Showing papers by "Nuffield Orthopaedic Centre published in 2012"

2012 Infectious Diseases Society of America Clinical Practice Guideline for the Diagnosis and Treatment of Diabetic Foot Infections

Abstract: Foot infections are a common and serious problem in persons with diabetes Diabetic foot infections (DFIs) typically begin in a wound, most often a neuropathic ulceration While all wounds are colonized with microorganisms, the presence of infection is defined by ≥2 classic findings of inflammation or purulence Infections are then classified into mild (superficial and limited in size and depth), moderate (deeper or more extensive), or severe (accompanied by systemic signs or metabolic perturbations) This classification system, along with a vascular assessment, helps determine which patients should be hospitalized, which may require special imaging procedures or surgical interventions, and which will require amputation Most DFIs are polymicrobial, with aerobic gram-positive cocci (GPC), and especially staphylococci, the most common causative organisms Aerobic gram-negative bacilli are frequently copathogens in infections that are chronic or follow antibiotic treatment, and obligate anaerobes may be copathogens in ischemic or necrotic wounds Wounds without evidence of soft tissue or bone infection do not require antibiotic therapy For infected wounds, obtain a post-debridement specimen (preferably of tissue) for aerobic and anaerobic culture Empiric antibiotic therapy can be narrowly targeted at GPC in many acutely infected patients, but those at risk for infection with antibiotic-resistant organisms or with chronic, previously treated, or severe infections usually require broader spectrum regimens Imaging is helpful in most DFIs; plain radiographs may be sufficient, but magnetic resonance imaging is far more sensitive and specific Osteomyelitis occurs in many diabetic patients with a foot wound and can be difficult to diagnose (optimally defined by bone culture and histology) and treat (often requiring surgical debridement or resection, and/or prolonged antibiotic therapy) Most DFIs require some surgical intervention, ranging from minor (debridement) to major (resection, amputation) Wounds must also be properly dressed and off-loaded of pressure, and patients need regular follow-up An ischemic foot may require revascularization, and some nonresponding patients may benefit from selected adjunctive measures Employing multidisciplinary foot teams improves outcomes Clinicians and healthcare organizations should attempt to monitor, and thereby improve, their outcomes and processes in caring for DFIs

Bayesian refinement of association signals for 14 loci in 3 common diseases.

Abstract: To further investigate susceptibility loci identified by genome-wide association studies, we genotyped 5,500 SNPs across 14 associated regions in 8,000 samples from a control group and 3 diseases: type 2 diabetes (T2D), coronary artery disease (CAD) and Graves' disease. We defined, using Bayes theorem, credible sets of SNPs that were 95% likely, based on posterior probability, to contain the causal disease-associated SNPs. In 3 of the 14 regions, TCF7L2 (T2D), CTLA4 (Graves' disease) and CDKN2A-CDKN2B (T2D), much of the posterior probability rested on a single SNP, and, in 4 other regions (CDKN2A-CDKN2B (CAD) and CDKAL1, FTO and HHEX (T2D)), the 95% sets were small, thereby excluding most SNPs as potentially causal. Very few SNPs in our credible sets had annotated functions, illustrating the limitations in understanding the mechanisms underlying susceptibility to common diseases. Our results also show the value of more detailed mapping to target sequences for functional studies.

Expert opinion on the management of infections in the diabetic foot.

Abstract: Summary This update of the International Working Group on the Diabetic Foot incorporates some information from a related review of diabetic foot osteomyelitis (DFO) and a systematic review of the management of infection of the diabetic foot. The pathophysiology of these infections is now well understood, and there is a validated system for classifying the severity of infections based on their clinical findings. Diagnosing osteomyelitis remains difficult, but several recent publications have clarified the role of clinical, laboratory and imaging tests. Magnetic resonance imaging has emerged as the most accurate means of diagnosing bone infection, but bone biopsy for culture and histopathology remains the criterion standard. Determining the organisms responsible for a diabetic foot infection via culture of appropriately collected tissue specimens enables clinicians to make optimal antibiotic choices based on culture and sensitivity results. In addition to culture-directed antibiotic therapy, most infections require some surgical intervention, ranging from minor debridement to major resection, amputation or revascularization. Clinicians must also provide proper wound care to ensure healing of the wound. Various adjunctive therapies may benefit some patients, but the data supporting them are weak. If properly treated, most diabetic foot infections can be cured. Providers practising in developing countries, and their patients, face especially challenging situations. Copyright © 2012 John Wiley & Sons, Ltd.

The impact of 18F-FDG PET on the management of patients with suspected large vessel vasculitis

Abstract: Purpose We aimed to assess the impact of 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET) on the management of patients with suspected large vessel vasculitis.

Clinical indications for musculoskeletal ultrasound: a Delphi-based consensus paper of the European Society of Musculoskeletal Radiology.

