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General practitioners (GPs) are qualified and trained to administer therapeutic musculoskeletal injections when indicated. However, it is unknown to what extend Dutch GPs feel competent to administer these injections in clinical practice. Reluctance among GPs to inject might lead to unnecessary and costly referral to secondary care. An online and offline questionnaire was spread among Dutch GPs, querying demographics, GPs’ self-assessment of injection competence, the number of administered/referred injections and management strategy for musculoskeletal injections. A total of 355 GPs responded. In total, 81% of the GPs considered themselves competent in administering musculoskeletal injections. Self-assessed incompetent GPs performed less injections the last month than self-assessed competent GPs (1.2 ± 1.4 vs 4.8 ± 4.6 injections, P < 0.001). Additionally, they referred four times more often to a colleague GP (0.4 ± 1.0 vs 0.1 ± 0.6 injections per month, P < 0.001) and twice as often to secondary care (1.0 ± 1.3 vs 0.5 ± 0.9 injections per month, P = 0.001). Self-assessed incompetence was associated with female sex (OR [95% CI] = 4.94 [2.39, 10.21]) and part-time work (OR [95% CI] = 2.58 [1.43, 4.66]). The most frequently addressed barriers were a lack of confidence in injection skills, lack of practical training, and uncertainty about the effectiveness and diagnosis of musculoskeletal injections. Although most GPs considered themselves competent to administer musculoskeletal injections, the referral rate to secondary care for several injections was strikingly high. To decrease secondary care referrals, addressing some of the most frequently indicated barriers is highly recommended.

Mesenchymal stem cells (MSC) are promising candidates for use as a biological therapeutic. Since locally injected MSC disappear within a few weeks, we hypothesize that efficacy of MSC can be enhanced by prolonging their presence. Previously, encapsulation in alginate was suggested as a suitable approach for this purpose. We found no differences between the two alginate types, alginate high in mannuronic acid (High M) and alginate high in guluronic acid (High G), regarding MSC viability, MSC immunomodulatory capability, or retention of capsule integrity after subcutaneous implantation in immune competent rats. High G proved to be more suitable for production of injectable beads. Firefly luciferase-expressing rat MSC were used to track MSC viability. Encapsulation in high G alginate prolonged the presence of metabolically active allogenic MSC in immune competent rats with monoiodoacetate-induced osteoarthritis for at least 8 weeks. Encapsulation of human MSC for local treatment by intra-articular injection did not significantly influence the effect on pain, synovial inflammation, or cartilage damage in this disease model. MSC encapsulation in alginate allows for an injectable approach which prolongs the presence of viable cells subcutaneously or in an osteoarthritic joint. Further fine tuning of alginate formulation and effective dosage for might be required in order to improve therapeutic efficacy depending on the target disease. [Figure not available: see fulltext.].

BACKGROUND: The knee is symptomatically the most frequent affected joint in osteoarthritis and, in the Netherlands and other Western countries, is mainly managed by general practitioners (GPs). An intra-articular glucocorticoid injection is recommended in (inter) national guidelines for patients with knee osteoarthritis as an option for a flare of knee pain and/or for those who are not responding well to pain medication. An innovative approach that could replace the intra-articular injection is an intramuscular gluteal glucocorticoid injection. An intramuscular injection is easier to perform than an intra-articular injection with lesser risk of severe local adverse reactions. We hypothesize that intramuscular gluteal glucocorticoid injection is non-inferior in reducing knee pain compared to intra-articular glucocorticoid injection, with potentially a longer lasting effect than intra-articular injection. METHODS/DESIGN: The study will be a pragmatic randomized controlled non-inferiority trial with two parallel groups. A total of 140 patients aged 45 years and older with knee osteoarthritis who contacted their general practitioner and have persistent knee pain (score ≥ 3 on 0-10 numerical rating scale; 0 = no knee pain) will be included. Patients will be randomly allocated (1:1) to an injection of 40

Surgery of long bone metastases is associated with a significant risk of perioperative blood loss, which may necessitate blood transfusion. Successful embolization (> 70% obliteration of vascularity) can be achieved in 36-75% of cases. The reported rate of embolization-related complications is 0-9%. Three out of six level III evidence studies showed a reduction in perioperative blood loss and/orblood transfusion requirement after preoperative embolization of renal cell carcinoma metastasis in long bones; three out of six studies did not. One level III evidence study did not show a reduction in perioperative blood loss and/or transfusion requirement after preoperative embolization of hepatocellular carcinoma metastases in long bones. There were no studies found that support preoperative embolization of thyroid metastases or other frequent long bone metastases (e.g. mamma carcinoma, lung carcinoma, or prostate carcinoma). The clinical level of evidence of the studies found is low and randomized studies taking into account primary tumour, location of metastases and type of surgery are therefore desired.

