 1 had Raynaud's phenomenon. This antisynthetase was very rare among myositis patients (present in 0% of Japanese myositis patients), but it was found in 3% of Japanese ILD patients. Thus, most patients with anti‐AsnRS had chronic ILD with or without features of connective tissue disease. Interestingly, all 4 Japanese patients tested had DR2 (DRB1*1501/1502), compared with 33% of healthy controls.

Conclusion

These results indicate that anti‐AsnRS autoantibodies, like anti–alanyl–tRNA synthetase autoantibodies, have a stronger association with ILD than with myositis and may be associated with the DR2 phenotype.
Knee alignment does not predict incident osteoarthritis: The Framingham osteoarthritis study
Authors: Hunter David J. , Niu Jingbo , Felson David T. , Harvey William F. , Gross K. Douglas , McCree Paula , Aliabadi Piran , Sack Burton , Zhang Yuqing
Published: March 2007

Objective

To examine the relationship of knee malalignment to the occurrence of knee osteoarthritis (OA) among subjects without radiographic OA at baseline to determine whether malalignment is a risk factor for incident disease or simply a marker of increasing disease severity.

Methods

We selected 110 incident tibiofemoral (TF) OA case knees (76 subjects) and 356 random control knees (178 subjects) from among participants in the Framingham Osteoarthritis Study. Case knees did not have OA at baseline (1992–1994 examination) but had developed OA (Kellgren/Lawrence grade ≥2) at followup (2002–2005 examination) (mean of 8.75 years between examinations). Control knees did not have OA at baseline. Standardized digital radiographs of the fully extended knee with weight‐bearing were read using a standard protocol and eFilm viewing software. We measured the anatomic axis, the condylar angle, the tibial plateau angle, and the condylar tibial plateau angle. The interobserver intraclass correlation coefficient (ICC) ranged from 0.93 to 0.96 and the intraobserver ICC from 0.94 to 0.97. In a knee‐specific analysis, we examined the relationship of each alignment measurement to the risk of TF OA using generalized estimating equations, adjusting for age, sex, and body mass index (BMI). We used the same approach to assess the association between each alignment measurement and the risk of medial TF OA.

Results

Subjects in the case population were older and had a higher BMI than the controls. The alignment values were normally distributed and were not different between the cases and the controls. After adjustment for age, sex and BMI, there was no significant increase in incident OA in the highest quartile compared with the lowest quartile category for any of the alignment measures (P for trend for anatomic axis and condylar tibial plateau angle was 0.83 and 0.80, respectively). Similar results were also observed for medial compartment OA.

Conclusion

We found that baseline knee alignment is not associated with either incident radiographic TF OA or medial TF OA. These results suggest that malalignment is not a risk factor for OA, but rather is a marker of disease severity and/or its progression.
Reproductive and menopausal factors and risk of systemic lupus erythematosus in women
Authors: Costenbader Karen H. , Feskanich Diane , Stampfer Meir J. , Karlson Elizabeth W.
Published: March 2007

Objective

Systemic lupus erythematosus (SLE) occurs predominantly in women, and hormones may play a role in its etiology. This study was carried out to examine associations between female reproductive and menopausal factors and the development of SLE.

Methods

A cohort of 238,308 women was prospectively examined. Subjects were older women (ages 30–55 years at start) and younger women (ages 25–42 years at start) from the Nurses' Health Study (NHS) and NHSII cohorts. Incident SLE diagnosed between 1976 and 2003 was confirmed by medical record review. The relative risk (RR) of SLE was estimated separately in each cohort using Cox proportional hazards models, and then pooled using meta‐analysis random effects models.

Results

Two hundred sixty‐two incident cases of SLE were confirmed among the women. In multivariable models adjusted for reproductive and other risk factors, age ≤10 years at menarche (pooled RR 2.1, 95% confidence interval [95% CI] 1.4–3.2), oral contraceptive use (pooled RR 1.5, 95% CI 1.1–2.1), and use of postmenopausal hormones (RR 1.9, 95% CI 1.2–3.1) significantly increased the risk of SLE. An elevation of SLE risk was observed among postmenopausal women primarily after surgical menopause (RR 2.3, 95% CI 1.2–4.5), and also among women with earlier age at natural menopause (P for trend < 0.05). Menstrual irregularity was associated with an increased risk of SLE among women in the younger (NHSII) cohort. Age at first birth, parity, and total duration of breastfeeding were not associated with SLE.

