bluuebunny/crossref_metadata_2025 huggingface dataset:
Reenergizing Public Health Through Precaution
Authors: Kriebel David , Tickner Joel
Published: November 2008

The precautionary principle has provoked a spirited debate among environmentalists worldwide, but it is equally relevant to public health and shares much with primary prevention. Its central components are (1) taking preventive action in the face of uncertainty; (2) shifting the burden of proof to the proponents of an activity; (3) exploring a wide range of alternatives to possibly harmful actions; and (4) increasing public participation in decision making.

Precaution is relevant to public health, because it can help to prevent unintended consequences of well-intentioned public health interventions by ensuring a more thorough assessment of the problems and proposed solutions. It can also be a positive force for change. Three aspects are stressed: promoting the search for safer technologies, encouraging greater democracy and openness in public health policy, and stimulating reevaluation of the methods of public health science.
The Precautionary Principle and Electric and Magnetic Fields
Authors: Jamieson Dale , Wartenberg Daniel
Published: November 2008

Current environmental regulation represents a paternalistic policy, more concerned to avoid false positives than false negatives, limiting opportunities for individuals to make choices between risk-avoidance and risk-taking alternatives. For example, many exposures to magnetic fields could be reduced at little or no cost but are not considered seriously, owing to the uncertainty of risk and the concern to avoid false positives.

Even though precautionary approaches that focus on avoiding false negatives often do not lead to adverse economic consequences or irrational choices, such approaches usually are not taken. The value of autonomy and the proper role of governmental paternalism with respect to environmental policy need to be considered more carefully in environmental decision making.
Informational Privacy and the Public's Health: The Model State Public Health Privacy Act
Authors: Gostin Lawrence O. , Hodge James G. , Valdiserri Ronald O.
Published: November 2008

Protecting public health requires the acquisition, use, and storage of extensive health-related information about individuals. The electronic accumulation and exchange of personal data promises significant public health benefits but also threatens individual privacy; breaches of privacy can lead to individual discrimination in employment, insurance, and government programs. Individuals concerned about privacy invasions may avoid clinical or public health tests, treatments, or research.

Although individual privacy protections are critical, comprehensive federal privacy protections do not adequately protect public health data, and existing state privacy laws are inconsistent and fragmented. The Model State Public Health Privacy Act provides strong privacy safeguards for public health data while preserving the ability of state and local public health departments to act for the common good.
Estimation of Health Benefits From a Local Living Wage Ordinance
Authors: Bhatia Rajiv , Katz Mitchell
Published: November 2008

Objectives. This study estimated the magnitude of health improvements resulting from a proposed living wage ordinance in San Francisco.

Methods. Published observational models of the relationship of income to health were applied to predict improvements in health outcomes associated with proposed wage increases in San Francisco.

Results. With adoption of a living wage of $11.00 per hour, we predict decreases in premature death from all causes for adults aged 24 to 44 years working full-time in families whose current annual income is $20 000 (for men, relative hazard [RH] = 0.94, 95% confidence interval [CI] = 0.92, 0.97; for women, RH = 0.96, 95% CI = 0.95, 0.98). Improvements in subjectively rated health and reductions in the number of days sick in bed, in limitations of work and activities of daily living, and in depressive symptoms were also predicted, as were increases in daily alcohol consumption. For the offspring of full-time workers currently earning $20 000, a living wage predicts an increase of 0.25 years (95% CI = 0.20, 0.30) of completed education, increased odds of completing high school (odds ratio = 1.34, 95% CI = 1.20, 1.49), and a reduced risk of early childbirth (RH = 0.78, 95% CI = 0.69, 0.86).

Conclusions. A living wage in San Francisco is associated with substantial health improvement.
Keeping the Unemployed Healthy: The Effect of Means-Tested and Entitlement Benefits in Britain, Germany, and the United States
Authors: Rodriguez Eunice
Published: November 2008

Objectives. Although considerable evidence about the health effects of unemployment exists, little is known about the possible protective effects of various social interventions. This study examined the role that means-tested and entitlement programs could have in ameliorating the health impact of unemployment in Britain, Germany, and the United States.

Methods. Logistic regression models were used to analyze panel data from Britain (1991–1993), Germany (1991–1993), and the United States (1985–1987) available in the Household Panel Comparability Project database. The analysis included 8726 respondents from Britain, 11 086 from Germany, and 11 668 from the United States. The health-dependent variable used was a single measure of perceived health status.

Results. Evidence was found of differences in perceived health status between groups of unemployed people characterized by the types of benefits they receive. When socioeconomic characteristics and previous health and employment status are controlled for, means-tested benefits do not seem sufficient to reduce the impact of unemployment on health.

Conclusions. Monitoring the possible health effects of changes in public assistance benefits should be given priority in the research and political agenda.
Coverage of Smoking Cessation Treatment by Union Health and Welfare Funds
Authors: Barbeau Elizabeth M. , Li Yi , Sorensen Glorian , Conlan Kathleen M. , Youngstrom Richard , Emmons Karen
Published: November 2008

Objectives. This study determined the level of insurance coverage for smoking cessation treatment and factors associated with coverage among health and welfare funds affiliated with a large labor union.

Methods. A self-administered written survey was mailed to fund and union officials. Analyses were conducted by χ2 tests.

Results. Twenty-nine percent of funds provided coverage for some type of smoking cessation treatment, with the odds of coverage significantly increased among funds whose administrators reported having received members' requests for smoking cessation treatment in the past year (odds ratio = 4.9, P = .05).

