bluuebunny/crossref_metadata_2025 huggingface dataset:
Relationship between genetic variants in the adenosine pathway and outcome of methotrexate treatment in patients with recent‐onset rheumatoid arthritis
Authors: Wessels Judith A. M. , Kooloos Wouter M. , Jonge Robert De , De Vries‐Bouwstra Jeska K. , Allaart Cornelia F. , Linssen Annelies , Collee Gerard , Sonnaville Peter De , Lindemans Jan , Huizinga Tom W. J. , Guchelaar Henk‐Jan
Published: August 2006

Objective

Among patients with rheumatoid arthritis (RA), there is a high degree of interindividual variability in the degree of response to methotrexate (MTX) treatment. This study was undertaken to explore polymorphisms in genes contributing to antiinflammatory adenosine release as novel predictors of MTX treatment outcome.

Methods

In 205 patients with newly diagnosed RA, 5 polymorphisms in 5 genes coding for enzymes related to the release of adenosine were analyzed. All patients received standardized MTX treatment (up to 25 mg per week orally), combined with folic acid. MTX efficacy was evaluated by the Disease Activity Score (DAS) and compared among genotypes. The association between MTX‐related adverse events and genotype was also assessed. The following polymorphisms were determined: AMPD1 34C>T, ATIC 347C>G, ITPA 94C>A, MTR 2756A>G, and MTRR 66A>G. When significant differences were found by chi‐square analysis, odds ratios (ORs) and 95% confidence intervals were calculated.

Results

Patients carrying the AMPD1 34T allele, ATIC 347CC, or ITPA 94CC were more likely to have a good clinical response, as defined by a DAS of ≤2.4 (OR [95% confidence interval] 2.1 [1.0–4.5], 2.5 [1.3–4.7], and 2.7 [1.1–8.1], respectively). The likelihood of a good clinical response was increased if patients possessed all 3 favorable genotypes (OR 27.8 [95% confidence interval 3.2–250]). Regarding toxicity, only ATIC G allele carriers experienced a greater frequency of adverse events (OR 2.0 [95% confidence interval 1.1–3.7]).

Conclusion

Polymorphisms in the AMPD1, ATIC, and ITPA genes are associated with good clinical response to MTX treatment. These findings indicate that genotyping may help in the identification of patients who will benefit most from MTX treatment and may assist clinicians in making treatment decisions regarding patients with recent‐onset RA.
Double‐blind randomized controlled clinical trial of the interleukin‐6 receptor antagonist, tocilizumab, in European patients with rheumatoid arthritis who had an incomplete response to methotrexate
Authors: Maini R. N. , Taylor P. C. , Szechinski J. , Pavelka K. , Bröll J. , Balint G. , Emery P. , Raemen F. , Petersen J. , Smolen J. , Thomson D. , Kishimoto T.
Published: August 2006

Objective

To establish the safety and efficacy of repeat infusions of tocilizumab (previously known as MRA), a humanized anti–interleukin‐6 (IL‐6) receptor antibody, alone and in combination with methotrexate (MTX), for the treatment of rheumatoid arthritis (RA).

Methods

The study group comprised 359 patients with active RA in whom the response to MTX was inadequate. During a stabilization period, these patients received their current dose of MTX for at least 4 weeks. Following stabilization, they were randomized to 1 of 7 treatment arms, as follows: tocilizumab at doses of 2 mg/kg, 4 mg/kg, or 8 mg/kg either as monotherapy or in combination with MTX, or MTX plus placebo.

Results

A 20% response (improvement) according to the American College of Rheumatology criteria (ACR20 response) was achieved by 61% and 63% of patients receiving 4 mg/kg and 8 mg/kg of tocilizumab as monotherapy, respectively, and by 63% and 74% of patients receiving those doses of tocilizumab plus MTX, respectively, compared with 41% of patients receiving placebo plus MTX. Statistically significant ACR50 and ACR70 responses were observed in patients receiving combination therapy with either 4 mg/kg or 8 mg/kg of tocilizumab plus MTX (P < 0.05). A dose‐related reduction in the Disease Activity Score in 28 joints was observed from week 4 onward, in all patients except those receiving monotherapy with 2 mg/kg of tocilizumab. In the majority of patients who received 8 mg/kg of tocilizumab, the C‐reactive protein level/erythrocyte sedimentation rate normalized, while placebo plus MTX had little effect on these laboratory parameters. Tocilizumab was mostly well tolerated, with a safety profile similar to that of other biologic and immunosuppressive therapies. Alanine transaminase and aspartate transaminase levels followed a sawtooth pattern (rising and falling between infusions). There were moderate but reversible increases in the nonfasting total cholesterol and triglyceride levels and reversible reductions in the high‐density lipoprotein cholesterol and neutrophil levels. There were 2 cases of sepsis, both of which occurred in patients who were receiving combination therapy with 8 mg/kg of tocilizumab plus MTX.

Conclusion

These results indicate that targeted blockade of IL‐6 signaling is a highly efficacious and promising means of decreasing disease activity in RA.
Endothelin axis polymorphisms in patients with scleroderma
Authors: Fonseca Carmen , Renzoni Elizabeth , Sestini Piersante , Pantelidis Panagiotis , Lagan Anna , Bunn Christopher , McHugh Neil , Welsh Ken I. , Bois Ron M. Du , Denton Christopher P. , Black Carol , Abraham D.
Published: August 2006

Objective

To evaluate the distribution of polymorphisms in the endothelin 1 (EDN1), endothelin receptor A (EDNRA) and endothelin receptor B (EDNRB) genes in systemic sclerosis (SSc; scleroderma) and SSc subsets.

