Evaluation of an alternative in vitro test battery for detecting reproductive toxicants.

The application of alternative methods in developmental and reproductive toxicology is challenging in view of the complexity of mechanisms involved. A battery of complementary test systems may provide a better prediction of developmental and reproductive toxicity than single assays. We tested twelve compounds with varying mechanisms of toxic action in an assay battery including 24 CALUX transcriptional activation assays, mouse cardiac embryonic stem cell test, ReProGlo assay, zebrafish embryotoxicity assay, and two CYP17 and two CYP19 activity assays. The battery correctly detected 11/12 compounds tested, with one false negative occurring, which could be explained by the absence of the specific mechanism of action of this compound in the battery. Toxicokinetic modeling revealed that toxic concentrations were in the range expected from in vivo reproductive toxicity data. This study illustrates added value of combining assays that contain complementary biological processes and mechanisms, increasing predictive value of the battery over individual assays.

Experts' beliefs on physiotherapy for patients with ankylosing spondylitis and assessment of their knowledge on published evidence in the field. Results of a questionnaire among international ASAS members.

AIM: The aim of this study was to assess both the opinion of an international group of experts about the place and importance of physiotherapy in the management of ankylosing spondylitis (AS) as well as the awareness of the responders about scientific evidence on efficacy and cost-effectiveness of physiotherapy in AS. METHODS: An e-mail questionnaire ''Experts' Beliefs on Physiotherapy for Patients with Ankylosing Spondylitis'' has been sent to all 71 international ASsessment of Ankylosing Spondylitis (ASAS) members. Completion of the twenty-eight-item questionnaire was done through the ASAS website (www.ASAS-group.org). RESULTS: The number of responders was 53 (response rate 73%). Altogether 94% of the responders regard themselves as experts in the field of clinical care for AS patients. There is almost unanimous (86-92%) consensus on the efficacy of physiotherapy (widely defined, i.e. as physical therapy-including exercises, application of physical modalities and spa-therapy) for patients with axial and peripheral joint manifestations of AS. Physiotherapy is considered to be indicated for both early AS (less than 2 years after diagnosis) (88%) and AS of longer duration (2 to 10 years) (94%), implying that this non-pharmaceutical intervention should be made available for or should be prescribed to AS patients. Also daily exercises at home are considered indicated for both early (less than 2 years after diagnosis) AS (90%) and AS of longer duration of disease (90%). High-level evidence (Cochrane reviews or publications of one or more randomized controlled clinical trials) favoring efficacy of physiotherapy was considered available by 33% of the participants, whereas 43% replied ''no'' and 24% did not know. Finally, excluding the costs of the intervention, 39% of the participants reported that Spa-therapy might reduce health care costs as usage of NSAIDs, physician visits and ability to work or sick leave, whereas 26% said ''no'' and 35% did not know. CONCLUSIONS: The international ASAS experts hold a favorable opinion on the efficacy of physiotherapy in AS, including group exercises and spa therapy, almost irrespective of disease duration and type of articular involvement (axial/peripheral). Awareness of published evidence on physiotherapy in AS is unsatisfactory.

Assessment of disability with the World Health Organisation Disability Assessment Schedule II in patients with ankylosing spondylitis.