Conclusions. Coverage for smoking cessation services is low, comparable to coverage offered by other health insurers. Interventions with union members and fund officials are needed to provide union members with access to affordable and effective smoking cessation treatments.
Psychologic Distress and Natural Menopause: A Multiethnic Community Study
Authors: Bromberger Joyce T. , Meyer Peter M. , Kravitz Howard M. , Sommer Barbara , Cordal Adriana , Powell Lynda , Ganz Patricia A. , Sutton-Tyrrell Kim
Published: November 2008

Objectives. This study examined the association between psychologic distress and natural menopause in a community sample of African American, White, Chinese, Hispanic, and Japanese women participating in a national women's health study.

Methods. A cohort of 16 065 women aged 40 to 55 years provided information on menstrual regularity in the previous year, psychosocial factors, health, and somatic–psychologic symptoms. Psychologic distress was defined as feeling tense, depressed, and irritable in the previous 2 weeks.

Results. Rates of psychologic distress were highest in early perimenopause (28.9%) and lowest in premenopause (20.9%) and postmenopause (22%). In comparison with premenopausal women, early perimenopausal women were at a greater risk of distress, with and without adjustment for vasomotor and sleep symptoms and covariates. Odds of distress were significantly higher for Whites than for the other racial/ethnic groups.

Conclusions. Psychologic distress is associated with irregular menses in midlife. It is important to determine whether distress is linked to alterations in hormone levels and to what extent a mood–hormone relationship may be influenced by socioeconomic and cultural factors.
Modeling the Cost and Outcomes of Pharmacist-Prescribed Emergency Contraception
Authors: Marciante Kristin D. , Gardner Jacqueline S. , Veenstra David L. , Sullivan Sean D.
Published: November 2008

Objectives. This study investigated the effect on the risk and cost of unintended pregnancies of emergency contraceptive pills obtained directly from a pharmacist.

Methods. We used a decision model to compare outcomes for private and public payers following unprotected intercourse from.

Results. Obtaining emergency contraceptive pills from a pharmacy, compared with obtaining them from a physician or clinic, resulted in a $158 (95% confidence interval (CI) = $76, $269) reduction in costs for private payers and a $48 (95% CI = $16, $93) reduction for public payers.

Conclusions. Our findings suggest that under varied assumptions, obtaining emergency contraceptive pills directly from a pharmacist reduces the number of unintended pregnancies and is cost saving.
Drug Prices and Emergency Department Mentions for Cocaine and Heroin
Authors: Caulkins Jonathan P.
Published: November 2008

Objectives. In this report, the author illustrates the historic relation between retail drug prices and emergency department mentions for cocaine and heroin.

Methods. Price series based on the Drug Enforcement Administration's System to Retrieve Information From Drug Evidence database were correlated with data on emergency department mentions from the Drug Abuse Warning Network for cocaine (1978–1996) and heroin (1981–1996).

Results. A simple model in which emergency department mentions are driven by only prices explains more than 95% of the variation in emergency department mentions.

Conclusions. Fluctuations in prices are an important determinant of adverse health outcomes associated with drugs.
Eligibility Under State Children's Health Insurance Programs
Authors: Ullman Frank , Hill Ian
Published: November 2008

Objectives. This study analyzed associations between income eligibility criteria under the State Children's Health Insurance Program (SCHIP) and state characteristics.

Methods. We used multivariate methods to explore relations between eligibility expansions under SCHIP and percentages of uninsured children from low-income families, per capita income, and political characteristics.

Results. Proportions of uninsured children, per capita income, and states' preexisting eligibility thresholds were statistically associated with changes in eligibility thresholds, whereas only per capita income was associated with overall SCHIP eligibility thresholds. Political dynamics were not statistically related to SCHIP expansions.

Conclusions. State demographic characteristics were associated with changes in eligibility from preexisting levels but rarely were associated with SCHIP eligibility thresholds.
Health and Federal Budgetary Effects of Increasing Access to Antiretroviral Medications for HIV by Expanding Medicaid
Authors: Kahn James G. , Haile Brain , Kates Jennifer , Chang Sophia
Published: November 2008

Objectives. This study modeled the health and federal fiscal effects of expanding Medicaid for HIV-infected people to improve access to highly active antiretroviral therapy.

Methods. A disease state model of the US HIV epidemic, with and without Medicaid expansion, was used. Eligibility required a CD4 cell count less than 500/mm3 or viral load greater than 10 000, absent or inadequate medication insurance, and annual income less than $10 000. Two benefits were modeled, “full” and “limited” (medications, outpatient care). Federal spending for Medicaid, Medicare, AIDS Drug Assistance Program, Supplemental Security Income, and Social Security Disability Insurance were assessed.

Results. An estimated 38 000 individuals would enroll in a Medicaid HIV expansion. Over 5 years, expansion would prevent an estimated 13 000 AIDS diagnoses and 2600 deaths and add 5816 years of life. Net federal costs for all programs are $739 million (full benefits) and $480 million (limited benefits); for Medicaid alone, the costs are $1.43 and $1.17 billion, respectively. Results were sensitive to awareness of serostatus, highly active antiretroviral therapy cost, and participation rate. Strategies for federal cost neutrality include Medicaid HIV drug price reductions as low as 9% and private insurance buy-ins.