Methods

Two hundred five patients with SSc and 255 healthy controls were screened for polymorphisms in EDN1, EDNRA, and EDNRB, using sequence‐specific primer–polymerase chain reaction. The polymorphisms studied were at the following positions: for EDN1, −1370 (T‐1370G) of the promoter, +138 of exon 1 (+138 A/−), +85 of exon 3 (E106E), and +23 of exon 5 (K198N); for EDNRA, −231 of exon 1 (G‐231A), and +69(H323H) and +105 (E335E) of exon 6; for EDNRB, +2841 of exon 2 (EDNRB‐3), −2547 of exon 3 (EDNRB‐2), and −2446 of exon 3 (EDNRB‐1).

Results

No significant differences between the SSc group as a whole and control subjects were observed for any of the investigated polymorphisms in EDN1, EDNRA, and EDNRB. However, compared with patients with limited cutaneous SSc, patients with diffuse skin involvement had an increased frequency of allele carriage of EDNRB‐1A (76.8% versus 54.4%; P = 0.002), EDNRB‐2A (79.7% versus 60.2%; P = 0.006), and EDNRB‐3G (79.7% versus 56.6%; P = 0.001). Significantly increased carriage frequencies for EDNRA alleles H323H/C and E335E/A were observed in SSc patients with anti–RNA polymerase (anti‐RNAP) antibodies, compared with both anti‐RNAP–negative SSc patients (P < 0.05) and control subjects (P < 0.005).

Conclusion

The finding of associations between endothelin receptors A and B and distinct clinical and immunologic SSc subsets supports the role of endothelin and its receptors in the pathogenesis of SSc. However, these findings and their functional significance need to be confirmed and investigated in future studies.
Chimerism occurs twice as often in lupus nephritis as in normal kidneys
Authors: Hovinga Idske C. L. Kremer , Koopmans Marije , Baelde Hans J. , Wal Annemieke M. van der , Sijpkens Yvo W. J. , Heer Emile de , Bruijn Jan A. , Bajema Ingeborg M.
Published: August 2006

Objective

Systemic lupus erythematosus (SLE) is an immune‐mediated disease that particularly affects the kidneys, causing lupus nephritis. In experimental mouse models, lupus nephritis can be mimicked by inducing a chimeric state through the injection of parental T cells in offspring. In humans, pregnancy‐induced chimerism may play a role in the pathogenesis of autoimmune diseases such as SLE, but it is likely that only certain chimeric cells have pathogenic potential. In this study, we investigated whether the distribution of chimeric cells is different in the kidneys of women with SLE from that in normal kidneys, and we examined the phenotype of chimeric cells in women with SLE.

Methods

The presence of chimeric cells was investigated by in situ hybridization targeting the Y chromosome in 57 renal biopsy samples from 49 women with lupus nephritis. Fifty‐one kidney autopsy specimens without histomorphologic lesions served as controls. Double‐staining for the Y chromosome in combination with CD3 and CD34 markers was performed in 5 kidney specimens with lupus nephritis to identify the phenotype of the chimeric cells.

Results

Y chromosome–positive cells were found in 27 of 49 patients with lupus nephritis and in 13 of 51 normal controls (P < 0.01). Both CD3+ and CD34+ chimeric cells were identified in lupus nephritis kidney specimens.

Conclusion

Chimeric cells are present significantly more often in kidneys with lupus nephritis than in normal kidneys, and some of these chimeric cells are T cells. This finding is interesting in light of experimental models demonstrating that lupus nephritis is initiated by chimeric T cells.
Identification of fibronectin neoepitopes present in human osteoarthritic cartilage
Authors: Zack Marc D. , Arner Elizabeth C. , Anglin Charles P. , Alston James T. , Malfait Anne‐Marie , Tortorella Micky D.
Published: August 2006

Objective

Fibronectin fragments are present at high concentrations in the cartilage of patients with rheumatoid arthritis and patients with osteoarthritis (OA) and have been shown to promote cartilage catabolism in human cartilage cultures, suggesting that fibronectin fragments participate in the initiation and progression of arthritic disease. This study was undertaken to 1) identify the major fibronectin fragments in human OA cartilage and confirm their ability to elicit cartilage catabolism, 2) identify the cleavage sites in fibronectin and generate the corresponding neoepitope antibodies, and 3) explore the utility of fibronectin neoepitopes as biomarkers.

Methods

Fibronectin fragments were purified from human OA cartilage using affinity chromatography; their N‐termini were then identified by sequencing. Bovine nasal cartilage was treated with affinity‐purified fibronectin fragments and assayed for aggrecan breakdown by monitoring the release of glycosaminoglycans and the aggrecan neoepitope 1771AGEG. Fibronectin neoepitopes were detected by Western blotting in cytokine‐treated media of human cartilage explants, and by immunohistochemical analyses of human OA cartilage.

Results

Multiple fibronectin fragments were isolated from human OA cartilage, and all contained the N‐terminus 272VYQP. These fragments induced aggrecanase‐mediated cartilage catabolism in bovine cartilage explants. Fibronectin fragments with the N‐terminus 272VYQP and fragments with the C‐terminus VRAA271 were detected following cytokine treatment of human cartilage extracts. These neoepitopes localized with areas of aggrecan loss in OA cartilage.

