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1.  Type X collagen levels are elevated in serum from human osteoarthritis patients and associated with biomarkers of cartilage degradation and inflammation 
Osteoarthritis (OA) is the most common degenerative joint disease, of which the pathogenesis is inadequately understood. Hypertrophy-like changes have been observed as part of the progression of OA. The aim of the study was to develop and characterize a novel biomarker of chondrocytes hypertrophy and investigate how this marker was associated with cartilage degradation and inflammation in patients with various degrees of OA.
A competitive ELISA, C-Col10, applying a well-characterized monoclonal antibody was developed as a biomarker of chondrocyte hypertrophy through measurement of type X collagen (ColX). The levels of C-Col10, C2M (matrix metalloproteinase-derived fragments of type II collagen) and hsCRP (high sensitive C-reactive protein) were quantified by ELISAs in serum of 271 OA patients stratified by Kellgren-Lawrence (KL) score 0–4. Associations between serum levels of the three biomarkers (log transformed) were analyzed by Pearson’s correlation and differences in C-Col10 levels between patients with high and low levels of inflammation measured by hsCRP were analyzed by ANOVA.
We developed a C-Col10 assay measuring the C-terminus of ColX. We found significantly higher levels of ColX in patients with KL score 2 compared to patients with no radiographic evidence of OA (KL0) (p = 0.04). Levels of ColX were significantly elevated in OA patients with above normal hsCRP levels (p < 0.0001), as well as significantly correlated with levels of C2M (r = 0.55, p < 0.0001), which suggested that chondrocyte hypertrophy was associated with inflammation and cartilage degradation. There was no correlation between C2M and hsCRP. Age and BMI adjustment didn’t change the results. Immuno-staining revealed that ColX was predominately located around the hypertrophic chondrocytes and the clustered chondrocytes indicating that C-Col10 measures may be linked to cartilage hypertrophic changes.
We developed a novel assay, C-Col10, for measurement of chondrocyte hypertrophy and found its levels significantly elevated in OA patients with KL score of 2, and also in OA patients with above normal hsCRP levels. Concentration of C-Col10 strongly correlated with levels of C2M, a marker of cartilage destruction. The data suggest that chondrocyte hypertrophy and subsequent collagen X fragmentation seem to be increased in a subset of patients with inflammatory OA.
PMCID: PMC4179849  PMID: 25245039
Hypertrophic chondrocytes; Osteoarthritis; Type X collagen; Cartilage degradation; Biomarkers; Type II collagen; Inflammation
2.  ‘All in a box’ a concept for optimizing microbiological diagnostic sampling in prosthetic joint infections 
BMC Research Notes  2014;7:418.
Accurate microbial diagnosis is crucial for effective management of prosthetic joint infections. Culturing of multiple intraoperative tissue samples has increased diagnostic accuracy, but new preparatory techniques and molecular methods hold promise of further improvement. The increased complexity of sampling is, however, a tough challenge for surgeons and assistants in the operation theatre, and therefore we devised and tested a new concept of pre-packed boxes with a complete assortment of swabs, vials and additional tools needed in the operating theatre for non-standard samples during a clinical study of prosthetic joint infections.
The protocol for the clinical study required triplicate samples of joint fluid, periprosthetic tissue, bone tissue, and swabs from the surface of the prosthesis. Separate boxes were prepared for percutaneous joint puncture and surgical revision; the latter included containers for prosthetic components or the entire prosthesis. During a 2-year project period 164 boxes were used by the surgeons, 98 of which contained a complete set of samples. In all, 1508 (89%) of 1685 scheduled samples were received.
With this concept a high level of completeness of sample sets was achieved and thus secured a valid basis for evaluation of new diagnostics. Although enthusiasm for the project may have been a contributing factor, the extended project period suggests that the ‘All in a box’ concept is equally applicable in routine clinical settings with standardized but complex diagnostic sampling.