Conclusions. Expansion of the Medicaid eligibility to increase access to antiretroviral therapy would have substantial health benefits at affordable costs.
Use of Protease Inhibitors and Non-Nucleoside Reverse Transcriptase Inhibitors Among Medicaid Beneficiaries With AIDS
Authors: Sambamoorthi Usha , Moynihan Patrick J. , McSpiritt Elizabeth , Crystal Stephen
Published: November 2008

Objectives. This study compared the use of new antiretroviral treatments across sociodemographic subgroups during the 3 years after the introduction of these treatments and examined diffusion of the therapies over time.

Methods. Merged surveillance and claims data were used to examine use of protease inhibitors and non-nucleoside reverse transcriptase inhibitors (PI/NNRTIs) among New Jersey Medicaid beneficiaries with AIDS.

Results. In 1996, there were sharp disparities in use of PI/NNRTI therapy among racial minorities and injection drug users, even after control for other patient characteristics. These gaps had decreased by 1998. Higher PI/NNRTI treatment rates were also observed among beneficiaries enrolled in a statewide HIV/AIDS-specific home- and community-based Medicaid waiver program.

Conclusions. Even within a population of individuals similar in regard to health coverage, there were substantial sociodemographic differences in use of PI/NNRTIs during the early years after their introduction. These differences narrowed as new treatments became standard. Participation in a case-managed Medicaid waiver program seems to be associated with a more appropriate pattern of use. These results suggest a need to address nonfinancial barriers to care.
The Quality Improvement–Research Divide and the Need for External Oversight
Authors: Bellin Eran , Dubler Nancy Neveloff
Published: November 2008

Historically, quality assurance studies have received scant ethical attention. The advent of information systems capable of supporting research-grade continuous quality improvement projects demands that we clearly define how these projects differ from research and when they require external review. The ethical obligation for the performance of quality assurance projects, with its emphasis on identifiable immediate action for a served population, is a critical distinction. The obligation to perform continuous quality improvement is a deliverable of the social contract entered into implicitly by patients and health care providers and systems.

In this article, the authors review the ethical framework that requires these studies, evaluate the differences between quality assurance studies and classic research, and propose criteria for requiring external review.
THE VALIDITY AND RELIABILITY OF THE TURKISH VERSION OF THE SELF-COMPASSION SCALE
Authors: Deniz M. Engin , Kesici Şahin , Sümer A. Serkan
Published: November 2008

The purpose of this study was to adapt the Self-Compassion Scale (SCS; Neff, 2003) into Turkish and test the validity and reliability of the measure. The study was conducted in four phases with 341 (184 female, 157 male) university students. Both the Turkish and original versions of
the SCS were applied to 66 English language teachers to examine the language equivalence. Since the scale had high levels of language equivalence, validity and reliability studies were conducted. For construct validity, exploratory and confirmatory factor analysis, discriminant validity and
item-total correlations were employed. For reliability, internal consistency and test-retest analysis were employed. Results demonstrated that the Turkish version of the SCS is a valid and reliable measure.
INCLUSION AND ORDERING: THE COMPOUNDING EFFECTS OF TWO DISTINCT BUT RELATED STRUCTURAL POWER CONDITIONS
Authors: Corra Mamadi
Published: November 2008

A focal activity of network exchange theories is to discover structural conditions of power in exchange and, when more than one is present, to find their joint effect. In the 30 years since its inception, however, research in exchange networks has focused mostly on power conditions
that are “connection types” and hence, until recently, only conditions of connection and their joint effects have been experimentally investigated. Here the compounding effects of a connection type (inclusion) and its “variant” (ordering) are investigated. A network
position is “inclusively connected” when it must exchange with two or more others for benefits to come from any one. By contrast, ordering occurs when a series of exchanges must be completed in a given sequence. Resistance theory asserts that ordering is a variant (has similar
but distinct effects) of inclusion and, when found together, the joint effect of the two is greater than when either is found separately. Predictions of the combined effects of the two structural power conditions of exchange are offered and investigated. Results suggest stronger effects than
anticipated.
LAY THEORIES OF PERSONALITY AND HELPING AMONG CHINESE UNDERGRADUATES
Authors: Zhang Zhen , Zhang Jianxin
Published: November 2008

In all agencies, lay beliefs of a person are closely related to frequency, tendency and quality of prosocial behaviors. Potential helpers who hold an incremental theory of personality (belief that a person's attributes are malleable), will be more willing to help socially stigmatized
groups than those who hold an entity theory of personality (belief that a person's attributes are fixed (Karafantis & Levy, 2004; West, 2003). Based on this recent evidence, we examined the relationship between lay theories of personality and helping in a Chinese population.
THE ROLE OF PERSONALITY TRAITS IN ONLINE CONSUMER COMPLAINT BEHAVIOR AND SERVICE RECOVERY EXPECTATION
Authors: Huang Jen-Hung , Chang Chiao-Chen
Published: November 2008

To date, the literature on service failure and recovery has tended to be focused on bricks-and-mortar stores. In this study the relationships among service failures, consumer complaint behaviors, and service recovery expectations in an online setting were investigated. Data were collected
from 252 respondents in a questionnaire survey. Results of multiple regression analysis show that personality traits in terms of Type A and locus of control may moderate the relationships among e-service failures, consumer complaint behaviors, and service recovery expectations. When e-service
failures occur, Type A and internally oriented consumers engage in aggressive complaint behaviors and expect high service recovery efforts. Conversely, Type B and externally oriented consumers tend to tolerate e-service failures and refrain from complaining. Finally, theoretical and managerial
implications are discussed.
THE EFFECT OF A WOMAN'S SMILE ON MEN'S COURTSHIP BEHAVIOR
Authors: Guéguen Nicolas
Published: November 2008

