bluuebunny/crossref_metadata_2025 huggingface dataset:
Feasible products in complex batch reactive distillation
Authors: Chin James , Lee Jae W. , Choe Jaehoon
Published: February 2006

A new feasibility evaluation procedure for reactive mixtures is presented, where simple homogeneous reactive batch columns cannot produce pure products. Such columns are not feasible for producing pure products if no node products exist that are reachable by residue curves from the reaction equilibrium manifold. Three alternatives are presented. If an unstable node heterogenous azeotrope decants to an almost‐pure product, and that azeotrope is always reachable from the reaction equilibrium manifold, then a batch reactive rectifier can produce pure products with a decanter. If a homogeneous entrainer allows extractive section profiles to connect the reaction equilibrium manifold to an entrainer‐product binary edge, then a homogeneous batch reactive extractive distillation (BRED) column can produce a pure product. If these criteria are not met, then an entrainer that induces an unstable node heterogenous azeotrope between itself and one of the products should be used in a rectifier, a middle‐vessel column, or a BRED column. © 2006 American Institute of Chemical Engineers AIChE J, 2006
Arithmetic difficulties in females with the fragile X premutation
Authors: Lachiewicz Ave M. , Dawson Deborah V. , Spiridigliozzi Gail A. , McConkie‐Rosell Allyn
Published: February 2006

Females with the fragile X full mutation have been reported to have difficulty learning mathematics. Women with the fragile X premutation often give a history of mathematics difficulties in themselves especially with higher level math. In order to evaluate whether women with the premutation have difficulty with math, we asked women with both the fragile X premutation and full mutation to complete the Wide Range Achievement Test‐3. For the group of 39 women with the fragile X premutation, the median standard score on the Arithmetic portion was 93, which was significantly lower (P = 0.001) than the median of the standardized norm of 100. Only nine of the women had Arithmetic scores at or above the 50th centile, while over half of the women had standard scores at or above the 50th centile in Reading and Spelling. The eight women with the full mutation also had lower Arithmetic scores than Reading and Spelling scores. These data suggest that mathematics may be an area of relative weakness for the women with the premutation as well as the full mutation. This possibility should be evaluated further by using other measures. This information is important both for counseling purposes and to understand whether a mathematics deficit is evidence of low expression of the FMR1 gene in the premutation state. © 2006 Wiley‐Liss, Inc.
Haplotype‐based systematic association studies of ATP1A2 in migraine with aura
Authors: Netzer Christian , Todt Unda , Heinze Axel , Freudenberg Jan , Zumbroich Vera , Becker Tim , Goebel Ingrid , Ohlraun Stephanie , Goebel Hartmut , Kubisch Christian
Published: February 2006

Mutations in ATP1A2 cause familial hemiplegic migraine (FHM) type 2, a rare monogenic form of migraine with aura (MA). Moreover, rare ATP1A2 missense variants are found in familial clustering of common forms of migraine in single pedigrees. To determine whether also common ATP1A2 polymorphisms contribute to MA pathogenesis, we performed systematic case‐control association studies in 284 MA cases and 241 control individuals. By direct sequencing of the 23 coding exons and adjacent intronic regions in 45 MA patients, 16 polymorphisms (12 SNPs, 3 small indels, 1 microsatellite marker) were identified. The sequencing results were used to estimate seven common ATP1A2 haplotypes (with a frequency >5%) covering about 97% of total haplotype diversity for this region. Subsequently, six haplotype‐tagging SNPs/polymorphisms were genotyped in 95 individuals with a family history of MA, in 189 individuals with sporadic MA, and in a gender‐matched control sample. A haplotype analysis was performed using the program FAMHAP. No significant differences in the ATP1A2 haplotype distribution could be detected between MA patients (or patient subgroups) and the control group. In a single‐marker analysis the allele and genotype frequencies of ATP1A2 polymorphisms between cases and controls were compared. Neither the six ht‐SNPs nor a single allele of the microsatellite marker were significantly associated with MA. In summary, we found no evidence for a common contribution of ATP1A2 to the pathogenesis of complex inherited MA. © 2006 Wiley‐Liss, Inc.
Association of mitochondrial complex I subunit gene NDUFV2 at 18p11 with schizophrenia in the Japanese population
Authors: Washizuka Shinsuke , Kametani Mizue , Sasaki Tsukasa , Tochigi Mamoru , Umekage Tadashi , Kohda Kazuhisa , Kato Tadafumi
Published: February 2006

Schizophrenia and bipolar disorder share common genetic background. Several loci such as 18p11, 13q32, and 22q11–13 were commonly linked with these diseases. Since mitochondrial dysfunction has been suggested in both of these disorders, NDUFV2 at 18p11, encoding a subunit of the complex I, NADH ubiquinone oxidoreductase, is a candidate gene for these diseases. We previously reported that single nucleotide polymorphisms (SNPs) in the upstream region of NDUFV2 were associated with bipolar disorder in Japanese. The association of haplotype consisting of two SNPs, −3542G > A and −602G > A, with bipolar disorder was also seen both in Japanese and the National Institute of Mental Health Pedigrees trios. In this study, 2 polymorphisms, −3542G > A and −602G > A, were investigated in 229 schizophrenic patients as compared with controls. Individual genotypes were not associated with schizophrenia. However, the haplotype consisting of these two SNPs were significantly associated with schizophrenia. These results suggested that inter‐individual variation of the genomic sequence of the promoter region of NDUFV2 might be a genetic risk factor common to bipolar disorder and schizophrenia. © 2006 Wiley‐Liss, Inc.
Absence of coding mutations in the X‐linked genes neuroligin 3 and neuroligin 4 in individuals with autism from the IMGSAC collection
Authors: Blasi Francesca , Bacchelli Elena , Pesaresi Giulia , Carone Simona , Bailey Anthony J. , Maestrini Elena ,   and the International Molecular Genetic Study of Autism Consortium (IMGSAC)
Published: February 2006

