Home based exercise programme for knee pain and knee osteoarthritis: randomised controlled trial

Objectives To determine whether a home based exercise programme can improve outcomes in patients with knee pain. Design Pragmatic, factorial randomised controlled trial of two years' duration. Setting Two general practices in Nottingham. Participants 786 men and women aged >45 years with self reported knee pain. Interventions Participants were randomised to four groups to receive exercise therapy, monthly telephone contact, exercise therapy plus telephone contact, or no intervention. Patients in the no intervention and combined exercise and telephone groups were randomised to receive or not receive a placebo health food tablet. Main outcome measures Primary outcome was self reported score for knee pain on the Western Ontario and McMaster universities (WOMAC) osteoarthritis index at two years. Secondary outcomes included knee specific physical function and stiffness (scored on WOMAC index), general physical function (scored on SF­36 questionnaire), psychological outlook (scored on hospital anxiety and depression scale), and isometric muscle strength. Results 600 (76.3%) participants completed the study. At 24 months, highly significant reductions in knee pain were apparent for the pooled exercise groups compared with the non­exercise groups (mean difference –0.82, 95% confidence interval –1.3 to –0.3). Similar improvements were observed at 6, 12, and 18 months. Regular telephone contact alone did not reduce pain. The reduction in pain was greater the closer patients adhered to the exercise plan. Conclusions A simple home based exercise programme can significantly reduce knee pain. The lack of improvement in patients who received only telephone contact suggests that improvements are not just due to psychosocial effects because of contact with the therapist

Fluphenazine reduces proteotoxicity in C. elegans and mammalian models of alpha-1-antitrypsin deficiency

The classical form of α1-antitrypsin deficiency (ATD) is associated with hepatic fibrosis and hepatocellular carcinoma. It is caused by the proteotoxic effect of a mutant secretory protein that aberrantly accumulates in the endoplasmic reticulum of liver cells. Recently we developed a model of this deficiency in C. Elegans and adapted it for high-content drug screening using an automated, image-based array scanning. Screening of the Library of Pharmacologically Active Compounds identified fluphenazine (Flu) among several other compounds as a drug which reduced intracellular accumulation of mutant α1-antitrypsin Z (ATZ). Because it is representative of the phenothiazine drug class that appears to have autophagy enhancer properties in addition to mood stabilizing activity, and can be relatively easily re-purposed, we further investigated its effects on mutant ATZ. The results indicate that Flu reverses the phenotypic effects of ATZ accumulation in the C. elegans model of ATD at doses which increase the number of autophagosomes in vivo . Furthermore, in nanomolar concentrations, Flu enhances the rate of intracellular degradation of ATZ and reduces the cellular ATZ load in mammalian cell line models. In the PiZ mouse model Flu reduces the accumulation of ATZ in the liver and mediates a decrease in hepatic fibrosis. These results show that Flu can reduce the proteotoxicity of ATZ accumulation in vivo and, because it has been used safely in humans, this drug can be moved rapidly into trials for liver disease due to ATD. The results also provide further validation for drug discovery using C. elegans models that can be adapted to high-content drug screening platforms and used together with mammalian cell line and animal models. © 2014 Li et al

Deficient and null variants of SERPINA1 are proteotoxic in a Caenorhabditis elegans model of α1-antitrypsin deficiency

α1-antitrypsin deficiency (ATD) predisposes patients to both loss-of-function (emphysema) and gain-of-function (liver cirrhosis) phenotypes depending on the type of mutation. Although the Z mutation (ATZ) is the most prevalent cause of ATD, >120 mutant alleles have been identified. In general, these mutations are classified as deficient (<20% normal plasma levels) or null (<1% normal levels) alleles. The deficient alleles, like ATZ, misfold in the ER where they accumulate as toxic monomers, oligomers and aggregates. Thus, deficient alleles may predispose to both gain- and loss-of-function phenotypes. Null variants, if translated, typically yield truncated proteins that are efficiently degraded after being transiently retained in the ER. Clinically, null alleles are only associated with the loss-of-function phenotype. We recently developed a C. elegans model of ATD in order to further elucidate the mechanisms of proteotoxicity (gain-of-function phenotype) induced by the aggregationprone deficient allele, ATZ. The goal of this study was to use this C. elegans model to determine whether different types of deficient and null alleles, which differentially affect polymerization and secretion rates, correlated to any extent with proteotoxicity. Animals expressing the deficient alleles, Mmalton, Siiyama and S (ATS), showed overall toxicity comparable to that observed in patients. Interestingly, Siiyama expressing animals had smaller intracellular inclusions than ATZ yet appeared to have a greater negative effect on animal fitness. Surprisingly, the null mutants, although efficiently degraded, showed a relatively mild gainoffunction proteotoxic phenotype. However, since null variant proteins are degraded differently and do not appear to accumulate, their mechanism of proteotoxicity is likely to be different to that of polymerizing, deficient mutants. Taken together, these studies showed that C. elegans is an inexpensive tool to assess the proteotoxicity of different AT variants using a transgenic approach

