Effect of conformity and contact stress on wear in fixed-bearing total knee prostheses

Ultra high molecular weight polyethylene (PE) remains the primary bearing surface of choice in total knee replacements (TKR). Wear is controlled by levels of cross-shear motion and contact stress. The aim of this study was to compare the wear of fixed-bearing total knee replacements with curved and flat inserts and to test the hypothesis that the flat inserts which give higher contact stresses and smaller contact areas would lead to lower levels of surface wear. A low-conforming, high contact stress knee with a low-medium level of cross shear resulted in significantly lower wear rates in comparison to a standard cruciate sacrificing fixed-bearing knee. The low wear solution found in the knee simulator was supported by fundamental studies of wear as a function of pressure and cross shear in the pin on plate system. Current designs of fixed-bearing knees do not offer this low wear solution due to their medium cross shear, moderate conformity and medium contact stress.     

Secreted Protein Acidic and Rich in Cysteine (SPARC) in Human Skeletal Muscle

Secreted protein acidic and rich in cysteine (SPARC)/osteonectin is expressed in different tissues during remodeling and repair, suggesting a function in regeneration. Several gene expression studies indicated that SPARC was expressed in response to muscle damage. Studies on myoblasts further indicated a function of SPARC in skeletal muscle. We therefore found it of interest to study SPARC expression in human skeletal muscle during development and in biopsies from Duchenne and Becker muscular dystrophy and congenital muscular dystrophy, congenital myopathy, inclusion body myositis, and polymyositis patients to analyze SPARC expression in a selected range of inherited and idiopathic muscle wasting diseases. SPARC-positive cells were observed both in fetal and neonatal muscle, and in addition, fetal myofibers were observed to express SPARC at the age of 15–16 weeks. SPARC protein was detected in the majority of analyzed muscle biopsies (23 of 24), mainly in mononuclear cells of which few were pax7 positive. Myotubes and regenerating myofibers also expressed SPARC. The expression-degree seemed to reflect the severity of the lesion. In accordance with these in vivo findings, primary human-derived satellite cells were found to express SPARC both during proliferation and differentiation in vitro. In conclusion, this study shows SPARC expression both during muscle development and in regenerating muscle. The expression is detected both in satellite cells/myoblasts and in myotubes and muscle fibers, indicating a role for SPARC in the skeletal muscle compartment. (J Histochem Cytochem 57:29–39, 2009)     

Changes in Symptoms of Depression With Weight Loss: Results of a Randomized Trial

Recent studies of rimonabant have re‐awakened interest in the possible adverse psychiatric effects of weight loss, as well as of weight loss medications. This study examined changes in symptoms of depression in 194 obese participants (age = 43.7 ± 10.2 years; BMI = 37.6 ± 4.1 kg/m²) in a 1‐year randomized trial of lifestyle modification and medication. Participants were assigned to (i) sibutramine alone; (ii) lifestyle modification alone; (iii) sibutramine plus lifestyle modification (i.e., combined therapy); or (iv) sibutramine plus brief therapy. Participants completed the Beck Depression Inventory‐II (BDI‐II) at baseline and weeks 6, 10, 18, 26, 40, and 52. At 1 year, participants in combined therapy lost the most weight and those in sibutramine alone the least (12.1 ± 8.8% vs. 5.5 ± 6.5%; P < 0.01). Mean BDI‐II scores across all participants declined from 8.1 ± 6.9 to 6.2 ± 7.7 at 1 year (P < 0.001), with no significant differences among groups. Despite this favorable change, 13.9% of participants (across the four groups) reported potentially discernible increases (≥ 5 points on the BDI‐II) in symptoms of depression at week 52. They lost significantly less weight than participants in the rest of the sample (5.4 ± 7.8% vs. 9.0 ± 7.8%, respectively; P < 0.03). The baseline prevalence of suicidal ideation was 3.6%. Seven new cases of suicidal ideation were observed during the year, with three in lifestyle modification alone. Further research is needed to identify characteristics of obese patients at risk of negative mood changes (and suicidal ideation) in response to behavioral and pharmacologic therapies.     

Hypothalamic Neuroendocrine Functions in Rats with Dihydrotestosterone-Induced Polycystic Ovary Syndrome: Effects of Low-Frequency Electro-Acupuncture

Adult female rats continuously exposed to androgens from prepuberty have reproductive and metabolic features of polycystic ovary syndrome (PCOS). We investigated whether such exposure adversely affects estrous cyclicity and the expression and distribution of gonadotropin-releasing hormone (GnRH), GnRH receptors, and corticotrophin-releasing hormone (CRH) in the hypothalamus and whether the effects are mediated by the androgen receptor (AR). We also assessed the effect of low-frequency electro-acupuncture (EA) on those variables. At 21 days of age, rats were randomly divided into three groups (control, PCOS, and PCOS EA; n = 12/group) and implanted subcutaneously with 90-day continuous-release pellets containing vehicle or 5α-dihydrostestosterone (DHT). From age 70 days, PCOS EA rats received 2-Hz EA (evoking muscle twitches) five times/week for 4–5 weeks. Hypothalamic protein expression was measured by immunohistochemistry and western blot. DHT-treated rats were acyclic, but controls had regular estrous cycles. In PCOS rats, hypothalamic medial preoptic AR protein expression and the number of AR- and GnRH-immunoreactive cells were increased, but CRH was not affected; however, GnRH receptor expression was decreased in both the pituitary and hypothalamus. Low-frequency EA restored estrous cyclicity within 1 week and reduced the elevated hypothalamic GnRH and AR expression levels. EA did not affect GnRH receptor or CRH expression. Interestingly, nuclear AR co-localized with GnRH in the hypothalamus. Thus, rats with DHT-induced PCOS have disrupted estrous cyclicity and an increased number of hypothalamic cells expressing GnRH, most likely mediated by AR activation. Repeated low-frequency EA normalized estrous cyclicity and restored GnRH and AR protein expression. These results may help explain the beneficial neuroendocrine effects of low-frequency EA in women with PCOS.     

