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It has been 30 years since Lyme disease was first described in a cohort of patients from Connecticut. An understanding of disease transmission, clinical manifestations and prevention strategies has been established. With the number of new cases increasing each year, it is important that clinicians are aware of the available treatment options. Most patients respond well to a course of treatment with a recommended antibiotic; however, for those patients who develop post-Lyme disease syndrome, the management is unclear. This review provides an overview of Lyme disease and the recommended treatment options available to physicians.

Lithium and valproic acid (VPA) are two primary drugs used to treat bipolar mood disorder and have frequently been used in combination to treat bipolar patients resistant to monotherapy with either drug. Lithium, a glycogen synthase kinase-3 (GSK-3) inhibitor, and VPA, a histone deacetylase (HDAC) inhibitor, have neuroprotective effects. The present study was undertaken to demonstrate synergistic neuroprotective effects when both drugs were coadministered. Pretreatment of aging cerebellar granule cells with lithium or VPA alone provided little or no neuroprotection against glutamate-induced cell death. However, copresence of both drugs resulted in complete blockade of glutamate excitotoxicity. Combined treatment with lithium and VPA potentiated serine phosphorylation of GSK-3 alpha and beta isoforms and inhibition of GSK-3 enzyme activity. Transfection with GSK-3alpha small interfering RNA (siRNA) and/or GSK-3beta siRNA mimicked the ability of lithium to induce synergistic protection with VPA. HDAC1 siRNA or other HDAC inhibitors (phenylbutyrate, sodium butyrate or trichostatin A) also caused synergistic neuroprotection together with lithium. Moreover, combination of lithium and HDAC inhibitors potentiated beta-catenin-dependent, Lef/Tcf-mediated transcriptional activity. An additive increase in GSK-3 serine phosphorylation was also observed in mice chronically treated with lithium and VPA. Together, for the first time, our results demonstrate synergistic neuroprotective effects of lithium and HDAC inhibitors and suggest that GSK-3 inhibition is a likely molecular target for the synergistic neuroprotection. Our results may have implications for the combined use of lithium and VPA in treating bipolar disorder. Additionally, combined use of both drugs may be warranted for clinical trials to treat glutamate-related neurodegenerative diseases.

Smad proteins are intracellular transducers for transforming growth factor-beta (TGF-beta) signaling and play a critical role in differentiation, tissue repair and apoptosis of the central nervous system. Both TGF-beta and its regulated gene, plasminogen activator inhibitor type-1 (PAI-1), have been implicated in the etiology and progression of neurodegenerative diseases and mood disorders. We previously reported that GSK-3beta protein depletion suppresses Smad3/4-dependent gene transcription and causes a reduction in PAI-1 expression. Here, we provide evidence that lithium, the drug for the treatment and prophylaxis of bipolar disorder, inhibits Smad-dependent signaling by regulating cAMP-protein kinase A (PKA), AKT-glycogen synthase kinase-3beta (GSK-3beta), and CRE-dependent signaling pathways in neuron-enriched cerebral cortical cultures of rats. We demonstrate that lithium-induced activation of these pathways inhibits Smad3/4-dependent gene transcription through an increase in pCREB(Ser133) protein levels, an enhanced interaction between pCREB(Ser133) and p300/CBP, which causes Smad3/4-p300/CBP complex disruption and transcriptional suppression of Smad3/4-dependent genes. Therapeutic implications of our findings are discussed.

Objective: To evaluate the FDA's approval process and postmarket surveillance strategies for THR devices., Design: The FDA Center for Devices and Radiological Health (CDRH) 510k releasable database was used to document approved THR devices. The CDRH Medical Device Reporting data files were used to study the efficiency of the FDA's post-market surveillance system. Manufacturers were contacted to supply information regarding their implants. Medline was searched between 1966-1996 to determine the percentage of THR devices with published data on clinical outcomes., Results: Between 1976 and 1996, 701 new THR devices were approved by the Substantial Equivalent (SE) route and 34 were approved on the basis of Premarket Approval PMA. The number of approvals doubled between 1991-1995 compared to 1976-1990. Seventy-four different manufacturers obtained approval to market THR devices. Only four manufacturers obtained approval via the PMA application. Under Mandatory Device Reporting all revision arthroplasties should be reported. Using data from 2 independent services for which we had US hospital discharge data in 1993 we estimate that only 3% of all revision THR were reported to the FDA. Manufacturers of hip implants failed to provide useful information. Medline search revealed only 15% of the approved THR devices had published data on outcomes., Conclusion: Current FDA premarket approval and postmarket surveillance strategies fail to provide information for evidence-based selection of THR devices. Recommendations are made to avert problems with device failures.

Statin medications have been suggested for widespread use in patients with systemic lupus erythematosus (SLE). We studied the dose effectiveness and tolerability of pravastatin in SLE. We compared 41 SLE subjects in a two-month open-label dose-titration study of pravastatin to 22 SLE controls. Lipids, ALT, CPK, CRP, adverse effects were assessed. Linear mixed models assessed changes in lipids and CRP, comparing pravastatin subjects to controls. After 1 month of pravastatin 10 mg a day, total cholesterol decreased by 16% (+/-12.1%) and LDL by 24% (+/-17%), compared with 1.8% (+/-7.5%) and 2.6% (+/-8.6%) decreases in controls (P < 0.001). CRP did not decline. Glucocorticoids appeared to decrease pravastatin effectiveness. Serum CPK increased in one subject. Pravastatin reduced LDL and total cholesterol levels approximately the same degree observed in normal individuals, but the effect appeared blunted in those on modest doses of glucocorticoids and those with higher BMI.

