Microbicides Development Programme: design of a phase III trial to measure the efficacy of the vaginal microbicide PRO 2000/5 for HIV prevention

Background

Non-pharmacological, non-surgical interventions are recommended as the first line of treatment for osteoarthritis (OA) of the hip and knee. There is evidence that exercise therapy is effective for reducing pain and improving function in patients with knee OA, some evidence that exercise therapy is effective for hip OA, and early indications that manual therapy may be efficacious for hip and knee OA. There is little evidence as to which approach is more effective, if benefits endure, or if providing these therapies is cost-effective for the management of this disorder. The MOA Trial (Management of OsteoArthritis) aims to test the effectiveness of two physiotherapy interventions for improving disability and pain in adults with hip or knee OA in New Zealand. Specifically, our primary objectives are to investigate whether: 1. Exercise therapy versus no exercise therapy improves disability at 12 months; 2. Manual physiotherapy versus no manual therapy improves disability at 12 months; 3. Providing physiotherapy programmes in addition to usual care is more cost-effective than usual care alone in the management of osteoarthritis at 24 months.

Methods

This is a 2 × 2 factorial randomised controlled trial. We plan to recruit 224 participants with hip or knee OA. Eligible participants will be randomly allocated to receive either: (a) a supervised multi-modal exercise therapy programme; (b) an individualised manual therapy programme; (c) both exercise therapy and manual therapy; or, (d) no trial physiotherapy. All participants will continue to receive usual medical care. The outcome assessors, orthopaedic surgeons, general medical practitioners, and statistician will be blind to group allocation until the statistical analysis is completed. The trial is funded by Health Research Council of New Zealand Project Grants (Project numbers 07/199, 07/200).

Discussion

The MOA Trial will be the first to investigate the effectiveness and cost-effectiveness of providing physiotherapy programmes of this kind, for the management of pain and disability in adults with hip or knee OA.

Trial registration

Australian New Zealand Clinical Trials Registry ref: ACTRN12608000130369.     

Exercise-based cardiac rehabilitation in patients with coronary heart disease: a practice guideline

Background

To improve the quality of exercise-based cardiac rehabilitation (CR) in patients with coronary heart disease (CHD) the CR guideline from the Dutch Royal Society for Physiotherapists (KNGF) has been updated. This guideline can be considered an addition to the 2011 Dutch Multidisciplinary CR guideline, as it includes several novel topics.

Methods

A systematic literature search was performed to formulate conclusions on the efficacy of exercise-based interventions during all CR phases in patients with CHD. Evidence was graded (1–4) according the Dutch evidence-based guideline development (EBRO) criteria. In case of insufficient scientific evidence, recommendations were based on expert opinion. This guideline comprised a structured approach including assessment, treatment and evaluation.

Results

Recommendations for exercise-based CR were formulated covering the following topics: preoperative physiotherapy, mobilisation during the clinical phase, aerobic exercise, strength training, and relaxation therapy during the outpatient rehabilitation phase, and adoption and monitoring of a physically active lifestyle after outpatient rehabilitation.

Conclusions

There is strong evidence for the effectiveness of exercise-based CR during all phases of CR. The implementation of this guideline in clinical practice needs further evaluation as well as the maintenance of an active lifestyle after supervised rehabilitation.     

Spinal deformities rehabilitation - state of the art review

Background

Medical rehabilitation aims at an improvement in function, capacity and participation. For the rehabilitation of spinal deformities, the goal is to maintain function and prevent secondary symptoms in the short- and long-term. In patients with scoliosis, predictable signs and symptoms include pain and reduced pulmonary function.

Materials and methods

A Pub Med review was completed in order to reveal substantial evidence for inpatient rehabilitation as performed in Germany. No evidence has been found in general to support claims for actual inpatient rehabilitation programmes as used today. Nevertheless, as there is some evidence that inpatient rehabilitation may be beneficial to patients with spinal deformities complicated by certain additional conditions, the body of evidence there is for conservative treatment of spinal deformities has been reviewed in order to allow suggestions for outpatient conservative treatment and inpatient rehabilitation.