PMCID: PMC4105167  PMID: 24993888
Prosthesis; Infections; Specimen handling; Specimen types; Transport media
3.  Reliability and concurrent validity of a novel method allowing for in-shoe measurement of navicular drop 
Increased navicular drop is associated with increased risk of lower extremity overuse injuries and foot orthoses are often prescribed to reduce navicular drop. For laboratory studies, transparent shoes may be used to monitor the effect of orthoses but no clinically feasible methods exist. We have developed a stretch-sensor that allows for in-shoe measurement of navicular drop but the reliability and validity is unknown. The purpose of this study was to investigate: 1) the reliability of the stretch-sensor for measuring navicular drop, and 2) the concurrent validity of the stretch-sensor compared to the static navicular drop test.
Intra- and inter-rater reliability was tested on 27 participants walking on a treadmill on two separate days. The stretch-sensor was positioned 20 mm posterior to the tip of the medial malleolus and 20 mm posterior to the navicular tuberosity. The participants walked six minutes on the treadmill before navicular drop was measured. Reliability was quantified by the Intraclass Correlation Coefficient (ICC 2.1) and agreement was quantified by Limits of Agreement (LOA). To assess concurrent validity, static navicular drop was measured with the stretch-sensor and compared with static navicular drop measured with a ruler on 27 new participants. Linear regression was used to measure concurrent validity.
The reliability of the stretch-sensor was acceptable for barefoot measurement (intra- and inter-rater ICC: 0.76-0.84) but lower for in-shoe measurement (ICC: 0.65). There was a significant association between static navicular drop measured with the stretch-sensor compared with a ruler (r = 0.745, p < 0.001).
This study suggests that the stretch-sensor has acceptable reliability for dynamic barefoot measurement of navicular drop. Furthermore, the stretch-sensor shows concurrent validity compared with the static navicular drop test as performed by Brody. This new simple method may hold promise for both clinical assessment and research but more work is needed before the method can be recommended.
PMCID: PMC3924915  PMID: 24520975
Navicular drop; Foot kinematics; In-shoe; Stretch-sensor
4.  The gait pattern is not impaired in subjects with external snapping hip: a comparative cross-sectional study 
Symptomatic external snapping hip is a painful condition, where pain in the trochantor region and limitations of daily activity dominate clinical findings. The aetiology of symptomatic external snapping hip is elusive, but previous studies have suggested that weakness of the hip abductors and an altered walking pattern may play a role in the development of symptomatic external snapping hip. The aim of this study was to compare the walking pattern and muscular activity of the hip muscles between subjects with symptomatic external snapping hip and healthy subjects.
Thirteen subjects with diagnosed symptomatic external snapping hip (age: 25.5 years) were matched with 13 healthy subjects (age: 25.6 years). Joint kinematics and kinetics of the lower extremity were quantified by the peak hip adduction angle; the average knee rotation range of motion (ROM) and the peak valgus knee angle after data recording using a Vicon 612 motion capture system. Muscle activity was recorded bilaterally using surface electromyography (sEMG) on five muscles: gluteus maximus, gluteus medius, tensor fascia latae, rectus femoris and biceps femoris. A paired t-test was used to evaluate differences between the two groups.
No significant differences were found between the groups concerning the peak hip adduction angle, the average knee rotation ROM, and the static valgus knee angle. No significant between-group differences were found concerning all other kinematics, kinetics or muscle activity. In subjects with symptomatic external snapping hip activity of the gluteus medius muscle during the acceptance phase of walking was 0.58 ± 0.19 whereas the activity was 0.68±0.07 in the asymptomatic group (p=0.115).
No significant differences in the walking pattern were found between subjects with symptomatic external snapping hip and healthy subjects. This suggest that subjects with symptomatic external snapping hip does not have an impaired gait pattern.
PMCID: PMC3724713  PMID: 23870630
Iliotibial band; Trochantor pain; Healthy subjects; Walking; Electromyography; EMG
5.  Efficacy of multimodal, systematic non-surgical treatment of knee osteoarthritis for patients not eligible for a total knee replacement: a study protocol of a randomised controlled trial 
BMJ Open  2012;2(6):e002168.
