Published in 2009

Proposal for levels of evidence schema for validation of a soluble biomarker reflecting damage endpoints in rheumatoid arthritis, psoriatic arthritis, and ankylosing spondylitis, and recommendations for study design

Maksymowych, W. P., Fitzgerald, O., Wells, G. A., Gladman, D. D., Landewé, R., Østergaard, M., Taylor, W. J., Christensen, R., Tak, P-P., Boers, M., Syversen, S. W., Bathon, J. M., Ritchlin, C. J., Mease, P. J., Bykerk, V. P., Garnero, P., Geusens, P., El-Gabalawy, H., Aletaha, D., Inman, R. D., Kraus, V. B., Kvien, T. K. & van der Heijde, D. aug. 2009 I : Journal of Rheumatology. 36, 8, s. 1792-9 8 s.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

OBJECTIVE: At OMERACT 8 a framework for levels of evidence was proposed for the validation of biomarkers as surrogate outcome measures. We aimed to adapt this scheme in order to apply it in the setting of soluble biomarkers proposed to replace the measurement of damage endpoints in rheumatoid arthritis (RA), psoriatic arthritis (PsA), and ankylosing spondylitis (AS). We also aimed to generate consensus on minimum standards for the design of longitudinal studies aimed at validating biomarkers.

METHODS: Before the meeting, the Soluble Biomarker Working Group prepared a preliminary framework and discussed various models for association and prediction related to the statistical strength domain. In addition, 3 Delphi exercises addressing longitudinal study design for RA, PsA, and AS were conducted within the working group and members of the Assessments in SpondyloArthritis International Society (ASAS) and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA). This formed the basis for discussions among OMERACT 9 participants.

RESULTS: The proposed framework was accepted by consensus. In the study design domain a requirement for both prospective observational studies and randomized controlled trials (RCT) in different drug classes was noted. A template for determining the level of statistical strength was proposed. The addition of a new domain on biomarker assay performance was considered essential, and participants suggested that for any biomarker this domain should be addressed first, i.e., before starting clinical validation studies. Participants agreed on most elements of a longitudinal study design template. Where consensus was lacking the working group has drafted solutions that constitute a basis for prospective validation studies.

CONCLUSION: The OMERACT 9 Soluble Biomarker Group has successfully formulated a levels of evidence scheme and a study design template that will provide guidance to conduct validation studies in the setting of soluble biomarkers proposed to replace the measurement of damage endpoints in RA, PsA, and AS.

Originalsprog Engelsk
Tidsskrift Journal of Rheumatology
Vol/bind 36
Tidsskriftsnummer 8
Sider (fra-til) 1792-9
Antal sider 8
ISSN 0315-162X
DOI
Status Udgivet - aug. 2009
To test the hypothesis that fibromyalgia (FM) patients with reduced lower extremity strength are more symptomatic and tender than FM patients with normal muscle strength.
Originalsprog Engelsk
Tidsskrift Arthritis & Rheumatism
Vol/bind 61
Tidsskriftsnummer 6
Sider (fra-til) 732-9
Antal sider 8
ISSN 0004-3591
DOI
Status Udgivet - 2009

The Bath metrology index as assessed by a trained and an untrained rater in patients with spondylarthropathy: a study of intra- and inter-rater agreements

Madsen, O. R., Hansen, L. B., Rytter, A., Suetta, C. & Egsmose, C. jan. 2009 I : Clinical rheumatology. 28, 1, s. 35-40 6 s.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

The Bath ankylosing spondylitis metrology index (BASMI; range 0-10) has gained widespread use in daily clinical practice as an objective measure of spinal stiffness not only in patients with ankylosing spondylitis (AS) but also in patients with other spondylarthropathies (SpA). We examined intra-rater and inter-rater reproducibility of BASMI scoring in 30 Danish patients with SpA (median age 40 years, range 22-56 years) fulfilling the European Spondylarthropathy Study Group criteria, 25 of them satisfying the modified New York Criteria for AS. Measurements were performed twice on two different days (median interval 7 days, range 4-11) by a trained physiotherapist (PT) and by an untrained nurse who had undergone a single 1-h training session with the PT. The median BASMI score obtained by the PT on the two test days was 3.5 (range 1-8) and 3.0 (range 1-8), respectively (NS). Test-retest BASMI scores from the PT were significantly correlated (r(s) = 0.95, p < 0.0001). The 95% likely range for the difference between a patient's BASMI scores from two tests was +/-1.4 corresponding to a minimal detectable difference of +/-2 in the individual patient as the scale consists of intervals of 1. Similar results were achieved by the nurse. BASMI scores obtained by the two raters were significantly inter-correlated (r(s) = 0.95, p < 0.0001). The mean difference between paired BASMI scores obtained by the nurse and the PT on test day 1 was -0.2 with a minimal detectable difference of +/-2. A similar result was found using data from test day 2. In conclusion, a change in BASMI less than 2 may be due solely to expected random measurement error. A single 1-h training session allowed an untrained nurse to obtain BASMI results almost identical to those of an experienced PT.