Previous studies have found that various nonverbal behaviors performed by women are associated with men approaching. A female confederate was instructed either to smile or to not smile at a man when entering a bar. It was found that those men who were smiled at approached the woman
and considered her more favorably. This effect is explained in accordance with studies that found smiling enhanced attractiveness and that a smile is interpreted to be a signal of a woman's interest towards a man.
NEPOTISM, FAVORITISM AND CRONYISM: A STUDY OF THEIR EFFECTS ON JOB STRESS AND JOB SATISFACTION IN THE BANKING INDUSTRY OF NORTH CYPRUS
Authors: Arasli Huseyin , Tumer Mustafa
Published: November 2008

Nepotism, cronyism and favoritism are unprofessional practices giving preferential treatment to relatives and friends in employment. For this study a survey was carried out with 576 respondents working in the banking industry in northern Cyprus. An analysis was then conducted to assess
the impact of these practices on job stress, job satisfaction, and intention to quit behavior of employees, as well as word of mouth comments in their workplaces. Results of this study show that nepotism, favoritism and cronyism create job stress in the workplace and this increases dissatisfaction
of the staff about their organizations. Nepotism has the greatest negative effect on job stress.
Surgical treatment of a rostral mandibular complex odontoma in a 3‐year‐old horse
Authors: Snyder C. , Dubielzig R. R. , Gengler W. , Livesey M. A.
Published: November 2008

Complex odontomas are rare odontogenic tumours in horses comprised of a combination of mesenchymal and epithelial tissues. Examination, radiographic and histopathological findings in this patient all represent the typical behaviour of a complex odontoma. Oral tumours in horses may have treatment limitations due to tumour size and location. Similar to treatment in other species, surgical enucleation was curative for this type of tumour.
Regulation of articular chondrocyte proliferation and differentiation by indian hedgehog and parathyroid hormone–related protein in mice
Authors: Chen Xuesong , Macica Carolyn M. , Nasiri Ali , Broadus Arthur E.
Published: November 2008

Objective

Chondrocytes of the epiphyseal growth zone are regulated by the Indian hedgehog (IHH)–parathyroid hormone–related protein (PTHrP) axis. In weight‐bearing joints, this growth zone comes to be subdivided by the secondary ossification center into distinct articular and growth cartilage structures. The purpose of this study was to explore the cells of origin, localization, regulation of expression, and putative functions of IHH and PTHrP in articular cartilage in the mouse.

Methods

We assessed IHH and PTHrP expression in an allelic PTHrP‐LacZ–knockin mouse and several versions of PTHrP‐null mice. Selected joints were unloaded surgically to examine load‐induction of PTHrP and IHH.

Results

The embryonic growth zone appears to serve as the source of PTHrP‐expressing proliferative chondrocytes that populate both the forming articular cartilage and growth plate structures. In articular cartilage, these cells take the form of articular chondrocytes in the midzone. In PTHrP‐knockout mice, mineralizing chondrocytes encroach upon developing articular cartilage but appear to be prevented from mineralizing the joint space by IHH‐driven surface chondrocyte proliferation. In growing and adult mice, PTHrP expression in articular chondrocytes is load‐induced, and unloading is associated with rapid changes in PTHrP expression and articular chondrocyte differentiation.

Conclusion

We conclude that the IHH–PTHrP axis participates in the maintenance of articular cartilage. Dysregulation of this system might contribute to the pathogenesis of arthritis.
Disease activity–guided rituximab therapy in rheumatoid arthritis: The effects of re‐treatment in initial nonresponders versus initial responders
Authors: Thurlings Rogier M. , Vos Koen , Gerlag Daniëlle M. , Tak Paul P.
Published: November 2008

Objective

To explore the efficacy of re‐treatment with rituximab in patients with rheumatoid arthritis (RA) who were initial nonresponders to treatment, and to evaluate the effects of rituximab in RA when re‐treatment is given in a standardized way based on the Disease Activity Score in 28 joints (DAS28), according to the international consensus statement.

Methods

Patients with RA who had a DAS28 of ≥3.2 received up to 3 courses of rituximab at intervals of at least 6 months, regardless of whether the patient had responded to the first course of treatment with rituximab.

Results

Of the 30 patients with RA who were included in the study, 26 could be evaluated for the efficacy of treatment after 6 months. Eighteen patients qualified for re‐treatment at 6 months, 6 patients were re‐treated at a later time point because of a disease relapse, and 2 other patients were not re‐treated because they had low disease activity. Seven of the 24 patients who qualified for re‐treatment had not exhibited clinical improvement after the first treatment course. These patients typically did not respond to subsequent courses of rituximab. Of interest, in the 17 patients who had exhibited a clinical response to the first course of rituximab, the second and third treatment courses resulted in European League Against Rheumatism responses similar to those observed after the first course, and no major relapses occurred before re‐treatment.

