bluuebunny/crossref_metadata_2025 huggingface dataset:
Reduced CD4+,CD25− T cell sensitivity to the suppressive function of CD4+,CD25high,CD127−/low regulatory T cells in patients with active systemic lupus erythematosus
Authors: Chowdary Venigalla Ram Kumar , Tretter Theresa , Krienke Stefan , Max Regina , Eckstein Volker , Blank Norbert , Fiehn Christoph , Dick Ho Anthony , Lorenz Hanns‐Martin
Published: June 2008

Objective

CD4+,CD25high regulatory T (Treg) cells play a crucial role in the maintenance of self tolerance and prevention of organ‐specific autoimmunity. The presence of many in vivo–preactivated CD4+,CD25++ T cells in patients with systemic lupus erythematosus (SLE) poses a difficulty in discriminating CD25++ activated T cells from CD25high Treg cells. To overcome this problem, we analyzed the phenotype and function of CD4+,CD25high,CD127−/low natural Treg (nTreg) cells isolated from the peripheral blood of patients with SLE.

Methods

CD4+,CD25high,CD127−/low nTreg cells and CD4+,CD25− responder T (Tresp) cells from patients with SLE and normal donors were separated by fluorescence‐activated cell sorting. Cell proliferation was quantified by 3H‐thymidine incorporation, and immunophenotyping of the cells was done using FACScan.

Results

Comparable percentages of CD4+,CD25high,FoxP3+ T cells were observed in patients with SLE and normal donors. Proliferation of SLE nTreg cells sorted into the subset CD4+,CD25high,CD127−/low was significantly decreased compared with that of SLE nTreg cells sorted into the subset CD4+,CD25high (mean ± SEM 2,223 ± 351 counts per minute versus 9,104 ± 1,720 cpm, respectively), while in normal donors, these values were 802 ± 177 cpm and 2,028 ± 548 cpm, respectively, confirming that effector cell contamination was reduced. Notably, the suppressive activity of nTreg cells was intact in all groups. However, CD4+,CD25− Tresp cells isolated from patients with active SLE were significantly less sensitive than those from patients with inactive SLE to the suppressive function of autologous or normal donor CD4+,CD25high,CD127−/low nTreg cells. Furthermore, a significant inverse correlation was observed between the extent of T cell regulation in suppressor assays and the level of lupus disease activity.

Conclusion

This study is the first to show that, in human SLE, impaired sensitivity of Tresp cells to the suppressive effects of a comparably functional, highly purified nTreg cell population leads to a defective suppression of T cell proliferation in active SLE. Studies aiming to define the mechanisms leading to Tresp cell resistance might help in the development of highly specific, alternative immunotherapeutic tools for the control of systemic autoimmune diseases such as SLE.
Role of Rac1 in a bleomycin‐induced scleroderma model using fibroblast‐specific Rac1‐knockout mice
Authors: Liu Shangxi , Kapoor Mohit , Shi‐Wen Xu , Kennedy Laura , Denton Christopher P. , Glogauer Michael , Abraham David J. , Leask Andrew
Published: June 2008

Objective

Activated adhesive signaling is a hallmark of fibroblasts isolated from the scars of scleroderma (systemic sclerosis [SSc]) lesions. Rac1 plays a key role in adhesive signaling. The aim of the present study was to examine the role of Rac1 in bleomycin‐induced scleroderma, using mice with a fibroblast‐specific deletion of Rac1.

Methods

Cutaneous sclerosis was induced by subcutaneous injection of bleomycin. Control groups were treated with phosphate buffered saline. Mice with a fibroblast‐specific deletion of Rac1 and control mice were investigated. Dermal thickness, inflammation, collagen production, and the number of α‐smooth muscle actin–positive cells were determined. The quantity of the collagen‐specific amino acid hydroxyproline was also measured.

Results

Bleomycin treatment induced marked cutaneous thickening, inflammation, and fibrosis in control mice. Conversely, deletion of Rac1 resulted in resistance to bleomycin‐induced fibrosis and inflammation.

Conclusion

Rac1 expression by fibroblasts is required for fibrogenesis. Inhibition of Rac1 may be a viable method to alleviate the development of cutaneous sclerosis.
Premature aging of the immune system in children with juvenile idiopathic arthritis
Authors: Prelog Martina , Schwarzenbrunner Nora , Sailer‐Höck Michaela , Kern Hannelore , Klein‐Franke Andreas , Ausserlechner Michael J. , Koppelstaetter Christian , Brunner Andrea , Duftner Christina , Dejaco Christian , Strasak Alexander M. , Müller Thomas , Zimmerhackl Lothar Bernd , Brunner Jürgen
Published: June 2008

Objective

Juvenile idiopathic arthritis (JIA) is an autoimmune disease of the young. The pathogenesis is not completely understood. Premature aging, associated thymic involution, and compensatory autoproliferation could play important roles in the pathogenesis of autoimmunity. We undertook this study to determine whether patients with JIA demonstrate premature immunosenescence.

Methods

To test this hypothesis, we measured 3 indicators of aging: the percentages and total counts of peripheral blood naive T cells, the frequency of T cell receptor excision circles (TRECs) in naive T cells, and telomeric erosion and Ki‐67 expression as estimates of the replicative history of homeostatic proliferation.

Results

JIA patients showed an accelerated loss of CD4+,CD45RA+,CD62L+ naive T cells with advancing age and a compensatory increase in the number of CD4+,CD45RO+ memory T cells. JIA patients demonstrated a significantly decreased frequency of TRECs in CD4+,CD45RA+ naive T cells compared with age‐matched healthy donors (P = 0.002). TREC numbers correlated with age only in healthy donors (P = 0.0001). Telomeric erosion in CD4+,CD45RA+ naive T cells was increased in JIA patients (P = 0.01). The percentages of Ki‐67–positive CD4+,CD45RA+ naive T cells were increased in JIA patients (P = 0.001) and correlated with disease duration (P = 0.003), which was also an independent factor contributing to telomeric erosion (P = 0.04).