Abstract: To develop clinical guidelines for musculoskeletal ultrasound (MSKUS) referral in Europe. Sixteen musculoskeletal radiologists from seven European countries participated in a consensus-based interactive process (Delphi method) using consecutive questionnaires and consensus procedure meetings at several European radiology meetings. The evaluation of musculoskeletal diseases was established by literature reviews, followed by consensus on clinical utility in three consensus meetings. This involved a thorough, transparent, iterative approach which including interview, questionnaire, Delphi and standard setting methodologies. European MSK radiologists with a special interest in MSKUS formed two different expert groups who worked on reaching a consensus in the first two meetings. The third meeting resolved questions that did not achieve a consensus level of 67% using the first two questionnaires. On expert consensus, the use of MSKUS is indicated to detect joint synovitis, fluid and septic effusion for potential aspiration, and poorly indicated to detect loose bodies. Recommendations for most appropriate use of musculoskeletal ultrasound are reported in six areas relevant to musculoskeletal ultrasound: hand/wrist, elbow, shoulder, hip, knee and ankle/foot. A comprehensive evidence-based, expert consensus-defined educational framework on clinical ultrsound is presented. This should facilitate referrals for this important imaging technique throughout Europe. • Musculoskeletal ultrasound is indicated for detecting joint synovitis, effusions and fluid collections. • Musculoskeletal ultrasound is poor at detecting loose bodies. • Musculoskeletal ultrasound is relevant for most joints.

Executive Summary: 2012 Infectious Diseases Society of America Clinical Practice Guideline for the Diagnosis and Treatment of Diabetic Foot Infections

Abstract: Foot infections are a common and serious problem in persons with diabetes. Diabetic foot infections (DFIs) typically begin in a wound, most often a neuropathic ulceration. While all wounds are colonized with microorganisms, the presence of infection is defined by ≥2 classic findings of inflammation or purulence. Infections are then classified into mild (superficial and limited in size and depth), moderate (deeper or more extensive), or severe (accompanied by systemic signs or metabolic perturbations). This classification system, along with a vascular assessment, helps determine which patients should be hospitalized, which may require special imaging procedures or surgical interventions, and which will require amputation. Most DFIs are polymicrobial, with aerobic gram-positive cocci (GPC), and especially staphylococci, the most common causative organisms. Aerobic gram-negative bacilli are frequently copathogens in infections that are chronic or follow antibiotic treatment, and obligate anaerobes may be copathogens in ischemic or necrotic wounds. Wounds without evidence of soft tissue or bone infection do not require antibiotic therapy. For infected wounds, obtain a post-debridement specimen (preferably of tissue) for aerobic and anaerobic culture. Empiric antibiotic therapy can be narrowly targeted at GPC in many acutely infected patients, but those at risk for infection with antibiotic-resistant organisms or with chronic, previously treated, or severe infections usually require broader spectrum regimens. Imaging is helpful in most DFIs; plain radiographs may be sufficient, but magnetic resonance imaging is far more sensitive and specific. Osteomyelitis occurs in many diabetic patients with a foot wound and can be difficult to diagnose (optimally defined by bone culture and histology) and treat (often requiring surgical debridement or resection, and/or prolonged antibiotic therapy). Most DFIs require some surgical intervention, ranging from minor (debridement) to major (resection, amputation). Wounds must also be properly dressed and off-loaded of pressure, and patients need regular follow-up. An ischemic foot may require revascularization, and some nonresponding patients may benefit from selected adjunctive measures. Employing multidisciplinary foot teams improves outcomes. Clinicians and healthcare organizations should attempt to monitor, and thereby improve, their outcomes and processes in caring for DFIs.

A MRI classification of periprosthetic soft tissue masses (pseudotumours) associated with metal-on-metal resurfacing hip arthroplasty.

Abstract: Objective Metal-on-metal hip resurfacing arthroplasty (MoMHRA) has become a popular option for young patients requiring hip replacement A recognised complication is the formation of a symptomatic reactive periprosthetic soft tissue mass (pseudotumour) We present a radiological classification system for these reactive masses, dividing them into three groups: Type I are thin-walled cystic masses (cyst wall 3 mm, but less than the diameter of the cystic component) and Type III are predominantly solid masses

Effect of tranexamic acid on mortality in patients with traumatic bleeding: prespecified analysis of data from randomised controlled trial.

Abstract: Objectives To examine whether the effect of tranexamic acid on the risk of death and thrombotic events in patients with traumatic bleeding varies according to baseline risk of death. To assess the extent to which current protocols for treatment with tranexamic acid maximise benefits to patients. Design Prespecified stratified analysis of data from an international multicentre randomised controlled trial (the CRASH-2 trial) with an estimation of the proportion of premature deaths that could potentially be averted through the administration of tranexamic acid. Participants 13 273 trauma patients in the CRASH-2 trial who were treated with tranexamic acid or placebo within three hours of injury and trauma patients enrolled in UK Trauma and Audit Research Network, stratified by risk of death at baseline ( 50%). Intervention Tranexamic acid (1 g over 10 minutes followed by 1 g over eight hours) or matching placebo. Main outcome measure Odds ratios and 95% confidence intervals for death in hospital within four weeks of injury, deaths from bleeding, and fatal and non-fatal thrombotic events associated with the use of tranexamic acid according to baseline risk of death. Unless there was strong evidence against the null hypothesis of homogeneity of effects (P<0.001), the overall odds ratio was used as the most reliable guide to the odds ratios in all strata. Results Tranexamic acid was associated with a significant reduction in all cause mortality and deaths from bleeding. In each stratum of baseline risk, there were fewer deaths among patients treated with tranexamic acid. There was no evidence of heterogeneity in the effect of tranexamic acid on all cause mortality (P=0.96 for interaction) or deaths from bleeding (P=0.98) by baseline risk of death. In those treated with tranexamic acid there was a significant reduction in the odds of fatal and non-fatal thrombotic events (odds ratio 0.69, 95% confidence interval 0.53 to 0.89; P=0.005) and a significant reduction in arterial thrombotic events (0.58, 0.40 to 0.83; P=0.003) but no significant reduction in venous thrombotic events (0.83, 0.59 to 1.17; P=0.295). There was no evidence of heterogeneity in the effect of tranexamic acid on the risk of thrombotic events (P=0.74). If the effect of tranexamic acid is assumed to be the same in all risk strata ( 50% risk of death at baseline), the percentage of deaths that could be averted by administration of tranexamic acid within three hours of injury in each group is 17%, 36%, 30%, and 17%, respectively. Conclusions Tranexamic acid can be administered safely to a wide spectrum of patients with traumatic bleeding and should not be restricted to the most severely injured. Trial registration ISRCTN86750102.

