bluuebunny/crossref_metadata_2025 huggingface dataset:
The MAOA T941G polymorphism and short‐term treatment response to mirtazapine and paroxetine in major depression
Authors: Tadić André , Müller Matthias J. , Rujescu Dan , Kohnen Ralf , Stassen Hans H. , Dahmen Norbert , Szegedi Armin
Published: December 2006

This study investigated the possible association of the MAOA T941G gene variant with differential antidepressant response to mirtazapine and/or paroxetine in 102 patients with major depression (DSM‐IV criteria) participating in a randomized double‐blind controlled clinical trial. Female mirtazapine‐treated patients homozygous for the T‐allele had a significantly faster and better treatment response than TG/GG‐patients. In males, we failed to show an association between MAOA T941G gene variant and mirtazapine response. In the paroxetine‐treated group, there were no significant differences in treatment response between MAOA T941G genotype groups. Time course of response and antidepressant efficacy of mirtazapine, but not paroxetine, seem to be influenced in a clinically relevant manner by this allelic variation within the MAOA gene, at least in female patients. An independent replication of our finding is needed. If replicated, genotyping of this locus could become a promising tool to predict response to mirtazapine treatment in females suffering from major depression. © 2006 Wiley‐Liss, Inc.
Synaptotagmin XI as a candidate gene for susceptibility to schizophrenia
Authors: Inoue Shinichi , Imamura Akira , Okazaki Yuji , Yokota Hiroshi , Arai Makoto , Hayashi Naoki , Furukawa Aizo , Itokawa Masanari , Oishi Michio
Published: December 2006

Synaptotagmin XI (Syt11) is a member of the synaptotagmin family, which is localized in cells either in synaptic vesicles or the cellular membrane, and is known to act as a calcium sensor. The Syt11 gene is located on chromosome locus 1q21‐q22, which was previously reported as a major susceptibility locus of familial schizophrenia. Here, we present evidence for an association between the number of 33‐bp repeats in the promoter region of the Syt11 gene and schizophrenia. We found that the transcriptional activity of the gene is affected by the number of 33‐bp repeats, which include an Sp1 binding site, suggesting that the excessive expression of Syt11 can be associated with schizophrenia. Another (single nucleotide) polymorphism in the Syt11 5′UTR region, where the potent transcription factor YY1 can bind, also affects the transcriptional activity of Syt11. © 2006 Wiley‐Liss, Inc.
Antifertility and antimicrobial studies of pharmaceutically important organolead(IV) complexes of phenanthrolines
Authors: Chaudhary Ashu , Mahajan Karuna , Singh R. V.
Published: December 2006

The present study deals with a brief description of antifertility and antimicrobial aspects along with the spectral characterization of lead(IV) complexes. The testicular sperm density, testicular sperm morphology, sperm motility, density of cauda epididymal spermatozoa and fertility in mating trails and biochemical parameters of reproductive organs of an interesting class of biologically potent complexes on male albino rats at the dosages have been examined and discussed. Lead(IV) complexes have been synthesized using amino acids and 1,10‐phenanthroline, 4,7‐phenanthroline or 1,7‐phenanthroline. A series of di‐ and tri‐organolead(IV) [LPbRnL′] and [LPbClRnL′] complexes where, L = amino acid (tyrosine and phenylalanine) and L′ = 1, 10‐phenanthroline, 4,7‐phenanthroline or 1,7‐phenanthroline and n = 2 or 3 have been prepared by the conventional methods. Structure elucidation has been done by IR, UV, 1H, 13C and 207Pb NMR spectroscopy. On the basis of spectral evidences, it has been concluded that the carboxylic acid of the amino acid is behaving as a monodentate ligand in all these complexes and the complexes are octahedral in shape with a coordination number six around the lead atom. The complexes have been screened against a number of fungi and bacteria to assess their growth inhibiting potential. Lead complexes incorporating the chelating 1,10‐phenanthroline ligand showed a range of activities. The metal free non‐chelating ligands 1,7‐phenanthroline and 4,7‐phenanthroline were inactive and the complexes derived from 1,7‐phenanthroline displayed only marginal activity. Copyright © 2006 John Wiley & Sons, Ltd.
Sensitization of unmyelinated sensory fibers of the joint nerve to mechanical stimuli by interleukin‐6 in the rat: An inflammatory mechanism of joint pain
Authors: Brenn Daniel , Richter Frank , Schaible Hans‐Georg
Published: December 2006

Objective

Pain during mechanical stimulation of the joint and spontaneous pain are major symptoms of arthritis. An important neuronal process of mechanical hypersensitivity of the joint is the sensitization of thin myelinated Aδ fibers and unmyelinated C fibers innervating the joint. Because interleukin‐6 (IL‐6) is a major inflammatory mediator, we investigated whether this cytokine has the potential to sensitize joint afferents to mechanical stimuli.

Methods

In electrophysiologic experiments conducted on anesthetized rats, action potentials were recorded from afferent fibers supplying the knee joint. Responses to innocuous and noxious rotation of the tibia against the femur in the knee joint were monitored before and 1–2 hours after injection of test compounds into the joint cavity.

Results

Injection of IL‐6 and coinjection of IL‐6 plus soluble IL‐6 receptor (sIL‐6R) caused a gradual increase in the responses of C fibers to innocuous and noxious rotation within 1 hour. The increase in responses to IL‐6 and IL‐6 plus sIL‐6R was prevented by coadministration of soluble glycoprotein 130 (sgp130), but sgp130 did not reverse established mechanical hyperexcitability. Responses of Aδ fibers were not altered by the compounds. While injection of sIL‐6R alone into the normal knee joint did not influence responses to mechanical stimulation, injection of sIL‐6R into the acutely inflamed knee joint caused an increase in responses.