Conclusion

Rituximab re‐treatment is not effective in patients who do not exhibit clinical improvement after the first treatment course, which is consistent with the notion that such patients represent a different pathogenetic subset of RA. Patients who initially responded to rituximab treatment experienced sustained benefit from DAS28‐based systematic re‐treatment according to the international consensus statement.
Zonal gene expression of chondrocytes in osteoarthritic cartilage
Authors: Fukui Naoshi , Miyamoto Yoshinari , Nakajima Masahiro , Ikeda Yasuko , Hikita Atsuhiko , Furukawa Hiroshi , Mitomi Hiroyuki , Tanaka Nobuho , Katsuragawa Yozo , Yamamoto Seizo , Sawabe Motoji , Juji Takuo , Mori Toshihito , Suzuki Ryuji , Ikegawa Shiro
Published: November 2008

Objective

To determine the chondrocyte metabolism in respective zones of osteoarthritic (OA) cartilage.

Methods

OA cartilage was obtained from macroscopically intact areas of 4 knee joints with end‐stage OA. The cartilage was divided into 3 zones, and gene expression profiles were determined in the respective zones by a custom‐designed microarray that focused on chondrocyte‐related genes. For the genes whose expression was significantly different among the zones, the expression was compared between OA and control cartilage in the respective zones by an analysis using laser capture microdissection and real‐time polymerase chain reaction (PCR). For some genes, the correlation of expression was investigated in specific cartilage zones.

Results

A total of 198 genes (∼40% of those investigated) were found to be expressed at significantly different levels among the zones. Expression of 26 of those genes was evaluated by laser capture microdissection and real‐time PCR, which confirmed the validity of microarray analysis. The expression of cartilage matrix genes was mostly enhanced in OA cartilage, at similar levels across the zones but at different magnitudes among the genes. The expression of bone‐related genes was induced either in the superficial zone or in the deep zone, and positive correlations were found among their expression in the respective zones. The expression of 5 proteinase genes was most enhanced in the superficial zone, where their expression was correlated, suggesting the presence of a common regulatory mechanism(s) for their expression.

Conclusion

In OA cartilage, the metabolic activity of chondrocytes differed considerably among zones. Characteristic changes were observed in the superficial and deep zones.
Atheroprotective effects of methotrexate on reverse cholesterol transport proteins and foam cell transformation in human THP‐1 monocyte/macrophages
Authors: Reiss Allison B. , Carsons Steven E. , Anwar Kamran , Rao Soumya , Edelman Sari D. , Zhang Hongwei , Fernandez Patricia , Cronstein Bruce N. , Chan Edwin S. L.
Published: November 2008

Objective

To determine whether methotrexate (MTX) can overcome the atherogenic effects of cyclooxygenase 2 (COX‐2) inhibitors and interferon‐γ (IFNγ), both of which suppress cholesterol efflux protein and promote foam cell transformation in human THP‐1 monocyte/macrophages.

Methods

Message and protein levels of the reverse cholesterol transport proteins cholesterol 27‐hydroxylase and ATP‐binding cassette transporter A1 (ABCA1) in THP‐1 cells were evaluated by real‐time polymerase chain reaction and immunoblot, respectively. Expression was evaluated in cells incubated in the presence or absence of the COX‐2 inhibitor NS398 or IFNγ, with and without MTX. Foam cell transformation of lipid‐laden THP‐1 macrophages was detected with oil red O staining and light microscopy.

Results

MTX increased 27‐hydroxylase message and completely blocked NS398‐induced down‐regulation of 27‐hydroxylase (mean ± SEM 112.8 ± 13.1% for NS398 plus MTX versus 71.1 ± 4.3% for NS398 alone; P < 0.01). MTX also negated COX‐2 inhibitor–mediated down‐regulation of ABCA1. The ability of MTX to reverse inhibitory effects on 27‐hydroxylase and ABCA1 was blocked by the adenosine A2A receptor–specific antagonist ZM241385. MTX also prevented NS398 and IFNγ from increasing transformation of lipid‐laden THP‐1 macrophages into foam cells.

Conclusion

This study provides evidence supporting the notion of an atheroprotective effect of MTX. Through adenosine A2A receptor activation, MTX promotes reverse cholesterol transport and limits foam cell formation in THP‐1 macrophages. This is the first reported evidence that any commonly used medication can increase expression of antiatherogenic reverse cholesterol transport proteins and can counteract the effects of COX‐2 inhibition. Our results suggest that one mechanism by which MTX protects against cardiovascular disease in rheumatoid arthritis patients is through facilitation of cholesterol outflow from cells of the artery wall.
Disparate folding and stability of the ankylosing spondylitis–associated HLA–B*1403 and B*2705 proteins
Authors: Merino Elena , Galocha Begoña , Vázquez Miriam N. , López De Castro José A.
Published: November 2008

Objective

To investigate the folding, assembly, maturation, and stability of HLA–B*1402 and B*1403, which differ by 1 amino acid change and are differentially associated with ankylosing spondylitis (AS), and to compare these features with those of B*2705.

Methods

Stable transfectants expressing B*1402, B*1403, and B*2705 were used. Folding rates were estimated from the ratio of unfolded heavy chains to folded heavy chains that had been immunoprecipitated with specific antibodies in pulse–chase experiments. Heavy chain misfolding was measured as the half‐life of endoglycosidase H (Endo H)–sensitive β2‐microglobulin–free heavy chains. Maturation/export rates were measured by acquisition of Endo H resistance. Association with calnexin or tapasin was analyzed by coprecipitation with chaperone‐specific antibodies, and surface expression was estimated by flow cytometry. Thermostability of HLA–peptide complexes was assessed by immunoprecipitation after incubation at various temperatures. Heavy chain expression was quantified by Western blotting.