The ten-year survival of the Birmingham hip resurfacing: An independent series

Abstract: Recent events have highlighted the importance of implant design for survival and wear-related complications following metal-on-metal hip resurfacing arthroplasty. The mid-term survival of the most widely used implant, the Birmingham Hip Resurfacing (BHR), has been described by its designers. The aim of this study was to report the ten-year survival and patient-reported functional outcome of the BHR from an independent centre. In this cohort of 554 patients (646 BHRs) with a mean age of 51.9 years (16.5 to 81.5) followed for a mean of eight years (1 to 12), the survival and patient-reported functional outcome depended on gender and the size of the implant. In female hips (n = 267) the ten-year survival was 74% (95% confidence interval (CI) 83 to 91), the ten-year revision rate for pseudotumour was 7%, the mean Oxford hip score (OHS) was 43 (SD 8) and the mean UCLA activity score was 6.4 (SD 2). In male hips (n = 379) the ten-year survival was 95% (95% CI 92.0 to 97.4), the ten-year revision rate for pseudotumour was 1.7%, the mean OHS was 45 (SD 6) and the mean UCLA score was 7.6 (SD 2). In the most demanding subgroup, comprising male patients aged < 50 years treated for primary osteoarthritis, the survival was 99% (95% CI 97 to 100). This study supports the ongoing use of resurfacing in young active men, who are a subgroup of patients who tend to have problems with conventional THR. In contrast, the results in women have been poor and we do not recommend metal-on-metal resurfacing in women. Continuous follow-up is recommended because of the increasing incidence of pseudotumour with the passage of time.

Responsiveness of the Manchester–Oxford foot questionnaire (MOXFQ) compared with AOFAS, SF-36 and EQ-5D assessments following foot or ankle surgery

Abstract: The responsiveness of the Manchester–Oxford Foot Questionnaire (MOXFQ) was compared with foot/ankle-specific and generic outcome measures used to assess all surgery of the foot and ankle. We recruited 671 consecutive adult patients awaiting foot or ankle surgery, of whom 427 (63.6%) were female, with a mean age of 52.8 years (18 to 89). They independently completed the MOXFQ, Short-Form 36 (SF-36) and EuroQol (EQ-5D) questionnaires pre-operatively and at a mean of nine months (3.8 to 14.4) post-operatively. Foot/ankle surgeons assessed American Orthopaedic Foot and Ankle Society (AOFAS) scores corresponding to four foot/ankle regions. A transition item measured perceived changes in foot/ankle problems post-surgery. Of 628 eligible patients proceeding to surgery, 491 (78%) completed questionnaires and 262 (42%) received clinical assessments both pre- and post-operatively. The regions receiving surgery were: multiple/whole foot in eight (1.3%), ankle/hindfoot in 292 (46.5%), mid-foot in 21 (3.3%), hallux in 196 (31.2%), and lesser toes in 111 (17.7%). Foot/ankle-specific MOXFQ, AOFAS and EQ-5D domains produced larger effect sizes (> 0.8) than any SF-36 domains, suggesting superior responsiveness. In analyses that anchored change in scores and effect sizes to patients’ responses to a transition item about their foot/ankle problems, the MOXFQ performed well. The SF-36 and EQ-5D performed poorly. Similar analyses, conducted within foot-region based sub-groups of patients, found that the responsiveness of the MOXFQ was good compared with the AOFAS. This evidence supports the MOXFQ’s suitability for assessing all foot and ankle surgery.

Structural changes of the brain in rheumatoid arthritis.

Abstract: Objective To investigate whether structural changes are present in the cortical and subcortical gray matter of the brains of patients with rheumatoid arthritis (RA). Methods We used two surface-based style morphometry analysis programs and a voxel-based style analysis program to compare high-resolution structural magnetic resonance imaging data obtained for 31 RA patients and 25 age- and sex-matched healthy control subjects. Results We observed an increase in gray matter content in the basal ganglia of RA patients, mainly in the nucleus accumbens and caudate nucleus. There were no differences in the cortical gray matter. Moreover, patients had a smaller intracranial volume. Conclusion Our results suggest that RA is associated with changes in the subcortical gray matter rather than with cortical gray matter atrophy. Since the basal ganglia play an important role in motor control as well as in pain processing and in modulating behavior in response to aversive stimuli, we suggest that these changes may result from altered motor control or prolonged pain processing. The differences in brain volume may reflect either generalized atrophy or differences in brain development. © 2012 American College of Rheumatology.

