High-intensity interval training improves cardiovascular and physical health in patients with rheumatoid arthritis: a multicentre randomised controlled trial.

OBJECTIVES: Patients with rheumatoid arthritis (RA) have substantially elevated risk for cardiovascular diseases, and low cardiorespiratory fitness (VO2max) is a major mediator. The aim of this assessor-blinded, two-armed multicentre randomised controlled trial was to evaluate the effects of high-intensity interval training (HIIT) and strength exercise on cardiovascular health, physical fitness and overall health in patients with RA. METHODS: In total, 87 patients (86% female; aged 20-60 years) were randomly assigned to an intervention group (IG) or a control group (CG). The IG performed HIIT and strength exercise for 12 weeks. The CG was instructed to be physically active on a moderately intensive level, ≥150 min/week. Primary outcome was change in VO2max. Secondary outcomes were changes in anthropometry measures, muscle strength, overall health (Visual Analogue Scale (VAS)-Global), Patient Global Impression of Change (PGIC), pain and disease activity (Disease Activity Score in 28 joints (DAS28)). RESULTS: There was a significant mean group difference of change on VO2max (3.71 mL/kg/min; 95% CI 2.16, 5.25) in favour of the IG. Significant mean group differences of change were also seen for O2-pulse (1.38; 95% CI 0.85 to 1.91), waist circumference (-2.6; 95% CI -5.09 to -0.18), 1-minute sit-to-stand (5.0; 95% CI 3.35 to 6.72), handgrip strength (28.5; 95% CI 3.80 to 52.8), overall health (-14.7; 95% CI -23.8 to -5.50) and PGIC (p<0.0001) in favour of the IG. No significant mean group differences of change were found for pain (-4.0; 95% CI -13.07 to 5.06), DAS28 (-0.25; 95% CI -0.60 to 0.10) and erythrocyte sedimentation rate (-0.64; 95% CI -3.23 to 1.90). CONCLUSION: Supervised HIIT and strength exercise improved cardiovascular health, physical fitness and overall health without a deterioration in pain and disease activity and should be considered in patients with well-controlled RA. TRIAL REGISTRATION NUMBER: NCT05768165.

Controlled, cross-sectional, multi-center study of physical capacity and associated factors in women with fibromyalgia.

BACKGROUND: Health and physical capacity are commonly associated with disease, age, and socioeconomic factors. The primary objective of this study was to investigate the degree to which physical capacity, defined as muscle strength and walking ability, is decreased in women with fibromyalgia (FM), as compared to healthy women, who are matched for age and level of education. The secondary aim was to investigate whether muscle strength and walking ability are associated with age, symptom duration, activity limitations and, Body Mass Index (BMI) in women with FM and control subjects. METHODS: This controlled, cross-sectional, multi-center study comprised 118 women with FM and 93 age- and education-level-matched healthy women. The outcome measures were isometric knee-extension force, isometric elbow-flexion force, isometric hand-grip force, and walking ability. Differences between the groups were calculated, and for the women with FM analyses of correlations between the measures of physical capacity and variables were performed. RESULTS: The women with FM showed 20% (p < 0.001) lower isometric knee-extension force, 36% (p < 0.001) lower isometric elbow-flexion force, 34% (p < 0.001) lower isometric hand-grip force, and 16% lower walking ability (p < 0.001), as compared to the healthy controls. All measures of muscle strength in women with FM showed significant weak to moderate relationship to symptom duration (rs = - 0.23-0.32) and walking ability (rs = 0.25-0.36). Isometric knee-extension force correlated with activity limitations, as measured using the SF-36 Physical function subscale (rs=0.23, p = 0.011). CONCLUSIONS: Physical capacity was considerably decreased in the women with FM, as compared to the age- and education-level-matched control group. All measures of physical capacity showed a significant association with symptom duration. Knee-extension force and walking ability were significantly associated with activity limitations, age, and BMI. It seems important to address this problem and to target interventions to prevent decline in muscle strength. Assessments of muscle strength and walking ability are easy to administer and should be routinely carried out in the clinical setting for women with FM. TRIAL REGISTRATION: ClinicalTrials.gov identification number: NCT01226784 , Oct 21, 2010.

Acute effects of physical exercise on the serum insulin-like growth factor system in women with fibromyalgia.