Discussion

Today, for both children and adolescents, we are able to offer intensive rehabilitation programmes lasting three to five days, which enable the patients to acquire the skills necessary to prevent postures fostering scoliosis in everyday life without missing too much of school teaching subjects at home. The secondary functional impairments adult scoliosis patients might have, as in the opinion of the author, still today require the time of 3-4 weeks in the clinical in-patient setting. Time to address psychosocial as well as somatic limitations, namely chronic pains and cardiorespiratory malfunction is needed to preserve the patients working capability in the long-term.

Conclusion

Outpatient treatment/rehabilitation is sufficient for adolescents with spinal deformities. Inpatient rehabilitation is recommended for patients with spinal deformities and pain or severe restrictive ventilation disorder.     

The relationship between hand osteoarthritis and serum leptin concentration in participants of the Third National Health and Nutrition Examination Survey

Introduction

Leptin has been suspected to contribute to the development of osteoarthritis (OA). However, this hypothesis has not been tested in large-scale hand OA cohorts. Our study aimed to determine whether there is a cross-sectional relationship between serum leptin levels and hand OA in a population-based sample of US adults.

Method

We used the Third National Health and Nutrition Examination Survey (NHANES III), a national cross-sectional population-based survey, to study the relationship between hand OA and serum leptin concentration. We applied previously established classification criteria for hand OA. Patients with rheumatoid arthritis were excluded. Potential confounders included sex, body mass index, the presence of polyarticular OA, diabetes, and total cholesterol. We estimated unadjusted mean leptin concentration by hand OA status and by all confounders. We further developed a linear regression model to assess mean leptin levels, adjusted for appropriate confounders.

Results

Of 2,477 subjects in the NHANES III sample that had a hand examination and did not have rheumatoid arthritis, 1,056 (42.6%) had a leptin measurement and were included in the analysis. Subjects with and without leptin measurement had similar demographic characteristics. We did not find any significant differences in mean serum leptin levels in subjects with symptomatic hand OA (7.38 ng/ml in males (95% confidence interval (CI) = 5.31, 9.46) and 21.55 ng/ml in females (95% CI = 17.08, 26.02)), asymptomatic hand OA (6.69 ng/ml in males (95% CI = 5.19, 8.18) and 17.09 ng/ml in females (95% CI = 15.00, 19.18)), and no hand OA (8.22 ng/ml in males (95% CI = 7.47, 8.97) and 20.77 ng/ml in females (95% CI = 18.01, 23.53)) in the unadjusted analysis. In a multivariable linear regression model that included variables of hand OA status, age, race/ethnicity, and obesity status, we found no statistically significant association between serum leptin and hand OA status.

Conclusions

In this cross-sectional study of a large representative US cohort, we did not find any evidence to support the hypothesis that serum leptin is associated with hand OA.     

Effectiveness of two physical therapy interventions, relative to dental treatment in individuals with bruxism: study protocol of a randomized clinical trial

Background

Bruxism is a parafunctional habit characterized by grinding and/or clenching of the teeth. It may happen while awake (awake bruxism) or while sleeping (sleep bruxism). In adults, the prevalence is 20% for the awake bruxism and 8% for the sleep bruxism. Peripheral, central, and psychosocial factors influence the disorder, which may predispose to pain in the masticatory muscles and neck, headache, decreased pain thresholds in the masticatory and cervical muscles, limitation mandibular range of motion, sleep disorders, stress, anxiety, depression, and overall impairment of oral health. The aim of this study is to compare two distinct physical therapy interventions with dental treatment in pain, mandibular range of motion, sleep quality, anxiety, stress, depression, and oral health in individuals with bruxism.

Methods/Design

Participants will be randomized into one of three groups: Group 1 (n?=?24) intervention will consist of massage and stretching exercises; Group 2 (n?=?24) will consist of relaxation and imagination therapies; and Group 3 (n?=?24) will receive dental treatment. The evaluations will be performed at baseline, immediately after treatment, and at 2-month follow-up. Pain intensity will be assessed using the visual analogical scale, while pain thresholds will be determined using dolorimetry. Mandibular range of motion will be assessed using digital pachymeter. Sleep quality will be assessed by the Pittsburgh Sleep Quality Index, anxiety by the State-Trait Anxiety Inventory, stress by the Perceived Stress Scale-10, depression by the Beck Depression Inventory, and oral health will be assessed using the Oral Health Impact Profile - 14. Significance level will be determined at the 5% level.