Conclusion

Human OA cartilage contains fibronectin fragments with catabolic activity and a major cleavage site within fibronectin. This study is the first to characterize fibronectin neoepitopes in OA cartilage, suggesting that they may represent a novel biomarker of arthritis.
Long‐term comparison of rituximab treatment for refractory systemic lupus erythematosus and vasculitis: Remission, relapse, and re‐treatment
Authors: Smith K. G. C. , Jones R. B. , Burns S. M. , Jayne D. R. W.
Published: August 2006

Objective

Current treatments for systemic lupus erythematosus (SLE) and vasculitis contribute to mortality and incapacity and are only partially effective; thus, newer therapies are clearly needed. Depletion of B cells has led to disease control in patients with autoimmune disorders. We sought to assess the long‐term efficacy and safety of a B cell–depleting therapy in patients with SLE and patients with vasculitis.

Methods

In a prospective study with a median followup of 24 months, 11 patients with active or refractory SLE and 11 patients with active or refractory antineutrophil cytoplasmic antibody–associated vasculitis (AAV) received a course of therapy with rituximab (an anti‐CD20 monoclonal antibody) along with a single dose of intravenous cyclophosphamide.

Results

Remission followed rapid B cell depletion, with response rates of 100% among the 11 patients with SLE (6 patients had a complete response, and 5 patients had a partial response) and 91% among the 11 patients with AAV (9 patients had a complete response, and 1 patient had partial remission). A renal response occurred in all 6 patients with lupus nephritis. Clinical improvement was accompanied by significant reductions in the daily dose of prednisolone. Relapse occurred in 64% of the patients with SLE and in 60% of those with AAV. B cell return preceded relapse in the majority of patients, and further treatment with rituximab proved effective. IgG and IgM levels were maintained in the normal range. The incidence of infective complications was low; however, infusion reactions were common, and human antichimeric antibodies developed in 5 of 14 patients.

Conclusion

B cell depletion offers the prospect of sustained disease remission and improved disease control combined with low toxicity in patients with active or refractory SLE or AAV. Relapse following treatment is common, but re‐treatment is rapidly effective.
Dysregulation of interleukin‐10–dependent gene expression in rheumatoid arthritis synovial macrophages
Authors: Antoniv Taras T. , Ivashkiv Lionel B.
Published: August 2006

Objective

The inflammatory cytokines tumor necrosis factor α (TNFα) and interleukin‐1 (IL‐1) are produced by activated macrophages, are key mediators of pathogenesis, and are validated therapeutic targets in rheumatoid arthritis (RA) and seronegative spondylarthritis (SpA). IL‐10 is a potent antiinflammatory cytokine that suppresses macrophage TNFα and IL‐1 production, yet is not effective in suppressing inflammatory arthritis. To gain insight into IL‐10 responses in inflammatory arthritis, we used microarray analysis to determine the patterns of IL‐10–inducible gene expression in freshly isolated RA and seronegative SpA synovial macrophages.

Methods

Macrophages from the synovial fluid of 5 patients with RA and 3 with seronegative SpA (2 with psoriatic arthritis and 1 with ankylosing spondylitis) were isolated by positive selection and stimulated ex vivo with IL‐10 or interferon‐γ (IFNγ). Gene expression was analyzed using Affymetrix microarrays and protocols. Real‐time polymerase chain reaction was used to confirm changes in gene expression.

Results

The number of genes induced by IL‐10 in arthritic macrophages was markedly smaller than that induced in control macrophages, and the strength of induction was lower in arthritic macrophages for most genes. The residual response of arthritic macrophages to IL‐10 stimulation was qualitatively altered, such that IL‐10 preferentially increased expression of IFNγ‐inducible genes. In contrast, arthritic macrophages expressed many IFNγ‐inducible genes prior to stimulation, and their response to IFNγ remained mostly intact.

Conclusion

These results demonstrate that IL‐10 responses are dysregulated in RA synovial macrophages. An altered biologic response to IL‐10, with attenuation of its antiinflammatory function and a concomitant retention of IFNγ‐like activating functions, provides a basis for the lack of efficacy of IL‐10 in suppressing inflammatory arthritis.
Cappuccino mutation in an autoimmune‐prone strain of mice suggests a role of platelet function in the progression of immune complex crescentic glomerulonephritis
Authors: Yoshida Minako , Saiga Kan , Hato Takaaki , Iwaki Shoko , Niiya Toshiyuki , Arita Norimasa , Komori Hiroaki , Tsubaki Takahito , Furukawa Hiroshi , Terada Miho , Maeyama Kazutaka , Nemoto Kyuichi , Nose Masato , Ono Masao
Published: August 2006

Objective

Crescent formation in the renal glomerulus is a typical manifestation of progressive glomerulopathy associated with fatal renal failure; therefore, its prevention is of clinical importance. Little is known about the pathogenic mechanism for crescent formation. This study was undertaken in an attempt to identify the events that are critical for crescent formation in immune complex crescentic glomerulonephritis (CGN) by analyzing a novel mutant strain of mice.

Methods

A spontaneous mutant strain of mice was isolated from the autoimmune‐prone strain EOD, which stably develops fatal CGN. The mutant phenotypes were assessed histopathologically, hematologically, and immunologically. The mutation was searched for with positional cloning using microsatellite markers.

Results

Compared with wild‐type EOD (WT‐EOD) mice, mutant EOD (mut‐EOD) mice showed marked improvement in CGN in conjunction with an improvement in spontaneous mortality. In WT‐EOD mice, an inverse correlation between blood urea nitrogen concentration and blood platelet count and massive accumulation of platelets in the glomerulus were evident, suggesting that an accumulation of platelets in the glomerulus contributes to the progression of CGN. The mutant platelets showed an abnormal aggregation in response to collagen and thrombin, associated with a bleeding tendency in mut‐EOD mice. Genetic analysis revealed a deleterious mutation in the cappuccino gene (cno), which encodes a protein that belongs to a complex called the biogenesis of lysosome‐related organelle complex 1 and is profoundly involved in platelet function. Morphologic examination revealed a partial defect in dense body formation in the δ‐granule of platelets.