It is recommended that non-operative treatment of knee osteoarthritis (KOA) should be individually tailored and include multiple treatment modalities. Despite these recommendations, no one has yet investigated the efficacy of combining several non-surgical treatment modalities in a randomised controlled study. The purpose of this randomised controlled study is to examine if an optimised, combined non-surgical treatment programme results in greater improvements in pain, function and quality of life in comparison with usual care in patients with KOA who are not eligible for total knee arthroplasty (TKA).
Methods and analysis
This study will include 100 consecutive patients from the North Denmark Region not eligible for TKA with radiographic KOA (K-L grade ≥1) and mean pain during the previous week of ≤60 mm (0–100). The participants will be randomised to receive either a 12-week non-surgical treatment programme consisting of patient education, exercise, diet, insoles, paracetamol and/or NSAIDs or usual care (two information leaflets containing information on KOA and advice regarding the above non-surgical treatment). The primary outcome will be the change from baseline to 12 months on the self-report questionnaire Knee Injury and Osteoarthritis Outcome Score (KOOS)4 defined as the average score for the subscale scores for pain, symptoms, activities of daily living and quality of life. Secondary outcomes include the five individual KOOS subscale scores, pain on a 100 mm Visual Analogue Scale, EQ-5D, self-efficacy, pain pressure thresholds, postural control and isometric knee flexion and knee extension strength.
Ethics and dissemination
This study was approved by the local Ethics Committee of The North Denmark Region (N-20110085) and the protocol conforms to the principles of the Declaration of Helsinki. Data collection will be completed by April 2014. Publications will be ready for submission in the summer of 2014.
Trial registration number
This study is registered with (NCT01535001).
PMCID: PMC3533085  PMID: 23151395
Rheumatology; Rehabilitation Medicine
6.  Autologous Blood Transfusion after Local Infiltration Analgesia with Ropivacaine in Total Knee and Hip Arthroplasty 
Aims. To study the safety of autotransfusion following local infiltration analgesia (LIA) with ropivacaine. Background. Knowledge of blood concentrations of ropivacaine after LIA and autotransfusion is crucial. However, very limited data are available for toxicological risk assessment. Methods. Autotransfusion was studied in patients after total knee arthroplasty (TKA: n = 25) and total hip arthroplasty (THA: n = 27) with LIA using 200 mg ropivacaine, supplemented with two postoperative bolus injections (150 mg ropivacaine). Drainage blood was reinfused within 6 h postoperatively. Results. Reinfusion caused a significant increase in the serum concentration of total ropivacaine for TKA from 0.54 ± 0.17 (mean ± SD) to 0.79 ± 0.20 μg/mL (P < 0.001) and a nonsignificant increase for THA from 0.62 ± 0.17 to 0.63 ± 0.18 μg/mL. The maximum free (unbound) concentration after reinfusion was 0.038 μg/mL. Peak total and free venous ropivacaine concentrations after 8 h and 16 h postoperative bolus injections were 2.6 μg/mL and 0.11 μg/mL, respectively. All concentrations observed were below the threshold for toxicity and no side effects were observed. Conclusion. Autotransfusion of patients undergoing knee or hip arthroplasty after local infiltration analgesia with 200 mg ropivacaine can be performed safely, even supplemented with 8 h and 16 h postoperative bolus injections.
PMCID: PMC3420087  PMID: 22919377
7.  Total knee replacement plus physical and medical therapy or treatment with physical and medical therapy alone: a randomised controlled trial in patients with knee osteoarthritis (the MEDIC-study) 
There is a lack of high quality evidence concerning the efficacy of total knee arthroplasty (TKA). According to international evidence-based guidelines, treatment of knee osteoarthritis (KOA) should include patient education, exercise and weight loss. Insoles and pharmacological treatment can be included as supplementary treatments. If the combination of these non-surgical treatment modalities is ineffective, TKA may be indicated. The purpose of this randomised controlled trial is to examine whether TKA provides further improvement in pain, function and quality of life in addition to optimised non-surgical treatment in patients with KOA defined as definite radiographic OA and up to moderate pain.