Conclusion

IL‐6 has the potential to sensitize C fibers in the joint to mechanical stimulation. Thus, IL‐6 contributes to mechanical hypersensitivity, most likely due to an action of IL‐6 on nerve fibers themselves.
Three‐dimensional cartilage tissue engineering using adult stem cells from osteoarthritis patients
Authors: Kafienah Wael , Mistry Sanjay , Dickinson Sally C. , Sims Trevor J. , Learmonth Ian , Hollander Anthony P.
Published: December 2006

Objective

To determine whether it is possible to engineer 3‐dimensional hyaline cartilage using mesenchymal stem cells derived from the bone marrow (BMSCs) of patients with osteoarthritis (OA).

Methods

Expanded BMSCs derived from patients with hip OA were seeded onto polyglycolic acid scaffolds and differentiated using transforming growth factor β3 in the presence or absence of parathyroid hormone–related protein (PTHrP) to regulate hypertrophy. Micromass pellet cultures were established using the same cells for comparison. At the end of culture, the constructs or pellets were processed for messenger RNA (mRNA) analysis by quantitative real‐time reverse transcription–polymerase chain reaction. Matrix proteins were analyzed using specific assays.

Results

Cartilage constructs engineered from BMSCs were at least 5 times the weight of equivalent pellet cultures. Histologic, mRNA, and biochemical analyses of the constructs showed extensive synthesis of proteoglycan and type II collagen but only low levels of type I collagen. The protein content was almost identical to that of cartilage engineered from bovine nasal chondrocytes. Analysis of type X collagen mRNA revealed a high level of mRNA in chondrogenic constructs compared with that in undifferentiated BMSCs, indicating an increased risk of hypertrophy in the tissue‐engineered cells. However, the inclusion of PTHrP at a dose of 1 μMor 10 μMduring the culture period resulted in significant suppression of type X collagen mRNA expression and a significant decrease in alkaline phosphatase activity, without any loss of the cartilage‐specific matrix proteins.

Conclusion

Three‐dimensional hyaline cartilage can be engineered using BMSCs from patients with OA. This method could thus be used for the repair of cartilage lesions.
Recombinant human anti–transforming growth factor β1 antibody therapy in systemic sclerosis: A multicenter, randomized, placebo‐controlled phase I/II trial of CAT‐192
Authors: Denton Christopher P. , Merkel Peter A. , Furst Daniel E. , Khanna Dinesh , Emery Paul , Hsu Vivien M. , Silliman Nancy , Streisand James , Powell John , Åkesson Anita , Coppock John , Hoogen Frank van den , Herrick Ariane , Mayes Maureen D. , Veale Douglas , Haas Joanna , Ledbetter Stephen , Korn Joseph H. , Black Carol M. , Seibold James R. ,   on Behalf Of The Cat‐192 Study Group The Scleroderma Clinical Trials Consortium
Published: December 2006

Objective

To evaluate CAT‐192, a recombinant human antibody that neutralizes transforming growth factor β1 (TGFβ1), in the treatment of early‐stage diffuse cutaneous systemic sclerosis (dcSSc).

Methods

Patients with SSc duration of <18 months were randomly assigned to the placebo group or to 1 of 3 CAT‐192 treatment groups: 10 mg/kg, 5 mg/kg, 0.5 mg/kg. Infusions were given on day 0 and weeks 6, 12, and 18. The primary objective of this study was to evaluate the safety, tolerability, and pharmacokinetics of CAT‐192. Secondary outcomes included the modified Rodnan skin thickness score (MRSS), the Scleroderma Health Assessment Questionnaire, assessment of organ‐based disease, serum levels of soluble interleukin‐2 receptor, collagen propeptides (N propeptide of type I [PINP] and type III collagen), and tissue levels of messenger RNA for procollagens I and III and for TGFβ1 and TGFβ2.

Results

Forty‐five patients were enrolled. There was significant morbidity and mortality, including 1 death in the group receiving 0.5 mg/kg of CAT‐192 and 3 deaths in the group receiving 5 mg/kg of CAT‐192. There were more adverse events and more serious adverse events in patients receiving CAT‐192 than in those receiving placebo, although these events were not more frequent in the high‐dose treatment group. The MRSS improved in all groups during the study, but there was no evidence of a treatment effect for CAT‐192. Improvement in the MRSS correlated with the disease duration (r = −0.54, P = 0.0008). Changes in the PINP level from baseline correlated with changes in the MRSS (r = 0.37, P = 0.027).

Conclusion

We report the first evaluation of a systemically administered and repeatedly dosed anti‐TGFβ1 drug. In this pilot study, CAT‐192, in doses up to 10 mg/kg, showed no evidence of efficacy. The utility of clinical and biochemical outcome measures and the feasibility of multicenter trials of early dcSSc were confirmed.
Microdamage and altered vascularity at the enthesis–bone interface provides an anatomic explanation for bone involvement in the HLA–B27–associated spondylarthritides and allied disorders
Authors: Benjamin M. , Toumi H. , Suzuki D. , Redman S. , Emery P. , McGonagle D.
Published: December 2006

Objective

To describe the basis for entheseal‐associated bone disease in the spondylarthritides, by analyzing microanatomic and histopathologic relationships between soft tissue, bone cortex, and adjacent trabeculae.

Methods

Serial sections from 52 entheses were examined; these entheses encompassed small and large insertions in the upper limb (n = 21), lower limb (n = 27), and spine (n = 4) from 60 cadavers. Enthesis microdamage (fissuring) as well as vascular and reparative changes were evaluated. Contact radiographs were used to ascertain the relationship between entheses and the trabecular network.