Originalsprog Engelsk
Tidsskrift Clinical rheumatology
Vol/bind 28
Tidsskriftsnummer 1
Sider (fra-til) 35-40
Antal sider 6
ISSN 0770-3198
DOI
Status Udgivet - jan. 2009

Toxic hepatitis induced by infliximab in a patient with rheumatoid arthritis with no relapse after switching to etanercept

Carlsen, K. M., Riis, L. & Madsen, O. R. 1 aug. 2009 I : Clinical Rheumatology. 28, 8, s. 1001-3 3 s.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

We present a case of toxic hepatitis related to infliximab treatment in a 38-year-old woman with rheumatoid arthritis (RA). The patient had previously been treated with different disease-modifying drugs (DMARDs) alone or in combination but had never revealed signs of liver dysfunction. Due to high disease activity, treatment with infliximab (3 mg/kg i.v.) was initiated in combination with methotrexate (MTX) (25 mg/week) and folic acid (5 mg/week). The patient stopped MTX and folic acid on her own initiative after 3 weeks due to improvement of joint symptoms. After seven infusions, progressive elevations of the transaminases up to five times the upper normal limit were noted and treatment with infliximab was terminated. Serological tests for viral and autoimmune hepatitis and for ANA and anti-dsDNA were all negative. Specific infliximab antibodies could not be detected. Ultrasound of the liver was normal. Liver biopsy showed late signs of acute toxic hepatitis without MTX-related fibrosis. This is one the first cases that convincingly demonstrates that infliximab treatment may cause toxic hepatitis. Moreover, the case suggests a lack of hepatic cross-toxicity between infliximab and etanercept as the patient continued with etanercept without new episodes of liver dysfunction.
Originalsprog Engelsk
Tidsskrift Clinical Rheumatology
Vol/bind 28
Tidsskriftsnummer 8
Sider (fra-til) 1001-3
Antal sider 3
ISSN 0770-3198
DOI
Status Udgivet - 1 aug. 2009

Ultrasound colour Doppler measurements in a single joint as measure of disease activity in patients with rheumatoid arthritis--assessment of concurrent validity

Ellegaard, K., Torp-Pedersen, S., Terslev, L., Danneskiold-Samsøe, B., Henriksen, M. & Bliddal, H. 2009 I : Rheumatology. 48, 3, s. 254-257 3 s.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

OBJECTIVE: Colour Doppler ultrasound (CDU) displays blood flow in the tissues and is able to detect hyperaemia. Because hyperaemia is part of the inflammatory response, the amount of CDU activity in the inflamed synovium may be used to quantify the inflammatory activity in RA. It has never been investigated if the amount of CDU activity in a single joint can be used to quantify disease activity in RA. METHODS: A total of 109 patients with RA and affection of the wrist joint underwent a standardized CDU examination assessing three positions in their most affected wrist at start up in biological treatment. On the same day the following measures of disease activity were collected: assessment of the number of tender and swollen joints, CRP, ESR and 28-joint disease activity score (DAS28). The amount of CDU activity was quantified by measuring the percentage of colour in the synovium--the colour fraction (CF). Correlation between CF and other measures of disease activity was calculated. RESULTS: There was a significant correlation between CF and DAS28 (r = 0.29; P < 0.001), swollen joint count (r = 0.35; P < 0.001), CRP (r = 0.5; P < 0.001) and ESR (r = 0.5; P < 0.001). No other significant correlations were found. CONCLUSION: A standardized ultrasound examination of a single affected wrist joint in patients with RA may be used as a measure of disease activity. More studies are needed to identify the number of joints needed to examine by CDU to obtain the best validity of Doppler measurements
Udgivelsesdato: 2009/3
Originalsprog Engelsk
Tidsskrift Rheumatology
Vol/bind 48
Tidsskriftsnummer 3
Sider (fra-til) 254-257
Antal sider 3
ISSN 1462-0324
Status Udgivet - 2009