Targeting tumour re-wiring by triple blockade of mTORC1, epidermal growth factor, and oestrogen receptor signalling pathways in endocrine-resistant breast cancer

Background Endocrine therapies are the mainstay of treatment for oestrogen receptor (ER)-positive (ER+) breast cancer (BC). However, resistance remains problematic largely due to enhanced cross-talk between ER and growth factor pathways, circumventing the need for steroid hormones. Previously, we reported the anti-proliferative effect of everolimus (RAD001-mTORC1 inhibitor) with endocrine therapy in resistance models; however, potential routes of escape from treatment via ERBB2/3 signalling were observed. We hypothesised that combined targeting of three cellular nodes (ER, ERBB, and mTORC1) may provide enhanced long-term clinical utility. Methods A panel of ER+ BC cell lines adapted to long-term oestrogen deprivation (LTED) and expressing ESR1wt or ESR1Y537S, modelling acquired resistance to an aromatase-inhibitor (AI), were treated in vitro with a combination of RAD001 and neratinib (pan-ERBB inhibitor) in the presence or absence of oestradiol (E2), tamoxifen (4-OHT), or fulvestrant (ICI182780). End points included proliferation, cell signalling, cell cycle, and effect on ER-mediated transactivation. An in-vivo model of AI resistance was treated with monotherapies and combinations to assess the efficacy in delaying tumour progression. RNA-seq analysis was performed to identify changes in global gene expression as a result of the indicated therapies. Results Here, we show RAD001 and neratinib (pan-ERBB inhibitor) caused a concentration-dependent decrease in proliferation, irrespective of the ESR1 mutation status. The combination of either agent with endocrine therapy further reduced proliferation but the maximum effect was observed with a triple combination of RAD001, neratinib, and endocrine therapy. In the absence of oestrogen, RAD001 caused a reduction in ER-mediated transcription in the majority of the cell lines, which associated with a decrease in recruitment of ER to an oestrogen-response element on the TFF1 promoter. Contrastingly, neratinib increased both ER-mediated transactivation and ER recruitment, an effect reduced by the addition of RAD001. In-vivo analysis of an LTED model showed the triple combination of RAD001, neratinib, and fulvestrant was most effective at reducing tumour volume. Gene set enrichment analysis revealed that the addition of neratinib negated the epidermal growth factor (EGF)/EGF receptor feedback loops associated with RAD001. Conclusions Our data support the combination of therapies targeting ERBB2/3 and mTORC1 signalling, together with fulvestrant, in patients who relapse on endocrine therapy and retain a functional ER

Effects of methods of descending stairs forwards versus backwards on knee joint force in patients with osteoarthritis of the knee: a clinical controlled study

<p>Abstract</p> <p>Background</p> <p>The aim of this study was to investigate the kinetic characteristics of compensatory backward descending movement performed by patients with osteoarthritis of the knee.</p> <p>Methods</p> <p>Using a three-dimensional motion analysis system, we investigated lower extremity joint angles, joint moments, joint force of the support leg in forward and backward descending movements on stairs, and joint force of the leading leg at landing in 7 female patients with osteoarthritis of the knee.</p> <p>Results</p> <p>Compared with the forward descending movement, knee joint angle, joint moment and joint force of the support leg all decreased in the backward descending movement. Joint force of the leading leg at landing was also reduced in the backward descending movement. In addition, we confirmed that the center of body mass was mainly controlled by the knee and ankle joints in the forward descending movement, and by the hip joint in the backward descending movement.</p> <p>Conclusions</p> <p>Since it has been reported that knee flexion angle and extensor muscle strength are decreased in patients with osteoarthritis of the knee, we believe that backward descending movement is an effective method to use the hip joint to compensate forthese functional defects. In addition, due to the decreased knee joint force both in the leading and support legs in backward descending movement, the effectiveness of compensatory motion for pain control and knee joint protection was also suggested.</p

Feasibility of using quadriceps-strengthening exercise to improve pain and sleep in a severely demented elder with osteoarthritis – a case report

BACKGROUND: Osteoarthritis (OA) of the knee, which is prevalent among older adults in nursing homes, causes significant pain and suffering, including disturbance of nocturnal sleep. One nonpharmacologic treatment option is quadriceps-strengthening exercise, however, the feasibility of such a treatment for reducing pain from OA in severely demented elders has not been studied. This report describes our test of the feasibility of such an exercise program, together with its effects on pain and sleep, in a severely demented nursing home resident. CASE PRESENTATION: The subject was an elderly man with severe cognitive impairment (Mini-Mental Status Exam score 4) and knee OA (Kellgren-Lawrence radiographic grade 4). He was enrolled in a 5-week, 10-session standardized progressive-resistance training program to strengthen the quadriceps, and completed all sessions. Pain was assessed with the Western Ontario and MacMaster OA Index (WOMAC) pain subscale, and sleep was assessed by actigraphy. The patient was able to perform the exercises, with a revision to the protocol. However, the WOMAC OA pain subscale proved inadequate for measuring pain in a patient with low cognitive functioning, and therefore the effects on pain were inconclusive. Although his sleep improved after the intervention, the influence of his medications and the amount of daytime sleep on his nighttime sleep need to be considered. CONCLUSIONS: A quadriceps-strengthening exercise program for treating OA of the knee is feasible in severely demented elders, although a better outcome measure is needed for pain