Results

At virtually all fibrocartilaginous entheses, the deep cortical boundary was extremely thin (typically 50–600 μm) or indistinguishable, and 96% of entheses had small holes in the cortical shell (typically 100–400 μm wide). Such regions were frequent sites of bone formation and renewal (96%) and microdamage (31%); these changes were more common in the lower limb. The presence of blood vessels near holes in the cortical shell was common; in 85% of attachments, blood vessels were present on the soft tissue side of the enthesis. Highly orientated trabeculae were more obvious in the lower limb than the upper limb (59% versus 29%).

Conclusion

The trabecular network supporting the cortical shell is an integral part of the enthesis, transferring load to an extensive skeletal region. In many cases, tendons/ligaments are anchored directly to such networks. This functional integration is associated with microdamage and repair at the hard tissue–soft tissue interface. These findings have implications for understanding bone involvement in SpA and for the SpA concept in general, especially the hypothesis that enthesis–bone architecture may be important in disease initiation.
Low levels of vitamin D and worsening of knee osteoarthritis: Results of two longitudinal studies
Authors: Felson David T. , Niu Jingbo , Clancy Margaret , Aliabadi Piran , Sack Burton , Guermazi Ali , Hunter David J. , Amin Shreyasee , Rogers Gail , Booth Sarah L.
Published: December 2006

Objective

To confirm reports that 25‐hydroxyvitamin D (25[OH]D) deficiency is associated with an increased risk of joint space narrowing or cartilage loss in osteoarthritis (OA).

Methods

We measured 25(OH)D levels in subjects from 2 longitudinal cohort studies, the Framingham Osteoarthritis Study and the Boston Osteoarthritis of the Knee Study (BOKS). In the first, weight‐bearing anteroposterior (AP) and lateral knee radiographs were obtained on subjects in 1993–1994 and again in 2002–2005 (mean interval 9 years); blood was drawn for measurement of vitamin D status in 1996–2000. In the second, subjects with symptomatic knee OA participating in a natural history study had fluoroscopically positioned semiflexed posteroanterior (PA) and lateral radiography of both knees and magnetic resonance imaging (MRI) of the more symptomatic knee performed at baseline and at 15 and 30 months. Blood was drawn at all visits, and the baseline specimen was used when available. In both studies, we defined radiographic worsening based on joint space loss in the tibiofemoral joint on either AP/PA or lateral weight‐bearing views, using a semiquantitative scale (worsening defined as increase by ≥1 on a 0–3 scale). In the BOKS, we evaluated cartilage loss semiquantitatively, using the Whole‐Organ Magnetic Resonance Imaging Score. In both studies, 25(OH)D levels were measured by radioimmunoassay. Analyses focused on whether vitamin D levels, defined in tertiles or as deficient (25[OH]D <20 ng/ml) versus nondeficient, predicted worsening of OA. Logistic regression analysis adjusted for age, body mass index, sex, and baseline OA level was used.

Results

The 715 subjects in the Framingham Study had a mean 25(OH)D level of 20 ng/ml at baseline, and 20.3% of the knees showed worsening, during the course of the study, with most knees having had no evidence of OA at baseline. The 277 subjects with OA in the BOKS had a mean 25(OH)D level of 20 ng/ml at baseline with 23.6% of knees showing radiographic worsening. We found no association of baseline 25(OH)D levels with radiographic worsening in either cohort, and confidence limits in the analyses of vitamin D deficiency were narrow, suggesting that results were not based on insufficient power. In fact, the risk of worsening was slightly, but not significantly, lower in persons with low levels of vitamin D than in persons with higher levels. In the BOKS, vitamin D levels were unrelated to cartilage loss seen on MRI.

Conclusion

The findings indicate that vitamin D status is unrelated to the risk of joint space or cartilage loss in knee OA.
Mechanisms of cartilage growth: Modulation of balance between proteoglycan and collagen in vitro using chondroitinase ABC
Authors: Asanbaeva Anna , Masuda Koichi , Thonar Eugene J.‐M. A. , Klisch Stephen M. , Sah Robert L.
Published: December 2006

Objective

To examine the cartilage growth–associated effects of a disruption in the balance between the swelling pressure of glycosaminoglycans (GAGs) and the restraining function of the collagen network, by diminishing GAG content prior to culture using enzymatic treatment with chondroitinase ABC.

Methods

Immature bovine articular cartilage explants from the superficial and middle layers were analyzed immediately or after incubation in serum‐supplemented medium for 13 days. Other explants were treated with chondroitinase ABC to deplete tissue GAG and also either analyzed immediately or after incubation in serum‐supplemented medium for 13 days. Treatment‐ and incubation‐associated variations in tissue volume, contents of proteoglycan and collagen network components, and tensile mechanical properties were assessed.

Results

Incubation in serum‐supplemented medium resulted in expansive growth with a marked increase in tissue volume that was associated with a diminution of tensile integrity. In contrast, chondroitinase ABC treatment on day 0 led to a marked reduction of GAG content and enhancement of tensile integrity, and subsequent incubation led to maturational growth with minimal changes in tissue volume and maintenance of tensile integrity at the enhanced levels.

Conclusion

The data demonstrate that a manipulation of GAG content in articular cartilage explants can distinctly alter the growth phenotype of cartilage. This may have practical utility for tissue engineering and cartilage repair. For example, the expansive growth phenotype may be useful to fill cartilage defects, while the maturational growth phenotype may be useful to induce matrix stabilization after filling defect spaces.
Restoration of the extracellular matrix in human osteoarthritic articular cartilage by overexpression of the transcription factor SOX9
Authors: Cucchiarini Magali , Thurn Tanja , Weimer Anja , Kohn Dieter , Terwilliger Ernest F. , Madry Henning
Published: December 2006

Objective

Human osteoarthritis (OA) is characterized by a pathologic shift in articular cartilage homeostasis toward the progressive loss of extracellular matrix (ECM). The purpose of this study was to investigate the ability of rAAV‐mediated SOX9 overexpression to restore major ECM components in human OA articular cartilage.

