Associations of components of sarcopenia with risk of fracture in the Osteoporotic Fractures in Men (MrOS) study.

Our aim was to evaluate the associations between the individual components of sarcopenia and fracture types. In this cohort, the risk of experiencing any clinical, hip, or major osteoporotic fracture is greater in men with slow walking speed in comparison to normal walking speed. INTRODUCTION: The association between the components of sarcopenia and fractures has not been clearly elucidated and has hindered the development of appropriate therapeutic interventions. Our aim was to evaluate the associations between the individual components of sarcopenia, specifically lean mass, strength, and physical performance and fracture (any fracture, hip fracture, major osteoporotic fracture) in the Osteoporotic Fractures in Men (MrOS) study. METHODS: The Osteoporotic Fractures in Men study (MrOS) recruited 5995 men ≥ 65 years of age. We measured appendicular lean mass (ALM) by dual-energy X-ray absorptiometry (low as residual value < 20th percentile for the cohort), walking speed (fastest trial of usual pace, values < 0.8 m/s were low), and grip strength (max score of 2 trials, values < 30 kg were low). Information on fractures was assessed tri-annually over an average follow-up of 12 years and centrally adjudicated. Cox proportional hazard models estimated the hazard ratio (HR) (95% confidence intervals) for slow walking speed, low grip strength, and low lean mass. RESULTS: Overall, 1413 men had a fracture during follow-up. Slow walking speed was associated with an increased risk for any HR = 1.39, 1.05-1.84; hip HR = 2.37, 1.54-3.63; and major osteoporotic, HR = 1.89, 1.34-2.67 in multi-variate-adjusted models. Low lean mass and low grip strength were not significantly associated with fracture. CONCLUSIONS: In this cohort of older adult men, the risk of experiencing any, hip, or major osteoporotic fracture is greater in men with slow walking speed in comparison to men with normal walking speed, but low grip strength and low lean mass were not associated with fracture.

Synovitis in knee osteoarthritis: a precursor of disease?

OBJECTIVES: It is unknown whether joint inflammation precedes other articular tissue damage in osteoarthritis. Therefore, this study aims to determine if synovitis precedes the development of radiographic knee osteoarthritis (ROA). METHODS: The participants in this nested case-control study were selected from persons in the Osteoarthritis Initiative with knees that had a Kellgren Lawrence grading (KLG)=0 at baseline (BL). These knees were evaluated annually with radiography and non-contrast-enhanced MRI over 4 years. MRIs were assessed for effusion-synovitis and Hoffa-synovitis. Case knees were defined by ROA (KLG≥2) on the postero-anterior knee radiographs at any assessment after BL. Radiographs were assessed at P0 (time of onset of ROA), 1 year prior to P0 (P-1) and at BL. Controls were participants who did not develop incident ROA (iROA) from BL to 48 months). RESULTS: 133 knees of 120 persons with ROA (83 women) were matched to 133 control knees (83 women). ORs for occurrence of iROA associated with the presence of effusion-synovitis at BL, P-1 and P0 were 1.56 (95% CI 0.86 to 2.81), 3.23 (1.72 to 6.06) and 4.7 (1.10 to 2.95), respectively. The ORs for the occurrence of iROA associated with the presence of Hoffa-synovitis at BL, P-1 and P0 were 1.80 (1.1 to 2.95), 2.47 (1.45 to 4.23) and 2.40 (1.43 to 4.04), respectively. CONCLUSIONS: Effusion-synovitis and Hoffa-synovitis strongly predicted the development of iROA.

Loss of anterior cruciate ligament integrity and the development of radiographic knee osteoarthritis: a sub-study of the osteoarthritis initiative.