Published in 2008

Influence of pain and gender on impact loading during walking: a randomised trial

Henriksen, M., Christensen, R., Alkjaer, T., Lund, H., Simonsen, E. B. & Bliddal, H. feb. 2008 I : Clinical biomechanics (Bristol, Avon). 23, 2, s. 221-30 10 s.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

BACKGROUND: Knee joint osteoarthritis is painful and with an overweight of female incidence. The cardinal symptom is pain, which causes compensatory gait changes, and gender differences in pain sensitivity exist. Impact loadings at heel strike during walking are suspected as a co-factor in development of knee osteoarthritis. Thus the purpose of this study was to investigate the influence of experimental muscle pain and gender on generation and attenuation of impact loading during walking.

METHODS: Ten healthy males and 10 healthy females were recruited. Impact loadings during walking were measured using force platforms and accelerometers attached to the tibia and sacrum. Impact ground reaction force peaks and loading rates, and peak accelerations were used to quantify impact loadings. Attenuation was quantified by means of a transfer function between the tibial and sacral accelerometer signals, and the relative peak acceleration reduction. Knee joint kinematics were collected using a three-dimensional movement analysis system. The study was a cross-over study and data were collected before, during, and after experimental vastus medialis pain and a control situation.

FINDINGS: Experimental muscle pain did not affect generation or attenuation of impact loading in either gender. While the impact loading magnitude was similar across genders, lower loading rates and more efficient attenuation were observed in females.

INTERPRETATION: It is concluded that generation and attenuation of impact loadings during walking are independent of quadriceps pain in both genders. The present study does not provide any evidence of the tested variables to address the gender differences in loading rates and attenuation.

Originalsprog Engelsk
Tidsskrift Clinical biomechanics (Bristol, Avon)
Vol/bind 23
Tidsskriftsnummer 2
Sider (fra-til) 221-30
Antal sider 10
ISSN 0268-0033
DOI
Status Udgivet - feb. 2008

Ion transporters involved in acidification of the resorption lacuna in osteoclasts

Henriksen, K., Sørensen, M. G., Jensen, V. K., Dziegiel, M. H., Nosjean, O. & Karsdal, M. A. sep. 2008 I : Calcified tissue international. 83, 3, s. 230-42 13 s.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Osteoclasts possess a large amount of ion transporters, which participate in bone resorption; of these, the vacuolar-adenosine trisphosphatase (V-ATPase) and the chloride-proton antiporter ClC-7 acidify the resorption lacuna. However, whether other ion transporters participate in this process is currently not well understood. We used a battery of ion channel inhibitors, human osteoclasts, and their subcellular compartments to perform an unbiased analysis of the importance of the different ion transporters for acidification of the resorption lacuna in osteoclasts. CD14(+) monocytes from human peripheral blood were isolated, and mature osteoclasts were generated using RANKL and M-CSF. The human osteoclasts were (1) used for acridine orange assays for evaluation of lysosomal acidification, (2) used for bone resorption assays, (3) used for generation of osteoclasts membranes for acid influx experiments, or (4) lysed in trizol for mRNA isolation for Affymetrix array analysis. Inhibitors targeted toward most of the ion transporters showed low potency in the acidification-based assays, although some inhibitors, such as carbonic anhydrase II and the sodium-hydrogen exchanger (NHE) inhibitors, reduced resorption potently. In contrast, inhibitors targeted at V-ATPase and ClC-7 potently inhibited both acidification and resorption, as expected. We here show evidence that acidification of the resorption lacuna is mainly mediated by V-ATPase and ClC-7. Furthermore, a group of other ion transporters, including carbonic anhydrase II, the NHEs, and potassium-chloride cotransporters, are all involved in resorption but do not seem to directly be involved in acidification of the lysosomes.