Informed Conditioning on Clinical Covariates Increases Power in Case-Control Association Studies

Abstract: Genetic case-control association studies often include data on clinical covariates, such as body mass index (BMI), smoking status, or age, that may modify the underlying genetic risk of case or control samples. For example, in type 2 diabetes, odds ratios for established variants estimated from low–BMI cases are larger than those estimated from high–BMI cases. An unanswered question is how to use this information to maximize statistical power in case-control studies that ascertain individuals on the basis of phenotype (case-control ascertainment) or phenotype and clinical covariates (case-controlcovariate ascertainment). While current approaches improve power in studies with random ascertainment, they often lose power under case-control ascertainment and fail to capture available power increases under case-control-covariate ascertainment. We show that an informed conditioning approach, based on the liability threshold model with parameters informed by external epidemiological information, fully accounts for disease prevalence and non-random ascertainment of phenotype as well as covariates and provides a substantial increase in power while maintaining a properly controlled falsepositive rate. Our method outperforms standard case-control association tests with or without covariates, tests of gene x covariate interaction, and previously proposed tests for dealing with covariates in ascertained data, with especially large improvements in the case of case-control-covariate ascertainment. We investigate empirical case-control studies of type 2 diabetes, prostate cancer, lung cancer, breast cancer, rheumatoid arthritis, age-related macular degeneration, and end-stage kidney disease over a total of 89,726 samples. In these datasets, informed conditioning outperforms logistic regression for 115 of the 157 known associated variants investigated (P-value=1610 29 ). The improvement varied across diseases with a 16% median increase in x 2 test statistics and a commensurate increase in power. This suggests that applying our method to

A systematic review of the histological and molecular changes in rotator cuff disease

Abstract: Introduction The pathogenesis of rotator cuff disease (RCD) is complex and not fully understood. This systematic review set out to summarise the histological and molecular changes that occur throughout the spectrum of RCD. Methods We conducted a systematic review of the scientific literature with specific inclusion and exclusion criteria. Results A total of 101 studies met the inclusion criteria: 92 studies used human subjects exclusively, seven used animal overuse models, and the remaining two studies involved both humans and an animal overuse model. A total of 58 studies analysed supraspinatus tendon exclusively, 16 analysed subacromial bursal tissue exclusively, while the other studies analysed other tissue or varying combinations of tissue types including joint fluid and muscle. The molecular biomarkers that were altered in RCD included matrix substances, growth factors, enzymes and other proteins including certain neuropeptides. Conclusions The pathogenesis of RCD is being slowly unravelled as a result of the significant recent advances in molecular medicine. Future research aimed at further unlocking these key molecular processes will be pivotal in developing new surgical interventions both in terms of the diagnosis and treatment of RCD.

Learning and retaining simulated arthroscopic meniscal repair skills

Abstract: Background: Previous studies of task-specific skills have suggested that a loss of technical performance occurs if the skill is not practiced for a six-month period. The aims of this study were to objectively demonstrate the learning curve for a complex arthroscopic task (meniscal repair) by means of motion analysis and to determine the impact of task repetition on the retention of this skill. Methods: Nineteen orthopaedic residents with experience in routine knee arthroscopy but not in arthroscopic meniscal repair were recruited into a randomized study. During the initial learning phase, all subjects performed twelve meniscal repairs on a knee simulator over a three-week period. A validated motion analysis tracking system was used to objectively record the performance and learning of each subject; the outcomes were the time taken, distance traveled, and number of hand movements. The subjects were then randomized into three groups. Group A performed one meniscal repair each month, Group B performed one meniscal repair at three months, and Group C performed no repairs during this interim phase. All three groups then returned at the six-month point for the final assessment phase, during which they carried out an additional twelve meniscal repairs over three weeks. Results: All subjects demonstrated a clear learning curve during the initial learning phase, with significant objective improvement in all motion analysis parameters over the initial twelve episodes (p 0.05). Conclusions: In contrast to previous studies, residents did not lose any skill over a six-month interruption in task performance, and other residents took longer to produce a more consistent performance. Clinical Relevance: These findings suggest the presence of task-specific and surgical group-specific factors that affect the retention of arthroscopic skills. The use of generic guidelines on minimum task frequency for learning and maintaining optimal performance of arthroscopic tasks by surgeons may not be appropriate.

Simulated hip arthroscopy skills: learning curves with the lateral and supine patient positions: a randomized trial.

Abstract: Background: Hip arthroscopy can be performed with the patient in the lateral or supine position, but it remains technically demanding. We aimed to objectively quantify and compare learning curves between two groups of orthopaedic trainees randomized to learn simulated hip arthroscopy with the patient in either a lateral or a supine position. We also compared learning curves between senior and junior trainees. Methods: A hip arthroscopy simulator with anterolateral and anterior portals, a 70° arthroscope, and fixed distraction was used. Rotation of the simulator by 90° enabled arthroscopy with the patient in a supine or lateral position. Twenty orthopaedic trainees with minimal hip arthroscopy experience were randomized into lateral and supine position groups, and were asked to perform a diagnostic hip arthroscopy of the central compartment on twelve occasions. Each episode involved a change in the portal and repetition of the diagnostic round. A validated motion analysis system objectively measured surgical performance by recording time taken, total path-length of the hands, and number of hand movements. Results: Both groups demonstrated learning with objective improvement in all parameters (p < 0.001). Initially, the lateral group was significantly slower and more variable in their performance during the second diagnostic round, after portal exchange (p = 0.006). However, they achieved parity with the supine group in all parameters by nine episodes. During the first three episodes, the junior trainees performed significantly worse for the first diagnostic round (p = 0.005) but not for the second diagnostic round (p = 0.200), and they rapidly achieved parity with the senior trainees, performing at a similar level by the end of the study period. Conclusions: Trainees with minimal experience with hip arthroscopy progressively learn and objectively improve their performance when using a hip simulator. Orientation after portal exchange is difficult for all trainees but particularly for those learning with a simulated patient lateral position. Trainees are likely to benefit from simulator training to learn orientation and basic competence prior to performing hip arthroscopy on patients. Level of Evidence: Therapeutic Level I. See Instructions for Authors for a complete description of levels of evidence.