INTRODUCTION: The aim of this study was to determine whether loss of ACL integrity in an older cohort precedes the onset of radiographic OA (ROA). METHODS: Participants in this nested case-control study were selected from the Osteoarthritis Initiative (OAI) study who had risk factors for OA development but did not have ROA (Kellgren-Lawrence grading (KLG) of 0 or 1) in both knees at baseline. The MRIs were assessed for the presence of ACL tears. Case knees were defined by the development of ROA on knee radiographs between the 12 and 48 month visits. Their radiographs were assessed at P0 (time of onset of radiographic knee OA), 1 year prior to P0 (P-1) and at baseline. Controls were selected from amongst those who did not develop incident ROA and were matched to cases. RESULTS: 355 persons who developed ROA were matched to 355 controls. No relationship between loss of ACL integrity and incident ROA was found at any assessment time point. Odds ratios (OR) for baseline, 1 year prior to incident ROA (P1) and at point of occurrence of incident ROA (P0) were 2.00 (0.66-6.06), 2.5 (0.76-8.24) and 2.75 (0.85-8.88) respectively. A significant risk of incident ROA was found in participants who had a history of knee injury with an OR of 1.51 (1.05-2.16). CONCLUSION: Loss of ACL integrity does not confer a significantly increased risk of incident ROA in an older adult cohort. In contrast, a history of knee injury was associated with an increased risk of incident ROA.

Brief report: symmetricity of radiographic and MRI-detected structural joint damage in persons with knee pain--the Joints on Glucosamine (JOG) Study.

OBJECTIVE: Most MRI-based osteoarthritis (OA) studies have focused on a single knee per person and thus, data on bilaterality is sparse. Study aim was to describe symmetricity of MRI-detected OA features in a cohort of subjects with knee pain. DESIGN: Participants were 169 subjects with chronic knee pain who had 3 T MRI of both knees using the same protocol as in the Osteoarthritis Initiative. Knees were read for cartilage damage, bone marrow lesions (BMLs), and meniscal damage according to the Whole-Organ Magnetic Resonance Imaging Score (WORMS) system. Chi(2) tests were used to compare the proportion of knees with unilateral tissue pathology to the proportion what would be expected if both knees were independent. We further used percent agreement and linear weighted kappa statistics to describe agreement of cartilage damage and BMLs in the same articular plates. RESULTS: 51.2% of participants were men, mean age was 52.1 (±6.2), mean BMI was 29.0 kg/m(2) (±4.1). All plates showed a significant higher degree of symmetricity for cartilage damage as evidenced by weighted kappas ranging from 0.32 to 0.59. For BMLs the degree of symmetricity was higher for the patella, trochlea, medial tibia, lateral femur, and medial femur; for meniscal damage the degree of unilaterality was lower for all medial meniscal subregions but not all lateral. Kappas ranged between 0.52 and 0.68 for cartilage and 0.30 and 0.55 for BMLs for the four subregions with highest agreement. CONCLUSION: A higher degree of symmetricity of tissue damage than expected by chance was observed in this cohort of subjects with knee pain.

Trajectory of cartilage loss within 4 years of knee replacement--a nested case-control study from the osteoarthritis initiative.

OBJECTIVE: Knee replacement (KR) represents a clinically important endpoint of knee osteoarthritis (KOA). Here we examine the 4-year trajectory of femoro-tibial cartilage thickness loss prior to KR vs non-replaced controls. METHODS: A nested case-control study was performed in Osteoarthritis Initiative (OAI) participants: Cases with KR between 12 and 60 month (M) follow-up were each matched with one control (without KR through 60M) by age, sex, and baseline radiographic stage. Femoro-tibial cartilage thickness was measured quantitatively using magnetic resonance imaging (MRI) at the annual visit prior to KR occurrence (T0), and at 1-4 years prior to T0 (T-1 to T-4). Cartilage loss between cases and controls was compared using paired t-tests and conditional logistic regression. RESULTS: One hundred and eighty-nine knees of 164 OAI participants [55% women; age 64 ± 8.7; body mass index (BMI) 29 ± 4.5] had KR and longitudinal cartilage data. Comparison of annualized slopes of change across all time points revealed greater loss in the central medial tibia (primary outcome) in KRs than in controls [94 ± 137 vs 55 ± 104 µm; P = 0.0017 (paired t); odds ratio (OR) 1.36 (95% confidence interval (CI): 1.08-1.70)]. The discrimination was stronger for T-2 → T0 [OR 1.61 (1.33-1.95), n = 127] than for T-1 → T0, and was not statistically significant for intervals prior to T-2 [i.e., T-4 → T-2, OR 0.97 (0.67-1.41), n = 60]. Results were similar for total medial femoro-tibial cartilage loss (secondary outcome), and when adjusting for pain and BMI. CONCLUSIONS: In knees with subsequent replacement, cartilage loss accelerates in the 2 years, and particularly in the year prior to surgery, compared with controls. Whether slowing this cartilage loss can delay KR remains to be determined.

