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1.  ATP Induced Brain-Derived Neurotrophic Factor Expression and Release from Osteoarthritis Synovial Fibroblasts Is Mediated by Purinergic Receptor P2X4 
PLoS ONE  2012;7(5):e36693.
Brain-derived neurotrophic factor (BDNF), a neuromodulator involved in nociceptive hypersensitivity in the central nervous system, is also expressed in synoviocytes of osteoarthritis (OA) and rheumatoid arthritis (RA) patients. We investigated the role of P2 purinoreceptors in the induction of BDNF expression in synovial fibroblasts (SF) of OA and RA patients. Cultured SF from patients with symptomatic knee OA and RA were stimulated with purinoreceptor agonists ATP, ADP, or UTP. The expression of BDNF mRNA was measured by quantitative TaqMan PCR. BDNF release into cell culture supernatants was monitored by ELISA. P2X4 expression in synovial tissue was detected by immunohistochemistry. Endogenous P2X4 expression was decreased by siRNA transfection before ATP stimulation. Kinase pathways were blocked before ATP stimulation. BDNF mRNA expression levels in OASF were increased 2 h and 5 h after ATP stimulation. Mean BDNF levels in cell culture supernatants of unstimulated OASF and RASF were 19 (±9) and 67 (±49) pg/ml, respectively. BDNF levels in SF supernatants were only elevated 5 h after ATP stimulation. BDNF mRNA expression in OASF was induced both by P2X receptor agonists ATP and ADP, but not by UTP, an agonist of P2Y purinergic receptors. The ATP-induced BDNF mRNA expression in OASF was decreased by siRNA-mediated reduction of endogenous P2X4 levels compared to scrambled controls. Inhibition of p38, but not p44/42 signalling reduced the ATP-mediated BDNF mRNA induction. Here we show a functional role of the purinergic receptor P2X4 and p38 kinase in the ATP-induced expression and release of the neurotrophin BDNF in SF.
PMCID: PMC3360754  PMID: 22715356
2.  Spinal segmental stabilisation exercises for chronic low back pain: programme adherence and its influence on clinical outcome 
European Spine Journal  2009;18(12):1881-1891.
Exercise rehabilitation is one of the few evidence-based treatments for chronic non-specific low back pain (cLBP), but individual success is notoriously variable and may depend on the patient’s adherence to the prescribed exercise regime. This prospective study examined factors associated with adherence and the relationship between adherence and outcome after a programme of physiotherapeutic spine stabilisation exercises. A total of 32/37 patients with cLBP completed the study (mean age, 44.0 (SD = 12.3) years; 11/32 (34%) male). Adherence to the 9-week programme was documented as: percent attendance at therapy, percent adherence to daily home exercises (patient diary) and percent commitment to rehabilitation (Sports Injury Rehabilitation Adherence Scale (SIRAS)). The average of these three measures formed a multidimensional adherence index (MAI). Psychological disturbance, fear-avoidance beliefs, catastrophising, exercise self-efficacy and health locus of control were measured by questionnaire; disability in everyday activities was scored with the Roland–Morris disability scale and back pain intensity with a 0–10 graphic rating scale. Overall, adherence to therapy was very good (average MAI score, 85%; median (IQR), 89 (15)%). The only psychological/beliefs variable showing a unique significant association with MAI was exercise self-efficacy (Rho = 0.36, P = 0.045). Pain intensity and self-rated disability decreased significantly after therapy (each P < 0.01). Adherence to home exercises showed a moderate, positive correlation with the reduction in average pain (Rho = 0.54, P = 0.003) and disability (Rho = 0.38, P = 0.036); higher MAI scores were associated with greater reductions in average pain (Rho = 0.48, P = 0.008) and a (n.s.) tendency for greater reductions in disability (Rho = 0.32, P = 0.07) Neither attendance at therapy nor SIRAS were significantly related to any of the outcomes. The benefits of rehabilitation depended to a large extent on the patient’s exercise behaviour outside of the formal physiotherapy sessions. Hence, more effort should be invested in finding ways to improve patients’ motivation to take responsibility for the success of their own therapy, perhaps by increasing exercise self-efficacy. Whether the “adherence–outcome” interaction was mediated by improvements in function related to the specific exercises, or by a more “global” effect of the programme, remains to be examined.
PMCID: PMC2899434  PMID: 19609785
Chronic low back pain; Exercise rehabilitation; Spinal segmental stabilisation exercises; Outcome; Adherence
3.  Sleep quality, the neglected outcome variable in clinical studies focusing on locomotor system; a construct validation study 
In addition to general health and pain, sleep is highly relevant to judging the well-being of an individual. Of these three important outcome variables, however, sleep is neglected in most outcome studies.