Originalsprog Engelsk
Tidsskrift Calcified tissue international
Vol/bind 83
Tidsskriftsnummer 3
Sider (fra-til) 230-42
Antal sider 13
ISSN 0171-967X
DOI
Status Udgivet - sep. 2008

Muskelstyrken hos patienter med fibromyalgi. Et litteraturstudie

Dombernowsky, T., Dreyer, L., Bartels, E. M. & Danneskiold-Samsøe, B. 2008 I : Ugeskrift for Laeger. 170, 4, s. 217-24 8 s.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Do patients with fibromyalgia (FM) have reduced muscular strength? We examined 22 articles and conclude from the results of these that FM patients have reduced muscular strength in their hands and quadriceps. The material also suggests generalised reduced muscular strength. However, the studies have several methodological shortcomings and future studies should be carefully designed with respect to patients as well as the control group and should be larger. To avoid CNS influence from e.g. fatigue and pain, muscular electro-stimulation may be used to ensure that the actual maximal muscular strength is also measured.
Originalsprog Dansk
Tidsskrift Ugeskrift for Laeger
Vol/bind 170
Tidsskriftsnummer 4
Sider (fra-til) 217-24
Antal sider 8
ISSN 0041-5782
Status Udgivet - 2008

Nordic Walking does not reduce the loading of the knee joint

Hansen, L., Henriksen, M., Larsen, P. & Alkjaer, T. aug. 2008 I : Scandinavian journal of medicine & science in sports. 18, 4, s. 436-41 6 s.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

The use of Nordic Walking (NW) as a rehabilitation modality has increased considerably. NW (walking with poles) is advocated as a healthy physical activity that reduces the load on the knees. Few studies using the techniques of NW exist, and the findings are contradictory. The aim of this study was to investigate whether NW reduces the loadings upon the knee joint compared with walking without poles (NP). Seven experienced female NW instructors volunteered. Three-dimensional gait analyses were performed. Internal flexor and extensor joint moments were calculated using an inverse dynamics approach and the knee joint compressive forces were calculated. No differences in compression or shear forces between NW and NP were found. The peak knee flexion angles were larger during NW (-32.5+/-6.0 degrees) compared with NP (-28.2+/-4.2 degrees). The hip range of motion (ROM) was significantly increased during NW (64.4+/-10.2 degrees) compared with NP (57.8+/-9.7 degrees); no differences in the knee and ankle joint ROM were observed. The changes in the joint angles were not followed by changes in the joint dynamics. The present study does not support the statement that NW reduces the load on the knees.

Originalsprog Engelsk
Tidsskrift Scandinavian journal of medicine & science in sports
Vol/bind 18
Tidsskriftsnummer 4
Sider (fra-til) 436-41
Antal sider 6
ISSN 0905-7188
DOI
Status Udgivet - aug. 2008

PURPOSE: The amount of colour Doppler activity in the inflamed synovium is used to quantify inflammatory activity. The measurements may vary due to image selection, quantification method, and point in cardiac cycle. This study investigated the test-retest reliability of ultrasound colour Doppler measurements in the wrist of patients with rheumatoid arthritis (RA) using different selection and quantification methods.

MATERIALS AND METHODS: 14 patients with RA had their wrist scanned twice by the same investigator with an interval of 30 minutes. The images for analysis were selected either by the anatomical position only or by the anatomical position with maximum colour Doppler activity. Subsequently, the amount of colour Doppler was measured in an area defined by either the synovial tissue or by specific anatomical structures surrounding the synovial tissue.

RESULTS: The best test-retest reliability was obtained when the images were selected guided by colour Doppler and the subsequent quantification was done in an area defined by anatomical structures. With this method, the intra-class coefficient ICC (2.1) was 0.95 and the within-subject SD (SW) was 0.017, indicating good reliability. In contrast, poor test-retest reliability was found if the images were selected by anatomical position only and the quantification was done in an area defined by the synovial tissue (ICC [2.1] = 0.48 and SW = 0.049).

CONCLUSION: The study showed that colour Doppler measurements are reliable if the images for analysis are selected by anatomical position in combination with colour Doppler activity and the subsequent analysis is performed in an area defined by anatomical structures.