Neuroligin abnormalities have been recently implicated in the aetiology of autism spectrum disorders (ASD), given the finding of point mutations in the two X‐linked genes NLGN3 and NLGN4X and the important role of neuroligins in synaptogenesis. To enquire on the relevance and frequency of neuroligin mutations in ASD, we performed a mutation screening of NLGN3 and NLGN4X in a sample of 124 autism probands from the International Molecular Genetic Study of Autism Consortium (IMGSAC). We identified a new non‐synonymous variant in NLGN3 (Thr632Ala), which is likely to be a rare polymorphism. Our data indicate that coding mutations in these genes are very rarely associated to ASD. © 2006 Wiley‐Liss, Inc.
Synthesis and characterization of organotin complexes with dithiocarbamates and crystal structures of (4‐NCC6H4CH2)2Sn(S2CNEt2)2 and (2‐ClC6H4CH2)2 Sn(Cl)S2CNBz2
Authors: Yin Han Dong , Xue Sheng Cai
Published: March 2006

Ten organotin derivatives with dithiocarbamates of the formulae (4‐NCC6H4CH2)2Sn(S2CNEt2)2 (1), (4‐NCC6H4CH2)2Sn(S2CNBz2)2 (2), (4‐NCC6H4CH2)2Sn[S2CN(CH2CH2)2NCH3]2 (3), (2‐ClC6H4CH2)2 Sn(S2CNEt2)2 (4), (2‐ClC6H4CH2)2Sn(S2CNBz2)2 (5), (4‐NCC6H4CH2)2Sn(Cl)S2CNEt2 (6), (4‐NCC6H4CH2)2Sn(Cl)S2CNBz2 (7), (4‐NCC6H4CH2)2Sn(Cl)S2CN(CH2CH2)2NCH3 (8), (2‐ClC6H4CH2)2 Sn(Cl)S2CNEt2 (9) and (2‐ClC6H4CH2)2Sn(Cl)S2CNBz2 (10) have been prepared. All complexes were characterized by elemental analyses, IR and NMR. The crystal structures of complexes 1 and 10 were determined by X‐ray single crystal diffraction. For complex 1, the central tin atom exists in a skew‐trapezoidal planar geometry defined by two asymmetrically coordinated dithiocarbamate ligands and two 4‐cyanobenzyl groups. In addition, because of the presence of close intermolecular non‐bonded contacts, complex 1 is a weakly‐bridged dimer. In complex 10, the central tin atom is rendered pentacoordinated in a distorted trigonal bipyramidal configuration by coordinating with S atoms derived from the dithiocarbamate ligand. In vitro assays for cytotoxicity against five human tumor cell lines (MCF‐7, EVSA‐T, WiDr, IGROV and M226) furnished the significant toxicities of the title complexes. Copyright © 2006 John Wiley & Sons, Ltd.
Critical comparative analyses of anti–α‐actinin and glomerulus‐bound antibodies in human and murine lupus nephritis
Authors: Kalaaji Manar , Sturfelt Gunnar , Mjelle Janne Erikke , Nossent Hans , Rekvig Ole Petter
Published: February 2006

Objective

Although anti–double‐stranded DNA (anti‐dsDNA) antibodies are important in lupus nephritis, the question regarding which glomerular structures (α‐actinin, nucleosomes, or others) are recognized by nephritogenic anti‐dsDNA antibodies is still controversial. In this study, we determined which glomerular structures are recognized by monoclonal and in vivo–bound nephritogenic antibodies.

Methods

Western blotting was used to analyze the ability of nephritogenic anti‐dsDNA antibodies to recognize glomerular and nucleosomal structures. Sera from patients with lupus nephritis, sera from random antinuclear antibody–positive patients, and paired antibodies from sera and kidney eluates from nephritic (NZB × NZW)F1 mice were analyzed for activity against proteins identified by monoclonal nephritogenic antibodies, and against α‐actinin, dsDNA, nucleosomes, histone H1, heparan sulfate, DNase I, and type IV collagen. Immunoelectron microscopy was used to determine the glomerular localization of α‐actinin and in vivo–bound autoantibodies in nephritic (NZB × NZW)F1 mouse kidneys.

Results

Anti–α‐actinin antibodies were observed in human and murine lupus nephritis sera and in sera from patients without systemic lupus erythematosus and were not detected in kidney eluates from nephritic mice. Antibodies to dsDNA and histone H1 were detected in all eluates. Western blot analyses revealed that nephritogenic anti‐dsDNA antibodies recognized a 32‐kd band, identified as histone H1. Competitive enzyme‐linked immunosorbent assay demonstrated that nephritogenic monoclonal antibodies, and dominant antibodies eluted from nephritic kidneys, cross‐reacted with dsDNA and H1. This cross‐reactive anti‐H1 specificity was largely absent in sera from those mice. Immunoelectron microscopic analysis of nephritic (NZB × NZW)F1 mouse kidneys revealed that antibodies eluted from kidneys, but not anti–α‐actinin antibodies, bound to distinct nephritis‐associated electron‐dense structures linked to glomerular basement membranes.

Conclusion

Cross‐reactive anti‐dsDNA/anti–histone H1 antibodies, but not anti–α‐actinin antibodies, are central among those deposited in nephritic glomeruli.
Sphingosine kinase 1–mediated inhibition of Fas death signaling in rheumatoid arthritis B lymphoblastoid cells
Authors: Pi Xiujun , Tan Shi‐Yu , Hayes Michael , Xiao Liqun , Shayman James A. , Ling Song , Holoshitz Joseph
Published: February 2006

Objective

It is becoming increasingly apparent that B cells play an important role in the pathogenesis of rheumatoid arthritis (RA). Due to the scarcity of B cells in RA, it has been technically difficult to functionally characterize B cell apoptosis in this disease. As a necessary first step to identify candidate aberrations, we investigated Fas‐mediated signaling events in immortalized peripheral blood B lymphoblastoid cell lines (LCLs) from patients with RA and controls.