Methods

We monitored the synthesis and content of proteoglycans and type II collagen in 3‐dimensional cultures of human normal and OA articular chondrocytes and in explant cultures of human normal and OA articular cartilage following direct application of a recombinant adeno‐associated virus (rAAV) SOX9 vector in vitro and in situ. We also analyzed the effects of this treatment on cell proliferation in these systems.

Results

Following SOX9 gene transfer, expression levels of proteoglycans and type II collagen increased over time in normal and OA articular chondrocytes in vitro. In situ, overexpression of SOX9 in normal and OA articular cartilage stimulated proteoglycan and type II collagen synthesis in a dose‐dependent manner. These effects were not associated with changes in chondrocyte proliferation. Notably, expression of the 2 principal matrix components could be restored in OA articular cartilage to levels similar to those in normal cartilage.

Conclusion

These data support the concept of using direct, rAAV‐mediated transfer of chondrogenic genes to articular cartilage for the treatment of OA in humans.
Isolation and chondroinduction of a dermis‐isolated, aggrecan‐sensitive subpopulation with high chondrogenic potential
Authors: Deng Ying , Hu Jerry C. , Athanasiou Kyriacos A.
Published: December 2006

Objective

To develop a process that yields tissue‐engineered articular cartilage constructs from skin‐derived cells.

Methods

Dermis‐isolated, aggrecan‐sensitive (DIAS) cells were isolated using a modified rapid adherence process. The chondrogenic potential was measured by quantitative reverse transcriptase–polymerase chain reaction, enzyme‐linked immunosorbent assay, and immunohistochemistry. Filamentous actin (F‐actin) and vinculin organization was detected using fluorescence microscopy.

Results

The rapid adherence process led to a selection of DIAS cells, <10% of the entire population. DIAS cells displayed greater chondroinduction potential, as evidenced by the formation of large numbers of chondrocytic nodules on aggrecan‐coated surfaces. In addition, these cells showed higher gene expression and protein production in terms of chondrocytic markers when compared with unpurified dermis cells. Similar patterns of F‐actin and vinculin organization were observed between DIAS cells and chondrocytes. Three‐dimensional constructs from chondroinduced DIAS cells produced greater amounts of cartilage matrix than constructs from the rest of the dermis populations.

Conclusion

These findings show a series of steps that work together to form tissue‐engineered articular cartilage constructs using DIAS cells. Since skin presents a minimally invasive, relatively abundant cell source for tissue engineering, this study offers evidence of an efficient and stable technique to form cartilage constructs for future cartilage regeneration with autologous cells from skin.
Sex and ethnic differences in the association of ASPN, CALM1, COL2A1, COMP, and FRZB with genetic susceptibility to osteoarthritis of the knee
Authors: Valdes Ana M. , Loughlin John , Oene Mark Van , Chapman Kay , Surdulescu Gabriela L. , Doherty Michael , Spector Tim D.
Published: December 2006

Objective

To assess whether the association of genetic polymorphisms with osteoarthritis (OA) in other populations could be replicated in a large, multicenter, mixed‐sex, case–control study of clinical knee OA.

Methods

Genetic polymorphisms in OA candidate genes were genotyped in 298 men and 305 women, ages 50–86 years, all of whom had a diagnosis of knee OA as assessed clinically and radiographically, and in 300 male and 299 female control subjects matched for age and ethnicity. Allele and haplotype frequencies for 5 genes (ASPN, CALM1, COL2A1, COMP, and FRZB) previously tested for association with hip and/or knee OA in other populations were compared between patients and control subjects, analyzing men and women separately.

Results

The same FRZB 2‐marker single‐nucleotide polymorphism (SNP) haplotype associated with hip OA in other populations of Caucasian women was shown to increase the risk of knee OA among the women (but not the men) in the current study (odds ratio [OR] 2.87, P < 0.04). The CALM1 SNP, which affects the risk of hip OA in Japanese individuals, was not shown to be associated with susceptibility to OA in men or women. COL2A1 haplotypes were demonstrated to be associated with a decreased risk of knee OA in men (OR 0.68, P < 0.005) but not in women. COMP haplotypes that were associated with susceptibility to knee OA were different in men and women (P < 0.014 and P < 0.032, respectively). A meta‐analysis of these data and those from previously published reports indicated a strong association between the FRZB G324 allele (P < 0.0003) and suggested that an ASPN allele is protective against the risk of knee OA in Caucasians (P < 0.02).

Conclusion

Our results indicate that genetic polymorphisms affecting knee OA vary between populations (Japanese versus Caucasian) and sexes and indicate a role for ASPN, COMP, FRZB, and COL2A1 in Caucasians.
Use of molecular imaging to quantify response to IKK‐2 inhibitor treatment in murine arthritis
Authors: Izmailova Elena S. , Paz Nancy , Alencar Herlen , Chun Miyoung , Schopf Lisa , Hepperle Michael , Lane Joan H. , Harriman Geraldine , Xu Yajun , Ocain Timothy , Weissleder Ralph , Mahmood Umar , Healy Aileen M. , Jaffee Bruce
Published: December 2006

Objective

The NF‐κB signaling pathway promotes the immune response in rheumatoid arthritis (RA) and in rodent models of RA. NF‐κB activity is regulated by the IKK‐2 kinase during inflammatory responses. To elucidate how IKK‐2 inhibition suppresses disease development, we used a combination of in vivo imaging, transcription profiling, and histopathology technologies to study mice with antibody‐induced arthritis.