To evaluate a theory-based educational program to prevent Lyme disease and other tick-borne illnesses (TBI), a randomized controlled trial of an educational program was delivered to ferry passengers traveling to an endemic area in southeastern Massachusetts. Rates of TBI and precautionary and tick check behaviors were measured over three summers in 30,164 passengers. There were lower rates of TBI among participants receiving TBI education compared with control participants receiving bicycle safety education (relative risk [RR] = 0.79) and a 60% reduction in risk among those receiving TBI education who visited Nantucket Island for more than 2 weeks compared to control participants (RR = 0.41, 95% confidence intervals = 0.18 to 0.95, p < .038). TBI-educated participants were also significantly more likely to take precautions (use repellent, protective clothing, limit time in tick areas) and check themselves for ticks. The study demonstrates that a theory-based Lyme disease prevention program can increase precautionary behavior and result in a significant reduction in TBI.

The surface hydroxyls in pyrite and slag were investigated, and the result showed that the hydroxyls in pyrite slag were induced by residual pyrite. The diffuse reflectance infrared Fourier transform spectroscopy (DRIFTS) indicated that the surface hydroxyls in pyrite and slag reacted with thallium ion in the process of wastewater treatment. The 3 550 cm(-1) peak and 3 402 cm(-1) peak weakened after pyrite and slag treatment, nevertheless the 3 550 cm(-1) peak lowered and shifted to higher frequencies by about 70 cm(-1) with slag treatment. The reflectance spectroscopy in visible region was used to characterize the change of particle and specific surface in these treatment process, and furthermore, the fact that the activity of both pyrite and slag increased in repetitive use was explained.

Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase consisting of two isoforms, alpha and beta. The activities of GSK-3 are regulated negatively by serine phosphorylation but positively by tyrosine phosphorylation. GSK-3 inactivation has been proposed as a mechanism to promote neuronal survival. We used GSK-3 isoform-specific small interfering RNAs, dominant-negative mutants, or pharmacological inhibitors to search for functions of the two GSK-3 isoforms in regulating neuronal survival in cultured cortical neurons in response to glutamate insult or during neuronal maturation/aging. Surprisingly, RNA interference-induced depletion of either isoform was sufficient to block glutamate-induced excitotoxicity, and the resulting neuroprotection was associated with enhanced N-terminal serine phosphorylation in both GSK-3 isoforms. However, GSK-3beta depletion was more effective than GSK-3alpha depletion in suppressing spontaneous neuronal death in extended culture. This phenomenon is likely due to selective and robust inhibition of GSK-3beta activation resulting from GSK-3beta Ser9 dephosphorylation during the course of spontaneous neuronal death. GSK-3alpha silencing resulted in reduced tyrosine phosphorylation of GSK-3beta, suggesting that tyrosine phosphorylation is also a critical autoregulatory event. Interestingly, GSK-3 inhibitors caused a rapid and long-lasting increase in GSK-3alpha Ser21 phosphorylation levels, followed by a delayed increase in GSK-3beta Ser9 phosphorylation and a decrease in GSK-3alpha Tyr279 and GSK-3beta Tyr216 phosphorylation, thus implying additional levels of GSK-3 autoregulation. Taken together, our results underscore important similarities and dissimilarities of GSK-3alpha and GSK-3beta in the roles of cell survival as well as their distinct modes of regulation. The development of GSK-3 isoform-specific inhibitors seems to be warranted for treating GSK-3-mediated pathology.

Lyme disease (borreliosis) incidence continues to increase despite a growing knowledge of primary and secondary prevention strategies. Primary prevention aims to reduce the risk of tick exposure and thereby decrease the incidence of new Lyme disease cases. Secondary prevention targets the development of disease or reduces disease severity among people who have been bitten by infected ticks. Numerous prevention strategies are available, and although they vary in cost, acceptability and effectiveness, uptake has been universally poor. Research in areas where Lyme disease is endemic has demonstrated that despite adequate knowledge about its symptoms and transmission, many people do not perform behaviors to reduce their risk of infection. New prevention strategies should aim to increase people's confidence in their ability to carry out preventive behaviors, raise awareness of desirable outcomes, and aid in the realization that the necessary skills and resources are available for preventive measures to be taken. In this article we evaluate the prevention and treatment strategies for Lyme disease, and discuss how these strategies can be implemented effectively. As many patients with Lyme disease develop arthritis and are referred to rheumatologists it is important that these health-care providers can educate patients about disease-prevention strategies.

The objective of this study was to identify reliable and valid instruments to measure cognitive impairment in systemic lupus erythematosus (SLE), and to define minimally important change of cognitive impairment in SLE for clinical trials. Neurocognitive measures used in randomized clinical trials in SLE were reviewed, and response criteria were developed using consensus expert opinion. The definition of cognitive impairment in the ACR nomenclature for neuropsychiatric lupus syndrome was adopted. Cognitive impairment is a deficit of 2.0 or more standard deviations (SD) below the mean, compared to normative data, in the key domains of attention, memory and psychomotor speed. Cognitive decline is defined as a deficit of 1.5-1.9 SD below the mean. Focal decline is defined if impairment exists in one or more measures within one domain, and multifocal decline if impairment exists on measures spanning two or more domains. The combination of ACR neuropsychological battery and the Cognitive Symptoms Inventory (CSI) is recommended to quantitate cognitive function. A clinically important response is defined as an improvement of > or = 1.0 SD with an effect size of 1.0 in the key domains of the ACR neuropsychological testing, and an improvement of > or = 1.0 SD with an effect size of 1.0 in functional performance of the CSI.

Treatment of acidic heavy metal wastewater by pyrite was studied by reflectance spectroscopy and absorption spectroscopy. The surface reaction in pyrite and the interaction between pyrite and heavy metal were investigated. The diffuse reflectance FTIR spectroscopy (DRIFTS) showed that the surface hydroxyls in pyrite reacted with heavy metal ion in the process of wastewater treatment, and furthermore, the phenomenon of the acidic wastewater driven to neutrality(pH 7) naturally after treatment was reasonably explained by analyzed carbonate in pyrite. The reflectance spectroscopy in visible region can be used to characterize the change of mineral particle and specific surface in this treatment process, and the reasons for the activity of pyrite increasing in repetitive use were explained. A process of adsorption-precipitation from Cr ( VI) to Cr3+ and to Cr(OH)3 was proved by absorption spectroscopy and XPS during the treatment of Cr(VI)-bearing wastewater by pyrite.