Originalsprog Engelsk
Tidsskrift Ultraschall in der Medizin (Stuttgart, Germany : 1980)
Vol/bind 29
Tidsskriftsnummer 4
Sider (fra-til) 393-8
Antal sider 6
ISSN 0172-4614
DOI
Status Udgivet - aug. 2008

Published in 2007

Characterization of osteoclasts derived from CD14+ monocytes isolated from peripheral blood

Sørensen, M. G., Henriksen, K., Schaller, S., Henriksen, D. B., Nielsen, F. C., Dziegiel, M. H. & Karsdal, M. A. 2007 I : Journal of Bone and Mineral Metabolism. 25, 1, s. 36-45 10 s.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Bone resorption is solely mediated by osteoclasts. Therefore, a pure osteoclast population is of high interest for the investigation of biological aspects of the osteoclasts, such as the direct effect of growth factors and hormones, as well as for testing and characterizing inhibitors of bone resorption. We have established a pure, stable, and reproducible system for purification of human osteoclasts from peripheral blood. We isolated CD14-positive (CD14+) monocytes using anti-CD14-coated beads. After isolation, the monocytes are differentiated into mature osteoclasts by stimulation with macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor kappaB ligand (RANKL). Osteoclast formation was only observed in the CD14+ population, not in the CD14- population, and only in the presence of both M-CSF and RANKL, confirming that the CD14+ system is a pure population of osteoclast precursors. No expression of osteoclast markers was observed in the absence of RANKL, whereas RANKL dose-dependently induced the expression of cathepsin K, tartrate-resistant acid phosphatase (TRACP), and matrix metallo proteinase (MMP)-9. Furthermore, morphological characterization of the cells demonstrated that actin rings were only formed in the presence of RANKL. Moreover, the osteoclasts were capable of forming acidic resorption lacunae, and inhibitors of lysosomal acidification attenuated this process. Finally, we measured the response to known bone resorption inhibitors, and found that the osteoclasts were sensitive to these and thereby provided a robust and valid method for interpretation of the effect of antiresorptive compounds. In conclusion, we have established a robust assay for developing osteoclasts that can be used to study several biological aspects of the osteoclasts and which in combination with the resorption marker CTX-I provides a useful tool for evaluating osteoclast function in vitro.

Originalsprog Engelsk
Tidsskrift Journal of Bone and Mineral Metabolism
Vol/bind 25
Tidsskriftsnummer 1
Sider (fra-til) 36-45
Antal sider 10
ISSN 0914-8779
DOI
Status Udgivet - 2007

Computerized cuff pressure algometry: A new method to assess deep-tissue hypersensitivity in fibromyalgia

Jespersen, A., Dreyer, L., Kendall, S., Graven-Nielsen, T., Arendt-Nielsen, L., Bliddal, H. & Danneskiold-Samsoe, B. sep. 2007 I : Pain. 131, 1-2, s. 57-62 6 s.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

The aim of this study was to evaluate the use of computerized cuff pressure algometry (CPA) in fibromyalgia (FM) and to correlate deep-tissue sensitivity assessed by CPA with other disease markers of FM. Forty-eight women with FM and 16 healthy age-matched women were included. A computer-controlled, pneumatic tourniquet cuff was placed over the gastrocnemius muscle. The cuff was inflated, and the subject rated the pain intensity continuously on an electronic Visual Analogue Scale (VAS). The subject stopped the inflation at the pressure-pain tolerance and the corresponding VAS-score was determined (pressure-pain limit). The pressure at which VAS firstly exceeded 0 was defined as the pressure-pain threshold. Other disease markers (FM only): Isokinetic knee muscle strength, tenderpoint-count, myalgic score, Beck Depression Inventory, and Fibromyalgia Impact Questionnaire. Student's T-test was used to compare pressure-pain threshold and pressure-pain tolerance and the Mann-Whitney test to compare pressure-pain limit. Pearson's correlation was used to detect linear relationships. Pressure-pain threshold and pressure-pain tolerance assessed by CPA were significantly lower in FM compared to healthy controls. There was no difference in pressure-pain limit. CPA-parameters were significantly correlated to isokinetic muscle strength where more hypersensitivity resulted in lower strength. Pressure-pain threshold and pressure-pain tolerance assessed by CPA were significantly lower in patients with FM indicating muscle hyperalgesia. CPA was associated with knee muscle strength but not with measures thought to be influenced by psychological distress and mood.

Originalsprog Engelsk
Tidsskrift Pain
Vol/bind 131
Tidsskriftsnummer 1-2
Sider (fra-til) 57-62
Antal sider 6
ISSN 0304-3959
DOI
Status Udgivet - sep. 2007

UNLABELLED: Dissolution of the inorganic phase of bone by the osteoclasts mediated by V-ATPase and ClC-7 is a prerequisite for bone resorption. Inhibitors of osteoclastic V-ATPase or ClC-7 are novel approaches for inhibition of osteoclastic bone resorption. By testing natural compounds in acidification assays, diphyllin was identified. We characterized diphyllin with respect to the pharmacological effects on osteoclasts.