Conclusion

Our findings suggest that age‐inappropriate T cell senescence and disturbed T cell homeostasis may contribute to the development of JIA. In patients with JIA, dysfunction in the ability to reconstitute the T cell compartment should be considered when exploring new therapeutic strategies.
Inflammation‐associated insulin resistance: Differential effects in rheumatoid arthritis and systemic lupus erythematosus define potential mechanisms
Authors: Chung Cecilia P. , Oeser Annette , Solus Joseph F. , Gebretsadik Tebeb , Shintani Ayumi , Avalos Ingrid , Sokka Tuulikki , Raggi Paolo , Pincus Theodore , Stein C. Michael
Published: June 2008

Objective

Insulin resistance is increased by inflammation, but the mechanisms are unclear. The present study was undertaken to test the hypothesis that decreased insulin sensitivity is differentially associated with mediators of inflammation by studying 2 chronic inflammatory diseases of different pathogenesis, systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA).

Methods

We measured fasting insulin, glucose, and lipid levels, erythrocyte sedimentation rate (ESR), C‐reactive protein (CRP), interleukin‐6 (IL‐6), tumor necrosis factor α (TNFα), and coronary artery calcification in 103 patients with SLE and in 124 patients with RA. Insulin sensitivity was measured using the homeostasis model assessment (HOMA) index.

Results

The HOMA value was higher in RA patients (median 2.05 [interquartile range (IQR) 1.05–3.54]) than in SLE patients (1.40 [0.78–2.59]) (P = 0.007). CRP and ESR did not differ significantly in RA and SLE patients. Body mass index (BMI) was significantly correlated with the HOMA index in both RA (ρ = 0.20) and SLE (ρ = 0.54), independently of age, sex, race, and current use of corticosteroids. In RA patients, the HOMA index was also significantly positively correlated with IL‐6 (ρ = 0.63), TNFα (ρ = 0.50), CRP (ρ = 0.29), ESR (ρ = 0.26), coronary calcification (ρ = 0.26), and Disease Activity Score in 28 joints (ρ = 0.21); associations adjusted for age, sex, race, BMI, and current use of corticosteroids remained significant (P < 0.05). In SLE patients, the HOMA index was also significantly correlated with ESR (ρ = 0.35) and CRP (ρ = 0.25), but not with other variables. The association between the ESR and the HOMA value in patients with SLE remained significant after adjustment for confounding covariates (P = 0.008). In multivariable models, the major contributing factors to the HOMA index were the BMI in SLE patients, and IL‐6 and TNFα levels in RA patients.

Conclusion

The pathogenesis of insulin resistance and its contribution to atherogenesis varies in different inflammatory settings.
The PTPN22 620W allele confers susceptibility to systemic sclerosis: Findings of a large case–control study of European Caucasians and a meta‐analysis
Authors: Dieudé P. , Guedj M. , Wipff J. , Avouac J. , Hachulla E. , Diot E. , Granel B. , Sibilia J. , Cabane J. , Meyer O. , Mouthon L. , Kahan A. , Boileau C. , Allanore Y.
Published: June 2008

Objective

To determine whether genetic variants of the PTPN22 gene, including the R620W (1858C>T) missense single‐nucleotide polymorphism (SNP), are associated with systemic sclerosis (SSc). Since PTPN22 is involved in multiple autoimmune diseases, we also examined the occurrence of a concomitant autoimmune disease. We then conducted a meta‐analysis of the most recent studies of SSc in order to verify the association or lack of association between the PTPN22 1858C>T variant and SSc.

Methods

Seven PTPN22 SNPs were analyzed in a French Caucasian cohort of 659 SSc patients and 504 healthy controls. All SSc patient sera were tested for the presence of autoantibodies against topoisomerase I (anti–topo I) and for anticentromere antibodies (ACAs).

Results

The co‐occurrence of an autoimmune disease was observed in 22% of the 416 SSc patients who were exhaustively screened. In 33 of the 416 patients (8%), the concomitant autoimmune disease was known to be associated with PTPN22 1858T; these patients were excluded prior to analysis. No association was detected for any of the SNPs tested. PTPN22 haplotype analysis identified a strong association between SSc and the presence of a risk haplotype carrying the 1858T allele (P = 1.52 × 10–7) and a protective haplotype carrying the 1858C allele (P = 2.20 × 10–16) in our French Caucasian population. The meta‐analysis provided evidence that the PTPN22 1858T allele is involved in the genetic susceptibility to SSc in Caucasian (P = 8.39 × 10–3, OR 1.08 [95% CI 1.02–1.15]) and mixed (P = 3.11 × 10–3, OR 1.09 [95% CI 1.04–1.16]) populations, particularly in the anti–topo I–positive subset.

Conclusion

Our results indicate that PTPN22, a shared genetic factor of multiple autoimmune diseases, also contributes to the genetic background of SSc.
Lack of association of functional CTLA4 polymorphisms with juvenile idiopathic arthritis
Authors: Prahalad Sampath , Bohnsack John F. , Whiting April , Clifford Bronte , Jorde Lynn B. , Guthery Stephen L. , Thompson Susan D. , Glass David N. , Bamshad Michael J.
Published: June 2008

Objective

Juvenile idiopathic arthritis (JIA) is an autoimmune disorder mediated by Th1 immune responses. CTLA‐4, expressed on the T cell surface, plays a negative role in regulating T cell activation. Single‐nucleotide polymorphisms (SNPs) in CTLA4 have been implicated in susceptibility to several autoimmune disorders, including JIA. This study was undertaken to test 3 functional CTLA4 variants for association with JIA.