BACKGROUND: Increased Serum insulin-like growth factor-1 (S-IGF-1) has been noted after physical activity in healthy subjects, while the acute release of S-IGF-1 in relation to exercise has not previously been studied in women with fibromyalgia (FM). S-IGF-1 and its binding protein (S-IGFBP-3) are mediated by growth hormone and have anabolic effects on the skeletal muscle. Aim of the study was to investigate acute release of IGF-1 after aerobic exercise in women with FM. METHODS: The acute effect of physical exercise on S-IGF-1 and S-IGFBP-3 were studied in 22 women with FM and in 27 healthy controls during moderate and high-intensity cycling (i.e. ratings 12-13 and 15-17, on Borg's perceived exertion scale (RPE), respectively). Self-reported pain and fatigue were recorded. Differences within and between the two groups were analyzed. RESULTS: After 15 min of bicycling, S-IGF-1 and S-IGFBP-3 increased both within the group with FM and in the healthy controls (p < 0.01). The increases in S-IGF-1 did not significantly differ between the women with FM and the healthy control group (mean increase 11 ± 10 vs. 11 ± 15 ng/ml and 13 ± 10 vs. 19 ± 22 ng/ml) when bicycling at moderate or high intensity, respectively. Self-reported pain and fatigue during exercise, irrespective of intensity, were higher in women with FM compared with healthy controls (p < 0.001). CONCLUSIONS: Fifteen minutes bicycling at moderate intensity was sufficient to acutely mobilise S-IGF-1 in women with FM similarly to healthy controls in spite of higher score of fatigue and pain in women with FM. Hence, patients with FM were able to activate their skeletal muscle metabolism during a short, moderate bout of exercise and were not resistant to training effects. The result is important for encouraging clinical rehabilitation of patients with FM who commonly exercise at a moderate, rather than at a high-intensity level. TRIAL REGISTRATION: ClinicalTrials.govNCT01592916 , May 4, 2012.

Benefits of resistance exercise in lean women with fibromyalgia: involvement of IGF-1 and leptin.

BACKGROUND: Chronic pain and fatigue improves by exercise in fibromyalgia (FM) but underlying mechanisms are not known. Obesity is increased among FM patients and associates with higher levels of pain. Symptom improvement after aerobic exercise is affected by body mass index (BMI) in FM. Metabolic factors such as insulin-like growth factor 1 (IGF-1) and leptin may be involved. In this study, the aim was to evaluate the role of metabolic factors in lean, overweight and obese women during resistance exercise, in relation to symptom severity and muscle strength in women with FM. METHODS: Forty-three women participated in supervised progressive resistance exercise, twice weekly for 15-weeks. Serum free and total IGF-1, IGF-binding protein 3 (IGFBP3), adiponectin, leptin and resistin were determined at baseline and after 15-weeks. Level of current pain was rated on a visual analogue scale (0-100 mm). Level of fatigue was rated by multidimensional fatigue inventory (MFI-20) subscale general fatigue (MFIGF). Knee extension force, elbow flexion force and handgrip force were assessed by dynamometers. RESULTS: Free IGF-1 (p = 0.047), IGFBP3 (p = 0.025) and leptin (p = 0.008) were significantly decreased in lean women (n = 18), but not in the overweight (n = 17) and the obese (n = 8). Lean women with FM benefited from resistance exercise with improvements in current pain (p= 0.039, n = 18), general fatigue (MFIGF, p = 0.022, n = 18) and improved elbow-flexion force (p = 0.017, n = 18). In overweight and obese women with FM there was no significant improvement in pain or fatigue but an improvement in elbow flexion (p = 0.049; p = 0.012) after 15 weeks of resistance exercise. CONCLUSION: The clearest clinical response to resistance exercise was found in lean patients with FM. In these individuals, individualized resistance exercise was followed by changes in IGF-1 and leptin, reduced pain, fatigue and improved muscular strength. In overweight and obese women FM markers of metabolic signaling and clinical symptoms were unchanged, but strength was improved in the upper limb. Resistance exercise combined with dietary interventions might benefit patients with FM and overweight. TRIAL REGISTRATION: The trial was registered 21 of October 2010 with ClinicalTrials.gov identification number: NCT01226784 .

Profile of circulating microRNAs in fibromyalgia and their relation to symptom severity: an exploratory study.