INTRODUCTION: Osteoclastic acidification of the resorption lacuna and bone resorption requires activity of both V-ATPase and the chloride channel ClC-7. Inhibition of these processes represents a novel approach for treatment of bone metabolic disorders. We identified diphyllin, a novel inhibitor of V-ATPase, and characterized this natural compound with respect to activity in human osteoclasts.

MATERIALS AND METHODS: Diphyllin was tested in the acid influx assay and V-ATPase assay using bovine chromaffin granules. Human osteoclasts were generated from CD14+ monocytes cultured with macrophage-colony stimulating factor (M-CSF) and RANKL. The effect of diphyllin on lysosomal acidification in human osteoclasts was studied using acridine orange. The effect of diphyllin on bone resorption by osteoclasts was measured as release of C-terminal cross-linked telopeptide of type I collagen (CTX-I) and calcium into the supernatants and by scoring pit area. Osteoclast number, TRACP activity, and cell viability were measured. Furthermore, the effect of diphyllin on bone nodule formation was tested using the mouse osteoblast cell line MC3T3-E1.

RESULTS: In the acid influx assay, diphyllin potently inhibited the acid influx (IC50 = 0.6 nM). We found that diphyllin inhibited V-ATPase with an IC50 value of 17 nM, compared with 4 nM for bafilomycin A1. Moreover, diphyllin dose-dependently inhibited lysosomal acidification in human osteoclasts. Furthermore, we found that diphyllin inhibited human osteoclastic bone resorption measured by CTX-I (IC50 = 14 nM), calcium release, and pit area, despite increasing TRACP activity, numbers of osteoclasts, and cell viability. Finally, diphyllin showed no effect on bone formation in vitro, whereas bafilomycin A1 was toxic.

CONCLUSIONS: We identified a natural compound that potently inhibits V-ATPase and thereby lysosomal acidification in osteoclasts, which leads to abrogation of bone resorption. Because recent studies indicate that inhibition of the osteoclastic acidification leads to inhibition of resorption without inhibiting formation, we speculate that diphyllin is a potential novel treatment for bone disorders involving excessive resorption.

Originalsprog Engelsk
Tidsskrift Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research
Vol/bind 22
Tidsskriftsnummer 10
Sider (fra-til) 1640-8
Antal sider 9
ISSN 0884-0431
DOI
Status Udgivet - okt. 2007

Dissolution of the inorganic phase of bone leading to release of calcium regulates osteoclast survival

Nielsen, R. H., Karsdal, M. A., Sørensen, M. G., Dziegiel, M. H. & Henriksen, K. 7 sep. 2007 I : Biochemical and Biophysical Research Communications. 360, 4, s. 834-9 6 s.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Osteoclasts are the sole cells possessing the ability to resorb calcified bone matrix. This occurs via secretion of hydrochloric acid mediated by the V-ATPase and the chloride channel ClC-7. Loss of acidification leads to osteopetrosis characterized by ablation of bone resorption and increased osteoclast numbers, indicating increased life span of the osteoclasts. To investigate the role of the inorganic phase of bone with respect to osteoclast life span, we used the V-ATPase inhibitor bafilomycin and the calcium uptake antagonist ryanodine on human osteoclasts cultured on calcified and decalcified bone slices. Bafilomycin inhibited bone resorption and increased osteoclast survival on calcified but not decalcified bones. Ryanodine attenuated calcium uptake and thereby augmented osteoclast survival on calcified bones. In summary, we found that acidification leading to calcium release from bone during resorption controls osteoclast survival, potentially explaining the increased numbers of osteoclasts in patients with osteopetrosis.