Objective: Subchondral bone changes, characterized by increased bone turnover and vascularity, are believed to stimulate progression and pain in knee osteoarthritis (OA). The objective of this study was to evaluate the bone perfusion in knee OA using quantitative dynamic contrast enhanced MRI (DCE-MRI). Design: Unicompartmental knee OA patients were included and underwent 3 Tesla DCE-MRI and T2-weighted MRI. Quantitative DCE-MRI analysis of Ktrans and Kep, representing perfusion parameters, was performed to evaluate differences between the most and least affected knee compartment. First, DCE-MRI parameter differences between epimetaphyseal and subchondral bone in both femur and tibia were assessed. Second, DCE-MRI parameters in subchondral bone marrow lesions (BMLs) were compared to surrounding subchondral bone without BMLs. Results: Twenty-three patients were analyzed. Median Ktrans and Kep in epimetaphyseal bone were significantly higher (p < 0.05) in the most affected (Ktrans: 0.014; Kep: 0.054 min−1) compared to least affected (Ktrans: 0.010; Kep: 0.016 min−1) compartment. For subchondral bone, DCE-MRI parameters were significantly higher (p < 0.05) in the most affected (Ktrans: 0.019; Kep: 0.091 min−1) compared to least affected (Ktrans: 0.014; Kep: 0.058 min−1) compartment as well. Subchondral BMLs detected on fat-saturated T2-weighted images were present in all patients. Median Ktrans (0.091 vs 0.000 min−1) and Kep (0.258 vs 0.000 min−1) were significantly higher within subchondral BMLs compared to surrounding subchondral bone without BMLs (p < 0.001). Conclusions: Increased perfusion parameters in epimetaphyseal bone, subchondral bone and BMLs are observed in unicompartmental knee OA. BMLs likely account for most of the effect of the higher bone perfusion in knee OA.

BACKGROUND: Computer Assisted Surgery (CAS) has proven to improve the accuracy in several orthopedic procedures. Therefore we used this technique to evaluate femoral component positioning in Hip Resurfacing Arthroplasty (HRA). The aim of this study was to evaluate imageless CAS compared to manually implanted femoral components and subsequently evaluates Patient Related Outcome Measures (PROMs). We hypothesized that the use of CAS optimizes the position of the femoral component and improves PROMs. METHODS: This is a multicenter, single-blinded, randomized, controlled trial of two groups. In the CAS group guiding of the femoral component was done with imageless navigation. In the Conventional (control) group the femoral component was placed manually according to the preplanned position. The primary outcome measure consists of a maximum of 3 degrees difference between the postoperative Stem Shaft Angle (SSA) and preplanned SSA. Secondary outcome measures consist of the Hip disability and Osteoarthritis Outcome Scale (HOOS), the Harris Hip Score (HHS) and Visual Analogue Scale (VAS) pain score. RESULTS: A total of 122 patients were randomized, 61 in the CAS group and 61 in the conventional group. There was no significant differences in accuracy of femoral implant position. The mean difference between the postoperative- and preplanned SSA was - 2.26 and - 1.75 degrees (more varus) respectively in the CAS and Conventional group. After surgery both groups show significant improvement in all PROMs compared to the baseline measurements, with no significant differences between the groups. CONCLUSION: Our cohort indicates no benefit for the use of CAS in accuracy of placement of the femoral component in HRA compared to manual implantation. There are no clinical differences in PROMs after 1 year follow up. This study showed no added value and no justification for the use of CAS in femoral component positioning in HRA. TRIAL REGISTRATION: This trial is registered at ClinicalTrai

Background: Predicting which patients with hip osteoarthritis are more likely to show disease progression is important for healthcare professionals. Therefore, the aim of this review was to assess which factors are predictive of progression in patients with hip osteoarthritis. Methods: A literature search was made up until 14 March 2019. Included were cohort and case-control studies evaluating the association between factors and progression (either clinical, radiological, or THR). Excluded were studies with a follow-up < 1 year or specific underlying pathologies of osteoarthritis. Risk of bias was assessed using the QUIPS tool. A best-evidence synthesis was conducted. Results: We included 57 articles describing 154 different factors. Of these, a best-evidence synthesis was p

Background: High molecular weight (HMW) hyaluronic acid (HA) is a treatment option for knee osteoarthritis (OA). The efficacy of HMW-HA in knee OA is investigated extensively, but the effectiveness in patients in the working age is unknown. Nevertheless, the number knee OA patients in the working age is increasing. Surgical treatment options are less eligible in these patients and productivity losses are high. In this study the effectiveness of intraarticular HMW-HA added to regular non-surgical usual care in everyday clinical practice (UC) compared to UC over 52 weeks in symptomatic knee OA patients in the working age was investigated. Methods: In this open labelled randomized controlled trial, subjects aged between 18 and 65 years with symptomatic knee OA (Kellgren and Lawrence I-III) were enrolled and randomized to UC + 3 weekly injections with HMW-HA (intervention) or UC only (control). The primary outcome was the between group difference in responders to therapy according to OMERACT-OARSI criteria after 52 weeks. These criteria include the domains pain, knee related function and patient’s global assessment (PGA). Function was evaluated with the KOOS questionnaire. Pain was assessed with the Numeric Rating Scale. Secondary outcome comprised the between group difference on the individual responder domains, as analysed with a random effects model. Odds Ratios (OR) were calculated by logistic regression analysis. Sensitivity analyses were performed. Results: In total, 156 subjects were included (intervention group 77, control group 79). Subjects in the intervention group (HMW-HA + UC) were more often responder compared to the controls (UC). Depending on whether pain during rest or pain during activity was included in the responder domains, 57.1% versus 34.2% (p = 0.006) and 54.5% versus 34.2% (p = 0.015) was responder to therapy respectively. The results of the secondary o