Fibromyalgia (FM) is characterized by generalized chronic pain and reduced pain thresholds. Disturbed neuroendocrine function and impairment of growth hormone/insulin-like growth factor-1 is common. However, the pathophysiology of FM is not clear. MicroRNAs are important regulatory factors reflecting interface of genes and environment. Our aim was to identify characteristic microRNAs in FM and relations of specific microRNAs with characteristic symptoms. A total of 374 circulating microRNAs were measured in women with FM (n = 20; median 52.5 years) and healthy women (n = 20; 52.5 years) by quantitative PCR. Pain thresholds were examined by algometry. Pain [fibromyalgia impact questionnaire (FIQ) pain] levels were rated (0-100 mm) using FIQ. Fatigue (FIQ fatigue) was rated (0-100 mm) using FIQ and multidimensional fatigue inventory general fatigue. Sleep quantity and quality (1-4) rated from satisfactory to nonsatisfactory. Higher scores indicate more severe symptoms. Eight microRNAs differed significantly between FM and healthy women. Seven microRNAs, miR-103a-3p, miR-107, let-7a-5p, miR-30b-5p, miR-151a-5p, miR-142-3p and miR-374b-5p, were lower in FM. However, levels of miR-320a were higher in FM. MiR-103a-3p correlated with pain (r = 0.530, p = 0.016) and sleep quantity (r = 0.593, p = 0.006) in FM. MiR-320a correlated inversely with pain (r = -0.468, p = 0.037). MiR-374b-5p correlated inversely with pain threshold (r = -0.612, p = 0.004). MiR-30b-5p correlated with sleep quantity (r = 0.509, p = 0.022), and let-7a-5p was associated with sleep symptoms. When adjusted for body mass index, the correlation of sleep quantity with miR-103a and miR-30b was no longer significant. To our knowledge, this is the first study of circulating microRNAs in FM. Levels of several microRNAs differed significantly in FM compared to healthy women. Three microRNAs were associated with pain or pain threshold in FM.

Smoking is associated with reduced leptin and neuropeptide Y levels and higher pain experience in patients with fibromyalgia.

Smoking deregulates neuroendocrine responses to pain supporting production of neuropeptide Y (NpY) by direct stimulation of nicotinic receptors or by inhibiting adipokine leptin. Present study addressed the effect of cigarette smoking on adipokines and pain parameters, in 62 women with fibromyalgia (FM) pain syndrome with unknown etiology. Pain was characterized by a visual analogue scale, tender point (TP) counts, pressure pain threshold, and neuroendocrine markers NpY and substance P (sP). Levels of IGF-1, leptin, resistin, visfatin, and adiponectin were measured in blood and cerebrospinal fluid. Current smokers (n = 18) had lower levels of leptin compared to ex-smokers (n = 25, P = 0.002), while the expected NpY increase was absent in FM patients. In smokers, this was transcribed in higher VAS-pain (P = 0.04) and TP count (P = 0.03), lower pain threshold (P = 0.01), since NpY levels were directly related to the pain threshold (rho = 0.414) and inversely related to TP counts (rho = -0.375). This study shows that patients with FM have no increase of NpY levels in response to smoking despite the low levels of leptin. Deregulation of the balance between leptin and neuropeptide Y may be one of the essential mechanisms of chronic pain in FM.

Which aspects of health differ between working and nonworking women with fibromyalgia? A cross-sectional study of work status and health.

BACKGROUND: Women with fibromyalgia (FM) describe great difficulties in managing work. Reported work ability in women with FM varies from 34 to 77 percent in studies from different countries. Many factors are suggested to affect the ability to work in women with FM, including pain, fatigue, impaired physical capacity and activity limitations. However, it is difficult to define to which extent symptom severity can be compatible with work. The aim of this study was to investigate which aspects of health differ between working women with FM and nonworking women with FM. METHODS: A cross-sectional study of 129 women of working age with FM which included clinical assessment, structured interviews, questionnaires and performance-based tests. The women were categorized as working or nonworking. Aspects of health are presented according to the International Classification of Functioning, Disability and Health (ICF). RESULTS: Working women with FM presented better health than nonworking women with FM in ratings of body function (FIQ pain p < 0.001, FIQ fatigue p = 0.006, FIQ stiffness p = 0.009, HADS-Depression p = 0.007). Ratings of overall health status were also significantly better in working women with FM than in nonworking women with FM (FIQ total, eight-item p = 0.001 and SF-36 PCS p < 0.001). No significant differences were found between working- and nonworking women in tests of physical capacity. FIQ pain was an independent explanatory factor for work in stepwise multiple logistic regression analysis (OR 0.95, CI 0.93- 0.98), p < 0.001. CONCLUSION: Working women with FM reported better health than nonworking women with FM in terms of pain, fatigue, stiffness, depression, disease specific health status and physical aspects of quality of life, which represent body functions and overall health status. However, they were equally impaired in tests of physical capacity. Moderate pain levels were compatible with work, while severe pain appeared to compromise work. Fatigue was better tolerated, as women scoring severe levels of fatigue worked.

Resistin competes with lipopolysaccharide for binding to toll-like receptor 4.