Discussion

This project describes the randomization method that will be used to compare two physical therapy interventions with dental treatment in the management of pain, mandibular range of motion, sleep quality, anxiety, stress, depression, and oral health in individuals with bruxism. The study will support the practice of evidence-based physical therapy for individuals with bruxism. Data will be published after study is completed.

Trial registration

ClinicalTrials.gov, NCT01778881     

Relationships between biomarkers of cartilage, bone, synovial metabolism and knee pain provide insights into the origins of pain in early knee osteoarthritis

Introduction

We tested the hypothesis that there exist relationships between the onset of early stage radiographically defined knee osteoarthritis (OA), pain and changes in biomarkers of joint metabolism.

Methods

Using Kellgren-Lawrence (K/L) grading early radiographic knee OA (K/L 2) was detected in 16 of 46 patients. These grades (K/L 1 is no OA and K/L 2 is early OA) were divided into two groups according to the presence or absence of persistent knee pain. Sera (s) and urines (u) were analysed with biomarkers for cartilage collagen cleavage (sC2C and uCTX-II) and synthesis (sCPII), bone resorption (uNTx) and synovitis (hyaluronic acid: sHA).

Results

sCPII decreased and sC2C/sCPII, uCTX-II/sCPII and sHA increased with onset of OA (K/L 2 versus K/L 1) irrespective of joint pain. In contrast, sC2C and uCTX-II remained unchanged in early OA patients. Of the patients with K/L grades 1 and 2 sC2C, sCPII, sHA, uNTX and uCTX-II were all significantly increased in patients with knee pain independent of grade. Among the K/L grade 2 subjects, only uCTX-II and uCTX-II/sCPII were increased in those with knee pain. In grade 1 patients both sC2C and sCPII were increased in those with knee pain. No such grade specific changes were seen for the other biomarkers including sHA.

Conclusions

These results suggest that changes in cartilage matrix turnover detected by molecular biomarkers may reflect early changes in cartilage structure that account directly or indirectly for knee pain. Also K/L grade 1 patients with knee pain exhibit biomarker features of early OA.     

Matrix metalloproteinase 28, a novel matrix metalloproteinase, is constitutively expressed in human intervertebral disc tissue and is present in matrix of more degenerated discs

Introduction

Comparison of intra-articular bacterial-derived hyaluronic acid (Hyalubrix^®) (HA) with local analgesia (mepivacaine) for osteoarthritis (OA) of the hip.

Methods

A pilot prospective, double-blind, 6-month randomized trial of 42 patients with hip OA. HA or mepivacaine was administered twice (once a month) under ultrasound guidance. Efficacy measurements included the Lequesne's algofunctional index, a visual analog scale for pain, concomitant use of analgesia, patient and physician global measurement, and safety.

Results

Patients in the HA group exhibited a significantly reduced Lequesne's algofunctional index 3 and 6 months after treatment (P < 0.001) and significantly reduced visual analog scale pain scores 3 and 6 months after treatment (P < 0.05) compared with the local anesthetic group. All primary and secondary measures were significantly improved versus baseline, but other than the above were not different from each other at 3 or 6 months. Adverse effects were minimal.

Conclusions

This comparative study suggests a beneficial effect and safety of intra-articular HA in the management of hip OA.

Trial registration number

ISRCTN39397064.     

A randomised controlled trial of a self-management education program for osteoarthritis of the knee delivered by health care professionals

Introduction

Our aim in the present study was to determine whether a disease-specific self-management program for primary care patients with osteoarthritis (OA) of the knee (the Osteoarthritis of the Knee Self-Management Program (OAK)) implemented by health care professionals would achieve and maintain clinically meaningful improvements in health-related outcomes compared with a control group.

Methods

Medical practitioners referred 146 primary care patients with OA of the knee. Volunteers with coexistent inflammatory joint disease or serious comorbidities were excluded. Randomisation was to either a control group or the OAK group. The OAK group completed a 6-week self-management program. The control group had a 6-month waiting period before entering the OAK program. Assessments were taken at baseline, 8 weeks and 6 months. The primary outcomes were the results measured using the Western Ontario and McMaster Universities Arthritis Index (WOMAC) Pain and Function subscales on the Short Form 36 version 1 questionnaire (SF-36) Secondary outcomes were Visual Analogue Scale (VAS) pain, Timed Up &; Go Test (TUG), knee range of motion and quadriceps and hamstring strength-isometric contraction. Responses to treatment (responders) and minimal clinically important improvements (MCIIs) were determined.