Conclusion

The present findings suggest that platelet functions have a critical role in crescent formation in autoimmune GN.
Immunohistologic analysis of zygapophyseal joints in patients with ankylosing spondylitis
Authors: Appel Heiner , Kuhne Maren , Spiekermann Simone , Ebhardt Harald , Grozdanovic Zarko , Köhler Dorothee , Dreimann Marc , Hempfing Axel , Rudwaleit Martin , Stein Harald , Metz‐Stavenhagen Peter , Sieper Joachim , Loddenkemper Christoph
Published: August 2006

Objective

Zygapophyseal joints of the spine are often affected in ankylosing spondylitis (AS). In this study, we undertook a systematic immunohistologic evaluation of the immunopathology of the zygapophyseal joints in patients with advanced AS.

Methods

We obtained zygapophyseal joints from 16 AS patients undergoing polysegmental correction of kyphosis and from 10 non‐AS controls (at autopsy). Immunohistologic analysis of the bone marrow was performed by analyzing the number of infiltrating T cells (CD3, CD4, CD8), B cells (CD20), osteoclasts (CD68), bone marrow macrophages (CD68), and microvessel density (CD34) per high‐power field.

Results

Zygapophyseal joints from 6 of 16 AS patients, but from none of the controls, exhibited 2 or more CD3+ T cell aggregates, signifying persistent inflammation. Interstitial CD4+ and CD8+ T cells were significantly more frequent in AS patients compared with non‐AS controls (P = 0.002 and P = 0.049, respectively). While there was no clear difference between the number of CD20+ B cells in AS patients overall compared with controls, there was a significant difference when persistently inflamed joints from patients with AS were compared with joints without active inflammation from patients with AS or joints from controls (both P = 0.03). Microvessel density in bone marrow from AS patients with active inflammation was significantly higher than that in bone marrow from controls.

Conclusion

This immunohistologic study of bone marrow from zygapophyseal joints demonstrates persistent inflammation in the spine of patients with AS, including those with longstanding disease. The findings of increased numbers of T cells and B cells and neoangiogenesis suggest that these features play a role in the pathogenesis of AS.
Vascular amine oxidases are needed for leukocyte extravasation into inflamed joints in vivo
Authors: Marttila‐Ichihara Fumiko , Smith David J. , Stolen Craig , Yegutkin Gennady G. , Elima Kati , Mercier Nathalie , Kiviranta Riku , Pihlavisto Marjo , Alaranta Sakari , Pentikäinen Ulla , Pentikäinen Olli , Fülöp Ferenc , Jalkanen Sirpa , Salmi Marko
Published: August 2006

Objective

Leukocyte traffic from the blood to the joints is crucial in the pathogenesis of arthritis. A bifunctional endothelial cell–surface glycoprotein, AOC3 (amine oxidase, copper‐containing 3; also known as vascular adhesion protein 1), has both adhesive and enzymatic properties. We undertook this study to determine the contribution of AOC3 and its oxidase activity to leukocyte trafficking into inflamed joints in vivo.

Methods

We used gene‐modified animals, molecular modeling, an AOC3 enzyme inhibitor, oxidase assays, and arthritis models (adjuvant‐induced arthritis [AIA] in rats and anti–type II collagen antibody–induced arthritis in mice) to dissect the importance of AOC3 in vivo.

Results

The AOC3 inhibitor fitted well with a covalent binding mode into the active site of the AOC3 crystal structure. It selectively blocked the oxidase activity of AOC3 in enzyme assays. Intraperitoneal and oral administration of the AOC3 inhibitor significantly ameliorated rat AIA. In anti–type II collagen antibody–induced arthritis in mice, the AOC3 inhibitor also improved the outcome of the joint inflammation. The acute semicarbazide‐sensitive amine oxidase blockade by the inhibitor had even more pronounced effects than genetic deletion of AOC3. Enzymatic analyses showed that the inhibitor also blocked 2 other structurally very closely related AOCs, but not any of more than 100 other enzymes tested.

Conclusion

These are the first data to demonstrate that the enzymatic activity of the atypical endothelial adhesion molecule AOC3, and possibly that of other closely related ecto‐oxidases, is crucial for leukocyte exit from the vessels in inflamed joints in vivo.
Safety of the selective costimulation modulator abatacept in rheumatoid arthritis patients receiving background biologic and nonbiologic disease‐modifying antirheumatic drugs: A one‐year randomized, placebo‐controlled study
Authors: Weinblatt M. , Combe B. , Covucci A. , Aranda R. , Becker J. C. , Keystone E.
Published: August 2006

Objective

To assess the safety of abatacept, a selective costimulation modulator, in patients with active rheumatoid arthritis (RA) who had been receiving ≥1 traditional nonbiologic and/or biologic disease‐modifying antirheumatic drugs (DMARDs) approved for the treatment of RA for at least 3 months prior to entry into the study.

Methods

This was a 1‐year, multicenter, randomized, double‐blind, placebo‐controlled trial. Patients were randomized 2:1 to receive abatacept at a fixed dose approximating 10 mg/kg by weight range, or placebo.

Results

The abatacept and placebo groups exhibited similar frequencies of adverse events (90% and 87%, respectively), serious adverse events (13% and 12%, respectively), and discontinuations due to adverse events (5% and 4%, respectively). Five patients (0.5%) in the abatacept group and 4 patients (0.8%) in the placebo group died during the study. Serious infections were more frequent in the abatacept group than in the placebo group (2.9% versus 1.9%). Fewer than 4% of patients in either group experienced a severe or very severe infection. The incidence of neoplasms was 3.5% in both groups. When evaluated according to background therapy, serious adverse events occurred more frequently in the subgroup receiving abatacept plus a biologic agent (22.3%) than in the other subgroups (11.7–12.5%).