Originalsprog Engelsk
Tidsskrift Biochemical and Biophysical Research Communications
Vol/bind 360
Tidsskriftsnummer 4
Sider (fra-til) 834-9
Antal sider 6
ISSN 0006-291X
DOI
Status Udgivet - 7 sep. 2007

Impairment of the dynamic control of the lumbopelvic complex in LBP has gained increased focus both clinically and experimentally. The objectives of this study were to determine the reliability of inclinometry as a measure of dynamic lumbopelvic control. Lumbopelvic reposition accuracy during pelvic tilts was measured in 39 healthy subjects using an inclinometer attached to the skin at S2 level. The reposition accuracy was measured in sitting, standing and supported standing. Tests were performed three times with a 20 min recess between tests. Only data from the last two test sequences were used in order to account for learning effects. Intraclass correlation coefficients were low for the sitting (0.54) and supported standing positions (0.36). In the standing position, a significant difference between test and retest was observed (P = 0.003) and further reliability analysis was therefore abandoned. It is concluded that inclinometry is not reliable for measuring the dynamic lumbopelvic control in any of the test positions and prior work utilising inclinometry to evaluate dynamic lumbopelvic control should be interpreted with caution.

Originalsprog Engelsk
Tidsskrift European spine journal : official publication of the European Spine Society, the European Spinal Deformity Society, and the European Section of the Cervical Spine Research Society
Vol/bind 16
Tidsskriftsnummer 6
Sider (fra-til) 733-40
Antal sider 8
ISSN 0940-6719
DOI
Status Udgivet - jun. 2007

Experimental quadriceps muscle pain impairs knee joint control during walking

Henriksen, M., Alkjaer, T., Lund, H., Simonsen, E. B., Graven-Nielsen, T., Danneskiold-Samsøe, B. & Bliddal, H. jul. 2007 I : Journal of applied physiology (Bethesda, Md. : 1985). 103, 1, s. 132-9 8 s.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Pain is a cardinal symptom in musculoskeletal diseases involving the knee joint, and aberrant movement patterns and motor control strategies are often present in these patients. However, the underlying neuromuscular mechanisms linking pain to movement and motor control are unclear. To investigate the functional significance of muscle pain on knee joint control during walking, three-dimensional gait analyses were performed before, during, and after experimentally induced muscle pain by means of intramuscular injections of hypertonic saline (5.8%) into vastus medialis (VM) muscle of 20 healthy subjects. Isotonic saline (0.9%) was used as control. Surface electromyography (EMG) recordings of VM, vastus lateralis (VL), biceps femoris, and semitendinosus muscles were synchronized with the gait analyses. During experimental muscle pain, the loading response phase peak knee extensor moments were attenuated, and EMG activity in the VM and VL muscles was reduced. Compressive forces, adduction moments, knee joint kinematics, and hamstring EMG activity were unaffected by pain. Interestingly, the observed changes persisted when the pain had vanished. The results demonstrate that muscle pain modulated the function of the quadriceps muscle, resulting in impaired knee joint control and joint instability during walking. The changes are similar to those observed in patients with knee pain. The loss of joint control during and after pain may leave the knee joint prone to injury and potentially participate in the chronicity of musculoskeletal problems, and it may have clinically important implications for rehabilitation and training of patients with knee pain of musculoskeletal origin.

Originalsprog Engelsk
Tidsskrift Journal of applied physiology (Bethesda, Md. : 1985)
Vol/bind 103
Tidsskriftsnummer 1
Sider (fra-til) 132-9
Antal sider 8
ISSN 8750-7587
DOI
Status Udgivet - jul. 2007

Increased cancer risk in patients referred to hospital with suspected fibromyalgia

Dreyer, L., Mellemkjaer, L., Kendall, S., Jensen, B., Danneskiold-Samsøe, B. & Bliddal, H. jan. 2007 I : Journal of Rheumatology. 34, 1, s. 201-6 6 s.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

OBJECTIVE: To analyze whether fibromyalgia (FM) and FM-like symptoms are related to an increased incidence of cancer.

METHODS: We identified 1361 patients referred on suspicion of FM in the period 1984-99 from hospital records. Following the American College of Rheumatology (ACR) criteria, patients were divided into subgroups with and without confirmed FM. The cohort was followed to the end of 1999 and linked to the files of the Danish Cancer Register. Site-specific standardized incidence ratios (SIR) were calculated.

RESULTS: We found no association between FM and cancer in 1132 female patients with confirmed FM at our institution (SIR 1.2, 95% CI 0.8-1.8). In 106 women referred for muscle pain and/or tenderness who did not meet the criteria for FM, an increased overall SIR was observed (SIR 2.5, 95% CI 1.2-4.6), with increased risk for breast cancer (SIR 4.8, 95% CI 1.6-11.3) and lymphatic and hematological cancers (SIR 10.6, 95% CI 1.2-38.2). There were 4 lung cancers in 84 men with confirmed FM (SIR 12.6, 95% CI 3.4-32.4).