Methods

Cell death was determined by the MTS assay, and apoptosis was detected by the TUNEL assay and DNA laddering. Proteolytic activation of caspase 3 was determined by immunoblotting, and its enzymatic activity was determined by a fluorometric technique. Messenger RNA (mRNA) expression was quantified by real‐time polymerase chain reaction (PCR) analysis. The functional role of sphingosine kinase (SPHK) was determined by measuring its enzymatic activity, by quantifying the levels of its product, sphingosine 1‐phosphate (S1P), and by investigating the ability of the SPHK inhibitor N,N‐dimethylsphingosine and isozyme‐specific small interfering RNA (siRNA) oligonucleotides to reverse signaling aberrations.

Results

LCLs from patients with RA displayed disease‐specific Fas‐mediated signal transduction impairment with consequent resistance to cell death. RA LCLs displayed high constitutive SPHK activity and increased levels of S1P. Real‐time PCR analysis showed higher SPHK‐1 mRNA expression levels in RA patients compared with paired controls. Increased SPHK‐1 (but not SPHK‐2) mRNA levels were observed in synovial tissue from RA patients. Competitive inhibitors of SPHK reversed the resistance of RA LCLs to Fas‐induced apoptosis. Additionally, resistance to Fas‐mediated signaling was reversed by siRNA oligonucleotides specific for SPHK‐1 but not by oligonucleotides specific for SPHK‐2.

Conclusion

These findings demonstrate disease‐specific resistance to Fas‐mediated death signaling in patients with RA and implicate increased SPHK‐1 activity as the cause of this aberration.
Effects of a novel tylophorine analog on collagen‐induced arthritis through inhibition of the innate immune response
Authors: You Xin , Pan Meng , Gao Wenli , Shiah Her‐Shyong , Tao Jian , Zhang Dongqing , Koumpouras Fotios , Wang Shuang , Zhao Hongyu , Madri Joseph A. , Baker David , Cheng Yung‐Chi , Yin Zhinan
Published: February 2006

Objective

To test the effects of a novel tylophorine analog, DCB 3503, on the prevention and treatment of collagen‐induced arthritis (CIA) and to elucidate its underlying mechanisms.

Methods

DBA/1J mice were immunized with type II collagen, and in some cases, lipopolysaccharide (LPS) was used to boost the development of arthritis. DCB 3503 was injected intraperitoneally before or after the onset of CIA. Mice were monitored to assess the effects of DCB 3503 on the clinical severity of the disease, and pathologic changes in the joints were examined histologically. Levels of tumor necrosis factor α (TNFα) and interleukin‐1β (IL‐1β) in serum and joint tissues were measured by enzyme‐linked immunosorbent assay and by cytometric bead array analysis. The effect of DCB 3503 on LPS‐induced proinflammatory cytokines from bone marrow–derived dendritic cells was determined by flow cytometry.

Results

DCB 3503 significantly suppressed the development and progression of CIA. Moreover, DCB 3503 completely blocked the LPS‐triggered acceleration of joint inflammation and destruction. Consistent with its effects in vivo, DCB 3503 significantly suppressed the synthesis of proinflammatory cytokines in inflamed joints as well as cytokine synthesis by macrophages examined ex vivo. Treatment also reduced the levels of inflammatory cytokines (IL‐6, IL‐12, TNFα, and monocyte chemotactic protein 1) produced by bone marrow–derived dendritic cells in vitro. However, DCB 3503 showed no direct effects on T cell proliferation and B cell antibody response.

Conclusion

Because of its ability to specifically suppress innate immune responses, DCB 3503 may be a novel therapeutic agent for inflammatory arthritis in humans.
DNA topoisomerase I binding to fibroblasts induces monocyte adhesion and activation in the presence of anti–topoisomerase I autoantibodies from systemic sclerosis patients
Authors: Hénault Jill , Robitaille Geneviève , Senécal Jean‐Luc , Raymond Yves
Published: February 2006

Objective

Systemic sclerosis (SSc) is an autoimmune disease characterized by fibrosis due to excessive and dysregulated collagen production by fibroblasts. Previously, we reported that anti–DNA topoisomerase I (anti–topo I) antibodies bound specifically to fibroblast surfaces; however, we had not identified their antigenic target. We undertook this study to characterize the target of anti–topo I antibodies on fibroblasts and the effects of their binding.

Methods

Purified topo I or topo I released from apoptotic cells was tested for surface binding to a number of human cell types by cell‐based enzyme‐linked immunosorbent assay, flow cytometry, and indirect immunofluorescence. Antibodies purified from SSc patient and normal control sera were used to detect topo I binding. The consequences of topo I and anti–topo I binding to fibroblasts were assessed by coculture with THP‐1 monocytes.

Results

The autoantigen topo I itself was found to bind specifically to fibroblasts in a dose‐dependent and saturable manner, where it was recognized by anti–topo I from SSc patients. The binding of anti–topo I subsequently stimulated adhesion and activation of cocultured monocytes. Topo I released from apoptotic endothelial cells was also found to bind specifically to fibroblasts.

Conclusion

The findings of this study thus confirm and extend the findings of our previous study by showing that topo I binding to fibroblast surfaces is both necessary and sufficient for anti–topo I binding. Second, topo I–anti–topo I complex binding can then trigger the adhesion and activation of monocytes, thus providing a plausible model for the amplification of the fibrogenic cascade in anti–topo I–positive SSc patients.
Antigen‐induced, tolerogenic CD11c+,CD11b+ dendritic cells are abundant in Peyer's patches during the induction of oral tolerance to type II collagen and suppress experimental collagen‐induced arthritis
Authors: Min So‐Youn , Park Kyung‐Su , Cho Mi‐La , Kang Jung‐Won , Cho Young‐Gyu , Hwang Sue‐Yun , Park Min‐Jung , Yoon Chong‐Hyeon , Min Jun‐Ki , Lee Sang‐Heon , Park Sung‐Hwan , Kim Ho‐Youn
Published: February 2006

Objective

Although oral tolerance is a well‐known phenomenon, the role of dendritic cells (DCs) is not well characterized. This study was conducted to better understand the differential role played by each Peyer's patch DC subset in the induction of oral tolerance to type II collagen (CII) in murine collagen‐induced arthritis (CIA).

