bluuebunny/crossref_metadata_2025 huggingface dataset:
Excess of Loss Reinsurance with Reinstatements Revisited
Authors: Hürlimann Werner
Published: June 2005

The classical evaluation of pure premiums for excess of loss reinsurance with reinstatements requires the knowldege of the claim size distribution of the insurance risk. In the situation of incomplete information, where only a few characteristics of the aggregate claims to an excess of loss layer can be estimated, the method of stop-loss ordered bounds yields a simple analytical distribution-free approximation to pure premiums of excess of loss reinsurance with reinstatements. It is shown that the obtained approximation is enough accurate for practical purposes and improves the analytical approximations obtained using either a gamma, translated gamma, translated inverse Gaussian or a mixture of the last two distributions.
Proportional Hazard Estimation Adjusted by Continuous Credibility
Authors: Nielsen Jens Perch , Sandqvist Bjørn Lunding
Published: June 2005

This paper extends the continuous credibility weighting introduced to hazard estimation in Hardy and Panjer (1998) and Nielsen and Sandqvist (2000) to the more general case, where the common basis is a proportional hazard model.
Bonus-malus Systems with Varying Deductibles
Authors: Pitrebois Sandra , Walhin Jean-François , Denuit Michel
Published: June 2005

Bonus-malus systems typically lead to high maluses when claims at fault are reported. Such penalties are often difficult to implement in practice. It is shown in this paper that this drawback may be avoided by combining a posteriori premium corrections with a deductible varying according to the level occupied in the scale.
Fair Valuation of Various Participation Schemes in Life Insurance
Authors: Devolder Pierre , Domínguez-Fabián Inmaculada
Published: June 2005

Fair valuation is becoming a major concern for actuaries, especially in the perspective of IAS norms. One of the key aspects in this context is the simultaneous analysis of assets and liabilities in any sound actuarial valuation. The aim of this paper is to illustrate these concepts, by comparing three common ways of giving bonus in life insurance with profit: reversionary, cash or terminal. For each participation scheme, we compute the fair value of the contract taking into account liability parameters (guaranteed interest rate and participation level) as well as asset parameters (market conditions and investment strategy). We find some equilibrium conditions between all those coefficients and compare, from an analytical and numerical point of view, the systems of bonus. Developments are made first in the classical binomial model and then extended in a Black and Scholes economy.
Bonus-malus Systems in a Deregulated Environment: Forecasting Market Shares Using Diffusion Models
Authors: Viswanathan Krupa S. , Lemaire Jean
Published: June 2005

In a deregulated insurance market, insurance carriers have an incentive to be innovative in their pricing decisions by segmenting their portfolios and designing new bonus-malus systems (BMS). This paper examines the evolution of market shares and claim frequencies in a two-company market, when one insurer breaks off the existing stability by introducing a super-discount class in its BMS. Several assumptions concerning policyholders and insurers behavior are tested. Diffusion theory is used to model the spread of the information concerning the new BMS among prospective customers. A wide variety of market outcomes results: one company may take over the market or the two may survive with equal or unequal market shares, each specializing in a specific niche of the market. Before engaging in an aggressive competitive behavior, insurers should consequently be reasonably confident in their assumptions concerning the reactions of their policyholders to the new BMS.
On the Relationship between Impulsivity / Reflectivity Cognitive Style and Performance on TMU English Exam
Authors: Kiany Gholam Reza , Salimi Esmaeel Ali
Published: June 2005

Performance on language tests varies as a function of various factors. These factors, according to Bachman (1990) include: communicative language ability, test method facets, personal attributes that are not related to the ability we want to measure, and random factors which are unpredictable and temporary. Since the purpose of language tests is to measure language ability, a fundamental concern in the development and use of language tests is to identify potential sources of error and test bias in a given measure of language ability and to minimize the effects of these factors, hence to maximize the reliability and the validity of the tests. This study with 1984 male and female PhD candidates with an age range of 21-51 who took the Tarbiat Modarres University (TMU) TOEFL-like English Examination as a prerequisite for their admission for PhD programs attempted to identify one of the potential sources of test bias called impulsivity / reflectivity (Imp/Ref) cognitive style.

The purpose of the present study was two fold: On the one hand, the present research attempted to investigate the relationships and interaction between impulsivity/reflectivity, age, sex and performance on TMU English Exam. This, on the other hand, required restandardization of Persian Impulsiveness Questionnaire in Iran. To achieve this purpose of the study, having gone through the restandardization procedures, the data obtained from 1822 subjects regarding impulsivity/reflectivity were factor-analyzed through Principal Axis Factoring (PAF) and Maximum Likelihood (ML) in order to check the construct validity of the test. To achieve the main objective of the research, the subjects were classified into three groups of high, medium and low impulsives to see if this cognitive style has any relationship with Ph.D. candidates’ performance on TMU English Exam. Moreover, the role of gender and age in the subjects’ performance and the interaction effect of impulsivity, age and sex on their performance were taken into consideration. The results revealed that both impulsivity and gender are significant factors in the subjects’ performance. The overall main effect of age and the interaction effect were found to be non significant.
Global mixed‐integer dynamic optimization
Authors: Chachuat Benoît , Singer Adam B. , Barton Paul I.
Published: June 2005