Abdominal body composition measured by quantitative computed tomography and risk of non-spine fractures: the Osteoporotic Fractures in Men (MrOS) Study.

UNLABELLED: The effect of abdominal adiposity and muscle on fracture is unclear in older men; therefore, we examined the association among 749 men aged 65+. Among various adipose tissues and muscle groups, lower psoas muscle volume and higher fatty infiltration of abdominal muscle contribute to higher fracture risk independent of BMD. INTRODUCTION: The association of abdominal adiposity and muscle composition with incident fracture is unclear, especially in older men. Therefore, we examined the relationship of subcutaneous adipose tissue (SAT), visceral adipose tissue (VAT), abdominal intermuscular adipose tissue (IMAT), and muscle volume with incident non-spine fractures among 749 men aged 65 and older. METHODS: A case-cohort study design was used with a total of 252 fracture cases and 497 non-cases. We measured volumes (in centimeters) of adipose and muscle tissues obtained from quantitative computed tomography scan at the L4-5 intervertebral space. Three groups of muscle and IMAT were evaluated: total abdominal, psoas, and paraspinal. Cox proportional hazards regression with a robust variance estimator was used to estimate the hazard ratio (HR) of non-spine fractures per standard deviation (SD) increase in the abdominal body composition measures. The mean age among men in the random subcohort was 74.2 ± 6.1 years, and the average follow-up time was 5.2 ± 1.1 years. RESULTS: After adjusting for age, race, clinic site, percent body fat, and femoral neck bone mineral density (BMD), no significant relationship was found between incident fractures and SAT or VAT. One SD increase in muscle volume at the psoas, but not paraspinal, was associated with 28 % lower fracture risk (95 % CI = 0.55-0.95). When IMAT models were further adjusted for corresponding muscle volumes, only abdominal IMAT was significantly associated with fracture risk (HR = 1.30 (95 % CI = 1.04-1.63)). CONCLUSION: Our findings suggest that lower total psoas muscle volume and higher IMAT of the total abdominal muscle contribute to higher fracture risk in older men independent of BMD.

Renal function and nonvertebral fracture risk in multiethnic women: the Women's Health Initiative (WHI).

UNLABELLED: To examine the association between renal function and fracture in multiethnic women, we studied postmenopausal women enrolled in the Women's Health Initiative. Postmenopausal White women with mild renal dysfunction were at increased risk of nonvertebral fracture; this association was at least partially explained by effects of renal dysfunction on chronic inflammation. Reduced renal function appeared to increase fracture risk among Black women, but there was little evidence to support this association among other racial/ethnic groups. INTRODUCTION: The purpose of this study was to determine whether renal function is associated with fracture risk within racial/ethnic groups. METHODS: A nested case-control study was conducted among 93,673 postmenopausal women; incident nonvertebral fractures were identified in 362 Black, 183 Hispanic, 110 Asian, and 45 American-Indian women. A random sample of 395 White women with incident nonvertebral fracture was chosen. One nonfracture control for each case was selected (matched on age, race/ethnicity, and blood draw date). Cystatin C levels were measured using baseline serum, and estimated glomerular filtration rate calculated (eGFR(cys-c)). RESULTS: Each 1 SD increase in cystatin C was associated with a 1.2-fold increased risk of fracture among White women (adjusted odds ratios [OR], 1.23; 95% confidence intervals [CI], 1.04-1.46). The OR of fracture was 1.16 (95% CI, 0.85-1.58) among women with eGFR(cys-c) 60-90 mL/min/1.73 m(2) and 2.46 (95% CI, 1.16-5.21) among those with eGFR(cys-c) <60 mL/min/1.73 m(2) compared to the reference group (eGFR(cys-c) >90 mL/min/1.73 m(2)) (p trend = 0.05). The association was reduced after adjustment for cytokine TNFα soluble receptors (OR, 1.62; 95% CI, 0.59-4.46 for eGFR(cys-c) <60 mL/min/1.73 m(2)). Among Blacks, there was an association between cystatin C and fracture risk (OR per 1 SD increase, 1.15; 95% CI, 1.00-1.32); after adjustment, this association was only modestly attenuated, but no longer statistically significant. There was no evidence of significant associations among Hispanic, Asian, or American-Indian women. CONCLUSION: Postmenopausal White women with mild renal dysfunction are at increased risk of nonvertebral fracture. Effects of renal function on chronic inflammation may mediate this association. Reduced renal function may increase fracture risk among Black women, but there was little evidence to support this association among other racial/ethnic groups.