Conclusion

Abatacept in combination with synthetic DMARDs was well tolerated and improved physical function and physician‐ and patient‐reported disease outcomes. However, abatacept in combination with biologic background therapies was associated with an increase in the rate of serious adverse events. Therefore, abatacept is not recommended for use in combination with biologic therapy.
Soluble human p55 and p75 tumor necrosis factor receptors reverse spontaneous arthritis in transgenic mice expressing transmembrane tumor necrosis factor α
Authors: Edwards Carl K. , Bendele Alison M. , Reznikov Leonid I. , Fantuzzi Giamila , Chlipala Elizabeth S. , Li Li , Moldawer Lyle L. , Mountz John D. , Li Yi‐Yang Yvonne , Dinarello Charles A.
Published: August 2006

Objective

The roles of the transmembrane and secreted forms of tumor necrosis factor α (TNFα) in rheumatoid arthritis (RA) remain unclear. Agents used to inhibit TNFα have shown varying efficacy in RA patients, suggesting that anti‐TNFα agents possess dissimilar mechanisms of action, including the ability to neutralize transmembrane (tmTNFα) and secreted TNFα. In this study, TNFα‐knockout (TNFα‐KO) mice that were genetically altered to express elevated levels of tmTNFα were constructed to further understand the roles of the 17‐kd secreted, trimeric, and 26‐kd transmembrane forms of TNFα.

Methods

A speed‐congenic mating scheme was used to generate 3 unique strains of mice: 1) transgenic tmTgA86 mice overexpressing 26‐kd tmTNFα and also secreting 17‐kd trimeric TNFα (tmTNFα‐transgenic), 2) TNFα−/− mice (TNFα‐KO), and 3) transgenic mice overexpressing tmTNFα backcrossed to TNFα‐KO mice (tmTNFα‐transgenic/TNFα‐KO). Mice were treated with phosphate buffered saline (as vehicle control), dexamethasone (as positive control), or modified recombinant human soluble TNF receptor (sTNFR) p55 or p75, and were assessed clinically and histopathologically for signs of inflammation and development of arthritis.

Results

The tmTNFα‐transgenic/TNFα‐KO mice were born with crinkled tails and spinal deformities similar to those in ankylosing spondylitis. By 2–4 weeks, these mice developed symmetric inflammatory arthritis, characterized by tissue swelling, pannus formation, and bone deformities. The tmTNFα‐transgenic mice also developed spontaneous‐onset arthritis, but at a slower rate (100% incidence by 10–12 weeks). Clinical and histologic progression of arthritis in the tmTNFα‐transgenic/TNFα‐KO mice was reduced by treatment with dexamethasone or with the p55 or p75 sTNFR (69% and 63% reduction in total histologic score, respectively).

Conclusion

These data show that arthritis is sufficiently initiated and maintained in tmTNFα‐transgenic/TNFα‐KO mice, and that it can be neutralized by recombinant human p55 or p75 sTNFR, resulting in amelioration of the biologic and subsequent histologic destructive effects of tmTNFα.
The prevalence and incidence of biopsy‐proven lupus nephritis in the UK: Evidence of an ethnic gradient
Authors: Patel Mumtaz , Clarke Alexandra M. , Bruce Ian N. , Symmons Deborah P. M.
Published: August 2006

Objective

Renal involvement is a major complication of systemic lupus erythematosus (SLE) and is a strong determinant of morbidity and mortality. There have been no previous studies of the epidemiology of lupus nephritis. Our aim was to establish the prevalence and incidence of biopsy‐proven lupus nephritis in the northwest of England in 2001 and to examine the influence of age, sex, and ethnicity.

Methods

Adults (age 18 years and older) with biopsy‐proven lupus nephritis were identified from 5 sources: renal biopsy databases, dialysis/transplant databases, nephrologists' patients, clinic lists, and lupus patient groups. The denominator data for the northwest of England were ascertained from the 2001 census.

Results

We identified 208 cases of biopsy‐proven lupus nephritis (176 women, 32 men): the overall prevalence was 4.4 per 100,000 population (95% confidence interval [95% CI] 3.8–5.0), 7.1 per 100,000 (95% CI 6.1–8.2) in women, and 1.4 per 100,000 (95% CI 1.0–2.0) in men. The prevalence was significantly higher among women in the ethnic subgroups: 110.3 per 100,000 population (95% CI 55.0–197.3) in Chinese patients, 99.2 per 100,000 (95% CI 55.5–163.6) in Afro‐Caribbean, 21.4 per 100,000 (95% CI 12.0–35.2) in Indo‐Asian (Asians from the Indian subcontinent), and 5.6 per 100,000 (95% CI 4.7–6.7) in white patients. The overall annual incidence rate was 0.40 per 100,000 population per year (95% CI 0.24–0.63), with a rate of 0.68 (95% CI 0.40–1.10) in women and 0.09 (95% CI 0.01–0.32) in men. Capture–recapture methods did not suggest any additional cases.

Conclusion

This first estimate of the prevalence and incidence of biopsy‐proven lupus nephritis demonstrates dramatic differences in prevalence according to ethnicity, with an increasing gradient from the white to the Indo‐Asian, Afro‐Caribbean, and Chinese populations.
Early elevation in circulating levels of C‐telopeptides of type II collagen predicts structural damage in articular cartilage in the rodent model of collagen‐induced arthritis
Authors: Oestergaard Svetlana , Chouinard Luc , Doyle Nancy , Smith Susan Y. , Tankó László B. , Qvist Per
Published: August 2006

Objective

To investigate changes in the circulating levels of the C‐telopeptide of type II collagen (CTX‐II) with relation to disease onset and structural damage of cartilage in a rodent model of collagen‐induced arthritis (CIA), and to investigate immunolocalization of the CTX‐II epitope in the articular cartilage of affected joints.