Recent advances in process synthesis, design, operations, and control have created an increasing demand for efficient numerical algorithms for optimizing a dynamic system coupled with discrete decisions; these problems are termed mixed‐integer dynamic optimization (MIDO). In this communication, we develop a decomposition approach for a quite general class of MIDO problems that is capable of guaranteeing finding a global solution despite the nonconvexities inherent in the dynamic optimization subproblems. Two distinct algorithms are considered. On finite termination, the first algorithm guarantees finding a global solution of the MIDO within nonzero tolerance; the second algorithm finds rigorous bounds bracketing the global solution value, with a substantial reduction in computational expense relative to the first algorithm. A case study is presented in connection with the optimal design and operation of a batch process consisting of a series reaction followed by a separation with no intermediate storage. The developed algorithms demonstrate efficiency and applicability in solving this problem. Several heuristics are tested to enhance convergence of the algorithms; in particular, the use of bounds tightening techniques and the addition of cuts resulting from a screening model of the batch process are considered. © 2005 American Institute of Chemical Engineers AIChE J, 2005
Mill application of a new continuous digester model
Authors: Kayihan Ferhan , Bills Alan , Hart Peter W.
Published: June 2005

A new‐generation continuous digester model has been developed based on first principles of fundamental material, energy, and momentum balances. The modeling approach considers all of the important physical and chemical phenomena that are pertinent to digester operations: notably, chip size distribution, dynamics of chip column compaction, diffusion and reaction fluxes between entrapped and free liquor, and relative velocity differences between chip column and liquor flows. The model calculates time‐dependent behavior of process conditions including but not limited to chip levels, residual EA (effective alkali) density and Kappa (a measure of the extent of reaction) progression through the digester, temperature and dissolved solids profiles, conversion, and blow consistency. The model emulates real operational conditions as closely as possible so that all process decision variables available to an operator are also similar input variables to the model. The model is fast, nearly 300 times faster than real time on a modern PC, which makes it convenient for a variety of applications. High‐fidelity simulations of the model can be used for operating condition optimization, controller design improvements, transition policy development, and training. © 2005 American Institute of Chemical Engineers AIChE J, 2005
Association of articular cartilage degradation and loss of boundary‐lubricating ability of synovial fluid following injury and inflammatory arthritis
Authors: Elsaid K. A. , Jay G. D. , Warman M. L. , Rhee D. K. , Chichester C. O.
Published: June 2005

Objective

To study the relationship between the boundary‐lubricating ability of synovial fluid (SF) and articular cartilage damage in a rabbit knee injury model, to correlate collagen markers of such damage with SF boundary‐lubricating ability and elastase activity, and to examine the lubricating ability of SF, together with collagen markers of articular cartilage damage, under the inflammatory conditions of knee joint synovitis (KJS) and rheumatoid arthritis (RA).

Methods

SF was aspirated weekly from the affected knee joints of 10 adult rabbits following transection of the anterior and posterior cruciate ligaments. The boundary‐lubricating ability of SF was determined in vitro using a previously described friction apparatus. Lubricin concentrations and type II collagen (CII) peptides were quantified by sandwich enzyme‐linked immunosorbent assays (ELISAs). Levels of the C‐terminal neoepitope 9A4 (derived from collagenase degradation of CI, CII, and CIII) and of epitope 5‐D‐4 of keratan sulfate (a marker of proteoglycan depletion) were quantified by inhibition ELISAs. Elastase activity was measured spectrophotometrically. The sensitivity of purified human lubricin to digestion by neutrophil elastase (NE) was examined by Western blotting.

Results

The lubricating ability of SF from injured rabbit knees was significantly decreased at weeks 2 and 3 compared with week 1 after injury. Lubricin concentrations were significantly higher at week 1 than at weeks 2 and 3. CII peptide concentrations increased significantly at weeks 2 and 3 compared with week 1, while 9A4 neoepitope concentrations increased significantly at week 3 compared with weeks 1 and 2. There were no significant differences in epitope 5‐D‐4 concentrations among the 3 weeks. Elastase activity in SF increased significantly at weeks 2 and 3 compared with week 1. Elastase activity correlated significantly with diminishing lubrication at weeks 1, 2, and 3. SF from patients with KJS or RA exhibited deficient lubrication and elevated levels of CII peptides compared with SF from normal controls. NE was shown to completely degrade purified human lubricin in vitro.

Conclusion

Loss of boundary‐lubricating ability of SF after injury is associated with damage to the articular cartilage matrix. This can be attributed to inflammatory processes resulting from the injury, particularly in the early phases. This association also exists in patients with acute knee injuries or progressive chronic inflammatory arthritis.
Angiotensin receptor blockers suppress antigen‐specific T cell responses and ameliorate collagen‐induced arthritis in mice
Authors: Sagawa Kayo , Nagatani Katsuya , Komagata Yoshinori , Yamamoto Kazuhiko
Published: June 2005

Objective

The renin–angiotensin system plays an important role in the regulation of cardiovascular, renal, and endocrine functions. Recent studies have demonstrated that angiotensin II has proinflammatory effects that may contribute to the pathogenesis of immune‐mediated diseases. We used the collagen‐induced arthritis (CIA) model to investigate the influence of angiotensin II receptor blockers (ARBs) on antigen‐specific immune responses and determine whether ARBs have preventive or therapeutic effects on the development of arthritis.

Methods

We administered ARBs (olmesartan, candesartan, and telmisartan) to mice and evaluated antigen‐specific T cell proliferation and cytokine production following immunization with ovalbumin (OVA) or type II collagen in Freund's complete adjuvant (CFA) or aluminum hydroxide (alum). Next, we induced CIA in DBA/1 mice and administered olmesartan. The severity and incidence of arthritis were scored according to clinical manifestations, and joint tissue sections were examined histopathologically.