The effects of adiponectin and leptin on changes in bone mineral density.

UNLABELLED: We tested the hypothesis that low leptin and high adiponectin levels are associated with higher rates of bone mineral density (BMD) loss among 3,075 men and women, aged 70-79, from the Health Aging and Body Composition Study. Results suggest that adiponectin, but not leptin, is a risk factor for bone loss in women. INTRODUCTION: Adiponectin and leptin are hormones secreted by adipose cells that may impact BMD. Few studies have evaluated the longitudinal association of leptin and adiponectin levels with rates of BMD change. METHODS: Hip and whole-body areal BMD (aBMD) were measured five times using dual-energy X-ray absorptiometry over 10 years (average follow-up time, 7.95 ± 1.92 years). Trabecular lumbar spine volumetric BMD (vBMD) was measured using quantitative computed topography at baseline and year 6 in the Pittsburgh cohort only. Random slope and intercept models were used to account for within person correlation as a result of repeated measures of hip and whole-body aBMD. Linear regression was used to model changes in spine trabecular vBMD. RESULTS: Among women, the annualized rate of hip aBMD loss in the highest tertile of adiponectin was -0.67% (95% CI -0.77, -0.58) compared to [-0.43% (95% CI -0.51, -0.35)] in the lowest tertile (p trend = 0.019) after adjusting for age, race, BMI, diabetes, baseline hip aBMD, and weight change. In men, hip aBMD loss was greatest in the high adiponectin group (tertile 3), however this association was not significant (p trend = 0.148). After adjusting for weight change in women, the association between higher leptin and lower hip aBMD loss was attenuated and no longer significant (p trend = 0.134). Leptin and adiponectin levels were not associated with whole-body aBMD or trabecular lumbar spine vBMD loss. CONCLUSIONS: Adiponectin was associated with increased hip aBMD loss in women only, supporting evidence that adiponectin may have an important role in bone health.

Applying gene silencing technology to contraception.

Population control of feral animals is often difficult, as it can be dangerous for the animals, labour intensive and expensive. Therefore, a useful tool for control of animal populations would be a non-surgical method to induce sterility. Our laboratories utilize methods aimed at targeting brain cells in vivo with vehicles that deliver a payload of either inhibitory RNAs or genes intended to correct cellular dysfunction. A useful framework for design of a new approach will be the combination of these methods with the intended goal to produce a technique that can be used to non-invasively sterilize cats and dogs. For this approach to succeed, it has to meet several conditions: the target gene must be essential for fertility; the method must include a mechanism to effectively and specifically silence the gene of interest; the method of delivering the silencing agent must be minimally invasive, and finally, the silencing effect must be sustained for the lifespan of the target species, so that expansion of the population can be effectively prevented. In this article, we discuss our work to develop gene silencing technology to induce sterility; we will use examples of our previous studies demonstrating that this approach is viable. These studies include (i) the use of viral vectors able to disrupt reproductive cyclicity when delivered to the regions of the brain involved in the control of reproduction and (ii) experiments with viral vectors that are able to ameliorate neuronal disease when delivered systemically using a novel approach of gene therapy.

Targeted gene silencing to induce permanent sterility.

A non-surgical method to induce sterility would be a useful tool to control feral populations of animals. Our laboratories have experience with approaches aimed at targeting brain cells in vivo with vehicles that deliver a payload of either inhibitory RNAs or genes intended to correct cellular dysfunction. A combination/modification of these methods may provide a useful framework for the design of approaches that can be used to sterilize cats and dogs. For this approach to succeed, it has to meet several conditions: it needs to target a gene essential for fertility. It must involve a method that can selectively silence the gene of interest. It also needs to deliver the silencing agent via a minimally invasive method. Finally, the silencing effect needs to be sustained for many years, so that expansion of the targeted population can be effectively prevented. In this article, we discuss this subject and provide a succinct account of our previous experience with: (i) molecular reagents able to disrupt reproductive cyclicity when delivered to regions of the brain involved in the control of reproduction and (ii) molecular reagents able to ameliorate neuronal disease when delivered systemically using a novel approach of gene therapy.