Randomized Controlled Trial of the Safety and Efficacy of Daptomycin versus Standard-of-Care Therapy for Management of Patients with Osteomyelitis Associated with Prosthetic Devices Undergoing Two-Stage Revision Arthroplasty

Abstract: The prevalence of Staphylococcus aureus causing prosthetic joint infection (PJI) supports investigation of higher doses of daptomycin in the management of PJI. This was a prospective, randomized controlled trial studying safety and efficacy of daptomycin (6 and 8 mg/kg of body weight) compared with standard-of-care therapy for PJI. This open-label study randomized 75 patients undergoing 2-stage revision arthroplasty to daptomycin at 6 or 8 mg/kg or a comparator (vancomycin, teicoplanin, or semisynthetic penicillin). After prosthesis removal, patients received 6 weeks of antibiotic treatment and a 2- to 6-week antibiotic-free period before implantation of a new prosthesis. Test of cure (TOC) was within 1 to 2 weeks after reimplantation. The primary objective was evaluation of creatine phosphokinase (CPK) levels. Secondary objectives were clinical efficacy and microbiological assessments. Of 73 CPK safety population patients, CPK elevation of >500 U/liter occurred in 4 of 25 (16.0%) (daptomycin, 6 mg/kg) and 5 of 23 (21.7%) (daptomycin, 8 mg/kg) daptomycin-treated patients and 2 of 25 (8.0%) comparator patients. Adverse-event rates were similar among daptomycin and comparator groups. Among modified intent-to-treat patients at TOC, clinical success rates were 14 of 24 (58.3%) for 6 mg/kg daptomycin, 14 of 23 (60.9%) for 8 mg/kg daptomycin, and 8 of 21 (38.1%) for the comparator. Overall microbiological success at TOC was 12 of 24 (50.0%) for 6 mg/kg daptomycin, 12 of 23 (52.2%) for 8 mg/kg daptomycin, and 8 of 21 (38.1%) for comparator patients. In conclusion, daptomycin at 6 and 8 mg/kg given for up to 6 weeks was safe and appeared to be effective in managing staphylococcal PJI using a 2-stage revision arthroplasty technique in a total of 49 patients.

Reduced colon cancer incidence and mortality in postmenopausal women treated with an oral bisphosphonate--Danish National Register Based Cohort Study.

Abstract: In this Danish national register-based cohort study, we examined the effects of alendronate on the development of colon cancers and survival. The incidence of colon cancer and mortality rate, once colon cancer had been diagnosed, were lower in patients treated with alendronate, posing the question whether alendronate acts as chemopreventive. When bisphosphonates are given by mouth, around 99% remains non-absorbed in the intestine. Based on their biochemical actions, we predicted that oral bisphosphonates might prevent colon cancers. This is a Danish national register-based cohort study. We identified 30,606 women aged 50+, mean age 71.9 years, who had not previously taken treatments for osteoporosis, who began to take alendronate in 1996–2005, and assigned 124,424 individually age- and gender-matched control subjects. The main outcome measure was colorectal cancers incidence and post-diagnosis survival in patients taking oral alendronate for osteoporosis. Cox proportional hazards analysis of death due to colon cancer showed lower risk in alendronate users, crude hazard ratio (HR) 0.69 (95% CI 0.59–0.81) with an adjusted HR of 0.62 (95% CI 0.52–0.72). The reduction in risk comprised both a lower incidence of colon cancer-adjusted HR 0.69 (95% CI 0.60–0.79) and a lower mortality once colon cancer had been diagnosed, adjusted HR 0.82 (95% CI 0.70–0.97). Weekly alendronate was associated with a greater risk reduction than daily alendronate. The main findings were unaffected by excluding patients from the analysis who had pulmonary disease, a major co-morbid condition in users of alendronate and an important cause of death. The risk of overall deaths from cancer and in particular death caused by colon cancer was significantly and substantially decreased (40%) in patients treated with alendronate, with survival curves deviating progressively after 2 years. Also, the incidence of colon cancer was lower in those patients.