Methods

ML120B, a potent, small molecule inhibitor of IKK‐2, was administered to arthritic animals, and disease activity was monitored. NF‐κB activity in diseased joints was quantified by in vivo imaging. Quantitative reverse transcriptase–polymerase chain reaction was used to evaluate gene expression in joints. Protease‐activated near‐infrared fluorescence (NIRF) in vivo imaging was applied to assess the amounts of active proteases in the joints.

Results

Oral administration of ML120B suppressed both clinical and histopathologic manifestations of disease. In vivo imaging demonstrated that NF‐κB activity in inflamed arthritic paws was inhibited by ML120B, resulting in significant suppression of multiple genes in the NF‐κB pathway, i.e., KC, epithelial neutrophil–activating peptide 78, JE, intercellular adhesion molecule 1, CD3, CD68, tumor necrosis factor α, interleukin‐1β, interleukin‐6, inducible nitric oxide synthase, cyclooxygenase 2, matrix metalloproteinase 3, cathepsin B, and cathepsin K. NIRF in vivo imaging demonstrated that ML120B treatment dramatically reduced the amount of active proteases in the joints.

Conclusion

Our data demonstrate that IKK‐2 inhibition in the murine model of antibody‐induced arthritis suppresses both inflammation and joint destruction. In addition, this study highlights how gene expression profiling can facilitate the identification of surrogate biomarkers of disease activity and treatment response in an experimental model of arthritis.
CD56‐expressing T cells that have features of senescence are expanded in rheumatoid arthritis
Authors: Michel Joshua J. , Turesson Carl , Lemster Bonnie , Atkins Sarah R. , Iclozan Cristina , Bongartz Tim , Wasko Mary Chester , Matteson Eric L. , Vallejo Abbe N.
Published: December 2006

Objective

T cells deficient in CD28 expression have been implicated in the pathogenesis of rheumatoid arthritis (RA). Given that CD28‐null T cells are functionally heterogeneous, we undertook this study to screen for novel receptors on these cells.

Methods

Seventy‐two patients with RA (ages 35–84 years) and 53 healthy persons (32 young controls ages 19–34 years, 21 older controls ages 39–86 years) were recruited. Phenotypes and proliferative capacity of T cells from fresh leukocytes and of long‐term cultures were monitored by flow cytometry. Lung biopsy specimens from patients with RA‐associated interstitial pneumonitis (IP) were examined by immunohistochemistry. Receptor functionality was assessed by crosslinking bioassays.

Results

Chronic stimulation of CD28+ T cells in vitro yielded progenies that lacked CD28 but that gained CD56. Ex vivo analysis of leukocytes from patients with extraarticular RA showed a higher frequency of CD56+,CD28‐null T cells than in patients with disease confined to the joints or in healthy controls. CD56+,CD28‐null T cells had nil capacity for proliferation, consistent with cellular senescence. CD56+ T cells had skewed T cell receptor (TCR) α/β‐chain usage and restricted TCR third complementarity‐determining region spectra. Histologic studies showed that CD56+ T cells were components of cellular infiltrates in RA‐associated IP. CD56 crosslinking on T cells sufficiently induced cytokine production, although CD56/TCR coligation induced higher production levels.

Conclusion

Chronic activation of T cells induces counterregulation of CD28 and CD56 expression. The loss of CD28 is accompanied by the gain of CD56 that confers TCR‐independent and TCR‐dependent activation pathways. We propose that accumulation of CD56+ T cells in RA contributes to maladaptive immune responses and that CD56+ T cells are potential targets for therapy.
Interleukin‐17 as a molecular target in immune‐mediated arthritis: Immunoregulatory properties of genetically modified murine dendritic cells that secrete interleukin‐4
Authors: Sarkar Sujata , Tesmer Laura A. , Hindnavis Vindhya , Endres Judith L. , Fox David A.
Published: December 2006

Objective

Our previous studies have shown that murine dendritic cells (DCs) genetically modified to express interleukin‐4 (IL‐4) reduce the incidence and severity of murine collagen‐induced arthritis. The present studies were performed to assess the immunoregulatory mechanisms underlying this response, by assessing the effects of IL‐4 DCs on cytokine production by subsets of T helper cells.

Methods

Male DBA mice ages 6–8 weeks old were immunized with type II collagen. Splenic T cells obtained during the initiation phase and the end stage of arthritis were cultured with IL‐4 DCs or untransduced DCs in the presence of collagen rechallenge. Interferon‐γ (IFNγ) and IL‐17 responses were measured. Antibodies to IL‐4, IL‐12, and IL‐23, and recombinant IL‐4, IL‐12, and IL‐23 were used to further study the regulation of T cell cytokine production by IL‐4 DCs.

Results

Splenic T cells obtained during the initiation phase of arthritis produced less IL‐17 when cultured in the presence of IL‐4 DCs, despite their production of increased quantities of other proinflammatory cytokines (IFNγ and tumor necrosis factor). T cell IL‐17 production after collagen rechallenge was not inhibited by a lack of IL‐23, since IL‐4–mediated suppression of IL‐17 was not reconstituted by IL‐23, an otherwise potent inducer of IL‐17 production by T cells. Although IL‐4 DCs can produce increased quantities of IL‐12 and IFNγ, suppression of IL‐17 production by IL‐4 DCs was independent of both. While IL‐17 production by T cells obtained during the initiation phase of arthritis was regulated by IL‐4 DCs, IL‐17 production by T cells obtained during end‐stage arthritis was not altered.