Body Composition Across the Adult Lifespan in African Caribbean Men: The Tobago Longitudinal Study of Aging.

Body composition and muscle strength change vary by age and ethnicity, and have a major impact on health and physical function. Little is known about the patterns of these changes in African-ancestry populations. Herein, we examined age-specific (5-year age groups) rates-of-change in lean and fat mass in 1918 African-ancestry men on the Caribbean island of Tobago (baseline age: 62.0±11.8 years, range: 40-99 years). Body composition (DXA) and grip strength were measured at three time points (baseline, 4- and 9-year follow-up). Annualized rates of change were calculated with all 3 time-points using Generalized Estimating Equations. We found that whole body lean mass declined at constant rate until age 65 (-0.72%/year; 95% CI: -0.76, -0.67), which accelerated to -0.92 %/year (-1.02, -0.82) among those 65-69, and again to -1.16 %/year (-1.30, -1.03 ) among those aged 70+. Whole body fat mass increased by a near constant rate of 2.93 %/year (2.72, 3.15%) across the lifespan. Finally, grip strength decline accelerated at age 50, and about 2x faster than lean mass through the lifespan after the age of 50. To conclude, in African-Caribbean men, the acceleration in muscle strength decline precedes the acceleration in lean mass decline by 10-15 years, suggesting decrements in factors other than lean mass drive this initial acceleration in muscle strength decline. We also found that African-Caribbean men undergo a constant shift to a more adipogenic phenotype throughout the adult lifespan (aged 40-99), which likely contributes to age-related loss of muscle and physical function.

Evolution of semi-quantitative whole joint assessment of knee OA: MOAKS (MRI Osteoarthritis Knee Score).

OBJECTIVE: In an effort to evolve semi-quantitative scoring methods based upon limitations identified in existing tools, integrating expert readers' experience with all available scoring tools and the published data comparing the different scoring systems, we iteratively developed the magnetic resonance imaging (MRI) Osteoarthritis Knee Score (MOAKS). The purpose of this report is to describe the instrument and its reliability. METHODS: The MOAKS instrument refines the scoring of bone marrow lesions (BMLs) (providing regional delineation and scoring across regions), cartilage (sub-regional assessment), and refines the elements of meniscal morphology (adding meniscal hypertrophy, partial maceration and progressive partial maceration) scoring. After a training and calibration session two expert readers read MRIs of 20 knees separately. In addition, one reader re-read the same 20 MRIs 4 weeks later presented in random order to assess intra-rater reliability. The analyses presented here are for both intra- and inter-rater reliability (calculated using the linear weighted kappa and overall percent agreement). RESULTS: With the exception of inter-rater reliability for tibial cartilage area (kappa=0.36) and tibial osteophytes (kappa=0.49); and intra-rater reliability for tibial BML number of lesions (kappa=0.54), Hoffa-synovitis (kappa=0.42) all measures of reliability using kappa statistics were very good (0.61-0.8) or reached near-perfect agreement (0.81-1.0). Only intra-rater reliability for Hoffa-synovitis, and inter-rater reliability for tibial and patellar osteophytes showed overall percent agreement <75%. CONCLUSION: MOAKS scoring shows very good to excellent reliability for the large majority of features assessed. Further iterative development and research will include assessment of its validation and responsiveness.

The association of serum 25-hydroxyvitamin D with indicators of bone quality in men of Caucasian and African ancestry.

UNLABELLED: We examined the association of serum 25-hydroxyvitamin D [25(OH)D] with indices of bone quality in older men. Positive associations for 25(OH)D and bone mineral density, content, cortical thickness, and axial and polar strength strain indices were observed among Caucasians; however, among men of African descent findings were either null or negative. INTRODUCTION: There are limited data on serum 25(OH)D and bone measures in men of African ancestry. To better understand racial differences in vitamin D status and bone health, a cross-sectional study among 446 Caucasian men in the US and 496 men of African ancestry in Tobago (age ≥ 65 years) was conducted. METHODS: Serum 25(OH)D (liquid chromatography and tandem mass spectrometry) was measured, and peripheral quantitative computed tomography scans were administered. Bone measures estimated included trabecular and cortical volumetric bone mineral density (vBMD), bone mineral content (BMC), bone geometry (cross-sectional area and cortical thickness), and polar and axial strength strain indices (SSIp and SSIx). RESULTS: Men of African ancestry had higher 25(OH)D than Caucasians (34.7 vs. 27.6 ng/ml, p < 0.01). Among Caucasians, 25(OH)D was positively (p trend < 0.05) associated with cortical vBMD, total BMC, cortical thickness, SSIp, and SSIx at the distal radius after adjustment for potential confounders. Similar patterns were observed at the distal tibia. In contrast, in men of African ancestry, there was an inverse association (p trend < 0.05) between 25(OH)D and the cross-sectional area, and SSIx. Race modified (p for interaction < 0.05) the association between 25(OH)D and total BMC, cross-sectional area, SSIp, SSIx, and trabecular vBMD of the radius. In men of African ancestry, there was evidence of a threshold effect (at approximately 18 ng/ml) for 25(OH)D on tibial total BMC and cortical thickness. CONCLUSIONS: More studies are needed to better comprehend these race differences for 25(OH)D and bone density, geometry, and indices of bone strength.