Glycogen synthase kinase-3 (GSK-3) exists as two structurally similar isoforms, alpha and beta, whose activities are negatively regulated by serine phosphorylation but positively controlled by tyrosine phosphorylation. We used GSK-3 isoform-specific small interfering RNAs, dominant negative mutants, and pharmacological inhibitors to search for the differential roles for both GSK-3 isoforms in regulating transcriptional activation in cultured rat cerebral cortical neurons. GSK-3alpha and GSK-3beta were shown to have differentially regulated transactivation such that GSK-3alpha silencing/inhibition was more robust than GSK-3beta silencing/inhibition in causing cAMP-responsive element- and NF-kappaB-dependent transactivation. Moreover, protein-DNA array studies identified two novel GSK-3-regulated transcription factors, early growth response 1 and Smad3/4, which were oppositely affected by GSK-3alpha or GSK-3beta silencing or inhibition. Taken together, our results underscore critical variations in the function and regulation of GSK-3alpha and GSK-3beta. The development of GSK-3 isoform-specific inhibitors is thus crucial for therapeutic intervention of GSK-3-related neuropathological conditions.

Objective: To determine the radiographic joint space width (JSW) in undamaged metacarpophalangeal (MCP) and proximal interphalangeal (PIP) joints of patients with early rheumatoid arthritis (RA) and to identify important clinical determinants of JSW., Methods: Radiographs of patients with RA of <1 year's duration, from an early arthritis cohort at a tertiary care rheumatology clinic, were obtained. JSW was analyzed by joint, finger, age, sex, height, and a number of other clinically relevant variables. Multivariate analysis was also performed, to account for possible confounding between variables., Results: Thirty-eight patients were included in the study. We found that JSW was greater in the MCP joint than the PIP joint (P < 0.0001). JSW was significantly greater in men (P < 0.0001) and increased with increasing height (P < 0.003), but was not associated with age (P < 0.21). In multivariate analyses, sex was shown to be the most important predictor of JSW., Conclusion: In patients with early RA, MCP and PIP JSW is significantly associated with sex and height. In studies of RA in which JSW measurements are included as an outcome, these differences may need to be accounted for in the analysis.

This article discusses the clinimetrics of disease activity and organ damage, and response criteria using systemic lupus erythematosus as a paradigm. Similar considerations apply to the other systemic rheumatic illnesses. Clinically relevant and psychometrically tested measures of disease states aid the conduct of clinical studies and trials that are more rigorous, efficient, and relevant to patients' concerns. These same measures used in clinical trials will likely improve clinical outcomes if they are used in the monitoring and titration of therapy in patients who have these disorders. For this use to really occur, clinical trials will have to demonstrate treatments that alter these therapies in a meaningful way and the measures or modifications of them will need to meet the desiderata of techniques that can be used in practice.

A primary challenge for structural genomics is the automated functional characterization of protein structures. We have developed a sequence-independent method called S-BLEST (Structure-Based Local Environment Search Tool) for the annotation of previously uncharacterized protein structures. S-BLEST encodes the local environment of an amino acid as a vector of structural property values. It has been applied to all amino acids in a nonredundant database of protein structures to generate a searchable structural resource. Given a query amino acid from an experimentally determined or modeled structure, S-BLEST quickly identifies similar amino acid environments using a K-nearest neighbor search. In addition, the method gives an estimation of the statistical significance of each result. We validated S-BLEST on X-ray crystal structures from the ASTRAL 40 nonredundant dataset. We then applied it to 86 crystallographically determined proteins in the protein data bank (PDB) with unknown function and with no significant sequence neighbors in the PDB. S-BLEST was able to associate 20 proteins with at least one local structural neighbor and identify the amino acid environments that are most similar between those neighbors., (Proteins 2005. 2005 Wiley-Liss, Inc.)

Objective: In a cross-sectional study, we previously identified 2 potentially modifiable risk factors for adverse outcomes in systemic lupus erythematosus (SLE): self-efficacy and social support. The goal of this study was to evaluate in a randomized controlled trial a theory-based intervention to improve patient self-efficacy and partner support to manage SLE., Methods: Patients with SLE ages 18 years and older who met the American College of Rheumatology criteria and were able to identify a partner (spouse or family member) were recruited from 2 academic medical centers and randomized into an experimental group or a control group. Patients in the experimental group and their partners received an intervention designed to enhance self-efficacy, couples communication about lupus, social support, and problem solving, in the form of a 1-hour session with a nurse educator followed by monthly telephone counseling for 6 months. Patients in the control group and their partners received an attention placebo, including a 45-minute video presentation about lupus, and monthly telephone calls. Measures of physical and mental health status, disease activity, and psychosocial factors were collected at baseline, 6 months, and 12 months. The effect of the intervention on physical and mental health and disease activity at 6 and at 12 months was modeled with linear regression and adjusted for baseline health status, disease activity, sociodemographic factors, treatment change, and psychosocial factors., Results: One hundred twenty-two patients (plus their partners) were enrolled and randomized as follows: 64 to the experimental intervention and 58 to the attention control group. The participants were predominantly white, approximately half were college educated, and the groups were balanced for sociodemographic factors. At 6 months, significantly higher scores for couples communication (P = 0.01) and problem-focused coping (P = 0.03) were seen in the experimental group compared with the control group. At 12 months (6 months after the intervention ended), social support was higher (4.4 versus 4.1; P = 0.03), self-efficacy was higher (7.2 versus 6.2; P = 0.02), couples communication was higher (3.5 versus 3.1; P = 0.03), and fatigue was lower (5.1 versus 6.3; P = 0.02) in the experimental group compared with the control group. Global mental health status at 12 months, as measured by the Short Form 36 survey, was 69 points in the experimental group compared with 58 points in the control group (P = 0.04). In multivariate models, adjusting for baseline covariates, scores for couple communication (P = 0.01) were significantly higher at 6 months, and scores for self-efficacy (P = 0.004) and global mental health status (P = 0.03) were significantly higher at 12 months in the experimental group compared with the control group, and the mean score for global physical function was higher by 7 points, which was a clinically meaningful change (P = 0.2). The mean score for fatigue was also significantly lower in the experimental group than in the control group (P = 0.05). SLE disease activity was unchanged by this intervention., Conclusion: This randomized, controlled trial of a theory-based educational intervention in SLE demonstrated significantly higher scores for couple communication, self-efficacy, and mental health status, and lower fatigue scores in the experimental group compared with the control group. Because couple communication and self-efficacy appear to be modifiable risk factors, they may also be potential targets in more disadvantaged populations.