Background: Osteoarthritis (OA) is a degenerative joint disease leading to pain and disability for which no curative treatment exists. A promising biological treatment for OA is intra-articular administration of platelet-rich plasma (PRP). PRP injections in OA joints can relieve pain, although the exact working mechanism is unclear. Purpose: To examine the effects of PRP releasate (PRPr) on pain, cartilage damage, and synovial inflammation in a mouse OA model. Study Design: Controlled laboratory study. Methods: OA was induced unilaterally in the knees of male mice (n = 36) by 2 intra-articular injections of collagenase at days –7 and –5. At day 0, pain was measured by registering weight distribution on the hindlimbs, after which mice were randomly divided into 2 groups. Mice received 3 intra-articular injections of PRP or saline in the affected knee. Seven mice per group were euthanized at day 5 for assessment of early synovial inflammation and cartilage damage. Pain in the remaining mice was registered for a total of 3 weeks. These mice were euthanized at day 21 for assessment of cartilage damage and synovial inflammation on histological evaluation. Antibodies against iNOS, CD163, and CD206 were used to identify different subtypes of macrophages in the synovial membrane. Results: Mice in the PRPr group increased the distribution of weight on the affected joint in 2 consecutive weeks after the start of the treatment (P <.05), whereas mice in the saline group did not. At day 21, PRPr-injected knees had a thinner synovial membrane (P <.05) and a trend toward less cartilage damage in the lateral joint compartment (P =.053) than saline-injected knees. OA knees treated with saline showed less anti-inflammatory (CD206+ and CD163+) cells at day 5 than healthy knees, an observation that was not made in the PRPr-treated group. A higher level of pain at day 7 was associated with a thicker synovial membrane at day 21. The presence of CD206+ cells was negatively associated with

BACKGROUND:: Connective tissue progenitors (CTPs) from native bone marrow (BM) or their culture-expanded progeny, often referred to as mesenchymal stem/stromal cells, represents a promising strategy for treatment of cartilage injuries. But the cartilage regeneration capacity of these cells remains unpredictable because of cell heterogeneity. HYPOTHESIS:: The harvest technique of BM may highly influence stem cell heterogeneity and, thus, cartilage formation because these cells have distinct spatial localization within BM from the same bone. STUDY DESIGN:: Controlled laboratory study. METHODS:: CTPs obtained from the femur of patients undergoing total hip replacement by 2 harvest techniques-BM aspiration and BM collection-after bone rasping were immunophenotyped by flow cytometry and evaluated for chondrogenic ability. The spatial localization of different CTP subsets in BM was verified by immunohistochemistry. RESULTS:: Cells from the BM after rasping were significantly more chondrogenic than the donor-matched aspirate, whereas no notable difference in their osteogenic or adipogenic potential was observed. The authors then assessed whether distinct immunophenotypically defined CTP subsets were responsible for the different chondrogenic capacity. Cells directly isolated from BM after rasping contained a higher percentage (mean, 7.2-fold) of CD45-CD271+CD56+ CTPs as compared with BM aspirates. The presence of this subset in the harvested BM strongly correlated with chondrogenic ability, showing that CD271+CD56+ cells are enriched in chondroprogenitors. Furthermore, evaluation of these CTP subsets in BM revealed that CD271+CD56+ cells were localized in the bone-lining regions whereas CD271+CD56- cells were found in the perivascular regions. Since the iliac crest remains a frequent site of BM harvest for musculoskeletal regeneration, the authors also compared the spatial distribution of these subsets in trabeculae of femoral head and iliac crest and found CD271+CD56+ bon

Bone marrow formation requires an orchestrated interplay between osteogenesis, angiogenesis, and hematopoiesis that is thought to be mediated by endothelial cells. The nature of the endothelial cells and the molecular mechanisms underlying these events remain unclear in humans. Here, we identify a subset of endoglin-expressing endothelial cells enriched in human bone marrow during fetal ontogeny and upon regeneration after chemotherapeutic injury. Comprehensive transcriptional characterization by massive parallel RNA sequencing of these cells reveals a phenotypic and molecular similarity to murine type H endothelium and activation of angiocrine factors implicated in hematopoiesis, osteogenesis, and angiogenesis. Interleukin-33 (IL-33) was significantly overexpressed in these endothelial cells and promoted the expansion of distinct subsets of he