Results

In the OAK group, VAS pain improved from baseline to week 8 from mean (SEM) 5.21 (0.30) to 3.65 (0.29) (P ≤ 0.001). During this period, improvements in the OAK group compared with the control group and responses to treatment were demonstrated according to the following outcomes: WOMAC Pain, Physical Function and Total dimensions, as well as SF-36 Physical Function, Role Physical, Body Pain, Vitality and Social Functioning domains. In addition, from baseline to week 8, the proportion of MCIIs was greater among the OAK group than the control group for all outcomes. For the period between baseline and month 6, WOMAC Pain, Physical Function and Total dimensions significantly improved in the OAK group compared to the control group, as did the SF-36 Physical Function, Role Physical, Body Pain, Vitality and Social Functioning domains, as well as hamstring strength in both legs. During the same period, the TUG Test, range of motion extension and left-knee flexion improved compared with the control group, although these improvements had little clinical relevance.

Conclusions

We recorded statistically significant improvements compared with a control group with regard to pain, quality of life and function for participants in the OAK program on the basis of WOMAC and SF-36 measures taken 8 weeks and 6 months from baseline.     

Osteopathic manipulative treatment and its relationship to autonomic nervous system activity as demonstrated by heart rate variability: a repeated measures study

Background

Osteopathic manipulative treatment (OMT) and ultrasound physical therapy (UPT) are commonly used for chronic low back pain. Although there is evidence from a systematic review and meta-analysis that OMT generally reduces low back pain, there are no large clinical trials that specifically assess OMT efficacy in chronic low back pain. Similarly, there is a lack of evidence involving UPT for chronic low back pain.

Methods

The OSTEOPAThic Health outcomes In Chronic low back pain (OSTEOPATHIC) Trial is a Phase III randomized controlled trial that seeks to study 488 subjects between August 2006 and June 2010. It uses a 2 × 2 factorial design to independently assess the efficacy of OMT and UPT for chronic low back pain. The primary outcome is a visual analogue scale score for pain. Secondary outcomes include back-specific functioning, generic health, work disability, and satisfaction with back care.

Conclusion

This randomized controlled trial will potentially be the largest involving OMT. It will provide long awaited data on the efficacy of OMT and UPT for chronic low back pain.

Trial registration

http://www.clinicaltrials.gov, NCT00315120     

Phytalgic®, a food supplement, vs placebo in patients with osteoarthritis of the knee or hip: a randomised double-blind placebo-controlled clinical trial

Introduction

The medicinal treatment of osteoarthritis (OA) is mostly symptomatic to relieve pain and incapacity with analgesics and non-steroidal anti-inflammatory drugs (NSAIDs), drugs with well-known risks. Complementary medicines might reduce the symptoms of OA and decrease the need for NSAIDs. This study tested the effects of a food supplement, Phytalgic^®, on pain and function in patients with osteoarthritis and their use of analgesic and NSAIDs.

Methods

A randomized double-blind parallel-groups clinical trial compared Phytalgic^® (fish-oil, vitamin E, Urtica dioica) to a placebo for three months, in 81 patients with OA of the knee or hip using NSAIDs and/or analgesics regularly. The main outcome measures were use of NSAIDs (in Defined Daily Doses per day - DDD/day) or analgesics (in 500 mg paracetamol-equivalent tablets per week (PET/week) measured each month, and Western Ontario-McMaster University Osteo-Arthritis Index (WOMAC) function scales.

Results

After three months of treatment, the mean use of analgesics in the active arm (6.5 PET/week) vs. the placebo arm (16.5) was significantly different (P < 0.001) with a group mean difference of -10.0 (95% CI: -4.9 to -15.1). That of NSAIDs in the active arm (0.4 DDD/day) vs the placebo arm (1.0 DDD/day) was significantly different (P = 0.02) with a group mean difference of - 0.7 DDD/day (95% CI: -0.2 to -1.2). Mean WOMAC scores for pain, stiffness and function in the active arm (respectively 86.5, 41.4 and 301.6) vs the placebo arm (resp. 235.3, 96.3 and 746.5) were significantly different (P < 0.001) with group mean differences respectively of -148.8 (95% CI: -97.7 to -199.9), -54.9 (95% CI: -27.9 to -81.9) and -444.8 (95% CI: -269.1 to -620.4).