Results

The folding rates of B*1402 and B*1403 were similar, and both were faster and more efficient than B*2705, but some unfolded heavy chains from both B14 subtypes remained in the endoplasmic reticulum (ER) with a long half‐life. The export rates of B*1402 and B*1403 were slow, and the heterodimers partially dissociated after exiting the ER, as revealed by significant amounts of Endo H–resistant and surface‐expressed free heavy chains. Both interaction with tapasin and thermostability were higher for B*2705 than for B*1402 and higher for B*1402 than for B*1403, suggesting that the repertoires of the B*1402‐bound peptide and especially the B*1403‐bound peptide were less optimized than that of B*2705.

Conclusion

Our results indicate that the folding, maturation, and stability of B*1403 differ more from B*2705 than from B*1402. Thus, these features cannot account for the fact that only the 2 former allotypes are associated with AS.
Increased hydraulic conductance of human articular cartilage and subchondral bone plate with progression of osteoarthritis
Authors: Hwang Jennifer , Bae Won C. , Shieu Wendy , Lewis Chad W. , Bugbee William D. , Sah Robert L.
Published: November 2008

Objective

Osteoarthritis (OA) is characterized by progressive degeneration of articular cartilage and remodeling of the subchondral bone plate, comprising calcified cartilage and underlying subchondral bone. Calcified cartilage remodeling due to upward invasion by vascular canals or to calcified cartilage erosion may contribute to biomechanical alteration of the osteochondral tissue and its subchondral bone plate component. The study hypothesis was that hydraulic conductance of osteochondral tissue and subchondral bone plate increases with structural changes indicative of increasing stages of OA.

Methods

Osteochondral cores were harvested from the knees of cadaveric tissue donors and from discarded fragments from patients with OA undergoing knee surgery. The osteochondral cores from tissue donors were macroscopically normal, and the cores from patients with OA had partial‐thickness or full‐thickness erosion to bone. The cores were perfusion‐tested to determine the hydraulic conductance, or ease of fluid flow, in their native state and after enzymatic removal of cartilage. Adjacent portions were analyzed by 3‐dimensional histology for calcified cartilage, subchondral bone, and subchondral bone plate thickness and vascular canal density.

Results

Hydraulic conductance of native osteochondral tissue and subchondral bone plate was higher (2,700‐fold and 3‐fold, respectively) in fully eroded samples than in normal samples. The calcified cartilage layer was thicker (1.5‐fold) in partially eroded samples than in normal samples but thinner and incomplete in fully eroded samples. Subchondral bone plate vascularity was altered with increasing stages of OA.

Conclusion

During joint loading, increased hydraulic conductance of the osteochondral tissue and subchondral bone plate could have deleterious biomechanical consequences for cartilage. Increased fluid exudation from overlying and opposing cartilage, increased fluid depressurization, and increased cartilage tissue strains could lead to chondrocyte death and cartilage damage.
White and gray matter abnormalities in the brain of patients with fibromyalgia: A diffusion‐tensor and volumetric imaging study
Authors: Lutz Jürgen , Jäger Lorenz , de Quervain Dominique , Krauseneck Till , Padberg Frank , Wichnalek Martina , Beyer Antje , Stahl Robert , Zirngibl Ben , Morhard Dominik , Reiser Maximilian , Schelling Gustav
Published: November 2008

Objective

To use a combination of magnetic resonance diffusion‐tensor imaging (MR‐DTI) and MR imaging of voxel‐based morphometry (MR‐VBM) in patients with fibromyalgia syndrome (FMS) to determine microstructural and volume changes in the central neuronal networks involved in the sensory‐discriminative and affective‐motivational characteristics of pain, anxiety, memory, and regulation of the stress response.

Methods

Thirty female patients with FMS and 30 healthy female control subjects were studied. Predefined areas of the brain were measured for volume of gray matter by MR‐VBM and for diffusivity and fractional anisotropy (FA) by MR‐DTI. Higher FA values and reduced diffusivity are thought to reflect increased complexity of brain‐tissue microstructure.

Results

MR‐VBM and MR‐DTI demonstrated a striking pattern of changes in brain morphology in patients with FMS. Both thalami, the thalamocortical tracts, and both insular regions showed significant decreases in FA. In contrast, increases in FA and decreases in gray matter volume were seen in the postcentral gyri, amygdalae, hippocampi, superior frontal gyri, and anterior cingulate gyri. Increased pain intensity scores were correlated with changes in MR‐DTI measurements in the right superior frontal gyrus. Increased fatigue was correlated with changes in the left superior frontal and left anterior cingulate gyrus, and self‐perceived physical impairment was correlated with changes in the left postcentral gyrus. Higher intensity scores for stress symptoms were correlated negatively with diffusivity in the thalamus and FA in the left insular cortex. No relationship was found between MR‐VBM measurements and symptom intensity scores.

Conclusion

MR‐DTI allows the visualization of microstructural changes in the brain of patients with FMS, appears to be more sensitive than MR‐VBM, and may serve as an additional diagnostic technique in FMS and probably other dysfunctional pain syndromes.
Cited2 modulates hypoxia‐inducible factor–dependent expression of vascular endothelial growth factor in nucleus pulposus cells of the rat intervertebral disc
Authors: Agrawal Amit , Gajghate Sachin , Smith Harvey , Anderson D. Greg , Albert Todd J. , Shapiro Irving M. , Risbud Makarand V.
Published: November 2008

Objective

To determine whether nucleus pulposus cells of the intervertebral disc express hypoxia‐inducible factor 2α (HIF‐2α), and to assess the role of HIF‐1 and HIF‐2 in controlling cited2 and vascular endothelial growth factor (VEGF) expression.