The study will be conducted in The North Denmark Region. 100 participants with radiographic KOA (K-L grade ≥2) and mean pain during the previous week of ≤ 60 mm (0–100, best to worst scale) who are considered eligible for TKA by an orthopaedic surgeon will be included. The treatment will consist of 12 weeks of optimised non-surgical treatment consisting of patient education, exercise, diet, insoles, analgesics and/or NSAIDs. Patients will be randomised to either receiving or not receiving a TKA in addition to the optimised non-surgical treatment. The primary outcome will be the change from baseline to 12 months on the Knee Injury and Osteoarthritis Outcome Score (KOOS)4 defined as the average score for the subscale scores for pain, symptoms, activities of daily living, and quality of life. Secondary outcomes include the five individual KOOS subscale scores, EQ-5D, pain on a 100 mm Visual Analogue Scale, self-efficacy, pain pressure thresholds, and isometric knee flexion and knee extension strength.
This is the first randomised controlled trial to investigate the efficacy of TKA as an adjunct treatment to optimised non-surgical treatment in patients with KOA. The results will significantly contribute to evidence-based recommendations for the treatment of patients with KOA.
Trial registration reference: NCT01410409
PMCID: PMC3461437  PMID: 22571284
8.  A Novel Method for Measuring In-Shoe Navicular Drop during Gait 
Sensors (Basel, Switzerland)  2012;12(9):11697-11711.
Analysis of foot movement is essential in the treatment and prevention of foot-related disorders. Measuring the in-shoe foot movement during everyday activities, such as sports, has the potential to become an important diagnostic tool in clinical practice. The current paper describes the development of a thin, flexible and robust capacitive strain sensor for the in-shoe measurement of the navicular drop. The navicular drop is a well-recognized measure of foot movement. The position of the strain sensor on the foot was analyzed to determine the optimal points of attachment. The sensor was evaluated against a state-of-the-art video-based system that tracks reflective markers on the bare foot. Preliminary experimental results show that the developed strain sensor is able to measure navicular drop on the bare foot with an accuracy on par with the video-based system and with a high reproducibility. Temporal comparison of video-based, barefoot and in-shoe measurements indicate that the developed sensor measures the navicular drop accurately in shoes and can be used without any discomfort for the user.
PMCID: PMC3478805  PMID: 23112678
capacitive strain sensor; gait analysis; foot movement; foot dynamics; Danfoss PolyPower; dielectric electro active polymer (DEAP); navicular drop; multi-video sequence analysis
9.  Determination of normal values for navicular drop during walking: a new model correcting for foot length and gender 
The navicular drop test is a measure to evaluate the function of the medial longitudinal arch, which is important for examination of patients with overuse injuries. Conflicting results have been found with regard to differences in navicular drop between healthy and injured participants. Normal values have not yet been established as foot length, age, gender, and Body Mass Index (BMI) may influence the navicular drop. The purpose of the study was to investigate the influence of foot length, age, gender, and BMI on the navicular drop during walking.
Navicular drop was measured with a novel technique (Video Sequence Analysis, VSA) using 2D video. Flat reflective markers were placed on the medial side of the calcaneus, the navicular tuberosity, and the head of the first metatarsal bone. The navicular drop was calculated as the perpendicular distance between the marker on the navicular tuberosity and the line between the markers on calcaneus and first metatarsal head. The distance between the floor and the line in standing position between the markers on calcaneus and first metatarsal were added afterwards.
280 randomly selected participants without any foot problems were analysed during treadmill walking (144 men, 136 women). Foot length had a significant influence on the navicular drop in both men (p < 0.001) and women (p = 0.015), whereas no significant effect was found of age (p = 0.27) or BMI (p = 0.88). Per 10 mm increase in foot length, the navicular drop increased by 0.40 mm for males and 0.31 mm for females. Linear models were created to calculate the navicular drop relative to foot length.