Results

ARBs severely suppressed lymphocyte proliferation and interferon‐γ production in mice immunized with OVA or type II collagen in CFA. Olmesartan also suppressed lymphocyte proliferation in mice immunized with ovalbumin in alum. In the CIA model, olmesartan reduced the mean arthritis score and the incidence of severe arthritis, even when it was administered only after disease onset. Histopathologic findings for joint destruction were improved in olmesartan‐treated mice.

Conclusion

ARBs suppressed antigen‐specific immune responses for Th1 and Th2 in vivo. Furthermore, olmesartan suppressed the development of severe arthritis and joint destruction in the CIA model. These findings suggest that ARBs may have therapeutic potential in rheumatoid arthritis.
Dermatologic manifestations of the antiphospholipid syndrome: Two hundred consecutive cases
Authors: Francès Camille , Niang Suzanne , Laffitte Emmanuel , Pelletier Francois le , Costedoat Nathalie , Piette Jean Charles
Published: June 2005

Objective

To describe dermatologic manifestations of the antiphospholipid syndrome (APS) and to investigate possible correlations between livedo reticularis and other APS manifestations.

Methods

We conducted a single‐center study of 200 consecutive patients with primary or systemic lupus erythematosus–related APS. To qualify for the study, patients had to fulfill clinical and laboratory criteria from the most recent international consensus statement on classification of definite APS. Dermatologic manifestations were systematically evaluated by a dermatologist. Only dermatologic lesions that may be related to APS were included in the analyses. Correlations between livedo reticularis and other APS manifestations were determined using Fisher's 2‐tailed, chi‐square, and nonparametric Mann‐Whitney tests.

Results

Dermatologic manifestations were noted in 49% of the patients and were the presenting manifestations in 30.5%. Livedo reticularis was the most frequent manifestation, observed in 25.5% of the patients. Livedo reticularis was shown to be significantly associated with cerebral or ocular ischemic arterial events (odds ratio [OR] 10.8, 95% confidence interval [95% CI] 5.2–22.5), seizures (OR 6.5, 95% CI 2.6–16), all arterial events (OR 6, 95% CI 2.9–12.6), heart valve abnormalities detected on echocardiography (OR 7.3, 95% CI 3.6–14.7), and arterial systemic hypertension (≥160/90 mm Hg) (OR 2.9, 95% CI 1.5–5.7). Conversely, it was observed with decreased frequency in patients with only venous thrombosis (OR 0.2, 95% CI 0.1–0.5).

Conclusion

The dermatologic manifestations of APS are frequently the presenting feature of the syndrome, and livedo reticularis is significantly associated with the arterial subset of APS.
Elevated levels of soluble fractalkine in active systemic lupus erythematosus: Potential involvement in neuropsychiatric manifestations
Authors: Yajima Nobuyuki , Kasama Tsuyoshi , Isozaki Takeo , Odai Tsuyoshi , Matsunawa Mizuho , Negishi Masao , Ide Hirotsugu , Kameoka Yosuke , Hirohata Shunsei , Adachi Mitsuru
Published: June 2005

Objective

To determine levels of the soluble form of the chemokine fractalkine (sFkn) and its receptor, CX3CR1, in patients with systemic lupus erythematosus (SLE) with neuropsychiatric involvement (NPSLE) and in SLE patients without neuropsychiatric involvement, and to assess their relationship with disease activity and organ damage.

Methods

Levels of sFkn in serum and cerebrospinal fluid (CSF) were measured by enzyme‐linked immunosorbent assay. Expression of Fkn and CX3CR1 was quantified using real‐time polymerase chain reaction. Surface expression of CX3CR1 on peripheral blood mononuclear cells (PBMCs) was determined by flow cytometry. Disease activity and organ damage were assessed using the SLE Disease Activity Index (SLEDAI) and the Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index, respectively.

Results

Serum sFkn levels were significantly higher in patients with SLE than in patients with rheumatoid arthritis (RA) or healthy controls. In addition, significant correlations between serum sFkn levels and the SLEDAI, the SLICC/ACR Damage Index, anti–double‐stranded DNA and anti‐Sm antibody titers, immune complex levels (C1q), and serum complement levels (CH50) were observed. Expression of CX3CR1 was significantly greater in PBMCs from patients with active SLE than in those from RA patients or healthy controls. Levels of sFkn were also significantly higher in CSF from untreated patients with newly diagnosed NPSLE than in SLE patients without neuropsychiatric involvement; treatment reduced both serum and CSF levels of sFkn in patients with SLE.

Conclusion

Soluble Fkn and CX3CR1 may play key roles in the pathogenesis of SLE, including the neuropsychiatric involvement. Soluble Fkn is also a serologic marker of disease activity and organ damage in patients with SLE, and its measurement in CSF may be useful for the diagnosis of NPSLE and followup of patients with NPSLE.
Effectiveness of recommendations to prevent reactivation of latent tuberculosis infection in patients treated with tumor necrosis factor antagonists
Authors: Carmona Loreto , Gómez‐Reino Juan J. , Rodríguez‐Valverde Vicente , Montero Dolores , Pascual‐Gómez Eliseo , Mola Emilio Martin , Carreño Luis , Figueroa Manuel ,   BIOBADASER Group
Published: June 2005

Objective

To investigate the impact of official recommendations regarding the management of latent tuberculosis (TB) infection on the rate of active TB in patients receiving treatment with tumor necrosis factor (TNF) antagonists.