Methods

Rat cells were cultured under normoxic (21% O2) or hypoxic (2% O2) conditions, and expression and promoter activity of HIF‐2 target genes were evaluated. Gain‐ or loss‐of‐function experiments were performed to investigate the contribution of HIF isoforms to cited2 activity as well as the role of cited2 in regulating VEGF expression.

Results

We found that HIF‐2α protein was expressed in vivo and that protein and messenger RNA expression were similar under both normoxic and hypoxic conditions. However, there was a significant increase in HIF‐2α transactivation under hypoxic conditions. With respect to functional activity, unlike the case in most other tissues, HIF‐2 failed to increase the transcriptional activities of superoxide dismutase 2 and frataxin, 2 common target genes involved in radical dismutation. However, under hypoxic conditions, HIF‐2 preferentially regulated the expression and promoter activity of cited2, a p300 binding protein. When HIF‐2α or HIF‐1α was suppressed, cited2 promoter activity was inhibited. Finally, we showed that forced expression or suppression of cited2 resulted in corresponding changes in expression of VEGF, a common target gene for HIF‐1 and HIF‐2 in the nucleus pulposus cells.

Conclusion

Results of this study indicate that in nucleus pulposus cells, HIF‐2 and HIF‐1 modulate their own transcriptional activity through cited2. We suggest that the 2 arms of the regulatory circuit serve to maintain survival activities and inhibit angiogenesis in the healthy disc.
Stimulation of chondrocyte‐mediated cartilage destruction by S100A8 in experimental murine arthritis
Authors: van Lent P. L. E. M. , Grevers L. C. , Blom A. B. , Arntz O. J. , van de Loo F. A. J. , van der Kraan P. , Abdollahi‐Roodsaz S. , Srikrishna G. , Freeze H. , Sloetjes A. , Nacken W. , Vogl T. , Roth J. , van den Berg W. B.
Published: November 2008

Objective

To investigate whether S100A8 is actively involved in matrix metalloproteinase (MMP)–mediated chondrocyte activation.

Methods

S100A8 and S100A9 proteins were detected in inflamed knee joints from mice with various forms of murine arthritis, using immunolocalization. Murine chondrocyte cell line H4 was stimulated with proinflammatory cytokines or recombinant S100A8. Messenger RNA (mRNA) and protein levels were measured using reverse transcriptase–polymerase chain reaction and intracellular fluorescence‐activated cell sorting (FACS). Breakdown of aggrecan on the pericellular surface of the chondrocytes was measured using VDIPEN and NITEGE antibodies and FACS, and breakdown in patellar cartilage was measured by immunolocalization.

Results

S100A8 and S100A9 proteins were abundantly expressed in and around chondrocytes in inflamed knee joints after induction of antigen‐induced arthritis or onset of spontaneous arthritis in interleukin‐1 (IL‐1) receptor antagonist–knockout mice. Stimulation of chondrocytes by the proinflammatory cytokines tumor necrosis factor α, IL‐1β, IL‐17, and interferon‐γ caused strong up‐regulation of S100A8 mRNA and protein levels and up‐regulation to a lesser extent of S100A9 levels. Stimulation of chondrocytes with S100A8 induced significant up‐regulation of MMP‐2, MMP‐3, MMP‐9, MMP‐13, ADAMTS‐4, and ADAMTS‐5 mRNA levels (up‐regulated 4, 4, 3, 16, 8, and 4 times, respectively). VDIPEN and NITEGE neoepitopes were significantly elevated in a concentration‐dependent manner in chondrocytes treated with 0.2, 1, or 5 μg/ml of S100A8. (VDIPEN levels were elevated 17%, 67%, and 108%, respectively, and NITEGE levels were elevated 8%, 33%, and 67%, respectively.) S100A8 significantly increased the effect of IL‐1β on MMP‐3, MMP‐13, and ADAMTS‐5. Mouse patellae incubated with both IL‐1β and S100A8 had elevated levels of NITEGE within the cartilage matrix when compared with patellae incubated with IL‐1β or S100A8 alone.

Conclusion

These findings indicate that S100A8 and S100A9 are found in and around chondrocytes in experimental arthritis. S100A8 up‐regulates and activates MMPs and aggrecanase‐mediated pericellular matrix degradation.
Interleukin‐6 blockade suppresses autoimmune arthritis in mice by the inhibition of inflammatory Th17 responses
Authors: Fujimoto Minoru , Serada Satoshi , Mihara Masahiko , Uchiyama Yasushi , Yoshida Hiroto , Koike Nobuo , Ohsugi Yoshiyuki , Nishikawa Teppei , Ripley Barry , Kimura Akihiro , Kishimoto Tadamitsu , Naka Tetsuji
Published: November 2008

Objective

To investigate the mechanism of interleukin‐6 (IL‐6) blockade in autoimmune arthritis, by comparing the effect of anti–IL‐6 receptor (anti–IL‐6R) monoclonal antibody (mAb) treatment with the effect of soluble tumor necrosis factor (sTNFR)–Fc fusion protein treatment on T helper cell differentiation in collagen‐induced arthritis (CIA).