Methods

CII was fed 6 times to DBA/1 mice beginning 2 weeks before immunization, and the effect on arthritis was assessed. We compared the proportion of CD11c+,CD11b+ DCs and CD11c+,CD8α+ DCs in the Peyer's patches of CII‐fed tolerized and phosphate buffered saline–fed nontolerized mice after the induction of CIA. The immunosuppressive properties of each DC subset were determined using fluorescence‐activated cell sorter analysis for intracellular interleukin‐10 (IL‐10) and IL‐12 and mixed lymphocyte culture. The ability of each DC subset to induce CD4+,CD25+ T regulatory cells was also examined. Mice were injected with CII‐pulsed CD11c+,CD11b+ DCs isolated from Peyer's patches of tolerized mice, and the effect on CIA was examined.

Results

The severity of arthritis was significantly lower in tolerized mice. The proportion of CD11c+,CD11b+ DCs was increased in the Peyer's patches of tolerized mice and those DCs exhibited immunosuppressive characteristics, such as increased IL‐10 production, inhibition of T cell proliferative responses to CII, and CD4+,CD25+ regulatory T cell induction. Furthermore, the CD11c+,CD11b+ DCs suppressed the severity of arthritis upon adoptive transfer.

Conclusion

Our observations demonstrate that CD11c+,CD11b+ DCs, which are abundant in Peyer's patches during the induction of oral tolerance to CII, are crucial for the suppression of CIA and could be exploited for immunotherapy of autoimmune diseases.
Circulating levels of B lymphocyte stimulator in patients with rheumatoid arthritis following rituximab treatment: Relationships with B cell depletion, circulating antibodies, and clinical relapse
Authors: Cambridge Geraldine , Stohl William , Leandro Maria J. , Migone Thi‐Sau , Hilbert David M. , Edwards Jonathan C. W.
Published: February 2006

Objective

To assess the effects of B lymphocyte depletion on serum B lymphocyte stimulator (BLyS; trademark of Human Genome Sciences, Rockville, MD) levels in patients with rheumatoid arthritis (RA), and to assess the relationship of serum BLyS levels with peripheral blood B cell depletion, levels of autoantibodies and antimicrobial antibodies, the return of peripheral blood B cells, and clinical relapse.

Methods

Fifteen patients with active RA underwent rituximab‐based B cell depletion therapy (BCDT). Disease activity was assessed clinically, peripheral blood CD19+ B cell counts were determined by flow cytometry, and serum levels of BLyS, IgM, IgA, and IgG rheumatoid factors (RFs), anti–cyclic citrullinated peptide, and antimicrobial antibodies were assessed using enzyme‐linked immunosorbent assays.

Results

Peripheral blood B cell depletion was achieved in all 15 patients, and an American College of Rheumatology 20% response was achieved in 13 patients. Following clinical relapse, 7 patients underwent at least 1 additional cycle of BCDT. In every case, serum BLyS levels markedly rose post‐BCDT and remained elevated for at least 1–2 months. Serum levels of RF, but not those of anti–tetanus toxoid or anti–pneumococcal polysaccharide antibodies, fell significantly. A decline in serum BLyS levels was associated with the reemergence of B cells in peripheral blood, which, in turn, antedated clinical relapse by variable periods of time. The patterns of B cell depletion, serum BLyS and antibody levels, and clinical relapse for each BCDT cycle were remarkably similar in re‐treated patients.

Conclusion

Rituximab‐based BCDT leads to marked increases in serum BLyS levels. This may contribute significantly to the survival and/or regeneration of B cell populations capable of triggering clinical relapse.
Higher chondrogenic potential of fibrous synovium– and adipose synovium–derived cells compared with subcutaneous fat–derived cells: Distinguishing properties of mesenchymal stem cells in humans
Authors: Mochizuki Tomoyuki , Muneta Takeshi , Sakaguchi Yusuke , Nimura Akimoto , Yokoyama Akiko , Koga Hideyuki , Sekiya Ichiro
Published: February 2006

Objective

Mesenchymal stem cells from synovium have a greater proliferation and chondrogenic potential than do those from bone marrow, periosteum, fat, and muscle. This study was undertaken to compare fibrous synovium and adipose synovium (components of the synovium with subsynovium) to determine which is a more suitable source for mesenchymal stem cells, especially for cartilage regeneration, and to examine the features of adipose synovium–derived cells, fibrous synovium–derived cells, and subcutaneous fat–derived cells to determine their similarities.

Methods

Human fibrous synovium, adipose synovium, and subcutaneous fat were harvested from 4 young donors and 4 elderly donors. After digestion, the nucleated cells were plated at a density considered proper to expand at a maximum rate without colony‐to‐colony contact. The surface epitopes, proliferative capacity, cloning efficiency, and chondrogenic, osteogenic, and adipogenic differentiation potentials of the cells were compared.

Results

Fibrous synovium– and adipose synovium–derived cells were higher in STRO‐1 and CD106 and lower in CD10 compared with subcutaneous fat–derived cells. Cells derived from fibrous and adipose synovium had higher proliferative potential and colony‐forming efficiency compared with subcutaneous fat–derived cells, both in mixed‐population and in single‐cell–derived cultures. In chondrogenic assays, pellets from fibrous synovium– and adipose synovium–derived cells produced more cartilage matrix than did cell pellets from subcutaneous fat. Osteogenic ability was also higher in fibrous synovium– and adipose synovium–derived cells, whereas adipogenic potential was nearly indistinguishable among the 3 populations. Differentiation potential of the cells was similar between young and elderly donors.