Methods

Data on active TB rates and on screening and treatment of latent TB infection were extracted from the BIOBADASER (Spanish Society of Rheumatology Database on Biologic Products), a registry of patients with rheumatic conditions treated with TNF antagonists. The rates of active TB among the BIOBADASER patients were compared with those in the background Spanish population, and BIOBADASER patients with rheumatoid arthritis (RA) were compared with a cohort of RA patients from the EMECAR (Morbidity and Clinical Expression of Rheumatoid Arthritis) study who were not treated with TNF antagonists and were followed up for 5 years.

Results

Active TB developed in 34 patients, of whom 32 started taking TNF antagonists prior to the official recommendations on latent TB infection (pre‐OR) and 2 began treatment after the recommendations were issued (post‐OR). All cases of TB occurred during treatment with infliximab, and 28 of these patients had RA. Pre‐OR, the active TB rate in BIOBADASER patients was 20.9‐fold higher than in the background Spanish population, while RA patients in the BIOBADASER had rates 22.6‐ and 6.2‐fold higher than the background and EMECAR populations, respectively. Post‐OR, 324 patients with a tuberculin skin test result ≥5 mm and/or chest radiograph findings suggestive of past TB were treated for 9 months with isoniazid (INH). Post‐OR, active TB rates among the BIOBADASER patients decreased by 78% (incidence risk ratio [IRR] 0.22, 95% confidence interval [95% CI] 0.03–0.88; P = 0.008), while among RA patients in the BIOBADASER, the rate dropped by 83% and reached the EMECAR rate (IRR 1.0, 95% CI 0.02–8.2). There were no INH treatment–related hospitalizations or deaths.

Conclusion

Strategies to treat latent TB infection that are tailored to the at‐risk population can effectively and safely lessen the likelihood of active TB in patients treated with TNF antagonists.
Increased intraarticular interleukin‐7 in rheumatoid arthritis patients stimulates cell contact–dependent activation of CD4+ T cells and macrophages
Authors: van Roon Joel A. G. , Verweij Marieke C. , Wijk Marion Wenting‐van , Jacobs Kim M. G. , Bijlsma Johannes W. J. , Lafeber Floris P. J. G.
Published: June 2005

Objective

To determine the level of intraarticular expression of interleukin‐7 (IL‐7) in patients with rheumatoid arthritis (RA) and to investigate the mechanisms by which IL‐7 facilitates activation of CD4+ T cells and monocyte/macrophages in RA.

Methods

IL‐7 levels were measured in synovial fluid obtained from patients with RA and patients with osteoarthritis (OA). Immunohistologic analysis was used to assess the expression of IL‐7 in synovial tissue from patients with RA. Proliferation and activation markers were determined in order to measure the effect of IL‐7 on mononuclear cells, isolated CD4+ T cells, and monocyte/macrophages from the peripheral blood and synovial fluid. Cocultures of CD4+ T cells and monocytic cells in the absence or presence of a semipermeable membrane were performed to assess the extent to which IL‐7 induces its effects, either contact dependently or via soluble mediators.

Results

IL‐7 levels were increased in synovial fluid from patients with RA compared with the levels in synovial fluid from patients with OA. Macrophages, fibroblasts, and endothelial cells in the joint lining tissue expressed abundant IL‐7. In vitro, synovial fluid CD4+ T cells and macrophages were hyperresponsive to IL‐7 when compared with peripheral blood cells. Furthermore, IL‐7 enhanced cell contact–dependent activation of CD4+ T cells and monocyte/macrophages.

Conclusion

The abundant intraarticular expression of IL‐7 and the stimulation by IL‐7 of contact‐dependent activation of CD4+ T cells and monocytic cells indicate that this cytokine plays an important proinflammatory role in RA synovitis. Further identification of IL‐7–induced pathways may improve understanding of the important interactive role of CD4+ T cells and monocytic cells in RA.
Systemic lupus erythematosus in a multiethnic US cohort (LUMINA): XXI. Disease activity, damage accrual, and vascular events in pre‐ and postmenopausal women
Authors: Fernández Mónica , Calvo‐Alén Jaime , Alarcón Graciela S. , Roseman Jeffrey M. , Bastian Holly M. , Fessler Barri J. , McGwin Gerald , Vilá Luis M. , Sanchez Martha L. , Reveille John D. ,   for the LUMINA Study Group
Published: June 2005

Objective

To determine the differences in clinical manifestations, disease activity, damage accrual, and medication use in systemic lupus erythematosus (SLE) patients as a function of menopausal status at disease onset.

Methods

Women with SLE as per the criteria of the American College of Rheumatology, with disease duration of ≤5 years and of Hispanic (Texas and Puerto Rico ancestries), African American, and Caucasian ethnicity, from LUMINA (LUpus in MInorities, NAture versus nurture), a multiethnic, longitudinal cohort, were studied. Menopause at the time of disease onset was defined as self‐report of climacteric symptoms, and/or amenorrhea lasting >6 months, and/or oophorectomy, and/or increased follicle‐stimulating hormone values for reproductive‐age women, and/or treatment with hormone replacement therapy. Patients were divided into premenopausal and postmenopausal categories. Socioeconomic status, cumulative clinical manifestations, disease activity (at study entry or time 0, last visit, and over time), as measured by the Systemic Lupus Activity Measure, and damage accrual, as measured by the Systemic Lupus International Collaborating Clinics/American College of Rheumatology damage index (at time 0 and at last visit) were compared between the 2 groups of women. Multivariable models were then examined making adjustments for all possible known confounders. Dependent variables in the models were renal involvement, damage accrual, arterial vascular events, and venous thrombosis.