Objective: To study the prevalence of chondromalacia patella among college students and the correlation with sports injury., Methods: 354 students from gymnastic department and 429 from nongymnastic department with knee joint pain were selected. 184 students from gymnastic department and 342 from nongymnastic department were checked randomly by a surgeon. 77 patients (37 males, 40 females) from gymnastic department and 119 patients (62 males, 57 females) from nongymnastic department were diagnosed as chondromalacia patellae. The amount of exercise and the occurrence of sports injury were investigated in each student. All data were analyzed with SPSS 10.0 statistical software., Results: The prevalence of chondromalacia patella was 20.1% in female students and 11.6% in male students from gymnastic department, and 5.61% in female students and 4.92% in male students from nongymnastic department. The amount of exercise and the occurrence of sports injury to the knee joint in students from gymnastic department were greater than those from nongymnastic department., Conclusions: In both female and male students, the prevalence of chondromalacia patella is higher in gymnastic department than nongymnastic department. Sports injury is an important cause of chondromalacia patella.

Human T-lymphotropic virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia. The HTLV-1 transactivator, Tax, is implicated as the viral oncoprotein. Naïve cells expressing Tax for the first time develop severe cell cycle abnormalities that include increased DNA synthesis, mitotic arrest, appearance of convoluted nuclei with decondensed DNA, and formation of multinucleated cells. Here we report that Tax causes a drastic reduction in Pds1p/securin and Clb2p/cyclin B levels in yeast, rodent, and human cells and a loss of cell viability. With a temperature-sensitive mutant of the CDC23 subunit of the anaphase-promoting complex (APC), cdc23(ts); a temperature-sensitive mutant of cdc20; and a cdh1-null mutant, we show that the diminution of Pds1p and Clb2p brought on by Tax is mediated via the Cdc20p-associated anaphase-promoting complex, APC(Cdc20p). This loss of Pds1p/securin and Clb2p/cyclin B1 occurred before cellular entry into mitosis, caused a G(2)/M cell cycle block, and was accompanied by severe chromosome aneuploidy in both Saccharomyces cerevisiae cells and human diploid fibroblasts. Our results support the notion that Tax aberrantly targets and activates APC(Cdc20p), leading to unscheduled degradation of Pds1p/securin and Clb2p/cyclin B1, a delay or failure in mitotic entry and progression, and faulty chromosome transmission. The chromosomal instability resulting from a Tax-induced deficiency in securin and cyclin B1 provides an explanation for the highly aneuploid nature of adult T-cell leukemia cells.

We studied whether several modifiable factors were associated with the risk of total hip replacement due to hip osteoarthritis among women.We identified 568 women from the Nurses' Health Study who reported total hip replacement due to primary hip osteoarthritis on questionnaires from 1990 to 1996, using a validated algorithm. The relation of potential risk factors, such as age, body mass index, physical activity, smoking, alcohol intake, and hormone use, to hip replacement was assessed using pooled logistic regression models. Higher body mass index was associated with an increased risk of hip replacement due to osteoarthritis (P for trend = 0.0001). Compared with women in the lowest category of body mass index (<22 kg/m(2)), those in the highest category of body mass index (> or =35 kg/m(2)) had a twofold increased risk (95% confidence interval [CI]: 1.4 to 2.8), whereas those in the highest category of body mass index at age 18 years had more than a fivefold increased risk (95% CI: 2.5 to 10.7). Age also had a positive association; women aged > or =70 years were nine times more likely to have hip replacement than those aged <55 years (95% CI: 5.4 to 13.9). Recreational physical activity, smoking, alcohol use, and postmenopausal hormone use were not associated with an increased risk of hip replacement. In the Nurses' Health Study, higher body mass index and older age significantly increased the risk of total hip replacement due to osteoarthritis. Part of this risk appeared to be established early in life.

Neuropsychiatric systemic lupus erythematosus (NPSLE) involves a wide range of peripheral and central nervous system manifestations. These manifestations are complex and their pathophysiology is poorly understood. NPSLE can precede the onset of lupus or occur at any time during its course. The American College of Rheumatology (ACR) developed a standardized nomenclature system providing case definitions for the neuropsychiatric syndromes of systemic lupus erythematosus (SLE) to facilitate and enhance patient classification and reporting requirements in clinical research. Estimates of NPSLE prevalence have ranged widely and most are based on research conducted before the introduction of ACR case definitions. This paper reviews the early experience with the ACR nomenclature use and possible future directions for its improvement. The identification and categorization of the major neuropsychiatric syndromes in SLE using ACR case definitions seems to be adequate, however the mildest and most subjective of the syndromes are the most problematic. Even if the definitions in their present form might have drawbacks the only way forward is further use of ACR nomenclature, pooling data from different populations, and collection of experience as a basis for improvement. The acquisition of normative data for ethnic, age and sex stratification would extend their usefulness.