Purpose: Varus medial knee osteoarthritis (OA) can be treated with a closing-wedge (CW) or opening-wedge (OW) high tibial osteotomy (HTO). Little is known about the adverse event (AE) rate of these techniques. The purpose of this study was to examine the AE rate and survival rate of a consecutive series of 412 patients undergoing CW- or OW-HTO. Methods: Medical records were retrospectively screened, and all patients who underwent HTO from 1993 to 2012 at the Erasmus University Medical Centre were assessed with a self-administered questionnaire. Patients filled in the intermittent and constant osteoarthritis pain score, knee injury and osteoarthritis outcome score, and a general questionnaire focusing on AE. Results: Medical records of 412 patients (354 CW- and 112 OW-HTOs) were screened. Of the 358 eligible patients, 291 (81 %) returned their questionnaire. A total of 80 AE (17 %) were found in 466 osteotomies. In the CW-group, 47 (13 %) serious adverse events (SAE) and 2 (0.6 %) AE were found. In the OW-group, 17 (15 %) SAE and 14 (13 %) AE were found. The most common AE was in 14 (4 %) patients of the CW-group sensory palsy of the common peroneal nerve. The most common AE in the OW-group was persistent pain at the iliac crest [11 (9.8 %) patients]. Hardware was removed in 48 % of the CW-osteotomies and 71 % of the OW-osteotomies (p < 0.05). The probability of survival was 75 % after 10 years in the CW-group versus 90 % in the OW-group (p < 0.05). In both groups, an equal number of patients were “in need for prosthesis” according to OARSI criteria. Conclusion: OW-HTO was associated with more AE than CW-HTO. OW-HTO resulted in better survival than CW-HTO. However, in both groups an equal number of patients were in need for prosthesis. Level of evidence: Retrospective comparative study, Level III.

Background: Atypical femur fractures (AFFs) present a rare but serious condition associated with use of bisphosphonates. Underlying mechanisms and clinical risk factors remain unclear. According to the diagnostic criteria formulated by the ASBMR, a lateral localization of an AFF is required. Case history: We present a patient who developed bilateral leg pain while using an oral bisphosphonate and aromatase inhibitor in the course of adjuvant treatment for breast cancer. Initially she was diagnosed with bone metastases and received radiotherapy on the right femur. However, the bilateral periosteal reactions of the subtrochanteric femur are highly suggestive of AFFs. Our case meets all criteria for AFF except that she presented with lesions at the medial side of the femur. Therefore they could be best described as "atypical" atypical femur fractures. Discussion: Since the pathogenesis of AFFs is not fully understood, we cannot rule out that AFFs also occur in the medial femur or in other weight-baring bones. Hence we propose that medial stress reactions belong to a spectrum of atypical fractures associated with use of antiresorptive drugs. The localization may depend on yet unknown biome-chanical factors. Conclusion: We propose that these periosteal reactions of the subtrochanteric femur are in fact AFFs with uncommon medial localization and could hence be considered "atypical" AFFs. We recommend being alert of AFFs in patients with bone pain and medial subtrochanteric lesions. More epidemiological studies are needed to investigate the occurrence of both medial and lateral AFFs and to gain more insight into its frequency and pathogenesis.

Purpose: To determine if T1r mapping can be used as an alternative to delayed gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) in the quantification of cartilage biochemical composition in vivo in human knees with osteoarthritis. Materials and Methods: This study was approved by the institutional review board. Written informed consent was obtained from all participants. Twelve patients with knee osteoarthritis underwent dGEMRIC and T1r mapping at 3.0 T before undergoing total knee replacement. Outcomes of dGEMRIC and T1r mapping were calculated in six cartilage regions of interest. Femoral and tibial cartilages were harvested during total knee replacement. Cartilage sulphated glycosaminoglycan (sGAG) and collagen content were assessed with dimethylmethylene blue and hydroxyproline assays, respectively. A four-dimensional multivariate mixed-effects model was used to simultaneously assess the correlation between outcomes of dGEMRIC and T1r mapping and the sGAG and collagen content of the articular cartilage. Results: T1 relaxation times at dGEMRIC showed strong correlation with cartilage sGAG content (r = 0.73; 95% credibility interval [CI] = 0.60, 0.83) and weak correlation with cartilage collagen content (r = 0.40; 95% CI: 0.18, 0.58). T1r relaxation times did not correlate with cartilage sGAG content (r = 0.04; 95% CI: 20.21, 0.28) or collagen content (r = 20.05; 95% CI = 20.31, 0.20). Conclusion: dGEMRIC can help accurately measure cartilage sGAG content in vivo in patients w

Background: The results of conservative treatment of knee osteoarthritis (OA) are generally evaluated in epidemiological studies with clinical outcome measures as primary outcomes. Biomechanical evaluation of orthoses shows that there are potentially beneficial biomechanical changes to joint loading; however, evaluation in relation to clinical outcome measures in longitudinal studies is needed.Questions/purposes: We asked (1) is there an immediate effect on gait in patients using a laterally wedged insole or valgus knee brace; (2) is there a late (6 weeks) effect; and (3) is there a difference between subgroups within each group with respect to patient compliance, body mass index, and OA status?Methods: This was a secondary analysis of data from a previous randomized controlled trial of patients with early medial knee OA. A total of 91 patients were enrolled in that trial, and 73 (80%) completed it after 6 months. Of the enrolled patients, 80 (88%) met prespecified inclusion criteria for analysis in the present study. The patients were randomized to an insole or brace. Gait was analyzed with and without wearing the orthosis (insole or brace) at baseline and after 6 weeks. Measurements were taken of the knee adduction moment, ground reaction force, moment arm, walking speed, and toe-out angle. Data were analyzed with regression analyses based on an intention-to-treat principle.Results: A mean reduction of 4% (± 10) (95% confidence interval [CI], −0.147 to −0.03, p = 0.003) of the peak knee adduction moment and 4% (± 13) (95% CI, −0.009 to −0.001, p = 0.01) of the moment arm at baseline was observed in the insole group when walking with an insole was compared with walking without an insole. A me