Conclusion

Cells derived from the fibrous synovium and from the adipose synovium demonstrate comparable chondrogenic potential. Adipose synovium–derived cells are more similar to fibrous synovium–derived cells than to subcutaneous fat–derived cells.
Treatment of murine collagen‐induced arthritis by the stress protein BiP via interleukin‐4–producing regulatory T cells: A novel function for an ancient protein
Authors: Brownlie Rebecca J. , Myers Linda K. , Wooley Paul H. , Corrigall Valerie M. , Bodman‐Smith Mark D. , Panayi Gabriel S. , Thompson Stephen J.
Published: February 2006

Objective

Following the demonstration that the stress protein, BiP, prevented induction of collagen‐induced arthritis (CIA) in HLA–DRB*0101+/+ (HLA–DR1+/+) mice, we investigated the immunotherapeutic ability of BiP to suppress disease during the active phase of CIA in HLA–DR1+/+ and DBA/1 mice.

Methods

BiP was administered either subcutaneously or intravenously to DBA/1, HLA–DR1+/+, or interleukin‐4 (IL‐4)–knockout mice at the onset of arthritis. Immune cells were used in adoptive transfer studies or were restimulated in culture with BiP or type II collagen (CII). Proliferation and cytokine release were measured. In addition, serum anti‐CII antibodies were measured by enzyme‐linked immunosorbent assay. Disease progression was scored using a visual analog scale.

Results

BiP was successful in suppressing established CIA in HLA–DR1+/+ and DBA/1 mice. Serum levels of anticollagen IgG antibodies were reduced in BiP‐treated mice. T cells from BiP‐immunized mice produced Th2 cytokines, in particular, IL‐4. Treatment with BiP was also shown to increase the production of CII‐specific IL‐5, IL‐10, and interferon‐γ at the termination of the study. Development of severe CIA was prevented by the intravenous transfer of BiP‐specific cells at the time of CIA induction in HLA–DR1+/+ mice or by transferring BiP‐specific cells to DBA/1 mice at the onset of disease. BiP failed to ameliorate the development of CIA in IL‐4−/−, HLA–DR1+/+ mice.

Conclusion

These novel results show that BiP can suppress active CIA by the induction of regulatory cells that act predominantly via IL‐4. Thus, BiP is a potential immunotherapeutic agent for the treatment of patients with rheumatoid arthritis.
Acute occlusive large vessel disease leading to fatal stroke in a patient with systemic lupus erythematosus: Arteritis or atherosclerosis?
Authors: Conen Katrin L. , Jeanneret Christina , Hecker Burkhard , Cathomas Gieri , Biedermann Barbara C.
Published: February 2006

A woman with a history of systemic lupus erythematosus presented with extensive bilateral strokes due to acute inflammatory, occlusive large vessel disease affecting several aortic branches including the carotid, subclavian, renal, and iliac arteries. We quantitatively characterized the arterial inflammation in this patient and compared it with the inflammatory infiltrates from 22 patients with conventional atherosclerosis. Profound histomorphologic differences from conventional atherosclerosis (predominance of CD8‐positive lymphocytes, relative absence of macrophages, no ectopic neovascularization, no signs of plaque hemorrhage, concentric instead of eccentrical stenosis) suggest that this patient's accelerated arteriopathy was precipitated by pathogenic events other than conventional atherosclerosis.
The impact of body mass index on later total hip arthroplasty for primary osteoarthritis: A cohort study in 1.2 million persons
Authors: Flugsrud Gunnar B. , Nordsletten Lars , Espehaug Birgitte , Havelin Leif I. , Engeland Anders , Meyer Haakon E.
Published: February 2006

Objective

To investigate the effects of body mass index (BMI), height, and age on the risk of later total hip arthroplasty for primary osteoarthritis (OA).

Methods

We matched screening data on body height and weight from 1,152,006 persons ages 18–67 years who attended a compulsory screening for tuberculosis in 1963–1975 with data from the Norwegian Arthroplasty Register for the years 1987–2003. We identified 28,425 total hip replacements because of primary OA.

Results

We found dose‐response associations between both height and BMI and later hip arthroplasty. The relative risk (RR) among men with a BMI ≥32 kg/m2versus a BMI of 20.5–21.9 kg/m2was 3.4 (95% confidence interval [95% CI] 2.9–4.0). The corresponding RR in women was 2.3 (95% CI 2.1–2.4). There was a decreasing trend in the RR with an increasing age at screening. Among men, the RR for an increase of 5 kg/m2in the BMI was 2.1 (95% CI 1.7–2.5) when measured at age <25 years and 1.5 (95% CI 1.3–1.7) when measured at ages 55–59 years. Among women, the corresponding RR values were 1.7 (95% CI 1.5–1.9) and 1.1 (95% CI 1.1–1.2).

Conclusion

There was a strong dose‐response association between BMI and later total arthroplasty for OA of the hip. Being overweight entailed the highest RR among young participants, and the participants who were overweight at a young age maintained an excess RR for arthroplasty throughout the followup period.
Infliximab treatment maintains employability in patients with early rheumatoid arthritis
Authors: Smolen Josef S. , Han Chenglong , Van Der Heijde Désirée , Emery Paul , Bathon Joan M. , Keystone Edward , Kalden Joachim R. , Schiff Michael , Bala Mohan , Baker Daniel , Han John , Maini Ravinder N. , St.Clair E. William
Published: February 2006

Objective

To evaluate the impact of infliximab therapy on the employment status of patients with early rheumatoid arthritis (RA).

Methods

Methotrexate (MTX)–naive patients with active early RA were randomly allocated to receive MTX plus placebo or MTX plus infliximab (3 mg/kg or 6 mg/kg) at weeks 0, 2, and 6 and then every 8 weeks through week 46. Data for patients younger than age 65 years were included in the analyses. A patient was categorized as employable if he or she was employed or felt well enough to work if a job were available.