Toll-like receptors (TLRs) are a family of cellular structures activated by recognition of pathogen associated molecular sequences. The activation of TLRs triggers a variety of intracellular mechanisms aiming to protect the host from the invading microorganisms. Lipopolysaccharide (LPS) is the main ligand for TLR4. Here we show that resistin, a cystein-rich protein believed to regulate carbohydrate metabolism, competes with LPS for binding to TLR4. Binding of recombinant resistin to human myeloid and epithelial cells was assessed by flow cytometry and its co-precipitation with TLR4 was demonstrated. Antibodies against TLR4 abolished resistin binding to human leucocytes and cytokine production by peripheral blood mononuclear cells in response to resistin stimulation. In contrast, isotype-matched murine IgG or TLR2 antibodies were unable to prevent binding of resistin to the cells. Similarly, TLR4-dependent pattern of resistin binding was observed in epithelial cell line HEK293 (human epithelial kidney cell), where TLR4 transfected, but not myeloid differentiation factor 2/CD14-transfected, TLR2 transfected or HEKnull cells, responded functionally to resistin stimulation. Intracellular signalling of resistin was assessed using inhibitors of transcription factors mitogen activated protein kinases, nuclear factor-kappaB, phosphoinositide 3-kinase and siRNA targeting TLR4 and human myeloid differentiation factor 88. Results demonstrate that TLR4 serves as a receptor for the pro-inflammatory effects of resistin in human cells. This may partly explain the multifunctional role of resistin in chronic inflammation, atherosclerosis and insulin resistance.

Survivin is an essential mediator of arthritis interacting with urokinase signalling.

Proto-oncogene survivin has recently been identified as a prognostic marker distinguishing patients with destructive rheumatoid arthritis (RA). In the present material of 132 RA patients and 82 controls, the levels of survivin correlated to urokinase (uPA) (r= 0.46), a plasminogen activator over-expressed in inflamed joints and known to exhibit potent arthritogenic properties. Here we evaluate the functional relationship between these proteins using primary synovial fibroblasts and leucocytes of RA patients, human monocytic (THP-1) and fibroblast (MRC-5) cell lines. Using inhibitors of intracellular signalling, we show that uPA and survivin share common transduction pathways in synovial fibroblasts being dependent on the activity of tyrosine kinases, phosphatidylinositide 3 kinase and mitogen effector kinase. Moreover, uPA production is significantly reduced in fibroblasts if survivin synthesis has been silenced by siRNA. Importantly, silencing of survivin in fibroblasts prevented their invasive growth in knee joints of severe combined immune deficient mice. Interaction of uPA with receptor up-regulates survivin expression in leucocytes. In turn, survivin is required for the up-regulation of uPA receptor on the cell surface. These findings indicate that survivin is an essential mediator of arthritogenic properties of uPA regulating its synthesis in synovial fibroblasts and uPAR expression in leucocytes. Close correlation between survivin and uPA levels in patients with RA supports the importance of this connection for the pathogenesis of arthritis.

Gene-to-gene interactions regulate endogenous pain modulation in fibromyalgia patients and healthy controls-antagonistic effects between opioid and serotonin-related genes.

Chronic pain is associated with dysfunctional endogenous pain modulation, involving both central opioid and serotonergic (5-HT) signaling. Fibromyalgia (FM) is a chronic pain syndrome, characterized by widespread musculoskeletal pain and reduced exercise-induced hypoalgesia (EIH). In this study, we assessed the effects of 3 functional genetic polymorphisms on EIH in 130 patients with FM and 132 healthy controls. Subjects were genotyped regarding the mu-opioid receptor (OPRM1) gene (rs1799971), the serotonin transporter (5-HTT) gene (5-HTTLPR/rs25531), and the serotonin-1a receptor (5-HT1a) gene (rs6296). The patients with FM had increased pain sensitivity and reduced EIH compared with healthy controls. None of the polymorphisms had an effect on EIH on their own. We found significant gene-to-gene interactions between OPRM1 x 5-HTT and OPRM1 x 5-HT1a regarding activation of EIH, with no statistically significant difference between groups. Better EIH was found in individuals with genetically inferred strong endogenous opioid signaling (OPRM1 G) in combination with weak 5-HT tone (5-HTT low/5-HT1a G), compared with strong 5-HT tone (5-HTT high/5-HT1a CC). Based on the proposed mechanisms of these genetic variants, the findings indicate antagonistic interactions between opioid and serotonergic mechanisms during EIH. Moreover, despite different baseline pain level, similar results were detected in FM and controls, not supporting an altered interaction between opioid and 5-HT mechanisms as the basis for dysfunction of EIH in patients with FM. In summary, our results suggest that, by genetic association, the mu-opioid receptor interacts with 2 major serotonergic structures involved in 5-HT reuptake and release, to modulate EIH.