Methods

Families of 531 children with JIA were genotyped for SNPs located in the promoter region (C−318T), exon 1 (A49G), and the 3′‐untranslated region (CT60) of CTLA4 by polymerase chain reaction amplification and digestion. Family Based Association Testing (FBAT) was used to test CTLA4 SNPs and haplotypes for association with JIA. A second independent cohort of >300 children with JIA and >500 controls were genotyped for case–control analyses. Case–control analyses of the combined cohorts, as well as meta‐analyses of published association studies of CTLA4 and JIA, were performed.

Results

There were no deviations of transmission of any of the CTLA4 variants to children with JIA, or JIA subtypes, determined by FBAT. No significant associations between CTLA4 C−318T or A49G SNPs and JIA were found in 650 JIA cases and 350 controls. Similarly, no significant associations with CT60 variants were found in >800 JIA cases and >500 controls. The meta‐analysis also failed to confirm an association between JIA and CTLA4 variants.

Conclusion

These results suggest that C−318T, A49G, CT60, and haplotypes tagged by these CTLA4 SNPs are not associated with JIA or major JIA subtypes.
Risk factors for cardiovascular complications following total joint replacement surgery
Authors: Basilico Frederick C. , Sweeney Gerard , Losina Elena , Gaydos James , Skoniecki Debra , Wright Elizabeth A. , Katz Jeffrey N.
Published: June 2008

Objective

To determine risk factors for cardiac complications following total joint replacement (TJR) surgery.

Methods

We performed a case–control study of patients who had undergone a primary or revision total knee or total hip replacement surgery. Cases consisted of those who received a TJR and experienced a cardiac complication during the surgical admission period (myocardial infarction [MI], congestive heart failure [CHF], unstable angina, arrhythmia, symptomatic hypotension, or pulmonary embolus). Controls consisted of those who received a TJR and did not experience a cardiac complication during the surgical admission period. Controls were matched to the cases for age at surgery, year of surgery, and surgeon. Case and control status and identification of potential risk factors were ascertained by review of medical records. Conditional logistic regression analysis was used to identify independent predictors of cardiac complications.

Results

The sample included 209 cases and 209 controls. Factors associated with a higher risk of cardiac complications included a history of arrhythmia (adjusted odds ratio [OR] 2.6 [95% confidence interval (95% CI) 1.5–4.3]), a history of coronary artery disease, MI, CHF, or valvular heart disease (OR 1.6 [95% CI 0.9–2.6]), revision surgery (OR 2.2 [95% CI 1.2–3.9]), and bilateral surgery (adjusted OR 3.5 [95% CI 1.6–8.0]). Even though controls were matched for age (within age brackets), age was still associated with a higher risk of cardiac complications (OR 1.7 [95% CI 0.9–3.4]).

Conclusion

This case–control study identified 2 new risk factors for cardiac complications following TJR: bilateral and revision surgery. The study also confirmed previously documented risk factors, including older age at surgery and a history of arrhythmia and of other cardiac problems. These findings should help clinicians anticipate and prevent cardiac complications following TJR surgery.
Sjögren's syndrome and localized nodular cutaneous amyloidosis: Coincidence or a distinct clinical entity?
Authors: Meijer Jiska M. , Schonland Stefan O. , Palladini Giovanni , Merlini Giampaolo , Hegenbart Ute , Ciocca Olga , Perfetti Vittorio , Leijsma Martha K. , Bootsma Hendrika , Hazenberg Bouke P. C.
Published: June 2008

Objective

To report 8 patients with Sjögren's syndrome (SS) and localized nodular cutaneous amyloidosis and to examine serologic and immunohistologic findings that may link the 2 diseases.

Methods

The databases for 3 amyloidosis centers were searched for patients with localized nodular cutaneous amyloidosis and SS. Eight patients with this combination were identified, and clinical, serologic, and histologic parameters were retrospectively evaluated.

Results

Among the 8 patients with a clinical diagnosis of SS, 6 fulfilled the American–European Consensus Group criteria for SS. All of the patients were women in whom SS had been diagnosed at a median age of 47 years (range 30–61 years) and amyloid had been diagnosed at a median age of 60 years (range 42–79 years). The presence of the immunoglobulin light chain type of amyloid (AL amyloid) was confirmed in 4 patients. In 3 of these 4 patients as well as 2 other patients, a light chain–restricted plasma cell population was observed near the amyloid deposits. Progression to systemic amyloidosis was not observed in any patient during a median followup of 3.5 years.

Conclusion

SS should be considered in patients with cutaneous amyloidosis. The combination of cutaneous amyloidosis and SS appears to be a distinct disease entity reflecting a particular and benign part of the polymorphic spectrum of lymphoproliferative diseases related to SS.
Age‐ and sex‐related patterns of serum interferon‐α activity in lupus families
Authors: Niewold Timothy B. , Adler Jeremy E. , Glenn Stuart B. , Lehman Thomas J. A. , Harley John B. , Crow Mary K.
Published: June 2008

Objective

Interferon‐α (IFNα) levels are elevated in many patients with systemic lupus erythematosus (SLE) and may play a primary role in its pathogenesis. The purpose of this study was to determine whether serum IFNα activity in SLE patients and their healthy first‐degree relatives is highest in early adulthood, when the incidence of SLE is greatest.

Methods

Serum samples from 315 SLE patients, 359 healthy first‐degree relatives, and 141 healthy unrelated donors were measured for IFNα activity using a functional reporter cell assay. IFNα activity was analyzed in relation to age, and subgroups with high levels of IFNα activity were identified within the large data sets using a Mann‐Whitney sliding window segmentation algorithm. The significance of each subgrouping was ranked by Kruskal‐Wallis testing.