Results

Five hundred eighteen women from the LUMINA cohort were included; 436 (84.2%) were premenopausal and 82 (15.8%) were postmenopausal. Disease onset after menopause was more common among Caucasians. Renal involvement was more common in premenopausal women, whereas vascular arterial events were more frequent in postmenopausal women. All other disease manifestations, as well as disease activity, were comparable between both groups. The presence of damage accrual at time 0 and study end was more frequent in postmenopausal women. Age, rather than menopausal status, independently contributed to damage accrual, renal involvement, and vascular arterial events in these women.

Conclusion

A hypoestrogenemic state secondary to menopause appears not to be protective against disease activity and damage accrual. Age rather than menopausal status is a strong independent predictor of damage accrual and of vascular events in women with lupus.
Association between the PTPN22 gene and rheumatoid arthritis and juvenile idiopathic arthritis in a UK population: Further support that PTPN22 is an autoimmunity gene
Authors: Hinks Anne , Barton Anne , John Sally , Bruce Ian , Hawkins Clive , Griffiths Christopher E. M. , Donn Rachelle , Thomson Wendy , Silman Alan , Worthington Jane
Published: June 2005

Objective

The protein tyrosine phosphatase N22 (PTPN22) gene exhibits regulatory activities for both T cells and B cells. A missense single‐nucleotide polymorphism (SNP) within this gene (rs2476601) has recently been associated with 4 autoimmune diseases: rheumatoid arthritis (RA), systemic lupus erythematosus, autoimmune thyroid disease, and type 1 diabetes mellitus, all of which are T cell–mediated and associated with the elaboration of autoantibody. The aim of this study was to investigate associations of the missense SNP of PTPN22 in a number of autoimmune diseases in the UK population, including RA, juvenile idiopathic arthritis (JIA), psoriasis, psoriatic arthritis (PsA), and multiple sclerosis (MS), some of which have not been examined previously.

Methods

The PTPN22 missense SNP was genotyped in 886 RA, 661 JIA, 279 psoriasis, 455 PsA, and 379 MS patients and in 595 healthy controls. Association with the PTPN22 SNP was analyzed by chi‐square test as implemented in Stata software.

Results

There was a significant association between the PTPN22 SNP and RA (P = 1.8 × 10–8) and JIA (P = 0.0005). In contrast, no association with psoriasis, PsA, or MS was detected.

Conclusion

We replicated the findings of a previous association with RA and identified a novel association with JIA. Together with previous data showing associations with other autoimmune diseases, our findings provide further evidence that the PTPN22 gene plays a role in the pathogenesis of a subgroup of autoimmune diseases.
Association between physician volume and in‐hospital mortality in patients with systemic lupus erythematosus
Authors: Ward Michael M.
Published: June 2005

Objective

Systemic lupus erythematosus (SLE) is an uncommon, clinically complex disease for which prior experience treating similar patients may be particularly important. This study was undertaken to determine if physician volume is associated with the outcome of hospitalization of patients with SLE.

Methods

Data on in‐hospital mortality in a population‐based sample of 15,509 patients with SLE ages 18 years or older who were hospitalized in 2000, 2001, or 2002 in New York or Pennsylvania were obtained from state health planning agencies. Risks of in‐hospital mortality were examined in relation to the average annual number of patients with SLE hospitalized by the admitting physician.

Results

Physician volume was inversely associated with mortality. Mortality was 4.1% among patients of physicians who treated <1 hospitalized patient with SLE per year, 3.5% among patients of physicians who treated 1–3 patients per year, and 2.5% among patients of physicians who treated >3 patients per year. After adjustment for demographic characteristics, severity of illness, and hospital characteristics, the mortality risk was 20% lower among patients in the middle category of physician volume (odds ratio 0.80, 95% confidence interval 0.66–0.96, P =0.02), and 42% lower among patients in the highest category of physician volume (odds ratio 0.58, 95% confidence interval 0.42–0.82, P = 0.002), compared with patients in the lowest category. The association was stronger among patients with nephritis (n = 2,673), for whom the adjusted odds of mortality were ∼60% lower among those in the highest category of physician volume.

Conclusion

Our findings indicate that higher disease‐specific physician volume is associated with lower risks of in‐hospital mortality in patients with SLE.
Association of a PDCD1 polymorphism with renal manifestations in systemic lupus erythematosus
Authors: Johansson Martin , ärlestig Lisbeth , Möller Bozena , Rantapää‐Dahlqvist Solbritt
Published: June 2005

Objective

To analyze the association of the PD‐1.3 polymorphism within the PDCD1 gene in patients with systemic lupus erythematosus (SLE) from the homogeneous population in northern Sweden. The PD‐1.3A allele was analyzed in relation to disease manifestations and severity representing various phenotypes of SLE.

Methods

The study group comprised 260 patients fulfilling at least 4 of the American College of Rheumatology (ACR) criteria for SLE during 1 year. The Systemic Lupus Erythematosus Disease Activity Index (SLEDAI) and the Systemic Lupus International Collaborating Clinics/ACR damage index scores were recorded. Population‐based, randomly selected individuals (n = 670) from the same geographic area served as controls. DNA was extracted from blood samples from both patients and controls and was genotyped for the PD‐1.3 A/G polymorphism, using an ABI Prism 7900HT Sequence Detection System.