OBJECTIVE: To investigate in ankylosing spondylitis (AS) whether the newly developed World Health Organisation Disability Assessment Schedule II (WHODAS II) is a useful instrument for measuring disability, to assess its responsiveness in relation to other traditional disease specific instruments, and to identify factors that are associated with both short term and long term scores on the WHODAS II. METHODS: Patients with AS from a randomised controlled trial assessing the efficacy of spa treatment (n=117) and from a five year longitudinal observational study (n=97) participated. The patients completed several questionnaires, including the WHODAS II. After a three week course of spa treatment, 31 patients again completed all questionnaires to assess responsiveness. To determine to what degree the WHODAS II reflects some AS oriented measures on disease activity, functioning, and quality of life, correlation coefficients between the WHODAS II and these other questionnaires were calculated. Responsiveness was calculated by the effect size (ES) and standardised response mean (SRM). Linear regression analysis was performed to explore which factors might be associated with short term changes on the WHODAS II and to investigate (in the observational study) which factors of WHODAS II might predict disability five years later. RESULTS: Mean score on the WHODAS II was 23.9 (SD 15.5 (range 0.0-76.1)). Scores on the WHODAS II were significantly correlated with all disease specific questionnaires measured (all p<0.001). The WHODAS II showed a comparable short term responsiveness score (SRM 0.41; ES 0.39). In regression analysis these short term changes on the WHODAS II were significantly associated with changes in functioning (beta coefficient 4.25, 95% confidence interval (95% CI) 1.24 to 7.26, p=0.007). In the observational study, disease activity (beta coefficient 0.35, 95% CI 0.17 to 0.53, p<0.000) as well as functioning (beta coefficient 0.23, 95% CI 0.09 to 0.38, p=0.002) seemed to significantly predict disability (WHODAS II) after five years. CONCLUSION: The WHODAS II is a useful instrument for measuring disability in AS in that it accurately reflects disease specific instruments and that it shows similar responsiveness scores. In AS, a short term change on the WHODAS II is associated with a change in physical function. At the group level, disease activity and physical functioning may predict disability after five years.

A brief history of spa therapy.

Bathing in thermal water has an impressive history and continuing popularity. In this paper a brief overview of the use of water in medicine over the centuries is given.

Bone turnover, joint damage and bone mineral density in early rheumatoid arthritis treated with combination therapy including high-dose prednisolone.

OBJECTIVES: Exploration of bone metabolism changes at different levels of disease activity, both with and without oral corticosteroid therapy, and prediction of changes in joint damage and bone density from the observed changes in markers of bone turnover. METHODS: Data analysis from a randomized clinical trial with 155 rheumatoid arthritis (RA) patients; median age 50 yr, early and active disease (diagnosis < 2 yr); one group treated with a combination of sulphasalazine (SSZ; 2000 mg/day), methotrexate (MTX; 7.5 mg/week) and prednisolone (initially 60 mg/day, tapered in six weekly steps to 7.5 mg/day), the other group with SSZ alone. Prednisolone and MTX were tapered and stopped after weeks 28 and 40, respectively, while SSZ was continued. Urine and serum samples were collected at baseline and weeks 16, 28, 40 and 56. Measurements of urinary pyridinoline (PYD) and deoxypyridinoline (DPD) and serum alkaline phosphatase (tAP) and osteocalcin (OC) were performed, as well as standard clinimetry and bone densitometry. RESULTS: Over time and in both treatment groups, bone formation and bone resorption markers showed a pattern similar to erythrocyte sedimentation rate (ESR): a significant decrease compared with baseline and a larger decrease with combined treatment at weeks 16 and 28. PYD excretion, tAP, OC, and joint damage scores were significantly lower in the combined treatment group. Changes in bone density (of spine and hips) did not significantly differ between treatment groups. Mainly cumulative ESR explained progression of joint damage. CONCLUSIONS: Prednisolone and disease-modifying anti-rheumatic drug therapy in patients with early and active RA are both independently associated with decreased levels of urinary excretion of bone collagen resorption markers PYD and DPD. Markers of bone formation and resorption closely followed changes in ESR in both treatment groups. Reduced bone resorption together with reduced bone formation-initially at a somewhat faster pace-resulted in less bone turnover and explain the observed (non-significant and partially reversible) extra bone loss in the lumbar spine associated with prednisolone (combined treatment).

Combined spa-exercise therapy is effective in patients with ankylosing spondylitis: a randomized controlled trial.