The risk of Parkinson disease associated with urate in a community-based cohort of older adults.

BACKGROUND/AIMS: Studies suggest an inverse association between urate concentration and the risk of Parkinson disease (PD). We investigated this in the Cardiovascular Health Study in an elderly community-based cohort of adults. METHODS: The association of baseline urate (µmol/l) and incident PD over 14 years was assessed with locally weighted scatterplot smoothing (LOESS) regression from which categories of low (<300 µmol/l), middle (300-500 µmol/l), and high (>500 µmol/l) urate ranges were derived. Multivariate logistic regression models assessed the risk of PD for each urate range. Linear and quadratic terms were tested when modeling the association between urate and the risk of PD. RESULTS: Women had significantly lower urate concentrations than did men [316.8 µmol/l (SD 88.0) vs. 367.4 µmol/l (SD 87.7), p < 0.0001] and in women no associations between urate and PD risk were observed. In men, LOESS curves suggested a U-shaped or threshold effect between urate and PD risk. With the middle range as reference, the risk of developing PD was significantly increased for urate <300 µmol/l (OR 1.69, 95% CI 1.03-2.78) but not for urate >500 µmol/l (OR 1.55, 95% CI 0.72-3.32) in men. A negative linear term was significant for urate <500 µmol/l, and across the entire range a convex quadratic term was significant. CONCLUSIONS: Results suggest a more complex relationship than previously reported between urate levels and the risk of PD in men. Low urate concentrations were associated with a higher PD risk and high urate concentrations were not associated with a further decrease in PD risk.

The association of osteoarthritis risk factors with localized, regional and diffuse knee pain.

OBJECTIVE: To identify determinants of different patterns of knee pain with a focus on risk factors for knee osteoarthritis (OA). DESIGN: The Knee Pain Map is an interviewer-administered assessment that asks subjects to characterize their knee pain as localized, regional, or diffuse. A total of 2677 participants from the Osteoarthritis Initiative were studied. We used multinomial logistic regression to examine the relationship between risk factors for OA and knee pain patterns. We examined the bivariate and multivariate relationships of knee pain pattern with age, body mass index (BMI), sex, race, family history of total joint replacement, knee injury, knee surgery, and hand OA. RESULTS: We compared 2462 knees with pain to 1805 knees without pain. In the bivariate analysis, age, sex, BMI, injury, surgery, and hand OA were associated with at least one pain pattern. In the multivariate model, all of these variables remained significantly associated with at least one pattern. When compared to knees without pain, higher BMI, injury, and surgery were associated with all patterns. BMI had its strongest association with diffuse pain. Older age was less likely to be associated with localized pain while female sex was associated with regional pain. CONCLUSIONS: We have shown that specific OA risk factors are associated with different knee pain patterns. Better understanding of the relationship between OA risk factors and knee pain patterns may help to characterize the heterogeneous subsets of knee OA.

Post hoc Parkinson's disease: identifying an uncommon disease in the Cardiovascular Health Study.