Results

The frequency distribution of alleles, carriers, or genotypes did not differ between patients and controls. The PD‐1.3A allele and carriage of the A allele were highly associated with renal disorder (ACR criterion 7) (P = 0.005, odds ratio [OR] 2.71 [95% confidence interval (95% CI) 1.32–5.55] and P = 0.012, OR 2.62 [95% CI 1.28–5.35], respectively). In regression analysis adjusted for sex and age at disease onset, carriage of the A allele remained significantly associated with renal disorder (P = 0.002, OR 3.54 [95% CI 1.56–8.01]). The presence of proteinuria, as measured by the SLEDAI score, and the presence of renal damage were also significantly associated with carriage of the A allele (P = 0.007, OR 3.88 [95% CI 1.44–10.47] and P = 0.021, OR 2.98 [95% CI 1.18–7.54], respectively).

Conclusion

The PD‐1.3A allele is associated with renal manifestations in SLE patients from northern Sweden but not with susceptibility to SLE per se.
Increased expression of type I collagen induced by microfibril‐associated glycoprotein 2: Novel mechanistic insights into the molecular basis of dermal fibrosis in scleroderma
Authors: Lemaire Raphael , Korn Joseph H. , Shipley J. Michael , Lafyatis Robert
Published: June 2005

Objective

Mutations in fibrillin 1, a key component of extracellular microfibrils, are associated with connective tissue disorders such as Marfan's syndrome or skin fibrosis in the tight skin mouse model of scleroderma. Previous studies have suggested that fibrillin 1 mediates skin fibrosis via its interface with associated microfibrillar proteins and type I collagen; in particular, microfibril‐associated glycoprotein 2 (MAGP‐2), an extracellular matrix protein that binds to fibrillins and the αvβ3 integrin, is increased in TSK mouse and human scleroderma skin. Because the function of MAGP‐2 in the biologic processes of the matrix remains unknown, this study investigated whether MAGP‐2 regulates type I collagen.

Methods

Fibroblast cultures conditionally overexpressing MAGP‐2 were developed. Cells were analyzed by Western blotting, Northern blotting, pulse‐chase analysis, and immunofluorescence to assess the effect of MAGP‐2 on type I collagen.

Results

Cells overexpressing MAGP‐2 formed increased MAGP‐2 matrix and showed a 3‐fold increase in intracellular type I procollagen. This increase was associated with increased levels of type I collagen in the medium and matrix. Increased type I collagen colocalized with the MAGP‐2 matrix. MAGP‐2 overexpression had no effect on type I procollagen messenger RNA, but markedly increased the half‐life of type I procollagen. MAGP‐2 induced type I collagen even under conditions in which no MAGP‐2 matrix was detectable, and did not require the presence of the RGD motif of MAGP‐2 in its integrin‐binding site.

Conclusion

This study shows that MAGP‐2 stabilizes type I procollagen, identifying an important function of MAGP‐2 in extracellular matrix homeostasis. It also suggests that MAGP‐2 might mediate skin fibrosis in TSK mice and in patients with scleroderma.
Association of CXCL13 and CCL21 expression with the progressive organization of lymphoid‐like structures in Sjögren's syndrome
Authors: Barone F. , Bombardieri M. , Manzo A. , Blades M. C. , Morgan P. R. , Challacombe S. J. , Valesini G. , Pitzalis C.
Published: June 2005

Objective

Ectopic lymphoneogenesis can occur in the salivary glands of Sjögren's syndrome (SS) patients and is associated with local antigen‐driven B cell responses, autoantibody formation, and potential lymphomatous transformation. CXCL13 and CCL21 have been identified in salivary glands, but their role in ectopic lymphoneogenesis in SS remains unclear. This study aimed to evaluate the microanatomic association between CXCL13 and CCL21 expression and the acquisition of lymphoid features in periductal foci.

Methods

Salivary glands from 37 SS patients and 9 chronic sialadenitis patients were analyzed by immunohistochemistry for T cell/B cell segregation, CD21+ follicular dendritic cell networks, and peripheral lymph node addressin (PNAd)–positive high endothelial venules (HEVs) in relationship to the size of the aggregates and the expression of CXCL13 and CCL21 within infiltrating cells, epithelium, and endothelium.

Results

Grade 1 aggregates (10–50 lymphocytes) demonstrated predominance of nonorganized CD3+ cells, while grade 2 (>50 lymphocytes) and grade 3 (>50 with germinal centers) showed a progressive increase in CD20+ B cells and T cell/B cell segregation. This higher degree of lymphoid organization was significantly related to an increased expression of CXCL13 within infiltrating cells and PNAd+ HEV–associated CCL21‐producing cells. Conversely, no association between lymphoid organization and lymphoid chemokine expression by epithelial cells was observed.

Conclusion

The acquisition of lymphoid features by inflammatory foci in SS is critically associated with the enlargement of the inflammatory foci and with the expression of CXCL13 and CCL21 within the infiltrate, but is not associated with their expression by epithelial cells. These data strongly support an active participation of CXCL13 and CCL21 in regulating the progressive organization and maintenance of periductal foci.
Reduced capacity for the reactivation of glucocorticoids in rheumatoid arthritis synovial cells: Possible role of the sympathetic nervous system?
Authors: Schmidt Martin , Weidler Claudia , Naumann Heidrun , Anders Sven , Schölmerich Jürgen , Straub Rainer H.
Published: June 2005

Objective

Cortisol, the biologically active glucocorticoid, is a major endogenous antiinflammatory factor in rheumatoid arthritis (RA). The aim of this study was to examine the local conversion of cortisol to biologically inactive cortisone and vice versa (the cortisol–cortisone shuttle) in RA and osteoarthritis (OA) patients.

Methods

Thin‐layer chromatography and phosphorimaging were used to examine the cortisol–cortisone shuttle in mixed synovial cells. Double immunohistochemistry was used to assess the key enzymes 11β‐hydroxysteroid dehydrogenase 1 (11β‐HSD1) and 11β‐HSD2 and their possible cellular locations.