Pain and fear avoidance partially mediate change in muscle strength during resistance exercise in women with fibromyalgia.

OBJECTIVES: Resistance exercise results in health benefits in fibromyalgia. The aim of this study was to determine the factors that mediate change in muscle strength in women with fibromyalgia as a result of resistance exercise. METHODS: Sixty-seven women with fibromyalgia (age range 25-64 years) were included. Tests of muscle strength and questionnaires related to pain, fear avoidance and physical activity were carried out. Multivariable stepwise regression was used to analyse explanatory factors for change and predictors for final values of knee-extension force, elbow-flexion force and hand-grip force. RESULTS: Change in knee-extension force was explained by fear avoidance beliefs about physical activity at baseline, together with change in pain intensity, knee-extension force at baseline, age and body mass index (BMI) (R2=0.40, p = 0.013). Change in elbow-flexion force was explained by pain intensity at baseline, together with baseline fear avoidance beliefs about physical activity, BMI and elbow-flexion force at baseline (R2 = 0.32, p = 0.043). Change in hand-grip force was explained by hand-grip force at baseline, change in pain intensity and baseline fear avoidance (R2 = 0.37, p = 0.009). Final muscle strength was predicted by the same variables as change, except pain. CONCLUSION: Pain and fear avoidance are important factors to consider in rehabilitation using resistance exercise for women with fibromyalgia.

Decrease of fear avoidance beliefs following person-centered progressive resistance exercise contributes to reduced pain disability in women with fibromyalgia: secondary exploratory analyses from a randomized controlled trial.

BACKGROUND: Fibromyalgia (FM) is characterized by persistent widespread pain, increased pain sensitivity and tenderness. Women with FM also report disability, in terms of negative consequences on activities of daily living. Our recent randomized controlled trial (RCT) is the first study of resistance exercise to show positive effects on pain disability. The resistance exercise program of our RCT emphasized active involvement of participants in planning and progression of the exercise, using the principles of person-centeredness, to support each participant's ability to manage the exercise and the progress of it. The aim of this sub-study was to investigate explanatory factors for reduced pain disability in women with FM participating in a 15-week person-centered progressive resistance exercise program. METHODS: A total of 67 women with FM were included in this sub-study of an RCT examining the effects of person-centered progressive resistance exercise performed twice a week for 15 weeks. Tests of physical capacity and health-related questionnaires were assessed at baseline and after the intervention period. Multivariable stepwise regression was used to analyze explanatory factors for improvements in pain disability. RESULTS: Reduced pain disability was explained by higher pain disability at baseline together with decreased fear avoidance beliefs about physical activity (R (2) = 28, p = 0.005). The improvements in the disability domains of recreation and social activity were explained by decreased fear avoidance beliefs about physical activity together with higher baseline values of each disability domain respectively (R (2) = 32, p = 0.025 and R (2) = 30, p = 0.017). The improvement in occupational disability was explained by higher baseline values of occupational disability (R (2) = 19, p = 0.001). CONCLUSION: The person-centered resistance exercise intervention, based on principles of self-efficacy, had a positive effect on recreational, social and occupational disability. The reduced pain disability seemed to be mediated by decreased fear avoidance beliefs. Age, symptom duration, pain intensity, and muscle strength at baseline had no explanatory value for reduced pain disability, indicating that the person-centered resistance exercise program has the potential to work for anyone with FM who has interest in physical exercise. The trial was registered on October 21, 2010 with ClinicalTrials.gov identification number: NCT01226784 .

Effects of 15 weeks of resistance exercise on pro-inflammatory cytokine levels in the vastus lateralis muscle of patients with fibromyalgia.