BACKGROUND: Although ongoing cohort studies offer a unique opportunity to apply existing information collected prospectively to further the scientific understanding of Parkinson's disease (PD), they typically have limited information for clinical diagnosis. METHODS: We used combinations of self-report, International Classification of Diseases - 9th edition codes and antiparkinsonian medications to identify PD in the Cardiovascular Health Study. To determine whether the expected inverse association between smoking and PD is evident using our outcome definitions, we assessed baseline smoking characteristics for various definitions of PD. RESULTS: We identified 60 cases with prevalent PD (1.0%; 95% confidence interval, CI = 0.8-1.3%) and 154 with incident PD by year 14. Clear associations were observed for current smokers (odds ratio, OR = 0.50; 95% CI = 0.26-0.95) and for those who smoked ≥50 pack-years (OR = 0.53; 95% CI = 0.29-0.96). Estimates for smoking were similar when ≥2 data sources were required. Estimates for self-report alone were attenuated towards null. CONCLUSIONS: Using multiple data sources to identify PD represents an alternative method of outcome identification in a cohort that would otherwise not be possible for PD research. Ongoing cohort studies can provide settings in which rapid replication and explorations of new hypotheses for PD are possible.

Transition to a More even Distribution of Daily Protein intake Is Associated with Enhanced Fat Loss during a Hypocaloric and Physical Activity Intervention in Obese Older Adults.

BACKGROUND: Optimization of intentional weight loss in obese older adults, through preferential fat mass reduction, is challenging, as the concomitant lean mass loss may exacerbate sarcopenia. Recent studies have suggested within-day distribution of protein intake plays a role in determining body composition remodeling. Here, we assessed whether changes in within-day protein intake distribution are related to improvements in body composition in overweight/obese older adults during a hypocaloric and exercise intervention. METHODS: Thirty-six community-dwelling, overweight-to-obese (BMI 28.0-39.9 kg/m2), sedentary older adults (aged 70.6±6.1 years) were randomized into either physical activity plus successful aging health education (PA+SA; n=15) or physical activity plus weight loss (PA+WL; n=21) programs. Body composition (by CT and DXA) and dietary intake (by three-day food records) were determined at baseline, 6-month, and 12-month follow-up visits. Within-day protein distribution was calculated as the coefficient of variation (CV) of protein ingested per defined time periods (breakfast [5:00-10:59], lunch [11:00-16:59] and dinner [17:00-1:00]). Secondary analysis was performed to determine associations between changes in protein intake distribution and body composition. RESULTS: In both groups, baseline protein intake was skewed towards dinner (PA+SA: 49.1%; PA+WL: 54.1%). The pattern of protein intake changed towards a more even within-day distribution in PA+WL during the intervention period, but it remained unchanged in PA+SA. Transition towards a more even pattern of protein intake was independently associated with a greater decline in BMI (P<0.05) and abdominal subcutaneous fat (P<0.05) in PA+WL. However, changes in protein CV were not associated with changes in body weight in PA+SA. CONCLUSION: Our results show that mealtime distribution of protein intake throughout the day was associated with improved weight and fat loss under hypocaloric diet combined with physical activity. This finding provides a novel insight into the potential role of within-day protein intake on weight management in obese older people.

Intra- and inter-observer reproducibility of volume measurement of knee cartilage segmented from the OAI MR image set using a novel semi-automated segmentation method.

OBJECTIVE: We developed a semi-automated method based on a graph-cuts algorithm for segmentation and volumetric measurements of the cartilage from high-resolution knee magnetic resonance (MR) images from the Osteoarthritis Initiative (OAI) database and assessed the intra- and inter-observer reproducibility of measurements obtained via this method. DESIGN: MR image sets from 20 subjects of varying Kellgren-Lawrence (KL) grades (from 0 to IV) on fixed flexion knee radiographs were selected from the baseline double-echo and steady-state (DESS) knee MR images in the OAI database (0.B.1 Imaging Data set). Two trained radiologists independently performed the segmentation of knee cartilage twice using the semi-automated method. The volumes of segmented cartilage were computed and compared. The intra- and inter-observer reproducibility were determined by means of the coefficient of variation (CV%) of repeated cartilage segmented volume measurements. The subjects were also divided into the low- (0, I or II) and high-KL (III or IV) groups. The differences in cartilage volume measurements and CV% within and between the observers were tested with t tests. RESULTS: The mean (+/-SD) intra-observer CV% for the 20 cases was 1.29 (+/-1.05)% for observer 1 and 1.67 (+/-1.14)% for observer 2, while the mean (+/-SD) inter-observer CV% was 1.31 (+/-1.26)% for session 1 and 1.79 (+/-1.72)% for session 2. There was no significant difference between the two intra-observer CV%'s (P=0.272) and between the two inter-observer CV%'s (P=0.353). The mean intra-observer CV% of the low-KL group was significantly smaller than that for the high-KL group for observer 1 (0.83 vs 1.86%: P=0.025). The segmentation processing times used by the two observers were significantly different (observer 1 vs 2): (mean 49+/-12 vs 33+/-6min) for session 1 and (49+/-8 vs 32+/-8min) for session 2. CONCLUSION: The semi-automated graph-cuts method allowed us to segment and measure cartilage from high-resolution 3T MR images of the knee with high intra- and inter-observer reproducibility in subjects with varying severity of OA.