The goal of this work was to develop an economical way of tracking disease activity for large groups of systemic lupus erythematosus (SLE) patients in clinical studies. A Systemic Lupus Activity Questionnaire (SLAQ) was developed to screen for possible disease activity using items from the Systemic Lupus Activity Measure (SLAM) and tested for its measurement properties. The SLAQ was completed by 93 SLE patients just prior to a scheduled visit. At the visit, a rheumatologist, blinded to SLAQ results, examined the subject and completed a SLAM. Associations among SLAQ, and SLAM (omitting laboratory items) and between individual items from each instrument were assessed with Pearson correlations. Correlations between pairs of instruments were compared using Student's t-tests. The mean score across all 24 SLAQ items was 11.5 (range 0-33); mean SLAM without labs was 3.0 (range 0-13). The SLAQ had a moderately high correlation with SLAM-nolab (r = 0.62, P < 0.0001). Correlations between patient-clinician matched pairs of items ranged from r = 0.06 to 0.71. Positive predictive values for the SLAQ ranged from 56 to 89% for detecting clinically significant disease activity. In studies of SLE, symptoms suggesting disease can be screened by self-report using the SLAQ and then verified by further evaluation.

Objective: Non-steroidal anti-inflammatory drugs (NSAIDs) are used in nearly every patient with rheumatoid arthritis (RA) as part of a comprehensive management programme, but their use can be associated with side-effects. Low dose corticosteroid (<10 mg/day prednisone) in the treatment of RA is controversial. Although it is effective and possibly disease modifying, concerns exist about potential adverse events. We assessed costs and health effects of corticosteroids compared with NSAIDs and cyclo-oxgenase-2 (COX-2) inhibitors., Methods: Markov (state transition) models were used to simulate a cohort of RA patients taking disease-modifying antirheumatic drugs and either corticosteroids or NSAIDs. The regimens were assumed to be equally effective for the control of RA. Data on incidence, costs and consequences of adverse events from corticosteroids and from NSAIDs were taken from the literature. Costs were measured in 1999 US dollars; health effects expressed as quality-adjusted life years (QALYs). Sensitivity analyses were performed including best-case scenarios (0.5x adverse event rate) and worst-case scenarios (1.5x adverse event rate)., Results: In the base-case analysis corticosteroids were superior to NSAIDs. The sensitivity analyses of adverse event rate, using best-case and worst-case scenarios, and age showed that the results were sensitive to each combination of adverse event rate and age. In contrast, the sensitivity analyses of costs and utilities were robust. Using misoprostol or omeprazole prophylaxis with NSAIDs would make corticosteroids cost-effective. Compared with NSAIDs with COX-2 specific inhibition, corticosteroids were still cost-effective., Conclusion: Corticosteroids are more cost-effective than NSAIDs and COX-2 inhibitors in the long-term treatment of RA.

Accelerated atherosclerotic vascular disease (ASVD) is a major cause of death in systemic lupus erythematosus (SLE). Although many authorities are calling for aggressive assessment and management of cardiac risk factors in patients with SLE, both theoretical and practical barriers to this approach exist. It seems that SLE and/or its treatment are themselves strong risk factors for the development of ASVD and it is unclear how much this risk can be decreased by the control of traditional risk factors. Studies from several centers have shown that suboptimal risk factor management and barriers to acceptance of these measures must also be studied further.

Background: The German health care system, renowned for its unrestricted access, high quality care, and comprehensive coverage, is challenged by increasing health care costs. This has been attributed partly to inefficiencies in the in-patient sector, but has been studied little. Attempts at quality improvement need to relate costs to outcomes. Until now, there has been no standardized methodology to evaluate the appropriateness of hospital care., Objective: To develop and evaluate the metric properties of a method to assess inappropriate hospital care in Germany based on a widely used measure, the Appropriateness Evaluation Protocol (AEP)., Methods: The original AEP was translated and adapted to reflect differences in the provision of health care in Germany. Psychometric testing was performed in a stratified sample of all patients admitted to the Departments of Medicine and Surgery of a 400-bed teaching hospital during 1 year. Three board-certified physicians participated in each department to evaluate intra-rater reliability, while two additional independent physicians judged inter-rater reliability., Results: Inter-rater agreement for the evaluation of hospital days among surgical patients was 84% (80-87%), with an average kappa value of 0.58 (0.48-0.68). Corresponding figures for patients in medicine were 76% (73-80%) with a K value of 0.42 (0.34-0.42). Inter-rater agreement for hospital admissions and K was 74% (62-86%) and 0.44 (0.21-0.67) in surgery, and 92% (85-100%) and 0.31 (0-0.80) in medicine, respectively. Thirty-three per cent of all admissions and 28% of consecutive hospital days were judged inappropriate in surgery; among medicine patients, reviewers found 6% of admissions and 33% of hospital days inappropriate. Time since admission was the strongest predictor of inappropriate hospital use adjusted for length of stay, comorbidity, age, and gender.

A 21-year-old woman who has been suspected of mitochondrial cytopathy, but negative for common mitochondrial DNA (mtDNA) point mutations and deletions, was screened for unknown mutations in the entire mitochondrial genome by temporal temperature gradient gel electrophoresis (TTGE). Her asymptomatic mother's blood DNA was also analyzed and used as a reference. Two tRNA regions showing different TTGE patterns between the proband and her mother were sequenced. Two novel mutations, G15995A in tRNA(pro) and A8326G in tRNA(lys), were revealed. These mutations are present in heteroplasmic states. They both occurred at a nucleotide position that is highly conserved throughout evolution. This patient is also a compound heterozygote for the cystic fibrosis (CF) mutations, DeltaF508 and R347P. The phenotype for R347P has been associated with mild disease. Due to the mild features of the R347P mutation in the CF transmembrane conductance regulator (CFTR) gene and the heterogeneous clinical presentation of the mtDNA disease, the patient was not definitively diagnosed until age 21. This case underscores the importance of a complete mutational analysis of the entire mitochondrial genome when a patient suspected of mitochondrial disorder is negative for common mtDNA mutations., (Copyright 2002 Wiley-Liss, Inc.)