BACKGROUND: This study aimed at investigating the effect of a resistance exercise intervention on the interstitial muscle levels of pro-inflammatory cytokines in fibromyalgia (FMS) and healthy controls (CON). METHODS: Twenty-four female patients with FMS (54 ± 8 years) and 27 female CON (54 ± 9 years) were subjected to intramuscular microdialysis of the most painful vastus lateralis muscle before and after 15 weeks of progressive resistance exercise twice per week. Baseline dialysates were sampled in the resting muscle 140 min after insertion of the microdialysis catheter. The participants then performed repetitive dynamic contractions (knee extension) for 20 min, followed by 60 min rest. Pain intensity was assessed with a 0-100 mm visual analogue scale (VAS), and fatigue was assessed with Borg's RPE throughout microdialysis. Dialysates were sampled every 20 min and analyzed with Luminex for interleukin (IL)-1ß, tumor necrosis factor (TNF) alpha, IL-6, and IL-8. RESULTS: At both sessions and for both groups the dynamic contractions increased pain (P < 0.012) and fatigue (P < 0.001). The levels of TNF were lower in the FMS group than the CON group at both sessions (P < 0.05), but none of the other cytokines differed between the groups. IL-6 and IL-8 increased after the dynamic contractions in both groups (P < 0.010), while TNF increased only in CON (P < 0.05) and IL-1ß did not change. Overall pain intensity was reduced after the 15 weeks of resistance exercise in FMS (P < 0.05), but there was no changes in fatigue or cytokine levels. CONCLUSION: Progressive resistance exercise for 15 weeks did not affect the interstitial levels of IL-1ß, TNF, IL-6, and IL-8 in the vastus lateralis muscle of FMS patients or CON. TRIAL REGISTRATION: Clinicaltrials.gov NCT01226784 , registered 21 October 2010.

Resistance exercise improves physical fatigue in women with fibromyalgia: a randomized controlled trial.

BACKGROUND: Fibromyalgia (FM) affects approximately 1-3 % of the general population. Fatigue limits the work ability and social life of patients with FM. A few studies of physical exercise have included measures of fatigue in FM, indicating that exercise can decrease fatigue levels. There is limited knowledge about the effects of resistance exercise on multiple dimensions of fatigue in FM. The present study is a sub-study of a multicenter randomized controlled trial in women with FM. The purpose of the present sub-study was to examine the effects of a person-centered progressive resistance exercise program on multiple dimensions of fatigue in women with FM, and to investigate predictors of the potential change in fatigue. METHODS: A total of 130 women with FM (age 22-64 years) were included in this assessor-blinded randomized controlled multicenter trial examining the effects of person-centered progressive resistance exercise compared with an active control group. The intervention was performed twice a week for 15 weeks. Outcomes were five dimensions of fatigue measured with the Multidimensional Fatigue Inventory (MFI-20). Information about background was collected and the women also completed several health-related questionnaires. Multiple linear stepwise regression was used to analyze predictors of change in fatigue in the total population. RESULTS: A higher improvement was found at the post-treatment examination for change in the resistance exercise group, as compared to change in the active control group in the MFI-20 subscale of physical fatigue (resistance group Δ -1.7, SD 4.3, controls Δ 0.0, SD 2.7, p = 0.013), with an effect size of 0.33. Sleep efficiency was the strongest predictor of change in the MFI-20 subscale general fatigue (beta = -0.54, p = 0.031, R (2) = 0.05). Participating in resistance exercise (beta = 1.90, p = 0.010) and working fewer hours per week (beta = 0.84, p = 0.005) were independent significant predictors of change in physical fatigue (R (2) = 0.14). CONCLUSIONS: Person-centered progressive resistance exercise improved physical fatigue in women with FM when compared to an active control group. TRIAL REGISTRATION: ClinicalTrials.gov NCT01226784 . Registered 21 October 2010.

Synergistic action of immunostimulatory DNA and fcgamma receptor IIB-crosslinking on B-cell phenotype and function.

CpG DNA functions via the toll-like receptor-9 (TLR-9) receptor, inducing B cell proliferation and promoting immunoglobulin production. B cell responses to CpG DNA-containing immune complexes could be important in chronic autoimmunity and immune responses to bacterial components. Therefore, we investigated the potential synergy of CpG DNA-stimulation with FcgammaR clustering (CFR) on splenic B cell activity. CFR-induced splenocyte proliferation was significantly increased compared to treatment with CpG DNA alone. While the levels of interleukin-10 (IL-10) were increased in CpG DNA-treated splenocyte cultures, particularly following FcgammaRII/III-clustering, CFR treatment reduced IL-6 levels. B-cell maturation in culture was enhanced by CFR. Indeed, the frequency of IgG expressing cells after stimulation with CpG DNA was increased and was even higher after CFR stimulation. Furthermore, the frequency of plasma cell precursors was markedly increased by stimulation with CFR. Late splenic B cell subsets, transitional type 2 (T2) and mature (M) B cells, responded strongly to CpG DNA with proliferation and the response was enhanced by FcgammaR-clustering. Immature transitional type 1 (T1) B cells showed distinctly lower proliferative response to CpG DNA and very small effects of FcgammaR-clustering, despite similar expression of Fcgamma-receptors by all B cell subsets. In conclusion, these data show synergistic impact of CpG DNA and simultaneous FcgammaR-clustering on B cell proliferation and differentiation.