Conclusion

Our data suggest that IL‐4 DCs exert a therapeutic effect on collagen‐induced arthritis by targeting IL‐17. IL‐17 suppression by IL‐4 DCs is robust and is not reversed by IL‐23. Timing might be important in IL‐17–targeted therapy, since IL‐17 production by T cells obtained during end‐stage arthritis did not respond to suppression by IL‐4 DCs.
Evaluation of protease‐activated receptor 2 in murine models of arthritis
Authors: Busso Nathalie , Frasnelli Matthias , Feifel Roland , Cenni Bruno , Steinhoff Martin , Hamilton Justin , So Alexander
Published: December 2006

Objective

Protease‐activated receptor 2 (PAR‐2) activation has been linked to pro‐ and antiinflammatory cellular responses. We undertook this study to explore the importance of PAR‐2 activation in 4 murine models of arthritis and to analyze the expression of PAR‐2 in human arthritic synovium.

Methods

Zymosan‐induced arthritis (ZIA), K/BxN serum–induced arthritis, and Freund's complete adjuvant (CFA)–induced arthritis were generated in naive PAR‐2−/− mice and PAR‐2+/+ littermates. Antigen‐induced arthritis (AIA) was generated in immunized mice using methylated bovine serum albumin (mBSA). The severity of arthritis was assessed by clinical scoring, technetium uptake measurement, and histologic analysis. Immune responses to mBSA were also evaluated from AIA. The expression of PAR‐2 in synovial tissues from rheumatoid arthritis (RA) and osteoarthritis (OA) patients was compared.

Results

In AIA, arthritis was significantly decreased in PAR‐2–deficient mice and was associated with decreased levels of anti‐mBSA IgG antibodies and lymph node cell proliferation. No difference in arthritis severity was seen in mice with ZIA, K/BxN serum–induced arthritis, and CFA‐induced arthritis. Synovial biopsy specimens from RA patients demonstrated significantly increased expression of PAR‐2 compared with those from OA patients.

Conclusion

PAR‐2 deficiency was found to modulate articular inflammation in murine models of arthritis that require prior immunization and was associated with reduced levels of anti‐mBSA IgG and lymph node cell proliferation in AIA. Expression of PAR‐2 in RA synovium was significantly higher than that in OA synovium, and this suggests that PAR‐2 is implicated in the pathogenesis of immune‐mediated forms of arthritis.
Tenosynovitis and osteoclast formation as the initial preclinical changes in a murine model of inflammatory arthritis
Authors: Hayer Silvia , Redlich Kurt , Korb Adelheid , Hermann Sonja , Smolen Josef , Schett Georg
Published: December 2006

Objective

To determine the nature of the initial changes of joint inflammation occurring before, at the time of, and shortly after onset of clinically apparent arthritis.

Methods

Human tumor necrosis factor (TNF)–transgenic mice were assessed for clinical, histologic, immunophenotypic, serologic, and molecular changes at the preclinical phase of arthritis, at the onset of disease, and at the stage of early clinical disease. In addition, the effects of a genetic osteoclast deficiency and pharmacologic inhibition of TNF were studied in these initial phases of disease.

Results

Initial articular changes were observed even before the start of clinical symptoms. Infiltration of the tendon sheaths by granulocytes and macrophages as well as formation of osteoclasts next to the inflamed tendon sheaths were the first pathologic events. Tenosynovitis rapidly led to remodeling of the sheaths into pannus‐like tissue, which formed osteoclasts that invaded the adjacent mineralized cartilage. Early lesions were associated with up‐regulation of interleukin‐1 (IL‐1) and IL‐6 as well as activation of p38 MAPK and ERK. In contrast, absence of osteoclasts led to uncoupling of tenosynovitis from invasion into cartilage and bone. TNF blockade also attenuated the pathologic changes associated with tenosynovitis.

Conclusion

Structural damage begins even before the onset of clinical symptoms of arthritis and involves the tendon sheaths as well as adjacent cartilage and bone. These results suggest that tenosynovitis is an initiating feature of arthritis and that joint destruction starts right from the onset of disease. Our findings thus underscore the importance of immediate initiation of an effective therapy in patients with rheumatoid arthritis.
Reduced expression and proteolytic susceptibility of lubricin/superficial zone protein may explain early elevation in the coefficient of friction in the joints of rats with antigen‐induced arthritis
Authors: Elsaid Khaled A. , Jay Gregory D. , Chichester Clinton O.
Published: December 2006

Objective

To investigate the effect of arthritis development and progression on the integrity and function of lubricin and the relationship of lubricin to cartilage damage in a rat antigen‐induced arthritis model.

Methods

Arthritis was induced in the right knee joints, using methylated bovine serum albumin and Freund's complete adjuvant. Whole joint friction measurements were performed ex vivo with a modified Stanton pendulum configuration, and coefficients of friction (μ) were determined. Levels of messenger RNA (mRNA) for lubricin, cathepsin B, and interleukin‐1β (IL‐1β) in synovial tissue from control and affected joints were determined by quantitative polymerase chain reaction. Lubricin staining in cartilage was performed using a lubricin‐specific monoclonal antibody.

Results

The μ values in excised right joints following arthritis induction were significantly (P < 0.001) higher than those in excised left joints. Lubricin mRNA expression levels in synovial tissue on days 4 and 7 after arthritis induction were significantly (P < 0.001) lower in the right joints compared with the left joints, whereas levels of cathepsin B and IL‐1β mRNA expression on days 4, 7, and 14 were significantly (P < 0.001) higher in the right joints than the left joints. Lubricin staining was diminished in cartilage from the right joints compared with the left joints.