Conclusion

Early age at menarche, oral contraceptive use, early age at menopause, surgical menopause, and postmenopausal use of hormones were each associated with an increased risk of SLE. These associations may point to the mechanisms underlying the pathogenesis of SLE.
Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen‐induced arthritis
Authors: Augello Andrea , Tasso Roberta , Negrini Simone Maria , Cancedda Ranieri , Pennesi Giuseppina
Published: March 2007

Objective

Mesenchymal stem cells (MSCs) are precursors of tissue of mesenchymal origin, but they also have the capacity to regulate the immune response by suppressing T and B lymphocyte proliferation in a non–major histocompatibility complex–restricted manner. Use of MSCs as immunosuppressant agents in autoimmune diseases has been proposed and successfully tested in animal models. We explored the feasibility of using allogeneic MSCs as therapy for collagen‐induced arthritis, a mouse model for human rheumatoid arthritis.

Methods

DBA/1 mice were immunized with type II collagen in Freund's complete adjuvant, and some of the animals received an intraperitoneal injection of allogeneic MSCs.

Results

A single injection of MSCs prevented the occurrence of severe, irreversible damage to bone and cartilage. MSCs induced hyporesponsiveness of T lymphocytes as evidenced by a reduction in active proliferation, and modulated the expression of inflammatory cytokines. In particular, the serum concentration of tumor necrosis factor α was significantly decreased. MSCs exerted their immunomodulatory function by educating antigen‐specific Tregs.

Conclusion

Our results suggest an effective new therapeutic approach to target the pathogenic mechanism of autoimmune arthritis using allogeneic MSCs. However, further studies are required before these results can be translated to clinical settings.
Histone deacetylase/acetylase activity in total synovial tissue derived from rheumatoid arthritis and osteoarthritis patients
Authors: Huber Lars C. , Brock Matthias , Hemmatazad Hossein , Giger Olivier T. , Moritz Falk , Trenkmann Michelle , Distler Jörg H. W. , Gay Renate E. , Kolling Christoph , Moch Holger , Michel Beat A. , Gay Steffen , Distler Oliver , Jüngel Astrid
Published: March 2007

Objective

Rheumatoid arthritis (RA) is a chronic inflammatory disorder of unknown origin. Histone deacetylase (HDA) activity is considered to play a major role in the transcriptional regulation of proinflammatory genes. We undertook this study to investigate the balance of histone acetylase and HDA activity in synovial tissue from RA patients compared with that from patients with osteoarthritis (OA) and normal controls.

Methods

Activity of histone acetylases and HDAs was measured in nuclear extracts of total synovial tissue samples, which were obtained from RA and OA patients undergoing surgical joint replacement, and compared with the activity in synovial tissues from patients without arthritis. Tissue expression of HDAs 1 and 2 was quantified by Western blotting. In addition, immunohistochemistry was performed for HDA‐2.

Results

Mean ± SEM HDA activity in synovial tissue samples derived from patients with RA was measured as 1.5 ± 0.3 μmoles/μg, whereas the activity levels in OA (3.2 ± 0.7 μmoles/μg) and normal (7.1 ± 4.2 μmoles/μg) synovial tissue samples were significantly higher. Histone acetylase activity reached similar levels in RA and OA tissues and in normal tissues. The ratio of HDA activity to histone acetylase activity in RA synovial tissue was significantly reduced (12 ± 2%) compared with that in OA synovial tissue (26 ± 3%). The activity ratio in normal control samples was arbitrarily set at 100 ± 40%. In addition, the tissue expression of HDA‐1 and HDA‐2 proteins was clearly lower in RA samples than in OA samples.

Conclusion

The balance of histone acetylase/HDA activities is strongly shifted toward histone hyperacetylation in patients with RA. These results offer novel molecular insights into the pathogenesis of the disease that might be relevant to the development of future therapeutic approaches.
Risk factors for more severe regional musculoskeletal symptoms: A two‐year prospective study of a general working population
Authors: Andersen Johan H. , Haahr Jens P. , Frost Poul
Published: March 2007

Objective

To quantify the relative contribution of work‐related physical and psychosocial factors, individual factors, and health‐related factors to the development of more severe musculoskeletal pain in the neck and upper limbs and the back and lower limbs.