Ultralow Dose of Naloxone as an Adjuvant to Intrathecal Morphine Infusion Improves Perceived Quality of Sleep but Fails to Alter Persistent Pain: A Randomized, Double-blind, Controlled Study.

INTRODUCTION: This randomized, cross-over, double-blind, controlled study of continuous intrathecal morphine administration in patients with severe, long-term pain addresses whether the supplementation of low doses of naloxone in this setting is associated with beneficial clinical effects. METHODS: All of the study subjects (n=11) provided informed consent and were recruited from a subset of patients who were already undergoing long-term treatment with continuous intrathecal morphine because of difficult-to-treat pain. The patients were (in a randomized order) also given intrathecal naloxone (40 ng/24 h or 400 ng/24 h). As control, the patients' ordinary dose of morphine without any additions was used. The pain (Numeric Rating Scale, NRS) during activity, perceived quality of sleep, level of activity, and quality of life as well as the levels of several proinflammatory and anti-inflammatory cytokines in the blood were assessed. The prestudy pain (NRS during activity) in the study group ranged from 3 to 10. RESULTS: A total of 64% of the subjects reported improved quality of sleep during treatment with naloxone at a dose of 40 ng per 24 hours as compared with 9% with sham treatment (P=0.024). Although not statistically significant, pain was reduced by 2 NRS steps or more during supplemental treatment with naloxone in 36% of subjects when using the 40 ng per 24 hours dose and in 18% of the subjects when using naloxone 400 ng per 24 hours dose. The corresponding percentage among patients receiving unaltered treatment was 27%. CONCLUSIONS: To conclude, the addition of an ultralow dose of intrathecal naloxone (40 ng/24 h) to intrathecal morphine infusion in patients with severe, persistent pain improved perceived quality of sleep. We were not able to show any statistically significant effects of naloxone on pain relief, level of activity, or quality of life.

Comparison of the Levels of Pro-Inflammatory Cytokines Released in the Vastus Lateralis Muscle of Patients with Fibromyalgia and Healthy Controls during Contractions of the Quadriceps Muscle--A Microdialysis Study.

OBJECTIVE: Fibromyalgia is associated with central hyperexcitability, but it is suggested that peripheral input is important to maintain central hyperexcitability. The primary aim was to investigate the levels of pro-inflammatory cytokines released in the vastus lateralis muscle during repetitive dynamic contractions of the quadriceps muscle in patients with fibromyalgia and healthy controls. Secondarily, to investigate if the levels of pro-inflammatory cytokines were correlated with pain or fatigue during these repetitive dynamic contractions. MATERIAL AND METHODS: 32 women with fibromyalgia and 32 healthy women (controls) participated in a 4 hour microdialysis session, to sample IL-1ß, IL-6, IL-8, and TNF from the most painful point of the vastus lateralis muscle before, during and after 20 minutes of repeated dynamic contractions. Pain (visual analogue scale; 0-100) and fatigue Borg's Rating of Perceived Exertion Scale; 6-20) were assessed before and during the entire microdialysis session. RESULTS: The repetitive dynamic contractions increased pain in the patients with fibromyalgia (P < .001) and induced fatigue in both groups (P < .001). Perceived fatigue was significantly higher among patients with fibromyalgia than controls (P < .001). The levels of IL-1ß did not change during contractions in either group. The levels of TNF did not change during contractions in patients with fibromyalgia, but increased in controls (P < .001) and were significantly higher compared to patients with fibromyalgia (P = .033). The levels of IL-6 and IL-8 increased in both groups alike during and after contractions (P's < .001). There were no correlations between pain or fatigue and cytokine levels after contractions. CONCLUSION: There were no differences between patients with fibromyalgia and controls in release of pro-inflammatory cytokines, and no correlations between levels of pro-inflammatory cytokines and pain or fatigue. Thus, this study indicates that IL-1ß, IL-6, IL-8, and TNF do not seem to play an important role in maintenance of muscle pain in fibromyalgia.

Resistance exercise improves muscle strength, health status and pain intensity in fibromyalgia--a randomized controlled trial.