Conclusion

Elevated coefficients of friction in arthritic joints occur concurrently with enhanced proteolytic degradation by up‐regulated cathepsin B and other proteases, as well as decreased lubricin synthesis by synovial fibroblasts and superficial zone chondrocytes. Loss of joint lubrication is an early event in inflammatory arthropathy. Restoring chondroprotection and preventing potential wear‐induced cartilage degradation may require lubricin supplementation in synovial fluid.
Natural killer T cells in families of patients with systemic lupus erythematosus: Their possible role in regulation of IGG production
Authors: Green Matthew R. J. , Kennell Amy S. M. , Larche Maggie J. , Seifert Martin H. , Isenberg David A. , Salaman Myer R.
Published: December 2006

Objective

To determine whether there is a link between the frequency of natural killer T (NKT) cells and high levels of IgG in patients with systemic lupus erythematosus (SLE) and their relatives.

Methods

Blood samples were obtained from patients with SLE, their first‐degree relatives, patients with rheumatoid arthritis (RA), and healthy control subjects. The frequency of NKT cells (defined as CD56+ T cells) was expressed as a percentage of total blood lymphocytes. Plasma levels of total IgG and IgM, and IgG antibodies to double‐stranded DNA (dsDNA) were determined.

Results

The frequency of NKT cells was lower in patients with SLE than in control subjects. No such decrease was observed in the relatives of patients with SLE or in patients with RA. High levels of IgG were observed in both patients with SLE and their relatives, while low levels of IgM were observed in these same groups. In relatives of patients with SLE, an inverse correlation between the frequency of NKT cells and IgG levels was observed. Moreover, raised levels of IgG in patients with SLE and their relatives and high levels of IgG anti‐dsDNA in patients were associated with low frequencies of NKT cells.

Conclusion

These results suggest that NKT cells have an important role in the regulation of IgG production, although NKT cells with invariant T cell receptors may not necessarily be involved. NKT cells in the setting of SLE could lack the cytokine stimulus from NK or other cells that is needed to exert control on IgG production. Enhancement of NKT cell activity may provide a novel basis for therapy in SLE.
Postnatal induction of transforming growth factor β signaling in fibroblasts of mice recapitulates clinical, histologic, and biochemical features of scleroderma
Authors: Sonnylal Sonali , Denton Christopher P. , Zheng Bing , Keene Douglas R. , He Ruming , Adams Henry P. , VanPelt Carolyn S. , Geng Yong J. , Deng Jenny M. , Behringer Richard R. , de Crombrugghe Benoit
Published: December 2006

Objective

Increased signaling by transforming growth factor β (TGFβ) has been implicated in systemic sclerosis (SSc; scleroderma), a complex disorder of connective tissues characterized by excessive accumulation of collagen and other extracellular matrix components in systemic organs. To directly assess the effect of sustained TGFβ signaling in SSc, we established a novel mouse model in which the TGFβ signaling pathway is activated in fibroblasts postnatally.

Methods

The mice we used (termed TBR1CA; Cre‐ER mice) harbor both the DNA for an inducible constitutively active TGFβ receptor I (TGFβRI) mutation, which has been targeted to theROSAlocus, and a Cre‐ER transgene that is driven by a fibroblast‐specific promoter. Administration of 4‐hydroxytamoxifen 2 weeks after birth activates the expression of constitutively active TGFβRI.

Results

These mice recapitulated clinical, histologic, and biochemical features of human SSc, showing pronounced and generalized fibrosis of the dermis, thinner epidermis, loss of hair follicles, and fibrotic thickening of small blood vessel walls in the lung and kidney. Primary skin fibroblasts from these mice showed elevated expression of downstream TGFβ targets, reproducing the hallmark biochemical phenotype of explanted SSc dermal fibroblasts. The mouse fibroblasts also showed elevated basal expression of the TGFβ‐regulated promoters plasminogen activator inhibitor 1 and 3TP, increased Smad2/3 phosphorylation, and enhanced myofibroblast differentiation.

Conclusion

Constitutive activation of TGFβ signaling in fibroblastic cells of mice after birth caused a marked fibrotic phenotype characteristic of SSc. These mice should be excellent models with which to test therapies aimed at correcting excessive TGFβ signaling in human scleroderma.
Outcomes after switching from one anti–tumor necrosis factor α agent to a second anti–tumor necrosis factor α agent in patients with rheumatoid arthritis: Results from a large UK national cohort study
Authors: Hyrich Kimme L. , Lunt Mark , Watson Kath D. , Symmons Deborah P. M. , Silman Alan J. ,   British Society for Rheumatology Biologics Register
Published: December 2006

Objective

Patients with rheumatoid arthritis (RA) who experience treatment failure with one anti–tumor necrosis factor (anti‐TNF) agent, due to either inefficacy or toxicity, are frequently switched to a second anti‐TNF agent, although the benefits of switching are unknown. The present study was undertaken to compare drug continuation rates between the first course and second course of anti‐TNF therapy.

Methods

The study involved a prospective cohort of RA patients from a UK national register of new anti‐TNF treatment starts (n = 6,739; 876 starting adalimumab, 2,826 starting etanercept, and starting 3,037 infliximab). Over a mean 15 months of followup, 841 patients stopped taking the first drug due to inefficacy and 1,023 stopped the first drug due to toxicity, of whom 503 and 353, respectively, were switched to a second anti‐TNF agent. Kaplan‐Meier survival curves were plotted to determine continuation rates for each course, and Cox regression was used to compare each course for the risk of stopping and the reason for stopping (inefficacy or toxicity).