Results

The change in actual employment was not significantly different between patients receiving MTX plus infliximab and those receiving MTX plus placebo (0.5% versus 1.3%; P > 0.5). However, the proportion of patients whose status changed from employable at baseline to unemployable at week 54 was smaller in the group receiving MTX plus infliximab compared with that in the group receiving MTX alone (8% versus 14%; P = 0.05). Patients who were treated with infliximab plus MTX had a significantly greater likelihood of improvement rather than deterioration in employability (odds ratio 2.4; P < 0.001); this likelihood was not significantly greater in patients receiving MTX alone. The proportion of employed patients who lost workdays during the trial was smaller in the MTX plus infliximab group than in the MTX‐alone group (P = 0.010).

Conclusion

The actual employment rates among patients in the 2 treatment groups were not different. However, patients with early RA who were treated with MTX plus infliximab had a higher probability of maintaining their employability compared with those who were treated with MTX alone.
CXCL16‐mediated cell recruitment to rheumatoid arthritis synovial tissue and murine lymph nodes is dependent upon the MAPK pathway
Authors: Ruth Jeffrey H. , Haas Christian S. , Park Christy C. , Amin M. Asif , Martinez Rita J. , Haines G. Kenneth , Shahrara Shiva , Campbell Phillip L. , Koch Alisa E.
Published: February 2006

Objective

Rheumatoid arthritis (RA) is characterized by profound mononuclear cell (MNC) recruitment into synovial tissue (ST), thought to be due in part to tumor necrosis factor α (TNFα), a therapeutic target for RA. Although chemokines may also be involved, the mechanisms remain unclear. We undertook this study to examine the participation of CXCL16, a novel chemokine, in recruitment of MNCs to RA ST in vivo and to determine the signal transduction pathways mediating this process.

Methods

Using a human RA ST–SCID mouse chimera, immunohistochemistry, enzyme‐linked immunosorbent assay, real‐time reverse transcription–polymerase chain reaction, flow cytometry, and in vitro chemotaxis assays, we defined the expression and function of CXCL16 and its receptor, CXCR6, as well as the signal transduction pathways utilized by them for MNC homing in vitro and in vivo.

Results

CXCL16 was markedly elevated in RA synovial fluid (SF) samples, being as high as 145 ng/ml. Intense macrophage and lining cell staining for CXCL16 in RA ST correlated with increased CXCL16 messenger RNA levels in RA ST compared with those in osteoarthritis and normal ST. By fluorescence‐activated cell sorting analysis, one‐half of RA SF monocytes and one‐third of memory lymphocytes expressed CXCR6. In vivo recruitment of human MNCs to RA ST implanted in SCID mice occurred in response to intragraft injection of human CXCL16, a response similar to that induced by TNFα. Lipofection of MNCs with antisense oligodeoxynucleotides for ERK‐1/2 resulted in a 50% decline in recruitment to engrafted RA ST and a 5‐fold decline in recruitment to regional lymph nodes. Interestingly, RA ST fibroblasts did not produce CXCL16 in response to TNFα in vitro, suggesting that CXCL16 protein may function in large part independently of TNFα.

Conclusion

Taken together, these results point to a unique role for CXCL16 as a premier MNC recruiter in RA and suggest additional therapeutic possibilities, targeting CXCL16, its receptor, or its signaling pathways.
Sphingosine 1‐phosphate/sphingosine 1‐phosphate receptor 1 signaling in rheumatoid synovium: Regulation of synovial proliferation and inflammatory gene expression
Authors: Kitano Masayasu , Hla Timothy , Sekiguchi Masahiro , Kawahito Yutaka , Yoshimura Rikio , Miyazawa Keiji , Iwasaki Tsuyoshi , Sano Hajime
Published: February 2006

Objective

Sphingosine 1‐phosphate (S1P) is involved in various pathologic conditions and has been implicated as an important mediator of angiogenesis, inflammation, cancer, and autoimmunity. This study was undertaken to examine the role of S1P/S1P1 signaling in the pathogenesis of rheumatoid arthritis (RA).

Methods

We examined S1P1 messenger RNA (mRNA) and protein levels in RA synoviocytes and MH7A cells by reverse transcriptase–polymerase chain reaction and Western blotting. We also performed S1P1 immunohistochemistry analysis in synovial tissue from 28 RA patients and 18 osteoarthritis (OA) patients. We investigated the effects of S1P on proliferation by WST‐1 assay, and its effects on tumor necrosis factor α (TNFα)– or interleukin‐1β (IL‐1β)–induced cyclooxygenase 2 (COX‐2) expression and prostaglandin E2 (PGE2) production in RA synoviocytes and MH7A cells by Western blotting and enzyme‐linked immunosorbent assay, respectively. Finally, we examined whether these effects of S1P were sensitive to pertussis toxin (PTX), an inhibitor of the Gi/Go proteins.

Results

S1P1 mRNA and protein were detected in RA synoviocytes and MH7A cells. S1P1 was more strongly expressed in synovial lining cells, vascular endothelial cells, and inflammatory mononuclear cells of RA synovium compared with OA synovium. S1P increased the proliferation of RA synoviocytes and MH7A cells. S1P alone significantly enhanced COX‐2 expression and PGE2 production. Moreover, S1P enhanced expression of COX‐2 and production of PGE2 induced by stimulation with TNFα or IL‐1β in RA synoviocytes and MH7A cells. These effects of S1P were inhibited by pretreatment with PTX.