Conclusions

The food supplement tested appeared to decrease the need for analgesics and NSAIDs and improve the symptoms of osteoarthritis.

Trial registration

Clinicaltrials.gov NCT00666523.     

Multifactorial day hospital intervention to reduce falls in high risk older people in primary care: a multi-centre randomised controlled trial [ISRCTN46584556]

Background

There are many barriers to patient participation in randomised controlled trials of cancer treatments. To increase participation in trials, strategies need to be identified to overcome these barriers. Our aim was to assess the effectiveness of interventions to overcome barriers to patient participation in randomised controlled trials (RCTs) of cancer treatments.

Methods

A systematic review was conducted. Published and unpublished studies in any language were searched for in fifteen electronic databases, including MEDLINE, EMBASE, CINAHL and PsycINFO, from inception to the end of 2004. Studies of any interventions to improve cancer patient participation in RCTs, which reported the change in recruitment rates, were eligible for inclusion. RCTs and non-randomised controlled trials as well as before and after studies reporting baseline rates specific to the population being investigated were included. Data were extracted by one reviewer into structured summary tables and checked for accuracy by a second reviewer. Each included study was assessed against a checklist for methodological quality by one reviewer and checked by a second reviewer. A narrative synthesis was conducted.

Results

Eight studies were identified that met the inclusion criteria: three RCTs, two non-randomised controlled trials and three observational studies. Six of the studies had an intervention that had some relevance to the UK. There was no robust evidence that any of the interventions investigated led to an increase in cancer patient participation in RCTs, though one good quality RCT found that urologists and nurses were equally effective at recruiting participants to a treatment trial for prostate cancer. Although there was no evidence of an effect in any of the studies, the evidence was not of sufficient quality to be able to conclude that these interventions therefore do not work.

Conclusion

There is not a strong evidence-base for interventions that increase cancer patient participation in randomised trials. Further research is required to evaluate the effectiveness of strategies to increase participation in cancer treatment trials.     

Sodium pentosan polysulfate resulted in cartilage improvement in knee osteoarthritis - An open clinical trial-

Background

Pentosan polysulfate sodium (pentosan) is a semi-synthetic drug manufactured from beech-wood hemicellulose by sulfate esterification of the xylopyranose hydroxyl groups. From in vitro and animal model studies, pentosan has been proposed as a disease modifying osteoarthritis drug (DMOAD). The objective of this study was to assess the efficacy, safety, and patient satisfaction in patients with mild radiographic knee osteoarthritis (OA) findings and OA-associated symptoms and signs.

Methods

Twenty patients were assessed clinically at Nagasaki University Hospital. The radiographic indications of OA were grade 1 to 3 using the Kellgren-Lawrence Grading System (K/L grade). Pentosan used in this study was manufactured and supplied in sterile injectable vials (100 mg/ml) by bene GmbH, Munich, Germany. The study was a single-center, open-label trial. Treatment consisted of 6 weekly subcutaneous injections (sc) of pentosan (2 mg/kg). Patients were clinically assessed at entry and 1 to 8, 11, 15, 24 & 52 weeks post treatment. The results were analyzed using one way ANOVA and Dunnett's method.

Results

Hydrarthroses were reduced quickly in all cases. The clinical assessments, i.e., knee flexion, pain while walking, pain after climbing up and down stairs, etc, were improved significantly and these clinical improvements continued for almost one year. The dose used in this study affected the blood coagulation test, but was within safe levels. Slightly abnormal findings were noted in serum triglycerides.

Conclusions

Pentosan treatment in twenty patients with mild knee OA seemed to provide improvements in clinical assessments and C2C level of cartilage metabolism.

Trial Registration

UMIN Clinical Trials Registry (UMIN-CTR) UMIN000002790     

Interventions aimed at increasing research use in nursing: a systematic review

Background

There has been considerable interest recently in developing and evaluating interventions to increase research use by clinicians. However, most work has focused on medical practices; and nursing is not well represented in existing systematic reviews. The purpose of this article is to report findings from a systematic review of interventions aimed at increasing research use in nursing.