Phase II Open Label Study of Valproic Acid in Spinal Muscular Atrophy

Preliminary in vitro and in vivo studies with valproic acid (VPA) in cell lines and patients with spinal muscular atrophy (SMA) demonstrate increased expression of SMN, supporting the possibility of therapeutic benefit. We performed an open label trial of VPA in 42 subjects with SMA to assess safety and explore potential outcome measures to help guide design of future controlled clinical trials. Subjects included 2 SMA type I ages 2–3 years, 29 SMA type II ages 2–14 years and 11 type III ages 2–31 years, recruited from a natural history study. VPA was well-tolerated and without evident hepatotoxicity. Carnitine depletion was frequent and temporally associated with increased weakness in two subjects. Exploratory outcome measures included assessment of gross motor function via the modified Hammersmith Functional Motor Scale (MHFMS), electrophysiologic measures of innervation including maximum ulnar compound muscle action potential (CMAP) amplitudes and motor unit number estimation (MUNE), body composition and bone density via dual-energy X-ray absorptiometry (DEXA), and quantitative blood SMN mRNA levels. Clear decline in motor function occurred in several subjects in association with weight gain; mean fat mass increased without a corresponding increase in lean mass. We observed an increased mean score on the MHFMS scale in 27 subjects with SMA type II (p≤0.001); however, significant improvement was almost entirely restricted to participants <5 years of age. Full length SMN levels were unchanged and Δ7SMN levels were significantly reduced for 2 of 3 treatment visits. In contrast, bone mineral density (p≤0.0036) and maximum ulnar CMAP scores (p≤0.0001) increased significantly.

Conclusions

While VPA appears safe and well-tolerated in this initial pilot trial, these data suggest that weight gain and carnitine depletion are likely to be significant confounding factors in clinical trials. This study highlights potential strengths and limitations of various candidate outcome measures and underscores the need for additional controlled clinical trials with VPA targeting more restricted cohorts of subjects.

Trial Registration

ClinicalTrials.gov http://clinicaltrials.gov/ct2/show/NCT00374075?term=NCT00374075&rank=1     

Incidence and Prediction of Falls in Dementia: A Prospective Study in Older People

Background

Falls are a major cause of morbidity and mortality in dementia, but there have been no prospective studies of risk factors for falling specific to this patient population, and no successful falls intervention/prevention trials. This prospective study aimed to identify modifiable risk factors for falling in older people with mild to moderate dementia.

Methods and Findings

179 participants aged over 65 years were recruited from outpatient clinics in the UK (38 Alzheimer''s disease (AD), 32 Vascular dementia (VAD), 30 Dementia with Lewy bodies (DLB), 40 Parkinson''s disease with dementia (PDD), 39 healthy controls). A multifactorial assessment of baseline risk factors was performed and fall diaries were completed prospectively for 12 months. Dementia participants experienced nearly 8 times more incident falls (9118/1000 person-years) than controls (1023/1000 person-years; incidence density ratio: 7.58, 3.11–18.5). In dementia, significant univariate predictors of sustaining at least one fall included diagnosis of Lewy body disorder (proportional hazard ratio (HR) adjusted for age and sex: 3.33, 2.11–5.26), and history of falls in the preceding 12 months (HR: 2.52, 1.52–4.17). In multivariate analyses, significant potentially modifiable predictors were symptomatic orthostatic hypotension (HR: 2.13, 1.19–3.80), autonomic symptom score (HR per point 0–36: 1.055, 1.012–1.099), and Cornell depression score (HR per point 0–40: 1.053, 1.01–1.099). Higher levels of physical activity were protective (HR per point 0–9: 0.827, 0.716–0.956).

Conclusions

The management of symptomatic orthostatic hypotension, autonomic symptoms and depression, and the encouragement of physical activity may provide the core elements for the most fruitful strategy to reduce falls in people with dementia. Randomised controlled trials to assess such a strategy are a priority.     

Glycine uptake in heath plants and soil microbes responds to elevated temperature, CO2 and drought

Temperate terrestrial ecosystems are currently exposed to climatic and air quality changes with increased atmospheric CO₂, increased temperature and prolonged droughts. The responses of natural ecosystems to these changes are focus for research, due to the potential feedbacks to the climate. We here present results from a field experiment in which the effects of these three climate change factors are investigated solely and in all combinations at a temperate heath dominated by heather (Calluna vulgaris) and wavy hair-grass (Deschampsia flexuosa).Climate induced increases in plant production may increase plant root exudation of dissolved organic compounds such as amino acids, and the release of amino acids during decomposition of organic matter. Such free amino acids in soil serve as substrates for soil microorganisms and are also acquired as nutrients directly by plants. We investigated the magnitude of the response to the potential climate change treatments on uptake of organic nitrogen in an in situ pulse labelling experiment with ¹⁵N¹³C₂-labelled glycine (amino acid) injected into the soil.In situ root nitrogen acquisition by grasses responded significantly to the climate change treatments, with larger ¹⁵N uptake in response to warming and elevated CO₂ but not additively when the treatments were combined. Also, a larger grass leaf biomass in the combined T and CO₂ treatment than in individual treatments suggest that responses to combined climate change factors cannot be predicted from the responses to single factors treatments.The soil microbes were superior to plants in the short-term competition for the added glycine, as indicated by an 18 times larger ¹⁵N recovery in the microbial biomass compared to the plant biomass. The soil microbes acquired glycine largely as an intact compound (87%), with no effects of the multi factorial climate change treatment through one year.