Conclusion

These findings suggest that S1P signaling via S1P receptors plays an important role in cell proliferation and inflammatory cytokine–induced COX‐2 expression and PGE2 production by RA synoviocytes. Thus, regulation of S1P/S1P1 signaling may represent a novel therapeutic target in RA.
Expression of platelet‐derived growth factors C and D in the synovial membrane of patients with rheumatoid arthritis and osteoarthritis
Authors: Pohlers Dirk , Huber René , Ukena Bärbel , Kinne Raimund W.
Published: February 2006

Objective

To investigate the messenger RNA (mRNA) and protein expression of the recently discovered platelet‐derived growth factor C (PDGF‐C) and PDGF‐D in the synovial membrane (SM) of patients with rheumatoid arthritis (RA) and osteoarthritis (OA) and to assess the localization and cellular source of these proteins in the SM and their functional influence on synovial fibroblasts.

Methods

Expression of mRNA for PDGFs A, B, C, and D as well as for PDGF receptor (PDGFR) α and β chains in RA and OA SM samples was assessed by real‐time reverse transcription–polymerase chain reaction. Protein levels of PDGF‐C and PDGF‐D were quantified by immunoblotting. Regional and cellular localization of PDGF‐C and PDGF‐D in the SM was investigated by double‐staining immunohistochemistry. In addition, the influence of PDGF‐D on the proliferation of synovial fibroblasts and their matrix metalloproteinase (MMP‐1) mRNA expression were determined.

Results

The expression of mRNA for PDGFs A, B, and C and for PDGFR α and β chains was comparable in RA and OA SM samples; in contrast, the expression of mRNA for PDGF‐D was significantly higher in OA SM. PDGF‐C protein was not differentially expressed in OA and RA. The expression of PDGF‐D protein was significantly higher in RA SM (full‐length and activated form). PDGF‐C and PDGF‐D were expressed throughout the SM (lining layer, diffuse infiltrates, and stroma) by both synovial fibroblasts and macrophages. In addition, PDGF‐D increased the proliferation of synovial fibroblasts and the expression of mRNA for MMP‐1.

Conclusion

PDGF‐C and PDGF‐D are expressed by synovial fibroblasts and macrophages in RA and OA SMs. The levels of PDGF‐D protein were significantly higher in RA SM. In addition, PDGF‐D stimulated synovial fibroblast proliferation and expression of MMP‐1. These findings may have pathogenetic implications for cellular transformation and matrix remodeling in the RA SM.
Development of antiinfliximab antibodies and relationship to clinical response in patients with rheumatoid arthritis
Authors: Wolbink Gerrit Jan , Vis Marijn , Lems Willem , Voskuyl Alexandre E. , De Groot Els , Nurmohamed Michael T. , Stapel Steven , Tak Paul P. , Aarden Lucien , Dijkmans Ben
Published: February 2006

Objective

Treatment of patients with infliximab, a chimeric monoclonal IgG1 antibody against tumor necrosis factor, may result in the formation of infliximab‐specific IgG antibodies. This study evaluated the clinical significance of these antibodies in patients with rheumatoid arthritis (RA).

Methods

Antiinfliximab antibodies were measured using a newly developed radioimmunoassay in a cohort of 51 consecutive patients with RA treated with infliximab, with a followup of 1 year. In addition, serum infliximab levels were determined by enzyme‐linked immunosorbent assay. The results were analyzed in relation to the clinical response to treatment according to the European League Against Rheumatism criteria.

Results

Antibodies against infliximab were detected in 22 patients (43%). Patients without detectable antiinfliximab antibodies (n = 29 [57%]) were significantly more often classified as responders (20 of 29 [69%]) compared with patients with detectable antiinfliximab antibodies (8 of 22 [36%]; P = 0.04). Three patients had an infusion‐related allergic reaction, all of whom had detectable antiinfliximab antibodies.

Conclusion

In this study, nearly half of the RA patients treated with infliximab developed antiinfliximab antibodies within the first year of treatment. This seems to be clinically relevant, since development of antiinfliximab antibodies is associated with a reduced response to treatment.
Expression profiling of metalloproteinases and tissue inhibitors of metalloproteinases in normal and degenerate human achilles tendon
Authors: Jones Gavin C. , Corps Anthony N. , Pennington Caroline J. , Clark Ian M. , Edwards Dylan R. , Bradley Michelle M. , Hazleman Brian L. , Riley Graham P.
Published: February 2006

Objective

To profile the messenger RNA (mRNA) expression for the 23 known genes of matrix metalloproteinases (MMPs), 19 genes of ADAMTS, 4 genes of tissue inhibitors of metalloproteinases (TIMPs), and ADAM genes 8, 10, 12, and 17 in normal, painful, and ruptured Achilles tendons.

Methods

Tendon samples were obtained from cadavers or from patients undergoing surgical procedures to treat chronic painful tendinopathy or ruptured tendon. Total RNA was extracted and mRNA expression was analyzed by quantitative real‐time reverse transcription–polymerase chain reaction, normalized to 18S ribosomal RNA.

Results

In comparing expression of all genes, the normal, painful, and ruptured Achilles tendon groups each had a distinct mRNA expression signature. Three mRNA were not detected and 14 showed no significant difference in expression levels between the groups. Statistically significant (P< 0.05) differences in mRNA expression, when adjusted for age, included lower levels of MMPs 3 and 10 and TIMP‐3 and higher levels of ADAM‐12 and MMP‐23 in painful compared with normal tendons, and lower levels of MMPs 3 and 7 and TIMPs 2, 3, and 4 and higher levels of ADAMs 8 and 12, MMPs 1, 9, 19, and 25, and TIMP‐1 in ruptured compared with normal tendons.

Conclusion

The distinct mRNA profile of each tendon group suggests differences in extracellular proteolytic activity, which would affect the production and remodeling of the tendon extracellular matrix. Some proteolytic activities are implicated in the maintenance of normal tendon, while chronically painful tendons and ruptured tendons are shown to be distinct groups. These data will provide a foundation for further study of the role and activity of many of these enzymes that underlie the pathologic processes in the tendon.
Association of chronic inflammation, not its treatment, with increased lymphoma risk in rheumatoid arthritis
Authors: Baecklund Eva , Iliadou Anastasia , Askling Johan , Ekbom Anders , Backlin Carin , Granath Fredrik , Catrina Anca Irinel , Rosenquist Richard , Feltelius Nils , Sundström Christer , Klareskog Lars
Published: February 2006

Objective

Chronic inflammatory conditions such as rheumatoid arthritis (RA) have been associated with malignant lymphomas. This study was undertaken to investigate which patients are at highest risk, and whether antirheumatic treatment is hazardous or protective.