Sleep is a very important resource for recovery from daily stresses and strains, and any alteration of sleep will likely affect mental and physical health, especially during disease. Sleep assessment therefore should be standard in all population-based or clinical studies focusing on the locomotor system. Yet current sleep assessment tools are either too long or too specific for general use.
Based on a literature review and subsequent patient-based rating of items, an expert panel designed a four-item questionnaire about sleep. Construct validation of the questionnaire in a random sample of the German-speaking Swiss population was performed in 2003. Reliability, correlation, and tests for internal consistency and validity were analyzed.
Overall, 16,634 (70%) out of 23,763 eligible individuals participated in the study. Test-retest reliability coefficients ranged from 0.72 to 0.87, and a Cronbach's alpha of 0.83 indicates good internal consistency. Results show a moderate to good correlation between sleep disturbances and health perception, and between sleep disturbances and overall pain.
The Sleep Standard Evaluation Questionnaire (SEQ-Sleep) is a reliable and short tool with confirmed construct validity for sleep assessment in population-based observational studies. It is easy to administer and therefore suitable for postal surveys of the general population. Criterion validity remains to be determined.
PMCID: PMC3161400  PMID: 20920152
5.  Muscle thickness changes during abdominal hollowing: an assessment of between-day measurement error in controls and patients with chronic low back pain 
European Spine Journal  2008;17(4):494-501.
Spine stabilization exercises, in which patients are taught to perform isolated contractions of the transverses abdominus (TrA) during “abdominal hollowing”, are a popular physiotherapeutic treatment for low back pain (LBP). Successful performance is typically judged by the relative increase in TrA thickness compared with that of the internal (OI) and external (OE) oblique muscles, measured using ultrasound. The day-to-day measurement error (imprecision) associated with these indices of preferential activation has not been assessed but is important to know since it influences the interpretation of changes after treatment. On 2 separate days, 14 controls and 14 patients with chronic LBP (cLBP) performed abdominal hollowing exercises in hook-lying, while M-mode ultrasound images superimposed with tissue Doppler imaging (TDI) data were recorded from the abdominal muscles (N = 5 on each side). The fascial lines bordering the TrA, OI and OE were digitized, and muscle thicknesses were calculated. The between-day error (intra-observer) was expressed as the standard error of measurement, SEM; SEM as a percentage of the mean gave the coefficient of variation (CV). There were no significant between-day differences for the mean values of resting or maximal thickness for any muscle, in either group (P > 0.05). The median SEM and CV of all thickness variables was 0.71 mm and 10.9%, respectively for the controls and 0.80 mm or 11.3%, respectively for the cLBP patients. For the contraction ratios (muscle thickness contracted/thickness at rest), the CVs were 3–11% (controls) and 5–12% (patients). The CVs were unacceptably high (30–50%, both groups) for the TrA preferential activation ratio (TrA proportion of the total lateral abdominal muscle thickness when contracted minus at rest). In both the controls and patients, the precision of measurement of absolute muscle thickness and relative change in thickness during abdominal hollowing was acceptable, and commensurate with that typical of biological measurements. The TrA preferential activation ratio is too imprecise to be of clinical use. Knowledge of the SEM for these indices is essential for interpreting the clinical relevance of any changes observed following physiotherapy.
PMCID: PMC2295268  PMID: 18196294
Abdominal muscles; Physiotherapy exercises; Back pain; Reliability; Measurement error
6.  DREAM is reduced in synovial fibroblasts of patients with chronic arthritic pain: is it a suitable target for peripheral pain management? 
The endogenous pain-relieving system depends in part on the regulation of nociceptive signals through binding of opioids to the corresponding opioid receptor. Interfering with the trans-repression effect of downstream regulatory element antagonist modulator (DREAM) on the transcription of the opioid dynorphin-encoding prodynorphin (pdyn) gene might enhance pain relief in the periphery.
Expression levels were measured in osteoarthritis (OA) synovial fibroblast-like cells (SFLCs) (n = 8) and in peripheral blood mononuclear cells (PBMCs) from OA patients (n = 53) and healthy controls (n = 26) by real-time polymerase chain reaction. Lysed OA SFLCs were analyzed by immunoprecipitation. Translation of DREAM mRNA was inhibited by small interfering RNAs (siRNAs). Expressions of DREAM, pdyn, and c-fos mRNAs were measured at 24, 48, and 72 hours after transfection.
The expression of DREAM mRNA was shown in both healthy and OA SFLCs as well as PBMCs. Inhibiting transcription using siRNAs led to a marked reduction in DREAM expression after 24, 48, and 72 hours. However, no significant changes in c-fos and pdyn expression occurred. In addition, DREAM mRNA expression was significantly reduced in OA patients with chronic pain (pain intensity as measured by a visual analog scale scale of greater than 40), but no pdyn expression was detectable.