Outcome of combined unicompartmental knee replacement and combined or sequential anterior cruciate ligament reconstruction: A study of 52 cases with mean follow-up of five years

Abstract: The Oxford unicompartmental knee replacement (UKR) is an established treatment option in the management of symptomatic end-stage medial compartmental osteoarthritis (MCOA), which works well in the young and active patient. However, previous studies have shown that it is reliable only in the presence of a functionally intact anterior cruciate ligament (ACL). This review reports the outcomes, at a mean of five years and a maximum of ten years, of 52 consecutive patients with a mean age of 51 years (36 to 57) who underwent staged or simultaneous ACL reconstruction and Oxford UKR. At the last follow-up (with one patient lost to follow-up), the mean Oxford knee score was 41 (sd 6.3; 17 to 48). Two patients required conversion to TKR: one for progression of lateral compartment osteoarthritis and one for infection. Implant survival at five years was 93% (95% CI 83 to 100). All but one patient reported being satisfied with the procedure. The outcome was not significantly influenced by age, gender, femoral or tibial tunnel placement, or whether the procedure was undertaken at one- or two-stages. In summary, ACL reconstruction and Oxford UKR gives good results in patients with end-stage MCOA secondary to ACL deficiency.

Comparison of embedded and added motor imagery training in patients after stroke: results of a randomised controlled pilot trial

Abstract: Motor imagery (MI) when combined with physiotherapy can offer functional benefits after stroke. Two MI integration strategies exist: added and embedded MI. Both approaches were compared when learning a complex motor task (MT): 'Going down, laying on the floor, and getting up again'. Outpatients after first stroke participated in a single-blinded, randomised controlled trial with MI embedded into physiotherapy (EG1), MI added to physiotherapy (EG2), and a control group (CG). All groups participated in six physiotherapy sessions. Primary study outcome was time (sec) to perform the motor task at pre and post-intervention. Secondary outcomes: level of help needed, stages of MT-completion, independence, balance, fear of falling (FOF), MI ability. Data were collected four times: twice during one week baseline phase (BL, T0), following the two week intervention (T1), after a two week follow-up (FU). Analysis of variance was performed. Thirty nine outpatients were included (12 females, age: 63.4 ± 10 years; time since stroke: 3.5 ± 2 years; 29 with an ischemic event). All were able to complete the motor task using the standardised 7-step procedure and reduced FOF at T0, T1, and FU. Times to perform the MT at baseline were 44.2 ± 22s, 64.6 ± 50s, and 118.3 ± 93s for EG1 (N = 13), EG2 (N = 12), and CG (N = 14). All groups showed significant improvement in time to complete the MT (p < 0.001) and degree of help needed to perform the task: minimal assistance to supervision (CG) and independent performance (EG1+2). No between group differences were found. Only EG1 demonstrated changes in MI ability over time with the visual indicator increasing from T0 to T1 and decreasing from T1 to FU. The kinaesthetic indicator increased from T1 to FU. Patients indicated to value the MI training and continued using MI for other difficult-to-perform tasks. Embedded or added MI training combined with physiotherapy seem to be feasible and benefi-cial to learn the MT with emphasis on getting up independently. Based on their baseline level CG had the highest potential to improve outcomes. A patient study with 35 patients per group could give a conclusive answer of a superior MI integration strategy. ClinicalTrials.gov: NCT00858910

Inhibiting HLA-B27 homodimer-driven immune cell inflammation in spondylarthritis.

Abstract: Objective Spondylarthritides (SpA), including ankylosing spondylitis (AS), are common inflammatory rheumatic diseases that are strongly associated with positivity for the HLA class I allotype B27. HLA–B27 normally forms complexes with β2-microglobulin (β2m) and peptide to form heterotrimers. However, an unusual characteristic of HLA–B27 is its ability to form β2m-free heavy chain homodimers (HLA–B272), which, unlike classic HLA–B27, bind to killer cell immunoglobulin-like receptor 3DL2 (KIR-3DL2). Binding of HLA–B272 to KIR-3DL2–positive CD4+ T and natural killer (NK) cells stimulates cell survival and modulates cytokine production. This study was undertaken to produce an antibody to HLA–B272 in order to confirm its expression in SpA and to inhibit its proinflammatory properties. Methods We generated monoclonal antibodies by screening a human phage display library positively against B272 and negatively against B27 heterotrimers. Specificity was tested by enzyme-linked immunosorbent assay (ELISA), surface plasmon resonance (SPR) assay, and fluorescence-activated cell sorting (FACS) analysis of B272-expressing cell lines and peripheral blood mononuclear cells (PBMCs) and synovial fluid mononuclear cells (SFMCs) from patients with SpA. Functional inhibition of KIR-3DL2–B272 interactions was tested using cell lines and PBMCs from patients with SpA. Results Monoclonal antibody HD6 specifically recognized recombinant HLA–B272 by ELISA and by SPR assay. HD6 bound to cell lines expressing B272. FACS revealed binding of HD6 to PBMCs and SFMCs from patients with AS but not from controls. HD6 inhibited both the binding of HLA–B272 to KIR-3DL2 and the survival and proliferation of KIR-3DL2–positive NK cells. Finally, HD6 inhibited production of the proinflammatory disease–associated cytokine interleukin-17 by PBMCs from patients with AS. Conclusion These results demonstrate that antibody HD6 has potential for use in both the investigation and the treatment of AS and other B27-associated spondylarthritides.

'Sink or swim': an evaluation of the clinical characteristics of individuals with high bone mass.

Abstract: Summary High bone mineral density on routine dual energy X-ray absorptiometry (DXA) may indicate an underlying skeletal dysplasia. Two hundred fifty-eight individuals with unexplained high bone mass (HBM), 236 relatives (41% with HBM) and 58 spouses were studied. Cases could not float, had mandible enlargement, extra bone, broad frames, larger shoe sizes and increased body mass index (BMI). HBM cases may harbour an underlying genetic disorder.