To assess associations between uCTX-II or uCIIM and severity of hip pain in patients with mild-moderate hip osteoarthritis (OA) over a 2-year period, and establish whether the level of these biomarkers at baseline could estimate a specific trajectory of hip pain. Design: A cohort study with a 2-year follow-up and 6-monthly measurements of urinary biomarkers (uCTX-II and uCIIM) and symptom severity. Patients were recruited from general practices. The primary outcome was hip pain, measured with the Western Ontario and McMasters University Osteoarthritis Index (WOMAC) subscale and the Visual Analog Scale (VAS). Associations between hip pain and biomarkers were assessed using linear mixed-model analysis for repeated measurements. Five previously identified pain trajectories were used as outcome to investigate whether the level of biomarkers at baseline could estimate membership in one of the trajectories using multinomial regression analysis. Results: LoguCTX-II and loguCIIM were not associated with WOMAC pain or VAS pain during the 2-year follow-up. Patients in the highly progressive pain trajectory and the moderate pain trajectory were more likely to have a higher loguCTX-II at baseline (OR 6.7; 95% CI 1.6-28.2 and OR 4.8; 95% CI 1.0-22.8, respectively) than patients in the mild pain trajectory. Conclusion: This study shows that in patients with mild-moderate hip OA the urinary biochemical markers uCTX-II and uCIIM are not cross-sectionally associated with hip pain during the 2-year follow-up. Because the uCTX-II level estimated a progressive or moderate hip pain trajectory, this correlation needs to be confirmed in additional patients with hip OA.

Background: Despite intensive surveillance, a high rate of interval malignancies is still seen in women at increased breast cancer risk. Therefore, novel screening modalities aiming at early detection remain needed. The intraductal approach offers the possibility to directly sample fluid containing cells, DNA and proteins from the mammary ductal system where, in the majority of cases, breast cancer originates. Fluid from the breast can non-invasively be obtained by oxytocin-assisted vacuum aspiration, called nipple fluid aspiration (NFA). The goal of this feasibility study was to evaluate the potential of repeated NFA, which is a critical and essential step to evaluate its possible value as a breast cancer screening method. Methods: In this multicenter, prospective study, we annually collected nipple fluid for up to 5 consecutive years from women at increased breast cancer risk, and performed a questionnaire-based survey regarding discomfort of the aspiration. Endpoints of the current interim analyses were the feasibility and results of 994 NFA procedures in 451 women with total follow-up of 560 person years of observation. Results: In this large group of women at increased risk of breast cancer, repetitive NFA appeared to be feasible and safe. In 66.4% of aspirated breasts, nipple fluid was successfully obtained. Independent predictive factors for successful NFA were premenopausal status, spontaneous nipple discharge, smaller breast size, bilateral oophorectomy and previous use of hormone replacement therapy or anti-hormonal treatment. The procedure was well tolerated with low discomfort. Drop-out rate was 20%, which was mainly due to repeated unsuccessful aspiration attempts. Only 1.6% of women prematurely declined further participation because of side effects. Conclusions: Repeated NFA in women at increased breast cancer risk is feasible and safe. Therefore, NFA is a promising method to non-invasively obtain a valuable source of potential breast cancer specific b

Background: Fractures of the humeral shaft are associated with a profound temporary (and in the elderly sometimes even permanent) impairment of independence and quality of life. These fractures can be treated operatively or non-operatively, but the optimal tailored treatment is an unresolved problem. As no high-quality comparative randomized or observational studies are available, a recent Cochrane review concluded there is no evidence of sufficient scientific quality available to inform the decision to operate or not. Since randomized controlled trials for this injury have shown feasibility issues, this study is designed to provide the best achievable evidence to answer this unresolved problem. The primary aim of this study is to evaluate functional recovery after operative versus non-operative treatment in adult patients who sustained a humeral shaft fracture. Secondary aims include the effect of treatment on pain, complications, generic health-related quality of life, time to resumption of activities of daily living and work, and cost-effectiveness. The main hypothesis is that operative treatment will result in faster recovery. Methods/design. The design of the study will be a multicenter prospective observational study of 400 patients who have sustained a humeral shaft fracture, AO type 12A or 12B. Treatment decision (i.e., operative or non-operative) will be left to the discretion of the treating surgeon. Critical elements of treatment will be registered and outcome will be monitored at regular intervals over the subsequent 12 months. The primary outcome measure is the Disabilities of the Arm, Shoulder, and Hand score. Secondary outcome measures are the Constant score, pain level at both sides, range of motion of the elbow and shoulder joint at both sides, radiographic healing, rate of complications and (secondary) interventions, health-related quality of life (Short-Form 36 and EuroQol-5D), time to resumption of ADL/work, and cost-effectiveness. Data will be a