Epimorphin mediates mammary luminal morphogenesis through control of C/EBPbeta.

We have shown previously that epimorphin (EPM), a protein expressed on the surface of myoepithelial and fibroblast cells of the mammary gland, acts as a multifunctional morphogen of mammary epithelial cells. Here, we present the molecular mechanism by which EPM mediates luminal morphogenesis. Treatment of cells with EPM to induce lumen formation greatly increases the overall expression of transcription factor CCAAT/enhancer binding protein (C/EBP)beta and alters the relative expression of its two principal isoforms, LIP and LAP. These alterations were shown to be essential for the morphogenetic activities, since constitutive expression of LIP was sufficient to produce lumen formation, whereas constitutive expression of LAP blocked EPM-mediated luminal morphogenesis. Furthermore, in a transgenic mouse model in which EPM expression was expressed in an apolar fashion on the surface of mammary epithelial cells, we found increased expression of C/EBPbeta, increased relative expression of LIP to LAP, and enlarged ductal lumina. Together, our studies demonstrate a role for EPM in luminal morphogenesis through control of C/EBPbeta expression.

Normative Values of Muscle Power using Force Plate Jump Tests in Men Aged 77-101 Years: The Osteoporotic Fractures in Men (MrOS) Study.

OBJECTIVE: To determine normative values for weight-bearing, countermovement leg extension ("jump") tests in the oldest men and characteristics of those not completing vs. completing tests. DESIGN: 2014-16 cross-sectional exam. SETTING: Six U.S. sites from the Osteoporotic Fractures in Men (MrOS) Study. PARTICIPANTS: Community-dwelling men (N=1,841) aged 84.5±4.2 (range: 77-101) years. INTERVENTIONS: N/A. MEASUREMENTS: Jump tests on a force plate measured lower-extremity muscle peak power/kg, velocity and force/kg at peak power, with normative values for 5-year age groups and by limitations in moderate-intensity activities of daily living (ADLs) and climbing several flights of stairs. RESULTS: Jump completion was 68.9% (N=1,268/1,841) and 98% (1,242/1,268) had ≥1 analyzable trial/participant. Exclusions primarily were due to poor mobility and/or balance: 24.8% (456/1,841) prior to and 6.4% (N=117/1,841) after attempting testing. Peak power was 20.8±5.3 W/kg, with 1.2±0.3 m/s for velocity, and 16.7±1.9 N/kg for force at peak power. Each 5-year age group >80 years had subsequently 10% lower power/kg, with 30% lower power/kg at >90 vs. ≤80 years (all p<0.05). Velocity and force/kg at peak power were 24% and 9% lower respectively, at >90 vs. ≤80 years (all p<0.05). Limitations in both moderate ADLs and climbing several flights of stairs were associated with 16% lower age-adjusted power/kg, equivalent to 5-10 years of aging, with 11% and 6% lower age-adjusted velocity and force/kg respectively, vs. those without limitation (all p<0.05). Men not completing vs. completing jumps had older age, higher BMI, lower physical activity, more comorbidities, worse cognition, more IADLs/ADLs and more falls in the past year (all p<0.05). Post-jump pain occurred in 4.6% (58/1,268), with 2 participants stopping testing due to pain. Only 24/1,242 (2%) had all trials/participant without flight (i.e., inability to lift feet), with 323/1,242 having ≥1 trial/participant without flight (total of 28%). No serious adverse safety events (e.g., injury) occurred. CONCLUSIONS: A multicenter cohort of oldest men with a range of function had higher declines in jump power/kg and velocity vs. force/kg across each 5-year age group >80 years. Future research should examine age- and functional-related declines in jump measures related to physical performance decline, falls, fractures, and disability.