Results

Age was inversely correlated with IFNα activity in female SLE patients (r = –0.20, P = 0.001) as well as their healthy female first‐degree relatives (r = –0.16, P = 0.02). In male patients and their healthy male first‐degree relatives, there was no significant overall correlation between age and serum IFNα activity. The segmentation algorithm revealed significantly increased IFNα activity between the ages of 12 and 22 years in female SLE patients and between the ages of 16 and 29 years in male SLE patients. Both male and female healthy first‐degree relatives had significantly decreased IFNα activity after the age of 50 years.

Conclusion

Serum IFNα activity is higher in younger individuals in the SLE family cohorts, and this tendency is accentuated in affected individuals. This age‐related pattern of IFNα activity may contribute to the increased incidence of SLE in early adulthood, and interestingly, males and females had similar age‐related patterns of IFNα activity.
Modulation of RANKL and osteoprotegerin expression in synovial tissue from patients with rheumatoid arthritis in response to disease‐modifying antirheumatic drug treatment and correlation with radiologic outcome
Authors: Haynes David , Crotti Tania , Weedon Helen , Slavotinek John , Au Virginia , Coleman Mark , Roberts‐Thomson Peter J. , Ahern Michael , Smith Malcolm D.
Published: June 2008

Objective

To demonstrate the effect of treatment with disease‐modifying agents on the expression of osteoprotegerin (OPG) and RANKL in the synovial tissue from rheumatoid arthritis (RA) patients and to correlate these changes with radiologic damage measured on sequential radiographs of the hands and feet.

Methods

Synovial biopsy specimens were obtained at arthroscopy from 25 patients with active RA (16 of whom had a disease duration <12 months) before and at 3–6‐month intervals after starting treatment with a disease‐modifying agent. Immunohistologic analysis was performed using monoclonal antibodies to detect OPG and RANKL expression, with staining quantitated using computer‐assisted image analysis and semiquantitative analysis techniques. Serial radiographs of the hands and feet were analyzed independently by 2 radiologists and a rheumatologist using the van der Heide modification of the Sharp scoring method.

Results

Thirteen patients achieved a low disease state as defined by a disease activity score <2.6 while 19 patients achieved an American College of Rheumatology response >20% after disease‐modifying antirheumatic drug (DMARD) treatment. Successful DMARD treatment resulted in an increase in OPG expression and a decrease in RANKL expression at the synovial tissue level, which correlated with a reduction in erosion scores measured on annual radiographs of the hands and feet.

Conclusion

Successful treatment‐induced modulation of OPG and RANKL expression at the synovial tissue level, resulting in a reduction in the RANKL:OPG ratio, is likely to have a significant impact on osteoclast formation and joint damage in patients with active RA.
Rheumatoid arthritis patients' perceptions of mutuality in conversations with spouses/partners and their links with psychological and physical health
Authors: Kasle Shelley , Wilhelm Mari S. , Zautra Alex J.
Published: June 2008

Objective

Mutuality, measured as subjects' perceptions of responsiveness in conversations with their spouse/partners, is linked with women's psychological health. Our objectives were to examine physical and psychological health outcomes of married/partnered patients with rheumatoid arthritis (RA) in relation to their perceptions of their own responsiveness (self‐mutuality), their partner's responsiveness (partner‐mutuality), and combined responsiveness (overall mutuality), and to examine potential sex differences in the links between mutuality and depressive symptoms.

Methods

Symptoms of depression and anxiety, physical disability, and arthritis impact reported by RA patients were examined in correlation matrices with their perceptions of overall mutuality, partner‐mutuality, and self‐mutuality in conversations with spouses/partners in the whole sample (n = 148) and separately for men (n = 34) and women (n = 114). Sex moderation of the links between mutuality and depression was tested in hierarchical regressions.

Results

In the whole sample and among women, all mutuality measures had significant inverse correlations with all health outcomes. In men, physical disability was unrelated to mutuality measures, but otherwise correlations approximated those in the whole sample and for women. Sex (being female) interacted with self‐mutuality, but not overall or partner‐mutuality, in predicting fewer depressive symptoms.

Conclusion

RA patients' perceptions of mutuality in conversations with spouses/partners predicted better health across a spectrum of outcomes. Overall mutuality and partner‐mutuality predicted fewer depressive symptoms for both men and women, but self‐mutuality appeared more important for women than for men. The clinical relevance of findings and their implications for behavioral interventions with RA patients are discussed.
Identifying the clinical domains of fibromyalgia: Contributions from clinician and patient delphi exercises
Authors: Mease Phillip J. , Arnold Lesley M. , Crofford Leslie J. , Williams David A. , Russell I. Jon , Humphrey Louise , Abetz Linda , Martin Susan A.
Published: June 2008

Objective

In evaluating the effectiveness of fibromyalgia (FM) therapies, it is important to assess the impact of those therapies on the full array of domains considered important by both clinicians and patients. The objective of this research was to identify and prioritize the key clinically relevant and important domains impacted by FM that should be evaluated by outcome assessment instruments used in FM clinical trials, and to approach consensus among clinicians and patients on the priority of those domains to be assessed in clinical care and research.

Methods

Group consensus was achieved using the Delphi method, a structured process of consensus building via questionnaires together with systematic and controlled opinion feedback. The Delphi exercises involved 23 clinicians with expertise in FM and 100 patients with FM as defined by American College of Rheumatology criteria.

Results

The Delphi exercise revealed that the domains ranked most highly by patients were similar to the domain rankings by clinicians. Pain was consistently ranked highest by both panels. Fatigue, impact on sleep, health‐related quality of life, comorbid depression, and cognitive difficulty were also ranked highly. Stiffness was ranked highly by patients but not clinicians. In contrast, side effects was important to clinicians but was not identified as important in the patient Delphi exercise.