Introduction: Viscosupplementation with hyaluronic acid (HA) of osteoarthritic (OA) knee joints has a well-established positive effect on clinical symptoms. This effect, however, is only temporary and the working mechanism of HA injections is not clear. It was suggested that HA might have disease modifying properties because of its beneficial effect on cartilage sulphated glycosaminoglycan (sGAG) content. Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) is a highly reproducible, non-invasive surrogate measure for sGAG content and hence composition of cartilage. The aim of this study was to assess whether improvement in cartilage structural composition is detected using dGEMRIC 14 weeks after 3 weekly injections with HA in patients with early-stage knee OA. Methods: In 20 early-stage knee OA patients (KLG I-II), 3D dGEMRIC at 3T was acquired before and 14 weeks after 3 weekly injections with HA. To evaluate patient symptoms, the knee injury and osteoarthritis outcome score (KOOS) and a numeric rating scale (NRS) for pain were recorded. To evaluate cartilage composition, six cartilage regions in the knee were analyzed on dGEMRIC. Outcomes of dGEMRIC, KOOS and NRS before and after HA were compared using paired t-testing. Since we performed multiple t-tests, we applied a Bonferroni-Holm correction to determine statistical significance for these analyses. Results: All KOOS subscales ('pain', 'symptoms', 'daily activities', 'sports' and 'quality of life') and the NRS pain improved significantly 14 weeks after Viscosupplementation with HA. Outcomes of dGEMRIC did not change significantly after HA compared to baseline in any of the cartilage regions analyzed in the knee. Conclusions: Our results confirm previous findings reported in the literature, showing persisting improvement in symptomatic outcome measures in early-stage knee OA patients 14 weeks after Viscosupplementation. Outcomes of dGEMRIC, however, did not change after Viscosupplementation, indicating no chan

Introduction: Viscosupplementation with hyaluronic acid (HA) of osteoarthritic (OA) knee joints has a well-established positive effect on clinical symptoms. This effect, however, is only temporary and the working mechanism of HA injections is not clear. It was suggested that HA might have disease modifying properties because of its beneficial effect on cartilage sulphated glycosaminoglycan (sGAG) content. Delayed gadolinium-enhanced MRI of cartilage (dGEMRIC) is a highly reproducible, non-invasive surrogate measure for sGAG content and hence composition of cartilage. The aim of this study was to assess whether improvement in cartilage structural composition is detected using dGEMRIC 14 weeks after 3 weekly injections with HA in patients with early-stage knee OA. Methods: In 20 early-stage knee OA patients (KLG I-II), 3D dGEMRIC at 3T was acquired before and 14 weeks after 3 weekly injections with HA. To evaluate patient symptoms, the knee injury and osteoarthritis outcome score (KOOS) and a numeric rating scale (NRS) for pain were recorded. To evaluate cartilage composition, six cartilage regions in the knee were analyzed on dGEMRIC. Outcomes of dGEMRIC, KOOS and NRS before and after HA were compared using paired t-testing. Since we performed multiple t-tests, we applied a Bonferroni-Holm correction to determine statistical significance for these analyses. Results: All KOOS subscales ('pain', 'symptoms', 'daily activities', 'sports' and 'quality of life') and the NRS pain improved significantly 14 weeks after Viscosupplementation with HA. Outcomes of dGEMRIC did not change significantly after HA compared to baseline in any of the cartilage regions analyzed in the knee. Conclusions: Our results confirm previous findings reported in the literature, showing persisting improvement in symptomatic outcome measures in early-stage knee OA patients 14 weeks after Viscosupplementation. Outcomes of dGEMRIC, however, did not change after Viscosupplementation, indicating no chan

Purpose A possible cause of hip pain is the presence of radiating pain from the higher lumbar spine. Identification of factors associated with hip pain arising from the lumbar spine would aid the physician. The first step in identifying possible factors is to look at the association between hip pain and osteoarthritis of the lumbar spine. Methods In an open population based study of people 55 years and older (Rotterdam study), 2,819 lumbar radiographs were scored for the presence and severity of individual radiographic features of disk degeneration. Hip osteoarthritis was scored on anteroposterior pelvic radiographs, and questionnaires including self-reported hip pain were taken. Logistic regression adjusted for possible confounders was used to determine the association between self-reported hip pain and the individual radiographic features of lumbar disk degeneration. Results The presence of dis space narrowing grade C1 at level L1/L2 was significantly associated with hip pain in the last month (men OR = 2.0; 95 % CI 1.1-3.8 and women OR = 1.7; 95 % CI 1.1-2.5). The presence of disk space narrowing grade C1 at level L2/L3 was only significantly associated with hip pain in women. The strength of the associations increased for self-reported chronic hip pain, especially in men (L1/L2 OR = 2.5; 95 % CI 1.3-5.0). The presence of disk space narrowing at the lower levels (L3/L4/L5/S1) was not significantly associated with hip pain. Conclusion Our data provide evidence for an association between hip pain and disk space narrowing at disk level L1/L2 and L2/L3. In case of uncertainty of the cause of hip pain, evaluation of lumbar radiographs may help to identify those hip pain patients who might have pain arising from the lumbar spine.