Results

Double immunohistochemistry demonstrated 11β‐HSD1/2+ macrophages in the sublining area. The ratio of 11β‐HSD2+ cells to 11β‐HSD1+ cells was significantly higher in RA than in OA patients. Cortisol was converted to inactive cortisone in mixed synovial cells from RA and OA patients, which was largely inhibited by carbenoxolone (11β‐HSD1 and 11β‐HSD2 inhibitor). Using metyrapone to inhibit the 11β‐HSD1 reducing reaction (cortisone → cortisol), we demonstrated that the capacity for reactivation of cortisone to cortisol was significantly higher in OA than in RA patients. Although the capacity for the cortisone–cortisol shuttle was higher in synovial cells from less‐inflamed OA tissue compared with inflamed RA tissue, it was obvious that synovial inflammation in RA, but not OA, was related positively to the reactivation of cortisone. This indicates that in RA, a cause other than typical inflammatory factors inhibits the reactivation of cortisone. Since isoproterenol and adenosine inhibited the cortisol–cortisone shuttle, the loss of sympathetic nerve fibers (loss of β‐adrenergic agonist and adenosine) may be the missing link that accounts for the increased cortisol–cortisone shuttle in RA.

Conclusion

This study demonstrates a reduced capacity for local reactivation of cortisone in RA synovial cells. Since synthetic glucocorticoids also use this reactivation shuttle, the results also apply to therapeutic glucocorticoids. This defective reactivation of cortisone may be an important unrecognized pathophysiologic factor in RA.
Granzyme B is dispensable for immunologic tolerance to self in a murine model of systemic lupus erythematosus
Authors: Graham Kareem L. , Thibault Donna L. , Steinman Jonathan B. , Okeke Lance , Kao Peter N. , Utz Paul J.
Published: June 2005

Objective

Proteolytic autoantigen cleavage by the serine protease granzyme B has been implicated in the development of systemic autoimmune disease; however, there has been no conclusive demonstration of a pathogenic role for granzyme B in autoimmunity. In this study, we evaluated the role of granzyme B in a murine model of autoimmunity.

Methods

To identify potential novel granzyme B substrates, complementary DNAs encoding nuclear factor 45 (NF45) and NF90 were used to generate 35S‐methionine–labeled proteins by coupled in vitro transcription/translation. Radiolabeled proteins were then incubated with purified recombinant granzyme B or caspases, and the cleavage products were analyzed by autoradiography. We also immunized granzyme B–deficient and granzyme B–intact mice with the mineral oil pristane. Production of autoantibodies directed against granzyme B substrates in response to pristane was evaluated by Western blotting, immunoprecipitation, and enzyme‐linked immunosorbent assay.

Results

The double‐stranded RNA–binding protein NF90 was identified as a novel substrate for caspases and granzyme B, both in vitro and in vivo. NF90 is uniquely cleaved by granzyme B in vitro; however, pristane immunization still induced anti‐NF90 antibodies in granzyme B–deficient mice. Pristane‐treated granzyme B–deficient mice also produced antibodies directed against the U1–70‐kd antigen, a previously identified granzyme B substrate. Last, antibodies directed against U1–70 kd arose spontaneously in granzyme B–deficient mice.

Conclusion

These results demonstrate that granzyme B is not required for the production of autoantibodies directed against antigens that are granzyme B substrates in vitro. The data also suggest a protective role for this proapoptotic protease in systemic autoimmunity.
Arthritogenic anti–type II collagen antibodies are pathogenic for cartilage‐derived chondrocytes independent of inflammatory cells
Authors: Amirahmadi S. Fatemah , Whittingham Senga , Crombie Duncan E. , Nandakumar Kutty Selva , Holmdahl Rikard , Mackay Ian R. , van Damme Marie‐Paule , Rowley Merrill J.
Published: June 2005

Objective

Some monoclonal antibodies (mAb) to type II collagen (CII) are arthritogenic upon passive transfer to mice. We undertook this study to investigate whether such mAb are pathogenic in the absence of mediators of inflammation.

Methods

The arthritogenic mAb CIIC1 and M2139, and the nonarthritogenic mAb CIIF4, each reactive with a distinct and well‐defined conformational epitope on CII, were compared with control mAb GAD6. Bovine chondrocytes were cultured with one of the mAb, and on days 3, 6, and 9, antibody binding by chondrocytes and newly synthesized extracellular matrix (ECM) was examined by immunofluorescence, morphologic effects were studied by electron microscopy, and synthesis of matrix components was determined by metabolic labeling with 3H‐proline for collagen and 35S‐sulfate for proteoglycans.

Results

All 3 mAb to CII bound to the matrix. CIIC1 and M2139 adversely affected the cultures, whereas CIIF4 did not. CIIC1 caused disorganization of CII fibrils in the ECM without affecting chondrocyte morphology, and increased matrix synthesis. M2139 caused thickening and aggregation of CII fibrils in the ECM and abnormal chondrocyte morphology but matrix synthesis was unaffected.

Conclusion

The unique arthritogenic capacity of particular anti‐CII mAb upon passive transfer could be explained by their adverse, albeit differing, effects in primary cultures of chondrocytes. Such effects occur independent of inflammation mediators and are related to the epitope specificity of the mAb. Interference with the structural integrity of CII could precede, and even initiate, the inflammatory expression of disease.
Regulation of arthritis by p53: Critical role of adaptive immunity
Authors: Šimelyte Egle , Rosengren Sanna , Boyle David L. , Corr Maripat , Green Douglas R. , Firestein Gary S.
Published: June 2005

Objective

The p53 tumor‐suppressor protein is expressed in rheumatoid arthritis synovium, and loss of p53 function through somatic mutation can occur in longstanding disease. Previous studies demonstrated that p53 is protective in murine collagen‐induced arthritis (CIA). To determine if adaptive immune responses or synovial effector functions are responsible for this effect, passive models of arthritis were studied in p53 wild‐type and knockout mice.