CONCLUSION: Neither confirmed FM nor those without confirmed FM predicted cancer. An increased risk of breast cancer was found among those who did not meet the ACR criteria for FM. These patients should be investigated if they develop any new or warning symptoms of malignancy, and treating physicians should be vigilant with screening procedures such as mammography.

Originalsprog Engelsk
Tidsskrift Journal of Rheumatology
Vol/bind 34
Tidsskriftsnummer 1
Sider (fra-til) 201-6
Antal sider 6
ISSN 0315-162X
Status Udgivet - jan. 2007

Kønsforskelle ved autoimmune sygdomme illustreret ved reumatoid artritis

Danneskiold-Samsøe, B., Bartels, E. M. & Dreyer, L. 18 jun. 2007 I : Ugeskrift for læger [online]. 169, 25, s. 2440-2 3 s.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Many autoimmune diseases like rheumatoid arthritis (RA) show gender differences. RA is triggered by an interaction between genetic, hormonal, environmental and behavioural factors. 75% of cases are women under the age of 60; lover the age 60 the gender ratio is 1:1. Different genotypes predispose for RA. Pregnancy often suppresses RA, as does oral contraception. Lactation, smoking (w), BMI > 30, heavy vibrations and certain dust particles (m) may trigger RA, while the effect of male hormones is uncertain. Future prevention should focus on environment, behavioural factors and genetic profiling.

Originalsprog Dansk
Tidsskrift Ugeskrift for læger [online]
Vol/bind 169
Tidsskriftsnummer 25
Sider (fra-til) 2440-2
Antal sider 3
ISSN 1603-6824
Status Udgivet - 18 jun. 2007

Osteoclasts prefer aged bone

Henriksen, K., Leeming, D. J., Byrjalsen, I., Nielsen, R. H., Sorensen, M. G., Dziegiel, M. H., Martin, T. J., Christiansen, C., Qvist, P. & Karsdal, M. A. jun. 2007 I : Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA. 18, 6, s. 751-9 9 s.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

UNLABELLED: We investigated whether the age of the bones endogenously exerts control over the bone resorption ability of the osteoclasts, and found that osteoclasts preferentially develop and resorb bone on aged bone. These findings indicate that the bone matrix itself plays a role in targeted remodeling of aged bones.

INTRODUCTION: Osteoclasts resorb aging bone in order to repair damage and maintain the quality of bone. The mechanism behind the targeting of aged bone for remodeling is not clear. We investigated whether bones endogenously possess the ability to control osteoclastic resorption.

METHODS: To biochemically distinguish aged and young bones; we measured the ratio between the age-isomerized betaCTX fragment and the non-isomerized alphaCTX fragment. By measurement of TRACP activity, CTX release, number of TRACP positive cells and pit area/pit number, we evaluated osteoclastogenesis as well as osteoclast resorption on aged and young bones.

RESULTS: We found that the alphaCTX/betaCTX ratio is 3:1 in young compared to aged bones, and we found that both alpha and betaCTX are released by osteoclasts during resorption. Osteoclastogenesis was augmented on aged compared to young bones, and the difference was enhanced under low serum conditions. We found that mature osteoclasts resorb more on aged than on young bone, despite unchanged adhesion and morphology.

CONCLUSIONS: These data indicate that the age of the bone plays an important role in controlling osteoclast-mediated resorption, with significantly higher levels of osteoclast differentiation and resorption on aged bones when compared to young bones.

Originalsprog Engelsk
Tidsskrift Osteoporosis international : a journal established as result of cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA
Vol/bind 18
Tidsskriftsnummer 6
Sider (fra-til) 751-9
Antal sider 9
ISSN 0937-941X
DOI
Status Udgivet - jun. 2007

Pain from torture

Williams, A. C. D. C. & Amris, K. 15 dec. 2007 I : Pain. 133, 1-3, s. 5-8 4 s.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Originalsprog Engelsk
Tidsskrift Pain
Vol/bind 133
Tidsskriftsnummer 1-3
Sider (fra-til) 5-8
Antal sider 4
ISSN 0304-3959
DOI
Status Udgivet - 15 dec. 2007

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