Methods

In this cohort study of 5,604 workers from industrial and service companies, we collected information on work‐related physical and psychosocial exposures and on individual and health‐related factors. Questionnaires were completed at baseline by 4,006 participants (71.5%) and after 24 months by 3,276 (82%). At followup, participants with no or minor pain were included in Cox regression analyses to determine which factors predicted more severe regional pain.

Results

Of the 4,006 baseline respondents, only 7.7% were free of regional pain. A total of 1,513 participants were free of severe pain at baseline and completed the 24‐month followup. Highly repetitive work predicted arm pain, heavy lifting and prolonged standing predicted low back pain, and heavy pushing or pulling predicted lower limb pain. Low job satisfaction predicted neck/shoulder pain and lower limb pain, whereas other psychosocial work place factors were only of marginal importance. High levels of fear avoidance were associated with arm pain and lower limb pain. A high body mass index was highly associated with lower limb pain.

Conclusion

Very few workers are totally free of pain in musculoskeletal regions, and we question the concept of incidence of musculoskeletal pain. The transition from no or minor pain to more severe pain was influenced by physical and psychosocial work place factors together with individual and health‐related factors.
Sequential developmental changes in holoprosencephalic mouse embryos exposed to ethanol during the gastrulation period
Authors: Higashiyama Daisuke , Saitsu Hirotomo , Komada Munekazu , Takigawa Toshiya , Ishibashi Makoto , Shiota Kohei
Published: March 2007

BACKGROUND: Prenatal exposure to ethanol induces holoprosencephalic malformations in both humans and laboratory animals. However, its teratogenic window for inducing holoprosencephaly is narrow, and the teratogenic mechanism is not well understood. In the present study, we examined the morphological changes in the craniofacial structures of mouse embryos/fetuses at intervals following ethanol treatment and evaluated gene expression patterns in the embryos. METHODS: Pregnant C57BL/6J mice were given two doses of ethanol (30 mg/kg in total) on the morning (7:00 and 11:00 AM) of day 7. The fetuses were observed at E10.5 and E15.5 grossly and/or histologically. The expression of Shh and Nkx2.1 gene transcripts was examined at E8.5 by in situ hybridization. RESULTS: Gross and histological abnormalities of the brain and face were found in ethanol‐exposed fetuses, and their midline structures were most frequently affected. The midline commissural fibers were often lacking in ethanol‐exposed fetuses, even in those cases without external gross malformations. In situ hybridization revealed down‐regulation of Shh and Nkx2.1 genes in ethanol‐exposed embryos. CONCLUSIONS: The results indicate that ethanol may perturb the expression of some developmental genes at a critical stage of embryonic development and induce holoprosencephaly and other midline craniofacial malformations, including histological brain abnormalities. Birth Defects Research (Part A), 2007. © 2007 Wiley‐Liss, Inc.
Greek special educators' behavior analytic skills
Authors: Ntinas Konstantinos M. , Asteriou‐Yerofoka S. , Yiannaros V. , Koutsouridis I. , Nanna A. , Papadimitriou C.
Published: March 2007

The present study examined the ability of 52 special teachers in determining the underlying function of challenging behaviors in children with developmental disabilities and in linking the identified function with relevant intervention. Participants were presented with three questionnaire vignettes describing behavior maintained by attention, task avoidance and sensory consequences. They were then asked to identify the likely causes of the behaviors from a table of three possible functions and to link them with relevant intervention from a pool of 11 forms of intervention. The results indicated that teachers can reliably identify the cause of the behavior but they are not yet able to link function with relevant intervention without the provision of adequate support. The implications for teachers' in‐service training in the implementation of behavior analytic interventions are briefly discussed. Copyright © 2007 John Wiley & Sons, Ltd.
Free will from the viewpoint of teleological behaviorism
Authors: Rachlin Howard
Published: March 2007

A teleological and behavioral view is presented of the concept of free will. Free will is not something people essentially have or do not have. Instead, the following question is asked: Why does society find it useful to label some actions free and some actions not free? It is argued that the function of such labels is to aid in assigning responsibility to people for their actions. Responsibility in turn is useful in assigning rewards and punishments. The sort of actions that are typically seen as free are the same as those seen as self‐controlled. Such actions are responsive to environmental contingencies of relatively wide temporal extent. Copyright © 2007 John Wiley & Sons, Ltd.