Methods

We performed a matched case–control study of 378 consecutive Swedish RA patients in whom malignant lymphoma occurred between 1964 and 1995 (from a population‐based RA cohort of 74,651 RA patients), and 378 controls. Information on disease characteristics and treatment from onset of RA until lymphoma diagnosis was abstracted from medical records. Lymphoma specimens were reclassified and tested for Epstein‐Barr virus (EBV). Relative risks (odds ratios [ORs]) for lymphomas (by subtype) associated with deciles of cumulative disease activity were assessed, as were ORs associated with drug treatments.

Results

The relative risks of lymphoma were only modestly elevated up to the seventh decile of cumulative disease activity. Thereafter, the relative risk increased dramatically (OR ninth decile 9.4 [95% confidence interval 3.1–28.0], OR tenth decile 61.6 [95% confidence interval 21.0–181.0]). Most lymphomas (48%) were of the diffuse large B cell type, but other lymphoma subtypes also displayed an association with cumulative disease activity. Standard nonbiologic treatments did not increase lymphoma risk. EBV was present in 12% of lymphomas.

Conclusion

Risk of lymphoma is substantially increased in a subset of patients with RA, those with very severe disease. High inflammatory activity, rather than its treatment, is a major risk determinant.
Intracellular mammalian DNA stimulates myeloid dendritic cells to produce type I interferons predominantly through a toll‐like receptor 9–independent pathway
Authors: Martin David A. , Elkon Keith B.
Published: February 2006

Objective

Exogenous nucleic acids, including bacterial unmethylated DNA and viral single‐stranded RNA, are potent activators of innate immunity through interaction with the Toll‐like receptors (TLRs). In contrast, mammalian DNA has been generally thought to have a limited activation effect, or even a suppressive effect, on innate immunity. Since DNA is a major component of dying cells and recent studies indicate that mammalian nucleic acids may be stimulatory under certain conditions, we undertook this study to examine the effect of intracellular mammalian DNA on myeloid dendritic cell (DC) activation.

Methods

Mammalian DNA was introduced into murine bone marrow–derived DCs (BMDCs) by transfection. BMDC activation was determined by flow cytometry (CD40, CD86). Production of tumor necrosis factor α and interleukin‐6 was measured by enzyme‐linked immunosorbent assay, and production of type I interferons (IFNs) by bioassay. Parallel studies were conducted using BMDCs from mice deficient in myeloid differentiation 88 (MyD88), TLR‐9, and IFNα/β receptor.

Results

Intracellular mammalian DNA activated immature BMDCs, as determined by the up‐regulation of CD40 and CD86 as well as by the production of significant quantities of type I IFN. The interferogenic response was shown to be relatively independent of TLR‐9, and the TLR adaptor MyD88. The IFN response to intracellular DNA was reduced in BMDCs lacking IFNα/β receptor but was intact in embryonic fibroblasts lacking protein kinase R.

Conclusion

These results indicate that intracellular DNA stimulates BMDC maturation and IFN production predominantly through a TLR‐independent pathway, and support a model whereby inefficient clearance and/or degradation of endogenous DNA may stimulate innate immune responses similar to the TLR‐independent response to exogenous (i.e., viral) double‐stranded RNA.
Predictors of joint damage in patients with early rheumatoid arthritis treated with high‐dose methotrexate with or without concomitant infliximab: Results from the ASPIRE trial
Authors: Smolen Josef S. , Van Der Heijde Désirée M. F. M. , St.Clair E. William , Emery Paul , Bathon Joan M. , Keystone Edward , Maini Ravinder N. , Kalden Joachim R. , Schiff Michael , Baker Daniel , Han Chenglong , Han John , Bala Mohan ,   Active‐Controlled Study of Patients Receiving Infliximab for the Treatment of Rheumatoid Arthritis of Early Onset (ASPIRE) Study Group
Published: February 2006

Objective

To identify disease characteristics leading to progression of joint damage in patients with early rheumatoid arthritis (RA) treated with methotrexate (MTX) versus those treated with infliximab plus MTX.

Methods

Patients who had not previously been treated with MTX with active RA were randomly assigned to receive escalating doses of MTX up to 20 mg/week plus placebo or infliximab at weeks 0, 2, and 6, and every 8 weeks thereafter through week 46. Radiographic joint damage was assessed using the modified Sharp/van der Heijde score (SHS). The relationship between disease activity measures at baseline and week 14, as well as those averaged over time, were examined in relation to the change in SHS from baseline through week 54.

Results

C‐reactive protein (CRP) levels, erythrocyte sedimentation rate (ESR), and swollen joint count were associated with greater joint damage progression in the MTX‐only group, while none of these parameters was associated with progression in the infliximab plus MTX group. Mean changes in SHS among patients in the highest CRP (≥3 mg/dl) and ESR (≥52 mm/hour) tertiles in the MTX‐only group were 5.62 and 5.89, respectively, compared with 0.73 and 1.12 in the infliximab plus MTX group (P < 0.001). Patients with greater joint damage at baseline (SHS ≥10.5) showed less progression with infliximab plus MTX compared with MTX alone (−0.39 versus 4.11; P < 0.001). Patients receiving MTX alone who had persistently active disease at week 14 showed greater radiographic progression of joint damage than those taking MTX plus infliximab.

Conclusion

High CRP level, high ESR, or persistent disease activity was associated with greater radiographic progression in the group taking MTX alone, while little radiographic progression was seen in patients receiving both MTX and infliximab, regardless of the abnormal levels of these traditional predictors.