Background: Definitive molecular diagnosis of mitochondrial disorders has been greatly hindered by the tremendous clinical and genetic heterogeneity, the heteroplasmic condition of pathogenic mutations, and the presence of numerous homoplasmic mitochondrial DNA (mtDNA) variations with unknown significance. We used temporal temperature gradient gel electrophoresis (TTGE) to detect heteroplasmic mutations from homoplasmic variations in the whole mitochondrial genome., Methods: We screened 179 unrelated patients by TTGE with use of 32 overlapping primer pairs. Mutations were identified by direct sequencing of the PCR products and confirmed by PCR with allele-specific oligonucleotide or restriction fragment length polymorphism analysis., Results: We detected 71 heteroplasmic and 647 homoplasmic banding patterns. Sequencing of the heteroplasmic fragments identified 68 distinct novel mutations and 132 reported sequence variations and mutations; most of them occurred only once. The deleterious nature of some of the novel mutations was established by analyzing the asymptomatic family members and the biochemical and molecular characteristics of the mutation. When the number of mutations was normalized to the size of the region, the occurrence of mutations was 2.4 times more frequent in the tRNA genes than in the mRNA (protein coding) regions., Conclusions: Screening by TTGE detects low proportions of mutant mtDNA and distinguishes heteroplasmic from homoplasmic variations. Results from comprehensive molecular analysis should be followed up with clinical correlation to establish a guideline for complete mutational analysis of the entire mitochondrial genome and to facilitate the diagnosis of mitochondrial disorders.

In the United States, systemic lupus erythematosus (SLE) disproportionately affects African Americans. It has become a chronic disease with long-term morbidity including chronic renal disease, osteoporosis, cataracts, psychosocial impairment, and importantly, atherosclerotic vascular disease (ASVD). The latter (myocardial infarction, angina, peripheral vascular disease and stroke) are strikingly accelerated, occurring in subjects who are predominantly premenopausal women at an age when ASVD is rare or unusual. Although much is known about the biology, risk factors, and the prevention of atherosclerosis in normal individuals, little work has been done in SLE. In fact, ASVD in people with SLE may be a different disease. Approximately 1.5% of SLE patients per year will have a myocardial infarction or equivalent; about 0.5% of SLE patients per year will have a stroke. The risk factors for ASVD in SLE are based on small, retrospective, single center studies. These suggest that the risk factors known for the general population (i.e., smoking, obesity, sedentary lifestyle, high LDL cholesterol, etc.) are also observed in SLE. The best study of risk factors shows that even accounting for the known factors, SLE and/or its treatment (glucocorticoids) is by far the most important. Our current management of cardiovascular risk factors in SLE patients with ASVD is substandard and our adherence to national guidelines for prevention is substandard. It is not known whether improving either will prevent these disastrous outcomes. Very little is known about the risk factors in African Americans with SLE, although there is data to suggest that they may not be identical to those seen in Caucasian populations. The study of the best and most effective means to prevent ASVD in SLE and in African Americans with SLE and in African Americans with SLE should be a major priority.

Objective: To evaluate the relationship between patient expectations of total joint arthroplasty (TJA) and health related quality of life plus satisfaction 6 months after surgery. Methods. This prospective cohort study included patients undergoing primary total hip (THA) and knee arthroplasty (TKA). Patients were evaluated with self-report questionnaires prior to surgery and 6 months post-surgery. Medical Outcomes Study Short Form 36 (SF-36), the Western Ontario McMaster Universities Osteoarthritis Index (WOMAC), and a satisfaction scale were used to evaluate outcomes at final followup. Multivariate regression models were used to evaluate the impact of expectations on outcomes., Results: There were 102 patients with THA and 89 with TKA. Mean age was 66 years. All patients achieved significant improvements in their WOMAC and SF-36 scores following surgery. Patient expectations regarding surgery were not associated with their age, gender, index joint of surgery, marital status, or race. Expectations were not correlated with pre-operative functional health status. Expectation of complete pain relief after surgery was an independent predictor of better physical function and improvement in level of pain at 6 months post-surgery. Expectation of low risk of complications from TJA was an independent predictor of greater satisfaction., Conclusions: Patient expectations were important independent predictors of improved functional outcomes and satisfaction following TJA. Greater understanding of the relationship between expectations and outcomes may improve the process of care and outcomes of TJA.

Human T-lymphotropic virus type 1 (HTLV-1) Tax exerts pleiotropic effects on multiple cellular regulatory processes to bring about NF-kappaB activation, aberrant cell cycle progression, and cell transformation. Here we report that Tax stimulates cellular G(1)/S entry but blocks mitosis. Tax expression in naive cells transduced with a retroviral vector, pBabe-Tax, leads to a significant increase in the number of cells in the S phase, with an accompanying rise in the population of cells with a DNA content of 4N or more. In all cell types tested, including BHK-21, mouse NIH 3T3, and human diploid fibroblast WI-38, Tax causes an uncoupling of DNA synthesis from cell division, resulting in the formation of multinucleated giant cells and cells with decondensed, highly convoluted and lobulated nuclei that are reminiscent of the large lymphocytes with cleaved or cerebriform nuclei seen in HTLV-1-positive individuals. This contrasts with the Tax-transformed cell lines, PX1 (fibroblast) and MT4 (lymphocyte), which produce Tax at high levels, but without the accompanying late-stage cell cycle abnormalities. PX1 and MT4 may have been selected to harbor somatic mutations that allow a bypass of the Tax-induced block in mitosis.