INTRODUCTION: Fibromyalgia (FM) is characterized by persistent widespread pain, increased pain sensitivity and tenderness. Muscle strength in women with FM is reduced compared to healthy women. The aim of this study was to examine the effects of a progressive resistance exercise program on muscle strength, health status, and current pain intensity in women with FM. METHODS: A total of 130 women with FM (age 22-64 years, symptom duration 0-35 years) were included in this assessor-blinded randomized controlled multi-center trial examining the effects of progressive resistance group exercise compared with an active control group. A person-centred model of exercise was used to support the participants' self-confidence for management of exercise because of known risks of activity-induced pain in FM. The intervention was performed twice a week for 15 weeks and was supervised by experienced physiotherapists. Primary outcome measure was isometric knee-extension force (Steve Strong®), secondary outcome measures were health status (FIQ total score), current pain intensity (VAS), 6MWT, isometric elbow-flexion force, hand-grip force, health related quality of life, pain disability, pain acceptance, fear avoidance beliefs, and patient global impression of change (PGIC). Outcomes were assessed at baseline and immediately after the intervention. Long-term follow up comprised the self-reported questionnaires only and was conducted after 13-18 months. Between-group and within-group differences were calculated using non-parametric statistics. RESULTS: Significant improvements were found for isometric knee-extension force (p = 0.010), health status (p = 0.038), current pain intensity (p = 0.033), 6MWT (p = 0.003), isometric elbow flexion force (p = 0.02), pain disability (p = 0.005), and pain acceptance (p = 0.043) in the resistance exercise group (n = 56) when compared to the control group (n = 49). PGIC differed significantly (p = 0.001) in favor of the resistance exercise group at post-treatment examinations. No significant differences between the resistance exercise group and the active control group were found regarding change in self-reported questionnaires from baseline to 13-18 months. CONCLUSIONS: Person-centered progressive resistance exercise was found to be a feasible mode of exercise for women with FM, improving muscle strength, health status, and current pain intensity when assessed immediately after the intervention. TRIAL REGISTRATION: ClinicalTrials.gov identification number: NCT01226784, Oct 21, 2010.

Anti-proliferative effects of phosphodiester oligodeoxynucleotides.

The immunostimulatory effects of cytosine-phosphate-guanosine (CpG)-containing oligodeoxynucleotides (ODNs) have been extensively documented. In this paper, we describe the inhibitory effects of ODNs that contain natural phosphodiester backbones (O-ODNs) on the immunostimulation caused by CpG-containing phosphorothioated ODNs (CpG-S). CpG-S stimulation of mouse splenocyte proliferation was reduced by the addition of O-ODNs that contained or lacked the CpG-motif (CpG-containing phosphodiester oligodeoxynucleotide, CpG-O or GpC-O). The total number of cultured splenocytes was up-regulated by CpG-S, whereas repetitive addition of O-ODNs to the cell cultures inhibited this effect. The frequency of T2-like B cells was found to be increased by CpG-S. The culture supernatants of CpG-S-treated splenocytes contained elevated levels of IL-10 and IL-6. However, IL-10 and IL-6 production was down-regulated significantly by the combination of CpG-S and either CpG-O or GpC-O. The O-ODN mediated inhibition of proliferation was less pronounced in IL-10-/- mice. Thus, the O-ODNs, irrespective of CpG content, exerted inhibitory activities on the proliferation of B cells. These anti-proliferative effects appear to be mediated both by the down-regulation of IL-10 production and increased apoptosis.

The arthritogenic and immunostimulatory properties of phosphorothioate oligodeoxynucleotides rely on synergy between the activities of the nuclease-resistant backbone and CpG motifs.

Experiments with immunostimulatory unmethylated CpG-containing DNA are usually conducted with nuclease-protected phosphorothioate oligodeoxynucleotides (S-ODNs), rather than phosphodiester oligodeoxynucleotides (O-ODNs). We compared the murine immune responses to S-ODNs and O-ODNs that either contained or lacked CpG motifs. Both CpG and non-CpG S-ODNs induced synovitis, as did sequence-matched CpG O-ODN, but not GpC O-ODN. There was a minimum length requirement for arthritogenic S-ODNs since a CpC dinucleotide S-ODN did not induce arthritis. There were both sequence- (CpG > non-CpG) and backbone-dependent (S-ODN > O-ODN) differences in the levels of DNA-induced arthritis upon intra-articular injection with the ODNs. However, CpG O-ODN being an exception, induced more severe arthritis than the GpC S-ODN. The levels of in vitro proliferation and production of IL-6, TNF-alpha, IL-12, and RANTES by splenocytes following exposure to CpG S-ODN were significantly higher than those induced by CpG O-ODN. In addition, both proliferative responses and cytokine production induced by S-ODN-stimulated splenocytes increased significantly when the S-ODN contained a CpG motif. Transcription factor NFkappaB was activated by both CpG S-ODN and CpG O-ODN but interestingly not by GpC S-ODN. This indicates that the NFkappaB signal pathway modulates CpG-mediated immunostimulation, while sequence-independent immune activation by the phosphorothioate backbone is probably signalled via a different pathway.