Chondroclasts are mature osteoclasts which are capable of cartilage matrix resorption

Abstract: Multinucleated cells termed chondroclasts have been observed on the deep surface of resorbed hyaline cartilage but the relationship of these cells to macrophages and osteoclasts and their role in rheumatoid arthritis (RA) and other arthritic conditions is uncertain. Multinucleated cells in RA and other arthritic conditions showing evidence of cartilage resorption were characterised immunohistochemically for expression of macrophage/osteoclast markers. Mature human osteoclasts formed from circulating monocytes and tissue macrophages were cultured for up to 4 days on slices of human cartilage and glycosaminoglycan (GAG) release was measured. Multinucleated cells resorbing unmineralised cartilage were seen in osteoarthritis, RA, septic arthritis, avascular necrosis and in four cases of giant cell tumour of bone that had extended through the subchondral bone plate. Chondroclasts expressed an osteoclast-like phenotype (TRAP+, cathepsin K+, MMP9+, CD14−, HLA-DR−, CD45+, CD51+ and CD68+). Both macrophages and osteoclasts cultured on cartilage released GAG. These findings indicate that chondroclasts have an osteoclast-like phenotype and that mature human osteoclasts are capable of cartilage matrix resorption. Resorption of unmineralised subchondral cartilage by chondroclasts and macrophages can be a feature of joint destruction in inflammatory and non-inflammatory arthropathies as well as inflammatory and neoplastic subchondral bone lesions.

Bone and its adaptation to mechanical loading: a review

Abstract: Bone is a remarkable living material that comes in two forms with different porosities and different macrostructure, but with the same highly organised microstructure and nanostructure. As bone accumulates damage, it is removed and replaced. When the mechanical demands on bone increase the bone mass increases, while reductions in the loading leads to the removal of bone, thus bone can be considered a ‘smart material’. The ongoing replacement of old bone tissue by new bone tissue is called remodelling. Bone formation, repair and remodelling is controlled and produced by four types of cell, namely osteoblasts, osteoclasts, osteocytes and bone lining cells. Bone remodelling is regulated by signals to these cells generated by mechanical loading. Exactly how loads are transferred into bone, how the bone cells sense these loads and how the signals are translated into bone formation or removal is unknown. In this review, the structure of bone and the cells responsible for maintaining bone are described. The mechanisms that cause bone to adapt to mechanical loading have been investigated. The methods that have been employed in attempts to determine this mechanism are considered.

Risedronate in adults with osteogenesis imperfecta type I: increased bone mineral density and decreased bone turnover, but high fracture rate persists

Abstract: Bisphosphonates can increase bone mineral density (BMD) in children with osteogenesis imperfecta (OI). In this study of adults with OI type I, risedronate increased BMD at lumbar spine (but not total hip) and decreased bone turnover. However, the fracture rate in these patients remained high. Intravenous bisphosphonates given to children with OI can increase BMD and reduce fracture incidence. Oral and/or intravenous bisphosphonates may have similar effects in adults with OI. We completed an observational study of the effect of risedronate in adults with OI type I. Thirty-two adults (mean age, 39 years) with OI type I were treated with risedronate (total dose, 35 mg weekly) for 24 months. Primary outcome measures were BMD changes at lumbar spine (LS) and total hip (TH). Secondary outcome measures were fracture incidence, bone pain, and change in bone turnover markers (serum procollagen type I aminopropeptide (P1NP) and bone ALP). A meta-analysis of published studies of oral bisphosphonates in adults and children with OI was performed. Twenty-seven participants (ten males and seventeen females) completed the study. BMD increased at LS by 3.9% (0.815 vs. 0.846 g/cm2, p = 0.007; mean Z-score, −1.93 vs. −1.58, p = 0.002), with no significant change at TH. P1NP fell by 37% (p = 0.00041), with no significant change in bone ALP (p = 0.15). Bone pain did not change significantly (p = 0.6). Fracture incidence remained high, with 25 clinical fractures and 10 major fractures in fourteen participants (0.18 major fractures per person per year), with historical data of 0.12 fractures per person per year. The meta-analysis did not demonstrate a significant difference in fracture incidence in patients with OI treated with oral bisphosphonates. Risedronate in adults with OI type I results in modest but significant increases in BMD at LS, and decreased bone turnover. However, this may be insufficient to make a clinically significant difference to fracture incidence.

HLA-B27 Homodimers and Free H Chains Are Stronger Ligands for Leukocyte Ig-like Receptor B2 than Classical HLA Class I