Methods

Seven‐week‐old female Lewis rats were immunized with type II collagen and monitored using blood sampling at weekly intervals. At study termination (day 23), the animals were killed, synovial fluid was collected, and the affected joints were scored macroscopically for disease severity and underwent immunohistochemical evaluation.

Results

At the time of disease onset (day 15), which was characterized by redness and swelling of the affected joints (mean ± SD macroscopic severity score 9.1 ± 1.6), there was a 355% increase in serum CTX‐II levels. The early change in serum CTX‐II from day 0 to day 15 showed a significant association with the severity of cartilage damage (r = 0.61, P < 0.01). Immunostaining revealed extensive presence of the CTX‐II epitope in the damaged, uncalcified cartilage tissue.

Conclusion

The elevation in serum CTX‐II concomitant with the onset of disease and proportional to cartilage damage demonstrates that CTX‐II is a sensitive diagnostic tool for monitoring joint disease in the rodent model of CIA. Furthermore, the immunohistochemical findings are consistent with the concept that the major source of serum CTX‐II is the damaged articular cartilage.
Insulin‐like growth factor binding protein 5 induces skin fibrosis: A novel murine model for dermal fibrosis
Authors: Yasuoka Hidekata , Jukic Drazen M. , Zhou Zhihong , Choi Augustine M. K. , Feghali‐Bostwick Carol A.
Published: August 2006

Objective

To determine the role of insulin‐like growth factor binding protein 5 (IGFBP‐5) in the development of skin fibrosis in vivo, by examining the effect of overexpression of IGFBP‐5 in mouse skin.

Methods

Wild‐type C57BL/6J mice were injected subcutaneously with replication‐deficient serotype 5 adenovirus expressing human IGFBP‐3 (Ad3), IGFBP‐5 (Ad5), or no complementary DNA (cAd). Mice were killed 3, 8, or 22 days postinjection. The dermal thickness and dermal collagen bundle thickness in skin sections were measured. The deposition of collagen in the extracellular matrix (ECM) was quantified using the Sircol assay. Expression of proliferating cell nuclear antigen (PCNA) and fibronectin, as determined by immunohistochemical analysis, was used to evaluate fibroblast activation, and vimentin and α‐smooth muscle actin (α‐SMA) were used to evaluate the fibroblast phenotype.

Results

Adenovirally expressed IGFBP was detected in dermal fibroblasts, endothelial cells, epithelial cells, and muscle bundles in Ad3‐ and Ad5‐injected mice. Increased collagen deposition, denser dermal connective tissue, and increased collagen bundle thickness were observed in IGFBP‐5–overexpressing mice. Dermal thickness and collagen bundle thickness were significantly increased in Ad5‐injected mice compared with cAd‐ and Ad3‐injected mice. Treatment with Ad5 resulted in a dose‐dependent increase in dermal and collagen bundle thickness. Increased deposition of collagen and fibronectin, increased numbers of PCNA‐positive fibroblasts, as well as increased numbers of vimentin– and α‐SMA–double‐positive fibroblasts were detected in the dermis of IGFBP‐5–overexpressing mouse skin.

Conclusion

IGFBP‐5 is a key mediator of fibrosis. IGFBP‐5 mediates its profibrotic effects through fibroblast activation, increased ECM deposition, and myofibroblastic transformation of dermal fibroblasts. Overexpression of IGFBP‐5 provides a novel model for studying the pathogenesis of skin fibrosis in systemic sclerosis.
ASIS to ASIS&T: A society in transition?
Authors: Mackenzie Maureen L.
Published: August 2006

In May 2000, the Board of Directors of the American Society for Information Science (ASIS) changed the name of the association by adding the words, “and Technology” (&T). Today this change may be considered minor, but for many involved at the time—it was a change that had purpose and meaning. A study was initiated to trace the society's transition toward a professional association more inclusive of practitioners and applied research. The study was conducted in two stages, using quantitative and qualitative methods. Stage 1 compared the research published in the conference proceedings both prior to and following the society's name change. Stage 2 built upon the assumption that a professional association is a reflection of its membership. The Stage 1 results offer both an aggregate and a comparative view of the papers accepted for and presented at the annual conference. The results suggest that as an association of researchers, the society may be moving toward a renewed focus on practical and applied information. The Stage 2 results suggest that some ASIS&T members welcome the increased focus on technology, applied research, and the topics of interest to practitioners. Others view the changes as negative, perhaps even undermining the value of ASIS. The practical implications suggest that an annual conference can be an association's most important branding opportunity. It should reflect the interests of its membership as well as attract new members. A clear vision, supported by the membership, will guide the activities of the society and, in turn, will effectively serve its members professional needs.
Exploratory evaluation of several teratogen warning symbols
Authors: Goldsworthy Richard , Kaplan Brian
Published: August 2006