Conclusion

The clinician and patient Delphi exercises identified and ranked key domains that need to be assessed in FM research. Based on these results, a conceptual framework for measuring patient‐reported outcomes is proposed.
Trends in physician‐diagnosed osteoarthritis incidence in an administrative database in British Columbia, Canada, 1996–1997 through 2003–2004
Authors: Kopec Jacek A. , Rahman M. Mushfiqur , Sayre Eric C. , Cibere Jolanda , Flanagan William M. , Aghajanian Jaafar , Anis Aslam H. , Jordan Joanne M. , Badley Elizabeth M.
Published: June 2008

Objective

Prevalence of osteoarthritis (OA) is expected to increase due to population aging. However, there is little information on the trends in the incidence of OA over time. The purpose of this study was to describe changes in physician‐diagnosed OA incidence rates between 1996–1997 and 2003–2004 in British Columbia (BC), Canada.

Methods

We used data on all visits to health professionals and hospital admissions covered by the Medical Services Plan of BC (population ∼4 million) for the fiscal years 1991–1992 through 2003–2004. Rates were standardized to the BC population in 2000. We used 2 definitions of OA: 1) at least 1 visit or hospitalization with a diagnostic code for OA, and 2) at least 2 visits or 1 hospitalization with a code for OA. Incidence rates were calculated with a 5‐year run‐in period to exclude prevalent cases.

Results

Between 1996–1997 and 2003–2004, crude incidence rates of OA based on definition 1 increased from 10.5 to 12.2 per 1,000 in men and from 13.9 to 17.4 per 1,000 in women. The age‐standardized rates did not change in men and increased from 14.7 to 16.7 per 1,000 in women. Incidence rates based on definition 2 were almost 50% lower, but the trends were similar.

Conclusion

We observed an increase in the incidence of OA in both men and women due to population aging and an additional increase in women beyond the effect of aging. These trends have important implications for public health and provision of health services to this very large group of patients.
The role of aggressive corticosteroid therapy in patients with juvenile dermatomyositis: A propensity score analysis
Authors: Seshadri Roopa , Feldman Brian M. , Ilowite Norman , Cawkwell Gail , Pachman Lauren M.
Published: June 2008

Objective

To compare outcomes at 36 months in patients newly diagnosed with juvenile dermatomyositis (DM) treated with aggressive versus standard therapy.

Methods

At diagnosis, 139 untreated juvenile DM patients were given aggressive therapy (intravenous methylprednisolone or oral prednisone 5–30 mg/kg/day; n = 76) or standard therapy (1–2 mg/kg/day; n = 63) by the treating physician. Aggressive therapy patients were more ill at diagnosis. Matching was based on the propensity for aggressive therapy because propensity scoring can reduce confounding by indication. Logistic regression of the matched data determined predictors of outcomes, controlling for clinical confounders and propensity score. Outcomes comprised Disease Activity Score (DAS) for skin and muscle, range of motion (ROM), and calcification.

Results

Sex, race, and age were similar between groups, and initial DAS weakness and ROM significantly predicted the therapy chosen. Based on propensity scores, 42 patients from each group were well matched. In the matched pairs, there were no significant differences in outcomes. Methotrexate use (odds ratio [OR] 3.6, 95% confidence interval [95% CI] 1.15–11.5) and duration of untreated disease (OR 1.2, 95% CI 1–1.38) were associated with ROM loss, hydroxychloroquine use (OR 11.2, 95% CI 3.7–33) and calcification (OR 6.8, 95% CI 1.8–25.4) with persistent rash, abnormal baseline lactate dehydrogenase (OR 11.2, 95% CI 1.4–92) and age at onset (OR 1.3, 95% CI 1–1.4) with weakness, and duration of untreated disease (OR 1.2, 95% CI 1–1.39) with calcification.

Conclusion

Using a retrospective, nonrandomized design with propensity score matching, there was little difference in efficacy outcomes between aggressive and standard therapy; however, the sickest patients were treated with aggressive therapy and were not included in the matched analysis. Comprehensive clinical studies are needed to determine therapeutic pathways to the best outcome.
Arthritis in the family practice setting: Associations with education and community poverty
Authors: Callahan Leigh F. , Shreffler Jack , Mielenz Thelma , Schoster Britta , Kaufman Jay S. , Xiao Changfu , Randolph Randy , Sloane Philip D.
Published: June 2008

Objective

To examine associations of self‐reported arthritis in 25 urban and rural family practice clinics with education (individual socioeconomic status) and community poverty (community socioeconomic status).

Methods

A total of 7,770 patients at 25 family practice sites across North Carolina self‐reported whether they had arthritis. Education was measured as less than a high school (HS) degree, a HS degree, and more than a HS degree. The US Census 2000 block group poverty rate (percentage of households in poverty in that block group) was grouped into low, middle, and high tertiles. We assumed heterogeneity by race (non‐Hispanic white and African American) for the effects of these sociodemographic variables, and therefore stratified by race. Multilevel analyses were performed using a 2‐level mixed logistic model to examine the independent associations and joint effects of education and poverty with self‐reported arthritis as the outcome, adjusting for age, sex, and body mass index.

Results

White participants with less than a HS degree living in block groups with high poverty had 1.55 times the odds (95% confidence interval [95% CI] 1.10–2.17) of reporting arthritis compared with white participants with more than a HS degree and low poverty rates. African American participants with less than a HS degree and high poverty rates had 2.06 times the odds (95% CI 1.16–3.66) of reporting arthritis compared with African American participants with more than a HS degree and low poverty rates.