Results

Overall, 73% of patients who switched to a second anti‐TNF agent remained on the new therapy by the end of followup. First drug discontinuation due to inefficacy was associated with an increased rate of second drug discontinuation due to inefficacy (hazard ratio [HR] 2.7, 95% confidence interval [95% CI] 2.1–3.4) but not toxicity (HR 1.1, 95% CI 0.9–1.5). Similarly, first drug discontinuation due to toxicity was associated with an increased rate of second drug discontinuation due to toxicity (HR 2.3, 95% CI 1.9–2.9) but not inefficacy (HR 1.2, 95% CI 0.8–1.6).

Conclusion

RA patients who are switched to a second anti‐TNF drug have high rates of continuation, although among those who must discontinue treatment, the reasons for stopping a second drug are related to the reasons for stopping the first drug. This large data set from the UK provides the first estimates of the magnitude of these effects in patients with long‐standing severe RA.
Crucial role of macrophages in matrix metalloproteinase–mediated cartilage destruction during experimental osteoarthritis : Involvement of matrix metalloproteinase 3
Authors: Blom Arjen B. , van Lent Peter L. , Libregts Sten , Holthuysen Astrid E. , van der Kraan Peter M. , van Rooijen Nico , van den Berg Wim B.
Published: December 2006

Objective

To explore the involvement of synovial macrophages in early cartilage damage in osteoarthritis (OA), and to identify the role of matrix metalloproteinase 3 (MMP‐3) in the pathology of early and late OA.

Methods

The role of synovial macrophages in MMP‐mediated damage in OA was studied by depleting synovial macrophages prior to elicitation of a collagenase‐induced instability model of OA. The expression of MMP in synovium and cartilage was monitored using TaqMan analysis. In spontaneous and induced OA, cartilage pathology was scored in MMP‐3–knockout mice and control mice, by histologic assessment and VDIPEN staining.

Results

On day 14 following induction of OA, MMP‐mediated neoepitopes were detected in cartilage from mice with mild experimental OA (mean ± SD positively stained surface area 20 ± 3.2%). Remarkably, by depleting synovial macrophages prior to induction of OA, the generation of MMP‐induced neoepitopes was largely prevented (mean ± SD positively stained surface area 5 ± 1%; P< 0.001), indicating an important role for synovial macrophages in the occurrence of MMP‐mediated cartilage damage. We observed a strong decrease in MMP‐3 and MMP‐9 expression in synovial but not cartilage tissue in macrophage‐depleted joints. Among 2‐year‐old mice, spontaneous OA–like changes in the lining layer were significantly decreased in MMP‐3–knockout mice compared with control mice. Even more striking was the 67% reduction in the occurrence of severe cartilage damage in MMP‐3–knockout mice. In addition, MMP‐mediated VDIPEN expression was significantly decreased, indicating reduced MMP‐mediated cartilage breakdown.

Conclusion

The results of this study prove that MMP‐3 is involved in the generation of severe cartilage damage in murine OA. Synovial macrophages are crucial in early MMP activity and appear to mediate MMP production in synovium rather than cartilage.
Corpus‐based cross‐language information retrieval in retrieval of highly relevant documents
Authors: Talvensaari Tuomas , Juhola Martti , Laurikkala Jorma , Järvelin Kalervo
Published: December 2006

Information retrieval systems' ability to retrieve highly relevant documents has become more and more important in the age of extremely large collections, such as the World Wide Web (WWW). The authors' aim was to find out how corpus‐based cross‐language information retrieval (CLIR) manages in retrieving highly relevant documents. They created a Finnish–Swedish comparable corpus from two loosely related document collections and used it as a source of knowledge for query translation. Finnish test queries were translated into Swedish and run against a Swedish test collection. Graded relevance assessments were used in evaluating the results and three relevance criterion levels—liberal, regular, and stringent—were applied. The runs were also evaluated with generalized recall and precision, which weight the retrieved documents according to their relevance level. The performance of the Comparable Corpus Translation system (COCOT) was compared to that of a dictionary‐based query translation program; the two translation methods were also combined. The results indicate that corpus‐based CLIR performs particularly well with highly relevant documents. In average precision, COCOT even matched the monolingual baseline on the highest relevance level. The performance of the different query translation methods was further analyzed by finding out reasons for poor rankings of highly relevant documents.
An analysis of the delayed response to Hurricane Katrina through the lens of knowledge management
Authors: Chua Alton Y.K. , Kaynak Selcan , Foo Schubert S.B.
Published: December 2006

In contrast to many recent large‐scale catastrophic events, such as the Turkish earthquake in 1999, the 9/11 attack in New York in 2001, the Bali Bombing in 2002, and the Asian Tsunami in 2004, the initial rescue effort towards Hurricane Katrina in the U.S. in 2005 had been sluggish. Even as Congress has promised to convene a formal inquiry into the response to Katrina, this article offers another perspective by analyzing the delayed response through the lens of knowledge management (KM). A KM framework situated in the context of disaster management is developed to study three distinct but overlapping KM processes, namely, knowledge creation, knowledge transfer, and knowledge reuse. Drawing from a total of more than 400 documents—including local, national, and foreign news articles, newswires, congressional reports, and television interview transcripts, as well as Internet resources such as wikipedia and blogs— 14 major delay causes in Katrina are presented. The extent to which the delay causes were a result of the lapses in KM processes within and across the government agencies are discussed.
Random dynamics and finance: constructing implied binomial trees from a predetermined stationary density
Authors: Bahsoun Wael , Góra Paweł , Mayoral Silvia , Morales Manuel
Published: December 2006

We introduce a general binomial model for asset prices based on the concept of random maps. The asymptotic stationary distribution for such model is studied using techniques from dynamical systems. In particular, we present a technique to construct a general binomial model with a predetermined stationary distribution. This technique is independent of the chosen distribution making our model potentially useful in financial applications. We briefly explore the suitability of our construction as an implied binomial tree. Copyright © 2006 John Wiley & Sons, Ltd.