Knee complaints and consequences on work status; a 10-year follow-up survey among floor layers and graphic designers

<p>Abstract</p> <p>Background</p> <p>The purpose of the study was to examine if knee complaints among floor layers predict exclusion from the trade.</p> <p>Methods</p> <p>In 1994/95 self-reported data were obtained from a cohort of floor layers and graphic designers with and without knee straining work activities, respectively. At follow-up in 2005 the questionnaire survey was repeated. The study population consisted of 81 floor layers and 173 graphic designers who were presently working in their trades at baseline (1995). All participants were men aged 36–70 years in 2005.</p> <p>We computed the risk of losing gainful employment in the trade according to occurrence of knee complaints at baseline, using Cox proportional hazard regression adjusted for a number of potential confounding variables. Moreover, the crude and adjusted odds risk ratio for knee complaints according to status of employment in the trade were computed, using graphic designers as reference.</p> <p>Results</p> <p>A positive but non-significant association between knee complaints lasting more than 30 days the past 12 months and exclusion from the trade was found among floor layers (Hazard Ratio = 1.4, 95% CI = 0.6–3.5).</p> <p>The frequency of self-reported knee complaints was lower among floor layers presently at work in the trade in year 2005 (26.3%) compared with baseline in 1995 (41.1%), while the opposite tendency was seen among graphic designers (20.7% vs. 10.7%).</p> <p>Conclusion</p> <p>The study suggests that knee complaints are a risk factor for premature exclusion from a knee demanding trade. However, low power of the study precludes strong conclusions. The study also indicates a healthy worker effect among floor layers and a survivor effect among graphic designers.</p

The North Staffordshire Osteoarthritis Project – NorStOP: Prospective, 3-year study of the epidemiology and management of clinical osteoarthritis in a general population of older adults

BACKGROUND: The clinical syndrome of joint pain and stiffness in older people is the commonest cause of disability and health care consultation in this age group. Yet there have been few prospective studies of its course over time and its impact on personal and social life. We plan a cohort study in the general population aged 50 years and over to determine the course and prognosis of hand, hip, knee and foot pain, and the impact of these syndromes on participation levels and health care use. METHODS: All patients aged 50 years and over registered with 3 local general practices are to be recruited to a population-based cohort study through the use of a two-stage mailing process. Participants will initially complete a "Health Survey" questionnaire. This will collect information on several areas of life including socio-demographics, general health, physical function, participation, and bodily pain. Those who state that they have experienced any hand problem or any pain in their hands, hips, knees, or feet in the previous 12 months, and also give permission to be re-contacted, will be mailed a "Regional Pains Survey" questionnaire which collects detailed information on the four selected body regions (hand, hips, knees, feet). Follow-up data for the three-year period subsequent to cohort recruitment will be collected through two sources: i) general practice medical records and ii) repeat mailed survey

A cross sectional study of requests for knee radiographs from primary care

<p>Abstract</p> <p>Background</p> <p>Knee pain is the commonest pain complaint amongst older adults in general practice. General Practitioners (GPs) may use x rays when managing knee pain, but little information exists regarding this process. Our objectives, therefore, were to describe the information GPs provide when ordering knee radiographs in older people, to assess the association between a clinical diagnosis of osteoarthritis (OA) and the presence of radiographic knee OA, and to investigate the clinical content of the corresponding radiologists' report.</p> <p>Methods</p> <p>A cross sectional study of GP requests for knee radiographs and their matched radiologists' reports from a local radiology department. Cases, aged over 40, were identified during an 11-week period. The clinical content of the GPs' requests and radiologists' reports was analysed. Associations of radiologists' reporting of i) osteoarthritis, ii) degenerative disease and iii) individual radiographic features of OA, with patient characteristics and clinical details on the GPs' requests, were assessed.</p> <p>Results</p> <p>The study identified 136 cases with x ray requests from 79 GPs and 11 reporting radiologists. OA was identified clinically in 19 (14%) of the requests, and queried in another 31 (23%). The main clinical descriptor was pain in 119 cases (88%). Radiologists' reported OA in 22% of cases, and the features of OA were mentioned in 63%. Variation in reporting existed between radiologists. The commonest description was joint space narrowing in 52 reports (38%). There was an apparent although non significant increase in the reporting of knee OA when the GP had diagnosed or queried it (OR 1.95; 95% CI 0.76, 5.00).</p> <p>Conclusion</p> <p>The features of radiographic OA are commonly reported in those patients over 40 whom GPs send for x ray. If OA is clinically suspected, radiologists appear to be more likely to report its presence. Further research into alternative models of referral and reporting might identify a more appropriate imaging policy in knee disorders for primary care.</p