Conclusion

In the family practice setting, both disadvantaged white and African American participants showed increased odds of self‐reported arthritis, with stronger associations in African Americans.
Psoriatic skin lesions induced by tumor necrosis factor antagonist therapy: A literature review and potential mechanisms of action
Authors: Collamer Angelique N. , Guerrero Karen T. , Henning Jeffery S. , Battafarano Daniel F.
Published: June 2008

Objective

Numerous reports of the induction or worsening of psoriasis in patients treated with tumor necrosis factor (TNF) antagonists indicate that this is not a rare phenomenon. The etiology of this paradoxical clinical response remains unclear. The aim of this study was to describe similar cases, conduct a comprehensive analysis of the literature, explore possible immunologic mechanisms of action of this perplexing reaction, and recommend management options.

Methods

A systematic literature review was performed using the PubMed and Medline databases (1996 to September 2007) searching the index terms “infliximab,” “etanercept,” “adalimumab,” “tumor necrosis factor alpha inhibitor,” and “TNF inhibitor,” combined with the terms “psoriasis,” “pustular,” “skin,” “rash,” and “palmoplantar.” All relevant articles in English were reviewed. Pertinent secondary references were also analyzed.

Results

According to the literature, new‐onset psoriasis may occur any time after initiation of TNF antagonist therapy, is often of an uncommon morphology, may respond to psoriasis treatments, and usually resolves with TNF discontinuation. The pathogenesis of this response appears to involve a disruption in cytokine balance following TNF inhibition, resulting in the up‐regulation of plasmacytoid dendritic cells and the subsequent production of unopposed interferon‐α, following a triggering event in predisposed individuals.

Conclusion

TNF antagonist–induced psoriasis is a newly recognized adverse effect of these medications that typically does not require therapy cessation. We recommend aggressive treatment of the skin disease and consideration of a change in the TNF antagonist if the lesions are unresponsive to conventional psoriasis treatment.
Predictors of return to work following carotid endarterectomy
Authors: Vohra R S , Coughlin P A , McShane P , Bains M , Laughlan K A , Gough M J
Published: June 2008

Background

Carotid endarterectomy (CEA) is an important part of secondary prevention in selected patients following a transient ischaemic attack or stroke. A key marker of success, return to work following surgery, was assessed in a retrospective cohort study.

Methods

Patients from the UK aged less than 65 years at operation were sent a questionnaire concerning return to work after CEA. Data were analysed using univariable tests and logistic regression.

Results

Some 174 (64·4 per cent) of 270 patients responded; their median age was 60 (range 35–64) years and 124 were men. Seventy-five per cent of respondents employed preoperatively returned to work following CEA. Newly retiring patients were older (62 versus 58 years; P < 0·001). Univariable analysis confirmed that age and preoperative stroke influenced return to work. The adjusted odds ratio for patients with versus without a preoperative stroke was 0·46 (95 per cent confidence interval 0·22 to 0·97) (P = 0·040). Median convalescence was 4 weeks, but was shorter in the self-employed (P = 0·039) and prolonged in patients with symptomatic cardiovascular disease (P = 0·023) and those who required postoperative critical care (P = 0·039).

Conclusion

Return to work following CEA was influenced by age and preoperative stroke.
Synthesis, Conformation, and Activity of Human Insulin‐Like Peptide 5 (INSL5)
Authors: Akhter Hossain Mohammed , Bathgate Ross A. D. , Kong Chze K. , Shabanpoor Fazel , Zhang Suode , Haugaard‐Jönsson Linda M. , Rosengren K. Johan , Tregear Geoffrey W. , Wade John D.
Published: June 2008

Insulin‐like peptide 5 (INSL5) was first identified through searches of the expressed sequence tags (EST) databases. Primary sequence analysis showed it to be a prepropeptide that was predicted to be processed in vivo to yield a two‐chain sequence (A and B) that contained the insulin‐like disulfide cross‐links. The high affinity interaction between INSL5 and the receptor RXFP4 (GPCR142) coupled with their apparent coevolution and partially overlapping tissue expression patterns strongly suggest that INSL5 is an endogenous ligand for RXFP4. Given that the primary function of the INSL5–RXFP4 pair remains unknown, an effective means of producing sufficient quantities of this peptide and its analogues is needed to systematically investigate its structural and biological properties. A combination of solid‐phase peptide synthesis methods together with regioselective disulfide bond formation were used to obtain INSL5. Both chains were unusually resistant to standard synthesis protocols and required highly optimized conditions for their acquisition. In particular, the use of a strong tertiary amidine, DBU, as Nα‐deprotection base was required for the successful assembly of the B chain; this highlights the need to consider incomplete deprotection rather than acylation as a cause of failed synthesis. Following sequential disulfide bond formation and chain combination, the resulting synthetic INSL5, which was obtained in good overall yield, was shown to possess a similar secondary structure to human relaxin‐3 (H3 relaxin). The peptide was able to inhibit cAMP activity in SK‐N‐MC cells that expressed the human RXFP4 receptor with a similar activity to H3 relaxin. In contrast, it had no activity on the human RXFP3 receptor. Synthetic INSL5 demonstrates equivalent activity to the recombinant‐derived peptide, and will be an important tool for the determination of its biological function.
Photoinduced Intramolecular Charge Transfer and S2 Fluorescence in Thiophene‐π‐Conjugated Donor–Acceptor Systems: Experimental and TDDFT Studies
Authors: Zhao Guang‐Jiu , Chen Rui‐Kui , Sun Meng‐Tao , Liu Jian‐Yong , Li Guang‐Yue , Gao Yun‐Ling , Han Ke‐Li , Yang Xi‐Chuan , Sun Licheng
Published: June 2008