Objective: Health status and disease activity in patients with systemic lupus erythematosus (SLE) and other chronic diseases are strongly associated with social support, which suggests that enhanced social support in medical care might improve SLE outcome. There has been little or no study on identifying patients for whom social support would be most beneficial. It would allow practitioners to enable social support more effectively as a complement to disease management., Methods: A retrospective cohort (200 patients with SLE from 5 centers), balanced by race and insurance status, was studied in a cross sectional design. Demographic, clinical, socioeconomic, and psychosocial factors and disease outcomes [Systemic Lupus Activity Measure (SLAM), Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR), SF-36] were measured. Using multivariate linear regression and ANOVA (outcome = SF-36 physical function, mental health), we examined the interaction between social support and patients' characteristics, including race, age, income, occupation, insurance, employment, education, and social network, and characteristics of the disease itself such as disease activity (SLAM) at diagnosis, damage (SLICC/ACR) at diagnosis, and comorbidity., Results: In multivariate models, higher social support was significantly associated (p < 0.05) with better physical function when respondents were white, had income above poverty level, had Medicare or private insurance (vs Medicaid or no insurance), and had low disease activity at diagnosis. Social support was associated with better mental health, although there was no significant interaction between social support and other predictors of mental health., Conclusion: The data suggest that social support is beneficial for mental health for all groups, but has the greatest opportunity for influence among those already possessing social, economic, and health advantages.

Background: To determine the age-specific prevalence of Lyme disease and whether preventive behaviors on Nantucket Island correlate with Lyme disease, we surveyed island residents., Methods: A survey with questions on Lyme disease symptoms, history, and preventive behaviors was mailed to all residents. Respondents were stratified by likelihood of having had Lyme disease. A subsample was selected for examination, and then classified according to the Lyme disease national surveillance case definition., Results: The overall lifetime prevalence of Lyme disease for Nantucket residents was 15% (CI, 10%-19.8%): 19% among females, and 11% among males. The prevalence was highest among age groups 0-16 and 30-49 years. Overall, 86% of the population practiced at least one behavior. The most frequently reported preventive behavior was checking oneself for ticks (80%), followed by wearing protective clothing (53%), avoiding tick areas (34%), and using tick repellent (11%). Younger individuals practiced fewer preventive behaviors than older individuals (p=0.001). Although males reported greater tick exposure than females, females uniformly practiced preventive behaviors more frequently (p=0.001). The practice of preventive behaviors was not associated with a history of Lyme disease, but finding more than 5 ticks per year on oneself was (p=0.001)., Conclusion: Lyme disease is highly prevalent on Nantucket Island. Young people are particularly at risk and health education should emphasize preventive behaviors less frequently practiced: using tick repellent, avoiding tick areas, and wearing protective clothing.

Background: Animal studies and uncontrolled case series in humans have suggested a possible association between breast implant exposure and monoclonal gammopathy., Objective: To assess whether there is an increased risk of monoclonal gammopathy in women with silicone breast implants, we conducted a retrospective study of women exposed to breast implants and matched nonexposed women nested within a prospective cohort study (the Nurses' Health Study)., Methods: We used serum protein electrophoresis and immunoglobulin subtype by immunofixation to test 288 women exposed to breast implants and 288 age-matched, nonexposed women who previously had provided a blood sample (1989-1990) for monoclonal proteins., Results: Among the women exposed to breast implants, 5 had monoclonal gammopathy of undetermined significance (MGUS) compared with 4 women among those not exposed (odds ratio, 1.25; 95% confidence interval, 0.27-6.39). The distribution of isotypes was similar across exposure groups. The exposed women with MGUS tended to be older than the nonexposed women (mean age, 60.4 years vs 52.5 years, respectively; P =.03). None of the 9 women with MGUS had reported multiple myeloma or other hematologic malignancies up through 1996., Conclusions: We find little evidence to support a substantial increased risk of MGUS in women exposed to breast implants. Larger studies are needed to determine if a more modest relationship exists.

Background: Vaccination against Lyme disease appears to be safe and effective; however, the cost per quality-adjusted life-year (QALY) gained with vaccination is unknown., Methods: We developed a decision-analytic model to evaluate the cost-effectiveness of vaccination compared with no vaccination in individuals living in endemic areas of Lyme disease. Our analysis encompassed a 10-year time horizon including a 2-year vaccination schedule with an additional year of vaccine effectiveness. The costs and probabilities of vaccination risk, compliance and efficacy, and Lyme disease clinical sequelae and treatment were estimated from the literature. Health-related quality-of-life weights of the various clinical sequelae of Lyme disease infection were obtained from a sample of 105 residents from Nantucket Island, Massachusetts., Results: Vaccinating 10 000 residents living in endemic areas with a probability of Lyme disease per season of 0.01 averted 202 cases of Lyme disease during a 10-year period. The additional cost per QALY gained compared with no vaccination was $62 300. Vaccination cost $12 600/QALY gained for endemic areas with an attack rate of 2.5% per season, and $145 200/QALY gained for an attack rate of 0.5%. Vaccinating individuals over an accelerated 2-month vaccination schedule improved the cost-effectiveness to $53 700/QALY gained. If a yearly booster shot is required for persisting efficacy, the marginal cost-effectiveness ratio increases to $72 700/QALY. The cost-effectiveness of vaccination was most sensitive to the Lyme disease treatment efficacy and assumptions about the persistence of vaccination effect., Conclusion: Vaccination against Lyme disease appears only to be economically attractive for individuals who have a seasonal probability of Borrelia burgdorferi infection of greater than 1%.

Previous studies suggest that concurrent Lyme disease and babesiosis produce a more sever illness than either disease alone. The majority of babesiosis infections, however, are subclinical. Our objective was to characterize on the basis of a total-population survey of Nantucket Island, Massachusetts, whether coexposure to Lyme disease and babesiosis causes more severe illness or poorer long-term outcomes than Lyme disease alone. In this retrospective cohort study, residents indicating a history of Lyme disease were compared with randomly selected population controls on a standardized medical history, blinded physical examination, and serological studies for Borrelia burgdorferi and Babesia microti. Serological evidence of exposure to babesiosis was not associated with increased severity of acute Lyme disease. The groups did not differ with regard to the prevalence of constitutional, musculoskeletal, or neurological symptoms a mean of 6 years after acute Lyme disease. Prior Lyme disease and serological exposure to B. microti are not associated with poorer long-term outcomes or more persistent symptoms Lyme disease alone.