The study demonstrated that the dynamic navicular drop is influenced by foot length and gender. Lack of adjustment for these factors may explain, at least to some extent, the disagreement between previous studies on navicular drop. Future studies should account for differences in these parameters.
PMCID: PMC2685774  PMID: 19422696
10.  The effects of low-sodium peritoneal dialysis fluids on blood pressure, thirst and volume status 
Nephrology Dialysis Transplantation  2009;24(5):1609-1617.
Background. Poor ultrafiltration is associated with worse outcomes in peritoneal dialysis (PD) patients. This might in part reflect problems associated with salt and water excess. Increasing the diffusive component of peritoneal sodium removal using low-sodium PD fluids might have beneficial effects on blood pressure (BP), thirst and fluid status that could translate into clinical benefits.
Methods. Using a multicentre, prospective, baseline controlled (1 month), non-randomized intervention (2 months) design, two novel solutions designed from predictions using the three-pore model were investigated. In group A ([Na+] = 115 mmol/l), the glucose (G) was increased to 2.0% to compensate for reduced osmolality whereas in group B ([Na+] = 102 mmol/l), it was unchanged (2.5%). Both solutions were substituted for one 3- to 5-h exchange per day and no change was made to the rest of the dialysis regime.
Results. Ten patients in group A and 15 in group B completed the study. Both solutions resulted in significant increases (30–50 mmol/dwell) in diffusive sodium removal during the test exchanges, P < 0.001. Ultrafiltration was maintained in group A but reduced in group B. Ambulatory nocturnal mean BP fell in group A [93.1 ± 10.6 mmHg (±SD) versus 85.1 ± 10.2 mmHg, P < 0.05], but was stable in group B (95.4 ± 9.4 versus 95.1.1 ± 10.7 mmHg, NS). Thirst reduced independent of appetite and mood in both groups by 2 months, more markedly in group A. Indices of fluid status, including TBW by bioimpedance and D dilution also improved in group A, P < 0.05, whereas weight increased in group B.
Conclusions. Increasing the diffusive component of sodium removal whilst maintaining ultrafiltration is associated with improvements in BP, thirst and fluid status. The lack of effect seen with uncompensated low-sodium dialysate suggests that these benefits cannot be achieved by manipulation of dialysate sodium removal alone. These observations provide valuable information of the design of future randomized studies to establish the clinical role for low-sodium dialysis fluids.
PMCID: PMC2668964  PMID: 19145002
bioimpedance; blood pressure; deuterium; fluid status; thirst
11.  Fall risk in an active elderly population – can it be assessed? 
Falls amongst elderly people are often associated with fractures. Training of balance and physical performance can reduce fall risk; however, it remains a challenge to identify individuals at increased risk of falling to whom this training should be offered. It is believed that fall risk can be assessed by testing balance performance. In this study a test battery of physiological parameters related to balance and falls was designed to address fall risk in a community dwelling elderly population.
Ninety-four elderly males and females between 70 and 80 years of age were included in a one year follow-up study. A fall incidence of 15% was reported. The test battery scores were not different between the fallers and non-fallers. Test scores were, however, related to self-reported health. In spite of inclusion of dynamic tests, the test battery had low fall prediction rates, with a sensitivity and specificity of 50% and 43% respectively.
Individuals with poor balance were identified but falls were not predicted by this test battery. Physiological balance characteristics can apparently not be used in isolation as adequate indicators of fall risk in this population of community dwelling elderly. Falling is a complex phenomenon of multifactorial origin. The crucial factor in relation to fall risk is the redundancy of balance capacity against the balance demands of the individuals levels of fall-risky lifestyle and behavior. This calls for an approach to fall risk assessment in which the physiological performance is evaluated in relation to the activity profile of the individual.
PMCID: PMC1794539  PMID: 17257414

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