Experimental and theoretical methods were used to study newly synthesized thiophene‐π‐conjugated donor–acceptor compounds, which were found to exhibit efficient intramolecular charge‐transfer emission in polar solvents with relatively large Stokes shifts and strong solvatochromism. To gain insight into the solvatochromic behavior of these compounds, the dependence of the spectra on solvent polarity was studied on the basis of Lippert–Mataga models. We found that intramolecular charge transfer in these donor–acceptor systems is significantly dependent on the electron‐withdrawing substituents at the thienyl 2‐position. The dependence of the absorption and emission spectra of these compounds in methanol on the concentration of trifluoroacetic acid was used to confirm intramolecular charge‐transfer emission. Moreover, the calculated absorption and emission energies, which are in accordance with the experimental values, suggested that fluorescence can be emitted from different geometric conformations. In addition, a novel S2 fluorescence phenomenon for some of these compounds was also be observed. The fluorescence excitation spectra were used to confirm the S2 fluorescence. We demonstrate that S2 fluorescence can be explained by the calculated energy gap between the S2 and S1 states of these molecules. Furthermore, nonlinear optical behavior of the thiophene‐π‐conjugated compound with diethylcyanomethylphosphonate substituents was predicted in theory.
Hypervalent versus Nonhypervalent Carbon in Noble‐Gas Complexes
Authors: Pierrefixe Simon C. A. H. , Poater Jordi , Im Chan , Bickelhaupt F. Matthias
Published: June 2008

Silicon in [ClSiH3Cl]− is hypervalent, whereas carbon in [ClCH3Cl]− is not. We have recently shown how this can be understood in terms of the ball‐in‐a‐box model, according to which silicon fits perfectly into the box that is constituted by the five substituents, whereas carbon is too small and, in a sense, “drops to the bottom” of the box. But how does carbon acquire hypervalency in the isostructural and isoelectronic noble gas (Ng)/methyl cation complexes [NgCH3Ng]+ (Ng=He and Ne), which feature a delocalized D3h‐symmetric structure with two equivalent CNg bonds? From Ng=Ar onwards, the [NgCH3Ng]+ complex again acquires a propensity to localize one of its axial CNg bonds and to largely break the other one, and this propensity increases in the order Ng=Ar<Kr<Xe<Rn. The behavior of the helium and neon complexes violates the ball‐in‐a‐box principle. Why does this happen? The purpose of this study is to answer these questions and to understand why carbon can become truly hypervalent under certain conditions. To this end, we have carefully analyzed the structure and bonding in NgCH3Ng+ and, for comparison, CH3Ng+, NgHNg+, and NgH+. It appears that, at variance with [ClCH3Cl]−, the carbon atom in [NgCH3Ng]+ can no longer be considered as a ball in a box of the five substituents.
A Universal Model for Nanoporous Carbon Supercapacitors Applicable to Diverse Pore Regimes, Carbon Materials, and Electrolytes
Authors: Huang Jingsong , Sumpter Bobby G. , Meunier Vincent
Published: June 2008

Supercapacitors, commonly called electric double‐layer capacitors (EDLCs), are emerging as a novel type of energy‐storage device with the potential to substitute batteries in applications that require high power densities. In response to the latest experimental breakthrough in nanoporous carbon supercapacitors, we propose a heuristic theoretical model that takes pore curvature into account as a replacement for the EDLC model, which is based on a traditional parallel‐plate capacitor. When the pore size is in the mesopore regime (2–50 nm), counterions enter mesoporous carbon materials and approach the pore wall to form an electric double‐cylinder capacitor (EDCC); in the micropore regime (<2 nm), solvated/desolvated counterions line up along the pore axis to form an electric wire‐in‐cylinder capacitor (EWCC). In the macropore regime (>50 nm) at which pores are large enough so that pore curvature is no longer significant, the EDCC model can be reduced naturally to the EDLC model. We present density functional theory calculations and detailed analyses of available experimental data in various pore regimes, which show the significant effects of pore curvature on the supercapacitor properties of nanoporous carbon materials. It is shown that the EDCC/EWCC model is universal for carbon supercapacitors with diverse carbon materials, including activated carbon materials, template carbon materials, and novel carbide‐derived carbon materials, and with diverse electrolytes, including organic electrolytes, such as tetraethylammonium tetrafluoroborate (TEABF4) and tetraethylammonium methylsulfonate (TEAMS) in acetonitrile, aqueous H2SO4 and KOH electrolytes, and even an ionic liquid electrolyte, such as 1‐ethyl‐3‐methylimidazolium bis(trifluoromethanesulfonyl)imide (EMI‐TFSI). The EDCC/EWCC model allows the supercapacitor properties to be correlated with pore size, specific surface area, Debye length, electrolyte concentration and dielectric constant, and solute ion size It may lend support for the systematic optimization of the properties of carbon supercapacitors through experiments. On the basis of the insight obtained from the new model, we also discuss the effects of the kinetic solvation/desolvation process, multimodal (versus unimodal) pore size distribution, and exohedral (versus endohedral) capacitors on the electrochemical properties of supercapacitors.
Analysis of a merger from a governance perspective: the case of Abitibi‐Consolidated and Donohue
Authors: André Paul , Magnan Michel , St‐Onge Sylvie
Published: June 2008

Adopting a governance perspective, this study analyzes the merger between closely‐held Donohue Inc. and widely‐held Abitibi‐Consolidated Inc. Findings suggest that the absence of a controlling shareholder and weak board governance at Abitibi might explain both (a) its executives' interests in the transaction and (b) its CEO's compensation increase despite underperformance. Second, an intergeneration shift of control at Quebecor (Donohue's parent company) led to a strategic reorientation that (a) transformed Donohue into a target and (b) insured that Donohue's executives had incentives to pursue a deal. Finally, Donohue's noncontrolling shareholders benefited from the transaction while Abitibi shareholders experienced wealth reduction. The merger's aftermath provides some counter evidence regarding blockholders' power in widely‐held firms. Copyright © 2008 ASAC. Published by John Wiley & Sons, Ltd.
Estimation of the default risk of publicly traded companies: evidence from Canadian data
Authors: Dionne Georges , Laajimi Sadok , Mejri Sofiane , Petrescu Madalina
Published: June 2008