Objective

To assess the evidence on interventions aimed at increasing research use in nursing.

Methods

A systematic review of research use in nursing was conducted using databases (Medline, CINAHL, Healthstar, ERIC, Cochrane Central Register of Controlled Trials, and Psychinfo), grey literature, ancestry searching (Cochrane Database of Systematic Reviews), key informants, and manual searching of journals. Randomized controlled trials and controlled before- and after-studies were included if they included nurses, if the intervention was explicitly aimed at increasing research use or evidence-based practice, and if there was an explicit outcome to research use. Methodological quality was assessed using pre-existing tools. Data on interventions and outcomes were extracted and categorized using a pre-established taxonomy.

Results

Over 8,000 titles were screened. Three randomized controlled trials and one controlled before- and after-study met the inclusion criteria. The methodological quality of included studies was generally low. Three investigators evaluated single interventions. The most common intervention was education. Investigators measured research use using a combination of surveys (three studies) and compliance with guidelines (one study). Researcher-led educational meetings were ineffective in two studies. Educational meetings led by a local opinion leader (one study) and the formation of multidisciplinary committees (one study) were both effective at increasing research use.

Conclusion

Little is known about how to increase research use in nursing, and the evidence to support or refute specific interventions is inconclusive. To advance the field, we recommend that investigators: (1) use theoretically informed interventions to increase research use, (2) measure research use longitudinally using theoretically informed and psychometrically sound measures of research use, as well as, measuring patient outcomes relevant to the intervention, and (3) use more robust and methodologically sound study designs to evaluate interventions. If investigators aim to establish a link between using research and improved patient outcomes they must first identify those interventions that are effective at increasing research use.     

Regenerative potential of human muscle stem cells in chronic inflammation

Introduction

Chronic inflammation is a profound systemic modification of the cellular microenvironment which could affect survival, repair and maintenance of muscle stem cells. The aim of this study was to define the role of chronic inflammation on the regenerative potential of satellite cells in human muscle.

Methods

As a model for chronic inflammation, 11 patients suffering from rheumatoid arthritis (RA) were included together with 16 patients with osteoarthritis (OA) as controls. The mean age of both groups was 64 years, with more females in the RA group compared to the OA group. During elective knee replacement surgery, a muscle biopsy was taken from the distal musculus vastus medialis. Cell populations from four RA and eight OA patients were used for extensive phenotyping because these cell populations showed no spontaneous differentiation and myogenic purity greater than 75% after explantation.

Results

After mononuclear cell explantation, myogenic purity, viability, proliferation index, number of colonies, myogenic colonies, growth speed, maximum number of population doublings and fusion index were not different between RA and OA patients. Furthermore, the expression of proteins involved in replicative and stress-induced premature senescence and apoptosis, including p16, p21, p53, hTERT and cleaved caspase-3, was not different between RA and OA patients. Mean telomere length was shorter in the RA group compared to the OA group.

Conclusions

In the present study we found evidence that chronic inflammation in RA does not affect the in vitro regenerative potential of human satellite cells. Identification of mechanisms influencing muscle regeneration by modulation of its microenvironment may, therefore, be more appropriate.     

Degradome expression profiling in human articular cartilage

Introduction

The molecular mechanisms underlying cartilage destruction in osteoarthritis are poorly understood. Proteolysis is a key feature in the turnover and degradation of cartilage extracellular matrix where the focus of research has been on the metzincin family of metalloproteinases. However, there is strong evidence to indicate important roles for other catalytic classes of proteases, with both extracellular and intracellular activities. The aim of this study was to profile the expression of the majority of protease genes in all catalytic classes in normal human cartilage and that from patients with osteoarthritis (OA) using a quantitative method.

Methods

Human cartilage was obtained from femoral heads at joint replacement for either osteoarthritis or following fracture to the neck of femur (NOF). Total RNA was purified, and expression of genes assayed using Taqman^® low-density array quantitative RT-PCR.