BACKGROUND: Previous research has noted potential inadequacies in the warning labels and symbols used with some teratogenic medications. A clear teratogen warning symbol represents an important component of risk mitigation for accidental teratogen exposure. METHODS: Several teratogen warning symbols were developed through rapid prototyping and focus groups. A nationally distributed field trial (n = 300) examined the relative effectiveness of 6 candidate symbols, including the symbol in use at the time of the study. Measures included open‐ended interpretation, closed‐ended preference, and demographic surveys. Each participant was shown a single symbol and asked what it meant, to whom it applied, and what that person should do. Text statements were added to the symbol and participants were asked to reinterpret the warning. Participants were told the intended message of the warning, shown all 6 symbols, and asked to choose the most effective symbol. RESULTS: Four of 6 symbols achieved levels of correct interpretation close to or exceeding the American National Standards Institute (ANSI) benchmark of 85% and none exceeded the ANSI limit of 5% critical confusion. Symbols elicited varying conceptual responses. Respondents considered 1 symbol to be the most effective, by a 4 to 1 margin. Several outcomes varied by age and by ethnicity. CONCLUSIONS: Several symbols emerged as viable alternatives to the current symbol; however, no 1 symbol was clearly found to be the most effective. Instead, the symbol considered “best” depends on the messages that are considered most essential to the warning. Additionally, it appears a symbol without the addition of text can convey most, but possibly not all, of the meaning required of the warning label. Next steps should include further symbol refinement, closer examination of text additions to symbols, and validation of the candidate symbols and warnings through a large‐scale field trial. Birth Defects Research (Part A) 76:453–460, 2006. © 2006 Wiley‐Liss, Inc.
Estimation of Centres and Radial Intensity Profiles of Spherical Nano‐Particles in Digital Microscopy
Authors: Kvarnström Mats , Glasbey Chris A.
Published: August 2006

Control of the microscopic characteristics of colloidal systems is critical in a wealth of application areas, ranging from food to pharmaceuticals. To assist in estimating these characteristics, we present a method for estimating the positions of spherical nano‐particles in digital microscopy images. The radial intensity profiles of particles, which depend on the distances of the particles from the focal plane of the light microscope and have no closed functional form, are modelled using a local quadratic kernel estimate. We also allow for the case where pixel values are censored at an upper limit of 255. Standard errors of centre estimates are obtained using a sandwich estimator which takes into account spatial autocorrelation in the errors. The approach is validated by a simulation study. (© 2007 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
A Goodness‐of‐fit Test for the Marginal Cox Model for Correlated Interval‐censored Failure Time Data
Authors: Wang Lianming , Sun Liuquan , Sun Jianguo
Published: August 2006

The marginal Cox model approach is perhaps the most commonly used method in the analysis of correlated failure time data (Cai, 1999; Cai and Prentice, 1995; Lin, 1994; Wei, Lin and Weissfeld, 1989). It assumes that the marginal distributions for the correlated failure times can be described by the Cox model and leaves the dependence structure completely unspecified. This paper discusses the assessment of the marginal Cox model for correlated interval‐censored data and a goodness‐of‐fit test is presented for the problem. The method is applied to a set of correlated interval‐censored data arising from an AIDS clinical trial. (© 2006 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Statistical Designs for Two‐Color Spotted Microarray Experiments
Authors: Chai Feng‐Shun , Liao Chen‐Tuo , Tsai Shin‐Fu
Published: August 2006

Two‐color cDNA or oligonucleotide‐based spotted microarrays have been commonly used in measuring the expression levels of thousands of genes simultaneously. To realize the immense potential of this powerful new technology, budgeted within limited resources or other constraints, practical designs with high efficiencies are in demand. In this study, we address the design issue concerning the arrangement of the mRNA samples labeled with fluorescent dyes and hybridized on the slides. A normalization model is proposed to characterize major sources of systematic variation in a two‐color microarray experiment. This normalization model establishes a connection between designs for two‐color microarray experiments with a particular class of classical row‐column designs. A heuristic algorithm for constructing A‐optimal or highly efficient designs is provided. Statistical optimality results are found for some of the designs generated from the algorithm. It is believed that the constructed designs are the best or very close to the best possible for estimating the relative gene expression levels among the mRNA samples of interest. (© 2007 WILEY‐VCH Verlag GmbH & Co. KGaA, Weinheim)
Evidence for a strong selenium–aromatic interaction derived from crystallographic data and ab initio quantum chemical calculations
Authors: Hartman Izabela , Raia Carlo A. , Zauhar Randy J.
Published: August 2006

Increasing attention is being paid to the role of selenium, both as an essential component required for the activity of many enzymes and in the context of selenium‐based pharmaceutical agents. A wide range of therapeutics that include selenium are on the market and under development, such as antihypertensive, anticancerogenic, antiviral, and immunosuppressive agents. Computer‐aided drug design (CADD) has proven to be an important tool for the development of new drugs. Many CADD techniques, including docking, molecular dynamics simulation, and other receptor‐based approaches, require an accurate understanding of the nature of the intermolecular forces that act to stabilize protein–ligand complexes; moreover, a quantitative assessment of these interactions furthers our efforts to rationalize the drug design process. In this paper, we consider one class of interaction involving selenium, that between Se and aromatic rings. Prior work has shown that interactions between divalent sulfur and aromatic rings are observed much more frequently than would be expected on the basis of chance, both in protein structures and the crystal structures of organic compounds that include these moieties. Recent studies on the optimization of inhibitor‐protein binding also suggest that sulfur–aromatic interactions are important in stabilizing these complexes and may be crucial focal point for CADD. Given that selenium and sulfur have similar chemistry, and that selenium is significantly more polarizable, we propose that Se–aromatic interactions may also play an important stabilizing role in the structure of folded proteins and in drug–protein complexes. We have tested this hypothesis against data from the Cambridge Crystallographic Database and ab initio quantum chemical calculations. We have found evidence that selenium does interact strongly with aromatic rings and may play a role analogous to sulfur in stabilizing protein folds. In addition, selenium should be considered along with sulfur in rational drug design strategies that seek to improve binding to target protein sites that include aromatic rings. © 2006 Wiley Periodicals, Inc. Biopolymers 83: 595–613, 2006