We describe a consecutive series of patients with hydroxychloroquine (HCQ) retinopathy. Their clinical features illustrate that with normal renal function there is no threshold for total dosage for HCQ toxicity; that color vision testing is important; that almost all patients complain of altered central vision as their first symptom; and that a normal optic fundus does not exclude the diagnosis. Finally, HCQ retinopathy may progress even when the agent is stopped.

Objectives: Although widely used and reported in research for the evaluation of groups, measures of health status and health-related quality of life have had little application in clinical practice for the assessment of individual patients. One of the principal barriers is the demonstration that these measures add clinically significant information to measures of function or symptoms alone. Here, we review the methods for evaluation of construct validity in longitudinal studies and make recommendations for nomenclature, reporting of study results, and future research agenda., Methods: Analytical review., Results: The terms "sensitivity" and "responsiveness" have been used interchangeably, and there are few studies that evaluate the extent to which health status or health-related quality-of life measures capture clinically important changes ("responsiveness"). Current methods of evaluating responsiveness are not standardized or evaluated. Approaches for the assessment of a clinically significant or meaningful change are described; rather than normative information, however, standardized transition questions are proposed. They would be reported routinely and as separate axes of description to capture individual perceptions., Conclusions: Research in methods to assess the subject's evaluation of the importance and magnitude of a measured change are critical if health status and health-related quality-of-life measures are to have an impact on patient care.

Objective: To determine whether longterm lead accumulation is associated with hyperuricemia and gouty arthritis among middle aged and elderly men., Methods: In a retrospective cohort study, 777 male participants were evaluated between August 1991 and October 1996 in the Department of Veterans Affairs Normative Aging Study, a 35 year longitudinal study of aging. We examined the development of gout and an increased uric acid level in relation to lead, adjusting for other known risk factors. Lead levels were measured in blood and by K x-ray fluorescence (K-XRF) technique in tibial (cortical) and patellar (trabecular) bone., Results: Blood lead levels in this mostly Caucasian (97%) population were low (mean 5.9 microg/dl, SD 3.5). Bone lead levels were comparable to those described in other general populations. In a multivariate analysis adjusting for the risk factors, age, body mass index, diastolic blood pressure, alcohol intake, and serum creatinine level, there was a positive association between patellar bone lead and uric acid levels (p = 0.02). Of 777 participants, 52 (6.7%) had developed gouty arthritis. In logistic regression of similar covariates, body mass index (p < 0.0001) and serum creatinine level (p = 0.005) were the strongest determinants of gout; neither bone nor blood lead levels predicted gout in this cohort., Conclusion: The longterm accumulation of lead is associated with an increased uric acid level in middle aged and elderly men. However, this study shows no association between lead and gouty arthritis at the levels arising from community exposure.

Objective: New scales for the clinical assessment of patients with systemic lupus erythematosus (SLE) are valid and reliable, and quantitate disease activity. We assessed the responsiveness to change of 2 widely used standardized multi-item lupus activity measures, the revised Systemic Lupus Activity Measure (SLAM-R) and the Systemic Lupus Erythematosus Disease Activity Index (SLEDAI), and their ability to detect clinically relevant changes., Methods: Ninety-six (96) patients with definite SLE participated in this study. The group mean age was 45.0 (13.7) years, 91% were female, and the mean disease duration was 14.9 (7.5) years. Sociodemographic information, lupus activity (SLAM-R, SLEDAI), and damage were recorded at baseline. At each of the 5 monthly followup visits, the activity measures were repeated and a transition scale asked the physician if their patient's lupus activity had changed. Five different methods were used to compare the responsiveness of the activity measures studied: 1. the effect size; 2. the standardized response mean; 3. the control standardized response mean; 4. the area under the curve of a receiver operating characteristic (ROC) curve; and 5. a new multiple response modeling approach., Results: Both SLAM-R and SLEDAI are responsive. SLAM-R is consistently, although moderately, more responsive than SLEDAI. All 5 methods of evaluating responsiveness yielded a consistent ranking of disease activity measures., Conclusion: SLAM-R and SLEDAI are responsive measures of lupus activity. SLAM-R appears to be more responsive than SLEDAI.

Objective: To determine the prevalence and socioeconomic and clinical predictors of early organ damage in a cohort of patients with systemic lupus erythematosus (SLE) of 2-7 years' duration randomly sampled at 5 centers and balanced by socioeconomic status and race., Methods: The Systemic Lupus International Collaborating Clinics/American College of Rheumatology (SLICC/ACR) Damage Index was measured in 200 patients who met the ACR criteria for SLE with a mean disease duration of 3.8 years. The SLICC/ACR scores for each organ system and the prevalence of damage within organ systems were assessed. Logistic regression analyses evaluated the simultaneous effects of age at diagnosis, disease duration, disease activity, and sociodemographic factors., Results: Sixty-one percent of the patients had damage within 7 years of onset (mean 3.8 yrs). Neuropsychiatric (20.5%) and musculoskeletal (18.5%) systems were the most frequently involved, followed by renal (15.5%) and skin (12.5%) systems, all with median SLICC/ACR organ system scores of 1. In multivariate models, African-American race was associated with skin damage but not with damage in other specific organ systems. Socioeconomic status was not associated with organ system damage. Older age at diagnosis correlated with cardiovascular, musculoskeletal, gastrointestinal, ocular, and pulmonary damage. Clinical factors such as longer disease duration correlated with higher renal and cardiovascular damage, and greater disease activity at diagnosis of SLE correlated with greater renal, musculoskeletal, and pulmonary damage., Conclusion: There is evidence of organ system damage in SLE within a mean of 3.8 years after onset. We found little evidence for differences in early organ damage according to race or socioeconomic status. Damage to most organ systems was related to age at diagnosis of SLE and clinical factors such as disease duration.