Results

A total of 538 protease genes were profiled, of which 431 were expressed in cartilage. A total of 179 genes were differentially expressed in OA versus NOF cartilage: eight aspartic proteases, 44 cysteine proteases, 76 metalloproteases, 46 serine proteases and five threonine proteases. Wilcoxon ranking as well as the LogitBoost-NR machine learning approach were used to assign significance to each gene, with the most highly ranked genes broadly similar using each method.

Conclusions

This study is the most complete quantitative analysis of protease gene expression in cartilage to date. The data help give direction to future research on the specific function(s) of individual proteases or protease families in cartilage and may help to refine anti-proteolytic strategies in OA.     

A randomized, double-blind study of AMG 108 (a fully human monoclonal antibody to IL-1R1) in patients with osteoarthritis of the knee

Introduction

AMG 108 is a fully human, immunoglobulin subclass G2 (IgG2) monoclonal antibody that binds the human interleukin-1 (IL-1) receptor type 1, inhibiting the activity of IL-1a and IL-1b. In preclinical studies, IL-1 inhibition was shown to be beneficial in models of osteoarthritis (OA). The purpose of this two-part study was to evaluate the safety and pharmacokinetics (PK; Part A) and clinical effect (Part B) of AMG 108 in a double-blind, placebo-controlled, multiple-dose study in patients with OA of the knee.

Methods

In Part A, patients received placebo or AMG 108 subcutaneously (SC; 75 mg or 300 mg) or intravenously (IV; 100 mg or 300 mg) once every 4 weeks for 12 weeks; in Part B, patients received placebo or 300 mg AMG 108 SC, once every 4 weeks for 12 weeks. The clinical effect of AMG 108 was measured in Part B by using the Western Ontario and McMaster Universities (WOMAC) osteoarthritis index pain score.

Results

In Part A, 68 patients were randomized, and 64 received investigational product. In Part B, 160 patients were randomized, and 159 received investigational product. AMG 108 was well tolerated. Most adverse events (AEs), infectious AEs, serious AEs and infections, as well as withdrawals from the study due to AEs occurred at similar rates in both active and placebo groups. One death was reported in an 80-year-old patient (Part A, 300 mg IV AMG 108; due to complications of lobar pneumonia). AMG 108 serum concentration-time profiles exhibited nonlinear PK. The AMG 108 group in Part B had statistically insignificant but numerically greater improvement in pain compared with the placebo group, as shown by the WOMAC pain scores (median change, -63.0 versus -37.0, respectively).

Conclusions

The safety profile of AMG 108 SC and IV was comparable with placebo in patients with OA of the knee. Patients who received AMG 108 showed statistically insignificant but numerically greater improvements in pain; however, minimal, if any, clinical benefit was observed.

Trial Registration

This study is registered with ClinicalTrials.gov with the identifier NCT00110942.     

An integrative review of systematic reviews related to the management of breathlessness in respiratory illnesses

Background

Breathlessness is a debilitating and distressing symptom in a wide variety of diseases and still a difficult symptom to manage. An integrative review of systematic reviews of non-pharmacological and pharmacological interventions for breathlessness in non-malignant disease was undertaken to identify the current state of clinical understanding of the management of breathlessness and highlight promising interventions that merit further investigation.

Methods

Systematic reviews were identified via electronic databases between July 2007 and September 2009. Reviews were included within the study if they reported research on adult participants using either a measure of breathlessness or some other measure of respiratory symptoms.

Results

In total 219 systematic reviews were identified and 153 included within the final review, of these 59 addressed non-pharmacological interventions and 94 addressed pharmacological interventions. The reviews covered in excess of 2000 trials. The majority of systematic reviews were conducted on interventions for asthma and COPD, and mainly focussed upon a small number of pharmacological interventions such as corticosteroids and bronchodilators, including beta-agonists. In contrast, other conditions involving breathlessness have received little or no attention and studies continue to focus upon pharmacological approaches. Moreover, although there are a number of non-pharmacological studies that have shown some promise, particularly for COPD, their conclusions are limited by a lack of good quality evidence from RCTs, small sample sizes and limited replication.

Conclusions

More research should focus in the future on the management of breathlessness in respiratory diseases other than asthma and COPD. In addition, pharmacological treatments do not completely manage breathlessness and have an added burden of side effects. It is therefore important to focus more research on promising non-pharmacological interventions.     