This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com
Optical spectroscopic elucidation of β‐turns in disulfide bridged cyclic tetrapeptides
Authors: Borics Attila , Murphy Richard F. , Lovas Sándor
Published: August 2006

Vibrational circular dichroism (VCD) spectroscopic features of type II β‐turns were characterized previously, but, criteria for differentiation between β‐turn types had not been established yet. Model tetrapeptides, cyclized through a disulfide bridge, were designed on the basis of previous experimental results and the observed incidence of amino acid residues in the i + 1 and i + 2 positions in β‐turns, to determine the features of VCD spectra of type I and II β‐turns. The results were correlated with electronic circular dichroism (ECD) spectra and VCD spectra calculated from conformational data obtained by molecular dynamics (MD) simulations. All cyclic tetrapeptides yielded VCD signals with a higher frequency negative and a lower frequency positive couplet with negative lobes overlapping. MD simulations confirmed the conformational homogeneity of these peptides in solution. Comparison with ECD spectroscopy, MD, and quantum chemical calculation results suggested that the low frequency component of VCD spectra originating from the tertiary amide vibrations could be used to distinguish between types of β‐turn structures. On the basis of this observation, VCD spectroscopic features of type II and VIII β‐turns and ECD spectroscopic properties of a type VIII β‐turn were suggested. The need for independent experimental as well as theoretical investigations to obtain decisive conformational information was recognized. © 2006 Wiley Periodicals, Inc. Biopolymers 85: 1–11, 2007.

This article was originally published online as an accepted preprint. The “Published Online” date corresponds to the preprint version. You can request a copy of the preprint by emailing the Biopolymers editorial office at biopolymers@wiley.com
Emerging and re‐emerging viral infections in Europe
Authors: Pugliese Agostino , Beltramo Tiziana , Torre Donato
Published: August 2006

Emerging viral infections are becoming a serious problem in Europe in the recent years. This is particularly true for severe acute respiratory syndrome (SARS), West Nile virus (WNV) disease, Toscana virus (TOSV) disease, and potentially for avian influenza virus (H5N1). In contrast, emergence or re‐emergence of severe viral infections, including tick borne encephalitis virus, and viral haemorrhagic fever caused by Hantavirus and dengue virus have been frequently reported in several European countries. Laboratory diagnosis of these viral infections based on viral isolation or detection by immune electron microscopy, immunoassay and polymerase chain reaction (PCR) has dramatically improved in the recent years, and SARS represents a good example of a diagnostic approach to emerging viral infections. Finally, old and new promising agents are in the pipeline of pharmaceutical companies to treat emerging viral infections. However only prevention based on large epidemiological studies, and research and development of new vaccines may be able to control and eventually eradicate these deadly viral infections. Copyright © 2006 John Wiley & Sons, Ltd.
Numerical Simulation of Separation Factor of NaCl in Surface Force Pore Flow Model
Authors: Sen Gupta B. , Hashim M. A.
Published: August 2006

The surface force pore‐flow (SFPF) model is based on solute‐membrane material interactions at the membrane‐solution interface. It has been used to model the transport of solute and solvent through membranes under the influence of such forces and to determine the separation efficiency based on the assumption of circular pores. It is evident from the model that the pore diameter has a strong bearing upon the separation factor and the mean separation factor can be determined from the pore size distribution. In this work, the mean separation factor (fmean) of a cellulose acetate membrane based on the SFPF model has been determined by the Monte Carlo simulation technique. The value of fmean was calculated by averaging the separation efficiency of 100 000 pores, generated at random from a Gaussian distribution. The results have been compared with the experimental reverse osmosis data for a NaCl/cellulose acetate/water system. The Monte Carlo technique is an improvement over the numerical integration scheme reported in the literature, as it considers the collective effect of all pore sizes and is not restricted by the upper and lower boundaries of numerical integration.
Effects of Sparging Gas Properties and Substrate Size on Enzymatic Hydrolysis of Waste Paper in an Ultrasonic External Loop Airlift
Authors: Li C. , Matsunaga T. , Seki K. , Yoshimoto M. , Furumoto K. , Fukunaga K. , Nakao K.
Published: August 2006

Office paper shredded into various sizes was used as a model substrate for waste paper in the present work, aimed at developing an efficient utilization for waste cellulosics. The enzymatic hydrolysis of the office paper was carried out in an external loop airlift bubble column reactor equipped with an ultrasonic horn system, by sparging with water‐saturated or unsaturated gas. The enhanced hydrolysis was characterized by a two‐stage time course when either water‐unsaturated air or nitrogen was bubbled into the reaction suspension in the airlift reactor, without ultrasonic irradiation. In contrast, a much lower enhanced effect was observed when either saturated air or nitrogen was employed. The total sugar productivity with sparging by either saturated air or nitrogen was lower than in the case of sparging by unsaturated gas. This was ascribed to a shear stress acting on the surface of the paper in the gas sparging section in the riser. The critical superficial gas velocity for complete circulation of the substrate was reduced as its size was decreased. The smaller paper size for sparging with unsaturated air resulted in a more enhanced hydrolysis with a more remarkable two‐stage time course. In the case of sparging with saturated air, the continuous ultrasonic irradiation was effective for enhancing the enzymatic hydrolysis. The time courses of the glucose and total sugar concentrations were successfully analyzed and simulated, based on the kinetic model proposed previously. The variation in the paper size, sparging gas humidity and ultrasonic irradiation exerted an effect on the apparent rate constant and ultimate total sugar concentration, but had no effect on the apparent Michaelis, competitive inhibition and equilibrium constants.