Background Although recurrent hamstring injury is a frequent problem with a significant impact on athletes, data on factors determining the risk for a recurrent hamstring injury are scarce. Objective To systematically review the literature and provide an overview of risk factors for re-injury of acute hamstring muscle injuries. Study design Prospective studies on risk factors for re-injury following acute hamstring injuries were systematically reviewed. Medical databases and reference lists of the included articles were searched. Two reviewers independently selected potential studies and assessed methodological quality; one reviewer extracted the data. A best-evidence synthesis of all studied risk factors was performed. Results Of the 131 articles identified, five prospective follow-up studies fulfilled our inclusion criteria. These studies reported a recurrence incidence of 13.9-63.3% in the same playing season up to 2 years after initial injury. Limited evidence for three risk factors and one protective factor for recurrent hamstring injury was found; patients with a recurrent hamstring injury had an initial injury with a larger volume size as measured on MRI (47.03 vs 12.42 cm 3), more often had a Grade 1 initial trauma (Grade 0: 0-30.4%; Grade 1: 60.9-100%; Grade 2: 8.7%) and more often had a previous ipsilateral anterior cruciate ligament (ACL) reconstruction (66.6% vs 17.1%) independent of graft selection. Athletes in a rehabilitation programme with agility/stabilisation exercises rather than strength/stretching exercises had a lower risk for re-injury (7.7% vs 70%). No significant relationship with re-injury was found for 11 related determinants. There was conflicting evidence that a larger cross-sectional area is a risk factor for recurrent hamstring injury. Conclusions There is limited evidence that athletes with a larger volume size of initial trauma, a Grade 1 hamstring injury and a previous ipsilateral ACL reconstruction are at increased risk for recurre

Background Although recurrent hamstring injury is a frequent problem with a significant impact on athletes, data on factors determining the risk for a recurrent hamstring injury are scarce. Objective To systematically review the literature and provide an overview of risk factors for re-injury of acute hamstring muscle injuries. Study design Prospective studies on risk factors for re-injury following acute hamstring injuries were systematically reviewed. Medical databases and reference lists of the included articles were searched. Two reviewers independently selected potential studies and assessed methodological quality; one reviewer extracted the data. A best-evidence synthesis of all studied risk factors was performed. Results Of the 131 articles identified, five prospective follow-up studies fulfilled our inclusion criteria. These studies reported a recurrence incidence of 13.9-63.3% in the same playing season up to 2 years after initial injury. Limited evidence for three risk factors and one protective factor for recurrent hamstring injury was found; patients with a recurrent hamstring injury had an initial injury with a larger volume size as measured on MRI (47.03 vs 12.42 cm 3), more often had a Grade 1 initial trauma (Grade 0: 0-30.4%; Grade 1: 60.9-100%; Grade 2: 8.7%) and more often had a previous ipsilateral anterior cruciate ligament (ACL) reconstruction (66.6% vs 17.1%) independent of graft selection. Athletes in a rehabilitation programme with agility/stabilisation exercises rather than strength/stretching exercises had a lower risk for re-injury (7.7% vs 70%). No significant relationship with re-injury was found for 11 related determinants. There was conflicting evidence that a larger cross-sectional area is a risk factor for recurrent hamstring injury. Conclusions There is limited evidence that athletes with a larger volume size of initial trauma, a Grade 1 hamstring injury and a previous ipsilateral ACL reconstruction are at increased risk for recurre

Background:In diseased joints, the catabolic environment results in progressive joint damage. Mesenchymal stem cells (MSCs) can have immunomodulatory effects by secreting anti-inflammatory factors. To exert these effects, MSCs need to be triggered by proinflammatory cytokines. To explore the potential of MSCs as a treatment for diseased joints, we studied the effect of synovial fluid (SF) from donors with different joint diseases and donors without joint pathology on the immunomodulatory capacities of human MSCs in vitro. We hypothesized that SF of diseased joints influences the immunomodulatory effects of MSCs. Materials and Methods: MSCs were cultured in medium with SF of six osteoarthritis (OA) or six rheumatoid arthritis (RA) donors and three donors without joint pathology were used as control. Gene expressions of IL-6, HGF, TNFa, TGFb1, and indoleamine 2,3-dioxygenase (IDO) were analyzed. L-kynurenine concentration in conditioned medium (CM) by MSCs with SF was determined as a measure of IDO activity by MSCs. Furthermore, the effect of CM with SF on proliferation of activated lymphocytes was analyzed. Results: Addition of SF significantly up-regulated the mRNA expression of IL-6 and IDO in MSCs. SF(OA) induced significantly higher expression of IDO than SF(control), although no difference in IDO activity of the MSCs could be shown with a L-kynurenine assay. Medium conditioned by MSCs with SF(OA or RA) suppressed activated lymphocyte proliferation in vitro more than medium conditioned by MSCs without SF or with SF(control). Discussion: SF can influence the expression of genes involved in immunomodulation by MSCs and the effect on lymphocyte proliferation. We found indications for disease-specific differences between SFs but the variation between donors, even within one disease group was high. These data warrant further research to examine the potential application of MSC therapy in arthritic joints.