Preoperative muscle weakness as defined by handgrip strength and postoperative outcomes: a systematic review

Background

Reduced muscle strength- commonly characterized by decreased handgrip strength compared to population norms- is associated with numerous untoward outcomes. Preoperative handgrip strength is a potentially attractive real-time, non-invasive, cheap and easy-to-perform "bedside" assessment tool. Using systematic review procedure, we investigated whether preoperative handgrip strength was associated with postoperative outcomes in adults undergoing surgery.

Methods

PRISMA and MOOSE consensus guidelines for reporting systematic reviews were followed. MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Clinical Trials (1980-2010) were systematically searched by two independent reviewers. The selection criteria were limited to include studies of preoperative handgrip strength in human adults undergoing non-emergency, cardiac and non-cardiac surgery. Study procedural quality was analysed using the Newcastle-Ottawa Quality Assessment score. The outcomes assessed were postoperative morbidity, mortality and hospital stay.

Results

Nineteen clinical studies (17 prospective; 4 in urgent surgery) comprising 2194 patients were identified between1980-2010. Impaired handgrip strength and postoperative morbidity were defined inconsistently between studies. Only 2 studies explicitly ensured investigators collecting postoperative outcomes data were blinded to preoperative handgrip strength test results. The heterogeneity of study design used and the diversity of surgical procedures precluded formal meta-analysis. Despite the moderate quality of these observational studies, lower handgrip strength was associated with increased morbidity (n = 10 studies), mortality (n = 2/5 studies) and length of hospital stay (n = 3/7 studies).

Conclusions

Impaired preoperative handgrip strength may be associated with poorer postoperative outcomes, but further work exploring its predictive power is warranted using prospectively acquired, objectively defined measures of postoperative morbidity.     

Moving instead of asking? Performance-based tests and BASFI-questionnaire measure different aspects of physical function in ankylosing spondylitis

Introduction

Ankylosing Spondylitis (AS) is characterised by limitations in physical function. The Bath Ankylosing Spondylitis Functional Index (BASFI) is considered to be the gold-standard to assess physical function in AS patients. However, the BASFI questionnaire is a self-reported outcome measure and susceptible to subjective interpretation (under- or over-estimation). More objective outcome measures, like performance-based tests, could provide an objective outcome measurement for the evaluation of limitations in physical function. Therefore, the primary aim of this study was to determine the association between performance-based measures and the BASFI questionnaire.

Methods

In this cross-sectional study 126 AS patients completed the BASFI questionnaire and eight performance-based tests based on BASFI-items. Each test received three scores: one for performance (time or points) and a score for exertion and pain experienced during performance (using modified Borg-scale and VAS 0-100 mm, respectively). Linear regression analyses were used to assess the associations between the BASFI questionnaire and performance-based tests.

Results

The univariable association between performance and BASFI-score was moderate with a R-square of 0.31 and Beta of 0.56 (p's < 0.05). In a multivariable analysis, the association between performance, exertion and pain on the one hand and BASFI-score on the other was assessed; R-square increased to 0.54: the Beta's for exertion and pain during performance were 0.38 and 0.26, respectively; the Beta for performance decreased to 0.19 (p's < 0.05).

Conclusions

This study demonstrates that alongside actual performance, patients seem to incorporate exertion and pain in their assessment of perceived physical function on the BASFI questionnaire. Performance-based tests could provide an objective outcome measurement for the evaluation of physical function and give relevant new information in addition to the BASFI questionnaire.     

Pre-administration of rats with <Emphasis Type="Italic">Helicobacter pylori</Emphasis> γ-glutamyl-transpeptidase alleviates osteoarthritis

Objective

To determine the efficacy of Helicobacter pylori γ-glutamyl-transpeptidase (GGT) in osteoarthritis (OA) therapy.

Results

Oral administration of rats with rGGT alleviated joint pain in the acute phase of iodoacetate (IA)-induced OA. The CXCL1/IL-6 in blood and in articular tissue as well as circulating granulocytes in the recipients of GGT, were reduced. This might be associated with the expansion of regulatory T cells in the inguinal lymph nodes and increased articular IL-10.

Conclusion

We provide preclinical evidence that H. pylori GGT may represent a promising candidate for OA therapy.