To our knowledge, this is the first report showing the expression of DREAM in SFLCs and PBMCs on the mRNA level. However, DREAM protein was not detectable. Since repression of pdyn transcription persists after inhibiting DREAM translation, DREAM appears to play no functional role in the kappa opioid receptor system in OA SFLCs. Therefore, our data suggest that DREAM appears not to qualify as a target in peripheral pain management.
PMCID: PMC2483451  PMID: 18507845
7.  Microcirculation abnormalities in patients with fibromyalgia – measured by capillary microscopy and laser fluxmetry 
Arthritis Research & Therapy  2004;7(2):R209-R216.
This unblinded preliminary case-control study was done to demonstrate functional and structural changes in the microcirculation of patients with primary fibromyalgia (FM). We studied 10 women (54.0 ± 3.7 years of age) with FM diagnosed in accordance with the classification criteria of the American College of Rheumatology, and controls in three groups (n = 10 in each group) – age-matched women who were healthy or who had rheumatoid arthritis or systemic scleroderma (SSc). All 40 subjects were tested within a 5-week period by the same investigators, using two noninvasive methods, laser fluxmetry and capillary microscopy. The FM patients were compared with the healthy controls (negative controls) and with rheumatoid arthritis patients and SSc patients (positive controls). FM patients had fewer capillaries in the nail fold (P < 0.001) and significantly more capillary dilatations (P < 0.05) and irregular formations (P < 0.01) than the healthy controls. Interestingly, the peripheral blood flow in FM patients was much less (P < 0.001) than in healthy controls but did not differ from that of SSc patients (P = 0.73). The data suggest that functional disturbances of microcirculation are present in FM patients and that morphological abnormalities may also influence their microcirculation.
PMCID: PMC1065312  PMID: 15743467
capillary microscopy; fibromyalgia; laser fluxmetry; microcirculation
8.  Influence of an outpatient multidisciplinary pain management program on the health-related quality of life and the physical fitness of chronic pain patients 
Approximately 10 to 20 percent of the population is suffering from chronic pain. Since this represents a major contribution to the costs of the health care system, more efficient measures and interventions to treat these patients are sought.
The development of general health and physical activity of patients with chronic pain was assessed in an interdisciplinary outpatient pain management program (IOPP). 36 patients with an average age of 48 years were included in the IOPP. Subjective assessment of well-being was performed at five time points (baseline, post intervention and 3, 6, and 12 months thereafter) by using standardized questionnaires. The study focused on the quality of life survey Medical Outcomes Study Short Form-36, which is a validated instrument with established reliability and sensitivity. In addition, the patients participated in physical assessment testing strength, power, endurance, and mobility.
Prior to therapy a substantial impairment was found on different levels. Marked improvements in the psychological parameters were obtained by the end of the program. No success was achieved with regard to the physical assessments.
Although many different studies have evaluated similar programs, only few of them have attained positive results such as improvements of general quality of life or of physical strength. Often no difference from the control group could be detected only some months after the intervention. In the present study no significant persistent improvement of well-being occurred. Possible reasons are either wrong instruments, wrong selection of patients or wrong interventions.
PMCID: PMC404467  PMID: 15028119
Low back pain; depression; chronification; pain intervention program; quality of life
9.  Prospective Epidemiological Observations on the Course of the Disease in Fibromyalgia Patients 
The aim of the study was to carry out a survey in patients with fibromyalgia (FM), to examine their general health status and work incapacity (disability-pension status), and their views on the effectiveness of therapy received, over a two-year observation period.
48 patients diagnosed with FM, according to the American College of Rheumatology (ACR) criteria, took part in the study. At baseline, and on average two years later, the patients underwent clinical investigation (dolorimetry, laboratory diagnostics, medical history taking) and completed the Fibromyalgia questionnaire (Dettmer and Chrostek [1]).
27/48 (56%) patients participated in the two-year follow-up. In general, the patients showed no improvement in their symptoms over the observation period, regardless of the type of therapy they had received. General satisfaction with quality of life improved, as did satisfaction regarding health status and the family situation, although the degree of pain experienced remain unchanged. In comparison with the initial examination, there was no change in either work-capacity or disability-pension status.
The FM patients showed no improvement in pain, despite the many various treatments received over the two-year period. The increase in general satisfaction over the observation period was believed to be the result of patient instruction and education about the disease. To what extent a population of patients with FM would show similar outcomes if they did not receive any instruction/education about their disorder, cannot be ascertained from the present study; and, indeed, the undertaking of a study to investigate this would be ethically questionable. As present, no conclusions can be made regarding the influence of therapy on the primary and secondary costs associated with FM.
PMCID: PMC194775  PMID: 12969513
fibromyalgia; epidemiology; general health

Results 1-9 (9)