Abstract: Possession of HLA-B27 (B27) strongly predisposes to the development of spondyloarthritis. B27 forms classical heterotrimeric complexes with β(2)-microglobulin (β2m) and peptide and (β2m free) free H chain (FHC) forms including B27 dimers (termed B27(2)) at the cell surface. In this study, we characterize the interaction of HLA-B27 with LILR, leukocyte Ig-like receptor (LILR)B1 and LILRB2 immune receptors biophysically, biochemically, and by FACS staining. LILRB1 bound to B27 heterotrimers with a K(D) of 5.3 ± 1.5 μM but did not bind B27 FHC. LILRB2 bound to B27(2) and B27 FHC and B27 heterotrimers with K(D)s of 2.5, 2.6, and 22 ± 6 μM, respectively. Domain exchange experiments showed that B27(2) bound to the two membrane distal Ig-like domains of LILRB2. In FACS staining experiments, B27 dimer protein and tetramers stained LILRB2 transfectants five times more strongly than B27 heterotrimers. Moreover, LILRB2Fc bound to dimeric and other B27 FHC forms on B27-expressing cell lines more strongly than other HLA-class 1 FHCs. B27-transfected cells expressing B27 dimers and FHC inhibited IL-2 production by LILRB2-expressing reporter cells to a greater extent than control HLA class I transfectants. B27 heterotrimers complexed with the L6M variant of the GAG KK10 epitope bound with a similar affinity to complexes with the wild-type KK10 epitope (with K(D)s of 15.0 ± 0.8 and 16.0 ± 2.0 μM, respectively). Disulfide-dependent B27 H chain dimers and multimers are stronger ligands for LILRB2 than HLA class I heterotrimers and H chains. The stronger interaction of B27 dimers and FHC forms with LILRB2 compared with other HLA class I could play a role in spondyloarthritis pathogenesis.

Weekly Exercise Does Not Improve Fatigue Levels in Parkinson's Disease

Abstract: Background: Fatigue is one of the most disabling non-motor symptoms for people with Parkinson's disease. Exercise may modify fatigue. This study examines prescribed exercise effects on physical activity levels, well-being, and fatigue in Parkinson's disease. Methods: In this single-blinded trial, participants were randomly assigned to either a 12 week community exercise program or control group. Primary outcome measures were fatigue (Fatigue Severity Scale) and physical activity. Results: Thirty-nine people with Parkinson's disease were included: 20 in exercise and 19 in control. Sixty-five percent of the study group were fatigued (n = 24, mean 4.02, SD 1.48). Increased fatigue was associated with lower mobility and activity (P < .05). Individuals participated in a mean of 15 (SD 10) exercise sessions with no significant change in fatigue, mobility, well-being, or physical activity after exercise (P ≥ .05). Conclusion: Participation in weekly exercise did not improve fatigue in people with Parkinson's Disease. © 2011 Movement Disorder Society

Persistent non-specific low back pain and patients' experience of general practice: a qualitative study.

Abstract: Aim: This paper aims to present a conceptual analysis of patients’ experience of general practice in relation to their persistent non-specific low back pain (PLBP). Background: PLBP accounts for a considerable amount of the daily workload of the general practitioner (GP). GPs need to maintain a good relationship with their patient while following guidelines for best practice. The biomedical model can contribute to the tensions experienced by a person with PLBP and a shift in the prevailing model may facilitate the resolution of these tensions. Qualitative research can help clinicians to understand this process and thus facilitate the best possible outcome. Method: We conducted a series of three in-depth interviews over a period of one year with 20 patients with PLBP who had been invited to attend a pain management programme. We used the methods of constructivist grounded theory to analyse the data. Findings: Several themes emerged that provide a deeper understanding of the context in which patient and GP negotiate their relationship. Patients describe how they have been fobbed off by a GP who is just a general practitioner and not an expert. This allowed patients to continue to use the biomedical model; I have something real but the GP lacks knowledge. To think that ‘nothing can be done’, would involve accepting the limits of medical knowledge. We also found that over time, as diagnosis and cure is not achieved, patient began to question the concept of the medical expert. This tension opens up the possibility for a shift away from the biomedical towards a biopsychosocial explanatory model.

Defining physiologically “normal” vitamin D in African Americans

Abstract: The relationship between serum 25(OH)D and intact parathyroid hormone (iPTH) was evaluated in the Multicenter Osteoarthritis Study (MOST). No further change in iPTH was observed for African Americans with 25(OH)D levels above 20 ng/ml, suggesting that compared to Caucasians, lower vitamin D targets for sufficiency may be appropriate for African Americans. Vitamin D levels ≥30 ng/ml are commonly considered “normal” based upon maximal suppression of iPTH; however, this has recently been challenged and the optimal 25(OH)D level among non-Caucasians is unclear. We evaluated the cross-sectional relationship between serum 25(OH)D and iPTH in a sample of Caucasian and African American adults. We used baseline serum samples of participants from the Multicenter Osteoarthritis Study (MOST) for this analysis and used three methods to model the relationship between 25(OH)D and iPTH: ordinary least squares regression (OLS), segmented regression and Helmert contrasts. Among Caucasians (n = 1,258), 25(OH)D and iPTH ranged from 4 to 51 ng/ml and 2 to 120 pg/ml and from 3 to 32 ng/ml and 3 to 119 pg/ml in African Americans (n = 423). We observed different thresholds between African Americans and Caucasians using each analytic technique. Using 25(OH)D as a categorical variable in OLS, iPTH was statistically higher at lower 25(OH)D categories than the 24–32 ng/ml referent group among Caucasians. However, in African Americans, the mean iPTH was only significantly higher at 25(OH)D levels below 15 ng/ml. Using segmented regression, iPTH appeared to stabilize at a lower 25(OH)D level in African Americans (19–23 ng/ml) compared to in Caucasians (>32 ng/ml). Helmert contrasts also revealed a lower threshold in African Americans than Caucasians. Among MOST participants, the 25(OH)D thresholds at which no further change in iPTH was observed was approximately 20 ng/ml in African Americans versus approximately 30 ng/ml in Caucasians, suggesting optimal vitamin D levels in Caucasians may not be applicable to African Americans.