Methods

DBA/1 mice were immunized with type II collagen (CII) to induce arthritis and were left untreated or were treated with anti‐IL‐6R mAb or TNFR‐Fc. T helper cell differentiation and cytokine expression during the development of arthritis in these mice were analyzed.

Results

Immunization with CII predominantly increased the frequency of Th17 cells rather than Th1 cells. The frequency of FoxP3+ Treg cells was also increased after immunization. Treatment of mice with CIA with anti–IL‐6R mAb on day 0 markedly suppressed the induction of Th17 cells and arthritis development, but treatment with this antibody on day 14 failed to suppress both Th17 differentiation and arthritis. In contrast, treatment of mice with CIA with TNFR‐Fc from day 0 to day 14 suppressed neither Th17 differentiation nor arthritis, but treatment from day 21 to day 35 successfully ameliorated arthritis without inhibiting Th17 induction. Neither antibody treatment increased the frequency of Treg cells.

Conclusion

Our results indicate that the protective effect of IL‐6 blockade, but not tumor necrosis factor (TNF) blockade, in CIA correlates with the inhibition of Th17 differentiation. Our findings suggest that IL‐6 blockade in rheumatoid arthritis in human is also likely to involve a therapeutic mechanism distinct from that of TNF blockade and thus may represent an alternative therapy for patients in whom the disease is refractory to TNF blockade.
Overexpression of toll‐like receptors 3 and 4 in synovial tissue from patients with early rheumatoid arthritis: Toll‐like receptor expression in early and longstanding arthritis
Authors: Ospelt Caroline , Brentano Fabia , Rengel Yvonne , Stanczyk Joanna , Kolling Christoph , Tak Paul P. , Gay Renate E. , Gay Steffen , Kyburz Diego
Published: November 2008

Objective

To analyze the expression, regulation, and biologic relevance of Toll‐like receptors (TLRs) 1–10 in synovial and skin fibroblasts and to determine the expression levels of TLRs 2, 3, and 4 in synovial tissues from patients with early rheumatoid arthritis (RA), longstanding RA, and osteoarthritis (OA).

Methods

Expression of TLRs 1–10 in RA synovial fibroblasts (RASFs), OASFs, and skin fibroblasts was analyzed by real‐time polymerase chain reaction (PCR). Fibroblasts were stimulated with tumor necrosis factor α, interleukin‐1β (IL‐1β), bacterial lipopeptide, poly(I‐C), lipopolysaccharide, and flagellin. Production of IL‐6 was determined by enzyme‐linked immunosorbent assay and induction of TLRs 2–5, matrix metalloproteinases (MMPs) 3 and 13 messenger RNA by real‐time PCR. Expression of TLRs 2–4 in synovial tissues was analyzed by immunohistochemistry.

Results

Synovial fibroblasts expressed TLRs 1–6, but not TLRs 7–10. Among the expressed TLRs, TLR‐3 and TLR‐4 were the most abundant in synovial fibroblasts, and stimulation of synovial fibroblasts with the TLR‐3 ligand poly(I‐C) led to the most pronounced increase in IL‐6, MMP‐3, and MMP‐13. In contrast, skin fibroblasts did not up‐regulate MMP‐3 or MMP‐13 after stimulation with any of the tested stimuli. In synovial tissues from patients with early RA, TLR‐3 and TLR‐4 were highly expressed and were comparable to the levels of patients with longstanding RA. These expression levels were elevated as compared with those in OA.

Conclusion

Our findings of high expression of TLRs, particularly TLRs 3 and 4, at an early stage of RA and the reactivity of synovial fibroblasts in vitro to TLR ligands suggest that TLR signaling pathways resulting in persistent inflammation and joint destruction are activated early in the disease process.
Modulation of molecular imprints in the antigen‐experienced B cell repertoire by rituximab
Authors: Palanichamy Arumugam , Roll Petra , Theiss Regina , Dörner Thomas , Tony Hans‐Peter
Published: November 2008

Objective

Transient B cell depletion by rituximab has recently gained more importance in the treatment of rheumatic disorders. Nevertheless, little is known about the reemerging B cells. We analyzed dynamic changes in the repopulating B cells, particularly the postswitch B cells, and studied the mutational patterns of Ig genes in antigen‐experienced B cells.

Methods

Five patients with active rheumatoid arthritis (RA) were treated with rituximab. In 3 patients, B cell receptor (BCR) gene analysis was performed before treatment and during B cell recovery using genomic DNA. In 2 patients, B cell subsets were studied during the early recovery phase using single‐cell technology. For comparison, immunophenotyping of B cell subsets was performed.

Results

Early B cell recovery was marked by a relatively expanded population of highly mutated B cells, which were correlated with B cells with a plasmablast phenotype on comparative immunophenotyping. Analysis of the mutational pattern in these cells revealed increased RGYW/WRCY (where R = A/G, Y = C/T, and W = A/T) hotspot targeting (44% before rituximab versus 59% after) and elevated ratios of replacement to silent mutations within the complementarity‐determining regions in Ig genes (1.87 before rituximab versus 2.67 after; P ≤ 0.0025).

Conclusion

Our findings show that rituximab leads to qualitative changes in the imprints of highly mutated, antigen‐experienced BCRs, representing the result of selection, whereas molecular processes such as Ig V rearrangements are not affected by this treatment.