Background: Recent international guidelines recommend intra-articular corticosteroid injections for patients with hip osteoarthritis who have moderate to severe pain and do not respond satisfactorily to oral analgesic/anti- inflammatory agents. Of the five available randomized controlled trials, four showed positive effects with respect to pain reduction. However, intra-articular injection in the hip is complex because the joint is adjacent to important neurovascular structures and cannot be palpated. Therefore fluoroscopic or ultrasound guidance is needed. The systemic effect of corticosteroids has been studied in patients with impingement shoulder pain. Gluteal corticosteroid injection was almost as effective as ultrasound-guided subacromial corticosteroid injection. Such a clinically relevant effect of a systemic corticosteroid injection offers a less complex alternative for treatment of patients with hip osteoarthritis not responsive to oral pain medication. Methods/Design. This is a double-blinded, randomized controlled trial. A total of 135 patients (aged > 40 years) with hip osteoarthritis and persistent pain despite oral analgesics visiting a general practitioner or orthopaedic surgeon will be included. They will be randomized to a gluteal intramuscular corticosteroid injection or a gluteal intramuscular placebo (saline) injection. The randomization will be stratified for setting (general practitioner and outpatient clinics of department of orthopaedics). Treatment effect will be evaluated by questionnaires at 2, 4, 6, and 12 weeks follow-up and a physical examination at 12 weeks. Primary outcome is severity of hip pain reported by the patients at 2-week follow-up. Statistical analyses will be based on the intention-to-treat principle. Discussion. This study will evaluate the effectiveness of an intramuscular corticosteroid injection on pain in patients with hip osteoarthritis. Patient recruitment has started. Trial Registration. This trial is registered in

BACKGROUND: Articular cartilage has very limited intrinsic regenerative capacity, making cell-based therapy a tempting approach for cartilage repair. Cell tracking can be a major step towards unraveling and improving the repair process of these therapies. We studied superparamagnetic iron oxides (SPIO) for labeling human bone marrow-derived mesenchymal stem cells (hBMSCs) regarding effectivity, cell viability, long term metabolic cell activity, chondrogenic differentiation and hBMSC secretion profile. We additionally examined the capacity of synovial cells to endocytose SPIO from dead, labeled cells, together with the use of magnetic resonance imaging (MRI) for intra-articular visualization and quantification of SPIO labeled cells. METHODOLOGY/PRINICIPAL FINDINGS: Efficacy and various safety aspects of SPIO cell labeling were determined using appropriate assays. Synovial SPIO re-uptake was investigated in vitro by co-labeling cells with SPIO and green fluorescent protein (GFP). MRI experiments were performed on a clinical 3.0T MRI scanner. Two cell-based cartilage repair techniques were mimicked for evaluating MRI traceability of labeled cells: intra-articular cell injection and cell implantation in cartilage defects. Cells were applied ex vivo or in vit

The optimal stimulus to repair or regenerate cartilage is not known. We therefore modulated collagen deposition, collagen crosslinking and GAG deposition simultaneously during cartilage matrix production and integrative repair, creating more insight into their role in cartilage repair processes. Insulin-like growth factor 1 (IGF-1; increases proteoglycan and collagen synthesis), beta-aminopropionitrile (BAPN; a reversible inhibitor of collagen crosslinking) and para-nitrophenyl-beta-D-xyloside (PNPX; interferes with proteoglycan production) were used. Bovine articular chondrocytes were cultured in alginate beads for 3 weeks with or without IGF-1, BAPN or PNPX alone and in all possible combinations, followed by 3 weeks in control medium. DNA content, GAG and collagen deposition and collagen crosslinks were determined. Cartilage constructs were cultured under the same conditions and histologically analysed for integration of two opposing cartilage matrices. In alginate cultures, inhibition of collagen crosslinking with BAPN, in combination with promotion of matrix synthesis using IGF1, was most beneficial for matrix deposition. Addition of PNPX was always detrimental for matrix deposition. For integration of opposing cartilage constructs, the combination of BAPN, IGF1 and temporary prevention of proteoglycan formation with PNPX was most beneficial. When a new matrix is produced, proteoglycans are important to retain collagen in the matrix. When two already formed cartilage matrices have to integrate, a temporary absence of proteoglycans and temporary inhibition of collagen crosslinking might be more beneficial in combination with stimulation of collagen production, e.g. by IGF1. Therefore, the choice of soluble factors to promote cartilage regeneration depends on the type of therapy that will be used.

The objective of the present study was to investigate whether treatment of articular cartilage with hyaluronidase and collagenase enhances histological and mechanical integration of a cartilage graft into a defect. Discs of 3 mm diameter were taken from 8-mm diameter bovine cartilage explants. Both discs and annulus were either treated for 24 hours with 0.1% hyaluronidase followed by 24 hours with 10 U/ml collagenase or left untreated (controls). Discs and annulus were reassembled and implanted subcutaneously in nude mice for 5 weeks. Integration of disc with surrounding cartilage was assessed histologically and tested biomechanically by performing a push-out test. After 5 weeks a significant increase in viable cell counts was seen in wound edges of the enzyme-treated group as compared with controls. Furthermore, matrix integration (expressed as a percentage of the total interface length that was connected; mean +/- standard error) was 83 +/- 15% in the treated samples versus 44 +/- 40% in the untreated controls. In the enzyme-treated group only, picro-Sirius Red staining revealed collagen crossing the interface perpendicular to the wound surface. Immunohistochemical analyses demonstrated that the interface tissue contained cartilage-specific collagen type II. Collagen type I was found only in a small region of fibrous tissue at the level of the superficial layer, and collagen type III was completely absent in both groups. A significant difference in interfacial strength was found using the push-out test: 1.32 +/- 0.15 MPa in the enzyme-treated group versus 0.84 +/- 0.14 MPa in the untreated controls. The study shows that enzyme treatment of cartilage wounds increases histological integration and improves biomechanical bonding strength. Enzymatic treatment may represent a promising addition to current techniques for articular cartilage repair.