Through Canadian publicly traded companies, this study assessed how combining firms' continuous valuations by the market (structural model) with the value given in their financial statements (accounting model) could enhance prediction of a company's probability of default. The hybrid model outperformed other models. Specifically, estimated structural probabilities of default (PDs) contributed significantly to predicting default probabilities when they were included alongside accounting and macroeconomic variables in our hybrid model. These results were obtained with two versions of the structural model: the Merton model (Merton, 1973, 1974) and the default barrier model (Brockman & Turtle, 2003). Both models were estimated with the maximum likelihood method. Copyright © 2008 ASAC. Published by John Wiley & Sons, Ltd.
Reactivity of Cationic Lanthanide(III) Monoporphyrinates towards Anionic Cyanometallates – Preparation, Crystal Structure, and Luminescence Properties of Cyanido‐Bridged Di‐ and Trinuclear d–f Complexes
Authors: Zhu Xunjin , Wong Wai‐Kwok , Guo Jianping , Wong Wai‐Yeung , Zhang Jie‐Peng
Published: June 2008

The metathesis reaction between two equivalents of [Ln(tpp)(H2O)3]Cl (Ln = Yb, Er; tpp2– = tetraphenylporphyrinate dianion) and one equivalent of cyanometallate in dmf at room temperature under nitrogen for 24 hours gave the cyanido‐bridged d–f trinuclear complexes [{Ln(tpp)(dmf)n}2{(μ‐NC)2M(CN)2}] (Ln = Yb, n = 2, M = Ni, 1; Ln = Er, n = 3, M = Ni, 2; Ln = Yb, n = 2, M = Pt, 3; Ln = Er, n = 3, M = Pt, 4), a trinuclear complex [{Er(tpp)(dmf)2}{(μ‐NC)2Fe(CN)4}{Er(Htpp)(dmf)2}] (5), and a dinuclear complex [{Er(tpp)(dmf)(H2O)}(μ‐NC)Ag(CN)] (6) when the cyanometallate used was the dianion [M(CN)4]2– (M = Ni, Pt), the trianion [Fe(CN)6]3–, and monoanion [Ag(CN)2]–, respectively. The solid‐state structures of these complexes were ascertained by X‐ray crystallography. Photoluminescence studies of complexes 1–4 showed that these complexes displayed photophysical properties characteristic of normal metal–porphyrinato complexes. Their absorption bands and emission peaks in the visible region are typical of the intraligand π→π* transitions of the porphyrinato ligand. Furthermore, these complexes also exhibited emission characteristic of the lanthanide(III) ion in the near‐infrared (NIR) region, which was quenched by the cyanometallates. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)
Synthesis, X‐ray Crystallography, Spectroelectrochemistry and Computational Studies on Potential Copper‐Based Radiopharmaceuticals
Authors: Holland Jason P. , Barnard Peter J. , Collison David , Dilworth Jonathan R. , Edge Ruth , Green Jennifer C. , Heslop Julia M. , McInnes Eric J. L. , Salzmann Christoph G. , Thompson Amber L.
Published: June 2008

The synthesis of metal(II) complexes of a bis(thiosemicarbazonato) ligand derived from 1,2‐cyclohexanedione are reported. The compounds have been characterised by a range of techniques including reverse‐phase HPLC, cyclic voltammetry, NMR, UV/Vis, IR, Raman and EPR spectroscopy. X‐ray crystal structures of the proligand and two copper(II) complexes have been obtained, and the electronic structures have been analysed by using DFT calculations. DFT calculations have also been used to map the potential energy surface of a related bis(thiosemicarbazone) proligand and predict solution‐phase one‐electron reduction potentials of the copper(II) complex by using three polarisable continuum solvation models. Electrochemistry experiments show that the copper(II) complex undergoes quasi‐reversible one‐electron reduction at biologically accessible potentials and is within the range proposed for the complex to be hypoxia‐selective. In addition, UV/Vis spectroelectrochemistry experiments have been used to characterise the reduced copper(I) anion, and the reaction between the anion and dioxygen has been characterised by experiments and theory. Observation of this oxidation reaction has important implications for the proposed mechanisms of hypoxia selectivity of bis(thiosemicarbazonato)copper(II) complexes. The copper‐64 radiolabelled complex has been prepared in aqueous solution which demonstrates the potential of use of these complexes as medical imaging agents. (© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)
Epicoccalone, a Coumarin‐Type Chymotrypsin Inhibitor, and Isobenzofuran Congeners from an Epicoccum sp. Associated with a Tree Fungus
Authors: Kemami Wangun Hilaire V. , Ishida Keishi , Hertweck Christian
Published: June 2008

The bioactivity‐guided fractionation of metabolites from an Epicoccum sp. isolated from the fruiting body of the tree fungus Pholiota squarrosa led to the discovery of a new inhibitor of the serine protease α‐chymotrypsin. The structure of the active compound, epicoccalone (1), was fully elucidated by spectrometric and spectroscopic methods, revealing a coumarin ring system with an unprecedented substitution pattern. Two isobenzofuran‐derived co‐metabolites were identified that are remarkably similar to the epicoccalone coumarin core, strongly suggesting that these metabolites share the same orsellinic acid like polyketide pathway.(© Wiley‐VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2008)