Methods

Models of passive CIA, passive K/BxN serum transfer arthritis, and active CIA were induced in DBA/1 p53−/− or p53+ mice. Hind paws were evaluated for histologic evidence of inflammation and joint destruction. Synovial interleukin‐6 and matrix metalloproteinases 3 and 13 gene expression was analyzed by real‐time quantitative polymerase chain reaction. To evaluate T cell function in p53−/− mice, draining lymph node (LN) cells from mice immunized with type II collagen (CII) were evaluated in vitro.

Results

Increased disease severity in p53−/− mice was confirmed in the standard CIA model. However, clinical arthritis, joint destruction, and synovial gene expression in the passive CIA and K/BxN serum transfer arthritis models were similar in p53−/− and p53+ mice. To determine if the p53 effect was related to T cell function, LN cells from CII‐immunized mice were isolated and stimulated with antigen in vitro. CII‐stimulated T cell proliferation and interferon‐γ production were significantly higher in p53−/− mice. An independent assessment of Th1 function using the cutaneous delayed‐type hypersensitivity model confirmed that p53−/− mice have enhanced T cell responses in vivo.

Conclusion

Adaptive immune responses, rather than antibody‐mediated responses, in p53−/− mice account for increased disease severity in the active CIA model.
A comparative assessment of alignment angle of the knee by radiographic and physical examination methods
Authors: Kraus Virginia B. , Vail T. Parker , Worrell Ted , McDaniel Gary
Published: June 2005

Objective

To compare the knee‐alignment angle from a full‐limb radiograph (mechanical axis) with the anatomic‐axis angle as measured by physical examination using a goniometer and by 2 other radiographic methods.

Methods

The knee‐alignment angle was measured in 114 knees of 57 subjects who had radiographic osteoarthritis (OA), with a Kellgren/Lawrence grade of ≥1 in at least one knee. The mechanical axis was defined as the angle formed by the intersection of 2 lines, one from the center of the head of the femur to the center of the tibial spines, and a second from the center of the talus to the center of the tibial spines. The anatomic axis was defined as the angle formed by 2 lines, each originating from a point bisecting the femur and tibia and converging at the center of the tibial spine tips. The anatomic‐axis angle was measured by 3 methods: 1) physical examination using a goniometer, 2) a posteroanterior (PA) fixed‐flexion knee radiograph (anatomicPA axis), and 3) an anteroposterior (AP) full‐limb radiograph (anatomicAP axis).

Results

Significant correlations were found between the mechanical‐axis angle and the anatomic‐axis angle measured by each of the 3 methods: by goniometer (r = 0.70, P < 0.0001), by anatomicPA axis (r = 0.75, P < 0.0001), and by anatomicAP axis (r = 0.65, P < 0.0001). The anatomic axis was offset a mean 4.21° valgus from the mechanical axis (3.5° in women, 6.4° in men), which was consistent across all methods.

Conclusion

Knee alignment assessed clinically by goniometer or measured on a knee radiograph is correlated with the angle measured on the more cumbersome and costly full‐limb radiograph. These alternative measures have the potential to provide useful information regarding the risk of progression of knee OA when a full‐limb radiograph is not available.
Activation of the endoplasmic reticulum stress response in autoimmune myositis: Potential role in muscle fiber damage and dysfunction
Authors: Nagaraju Kanneboyina , Casciola‐Rosen Livia , Lundberg Ingrid , Rawat Rashmi , Cutting Shawna , Thapliyal Rachana , Chang Jason , Dwivedi Sunita , Mitsak Megan , Chen Yi‐Wen , Plotz Paul , Rosen Antony , Hoffman Eric , Raben Nina
Published: June 2005

Objective

The etiology and pathogenesis of human inflammatory myopathies remain unclear. Findings of several studies suggest that the degree of inflammation does not correlate consistently with the severity of clinical disease or of structural changes in the muscle fibers, indicating that nonimmune pathways may contribute to the pathogenesis of myositis. This study was undertaken to investigate these pathways in myositis patients and in a class I major histocompatibility complex (MHC)–transgenic mouse model of myositis.

Methods

We examined muscle tissue from human myositis patients and from class I MHC–transgenic mice for nonimmune pathways, using biochemical, immunohistochemical, and gene expression profiling assays.

Results

Up‐regulation of class I MHC in skeletal muscle fibers was an early and consistent feature of human inflammatory myopathies. Class I MHC staining in muscle fibers of myositis patients showed both cell surface and a reticular pattern of internal reactivity. The pathways of endoplasmic reticulum (ER) stress response, the unfolded protein response (glucose‐regulated protein 78 pathway), and the ER overload response (NF‐κB pathway) were significantly activated in muscle tissue of human myositis patients and in the mouse model. Ectopic expression of wild‐type mouse class I MHC (H‐2Kb) but not degradable glycosylation mutants of H‐2Kb induced ER stress response in C2C12 skeletal muscle cells.

Conclusion

These results indicate that the ER stress response may be a major nonimmune mechanism responsible for skeletal muscle damage and dysfunction in autoimmune myositis. Strategies to interfere with this pathway may have therapeutic value in patients with this disease.