OBJECTIVE: To determine the efficacy of combined spa-exercise therapy in addition to standard treatment with drugs and weekly group physical therapy in patients with ankylosing spondylitis (AS). METHODS: A total of 120 Dutch outpatients with AS were randomly allocated into 3 groups of 40 patients each. Group 1 (mean age 48 +/- 10 years; male:female ratio 25:15) was treated in a spa resort in Bad Hofgastein, Austria; group 2 (mean age 49 +/- 9 years; male:female ratio 28:12) in a spa resort in Arcen, The Netherlands. The control group (mean age 48 +/- 10 years; male:female ratio 34:6) stayed at home and continued their usual drug treatment and weekly group physical therapy during the intervention weeks. Standardized spa-exercise therapy of 3 weeks duration consisted of group physical exercises, walking, correction therapy (lying supine on a bed), hydrotherapy, sports, and visits to either the Gasteiner Heilstollen (Austria) or sauna (Netherlands). After spa-exercise therapy all patients followed weekly group physical therapy for another 37 weeks. Primary outcomes were functional ability, patient's global well-being, pain, and duration of morning stiffness, aggregated in a pooled index of change (PIC). RESULTS: Analysis of variance showed a statistically significant time-effect (P < 0.001) and time-by-treatment interaction (P = 0.004), indicating that the 3 groups differed over time with respect to the course of the PIC. Four weeks after start of spa-exercise therapy, the mean difference in PIC between group 1 and controls was 0.49 (95% confidence interval [CI] 0.16-0.82, P = 0.004) and between group 2 and controls was 0.46 (95% CI 0.15-0.78, P = 0.005). At 16 weeks, the difference between group 1 and controls was 0.63 (95% CI 0.23-1.02, P = 0.002) and between group 2 and controls was 0.34 (95% CI--0.05-0.73; P = 0.086). At 28 and 40 weeks, more improvement was found for group 1 compared with controls (P = 0.012 and P = 0.062, respectively) but not for group 2 compared with controls. CONCLUSION: In patients with AS, a 3-week course of combined spa-exercise therapy, in addition to drug treatment and weekly group physical therapy alone, provides beneficial effects. These beneficial effects may last for at least 40 weeks.

Patient utilities in fibromyalgia and the association with other outcome measures.

OBJECTIVE: To compare in patients with fibromyalgia (FM) utilities derived by rating scale and standard gamble methods; to gain insight into construct validity by relating utility values to other outcome measures; to assess the sensitivity to change of utilities. METHODS: A total of 73 patients with FM were randomized into one of 3 groups: low impact fitness training, biofeedback, or controls. At baseline and after 6 mo the Maastricht Utility Measurement Questionnaire was applied. By means of both the rating scale and standard gamble method patients were asked to value their own health status. Construct validity of patient utility measurements was evaluated by Spearman correlation and multiple regression of baseline values with pain, stiffness, patient's global assessment, Sickness Impact Profile (SIP), modified Health Assessment Questionnaire and Arthritis Impact Measurement Scale (AIMS). Sensitivity to change was assessed against changes in these outcomes. RESULTS: Rating scale utilities correlated significantly (p < 0.05) with patient's global assessment (rs = 0.53), pain (rs = -0.47), SIP (rs = -0.43), and with 9 of 11 dimensions of the AIMS (rs ranging from 0.23 to 0.62). Standard gamble utilities correlated significantly with mobility, pain, and arthritis impact of the AIMS scale (rs from 0.22 to 0.36) and with pain by visual analog scale (rs = -0.24) and patient's global assessment (rs = 0.32). Multiple regression analysis showed that patient's global assessment explained 41% (rating scale) and 10% (standard gamble) of total variance in baseline utilities. Also, 16% of the variance in change in rating scale utility values was explained by changes in patient's global assessment. In contrast, variance of changes in standard gamble utility values was not explained significantly by changes in other disease outcomes. CONCLUSION: Rating scale utilities correlated more strongly with disease outcome measures than standard gamble utilities. Also, construct validity for the rating scale was better than for the standard gamble. In FM, utility measurement is sensitive to the method chosen to elicit patient priorities.