A systematic approach to predicting the risk of unicompartmental knee arthroplasty revision.

OBJECTIVE: Unicompartmental knee arthroplasty (UKA) revision is usually due to the degenerative degree of knee articular osteochondral tissue in the untreated compartment. However, it is difficult to simulate the biomechanical behavior on this tissue accurately. This study presents and validates a reliable system to predict which osteoarthritis (OA) patients may suffer revision as a result of biomechanical reasons after having UKA. DESIGN: We collected all revision cases available (n = 11) and randomly selected 67 UKA cases to keep the revision prevalence of almost 14%. All these 78 cases have been followed at least 2 years. An elastic model is designed to characterize the biomechanical behavior of the articular osteochondral tissue for each patient. After calculated the force on the tissue, finite element method (FEM) is applied to calculating the strain of each tissue node. Kernel Ridge Regression (KRR) method is used to model the relationship between the strain information and the risk of revision. Therefore, the risk of UKA revision can be predicted by this integrated model. RESULTS: Leave-one-out (LOO) cross-validation (CV) is implemented to assess the prediction accuracy. As a result, the mean prediction accuracy is 93.58% for all these cases, demonstrating the high value of this model as a decision-making assistant for surgical plaining of knee OA. CONCLUSIONS: The results of this study demonstrated that this integrated model can predict the risk of UKA revision with theoretically high accuracy. It combines bio-mechanical and statistical learning approach to create a surgical planning tool which may support clinical decision in the future.

Factors associated with failure to achieve a glycated haemoglobin target of <8.0% in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial.

The aim of this study was to identify the clinical features of participants in the standard therapy arm of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) glycaemia trial who failed to reach the glycated haemoglobin (HbA1c) target. We analysed 4685 participants in the standard therapy arm, comparing participants who reached the HbA1c target of <8.0% with those whose HbA1c level was ≥8.0% 12 months after randomization. Baseline and 12-month clinical characteristics were compared. At 12 months after randomization, 3194 participants had HbA1c <8.0% and 1491 had HbA1c ≥8.0%. Black race [odds ratio (OR) 0.74, 95% confidence interval (CI) 0.61-0.89; p = 0.002], severe hypoglycaemia (OR 0.57, CI 0.37-0.89; p = 0.014) and insulin use (OR 0.51, CI 0.40-0.65; p < 0.001) were associated with failure to reach HbA1c goal at 12 months in the adjusted model. Even with free medications, free visits with clinicians and aggressive titration of medications, >30% of participants in the standard arm of the ACCORD trial had an HbA1c ≥8.0% at 1 year. Participants who were black, had severe hypoglycaemia and were on insulin were more likely to have an above-target HbA1c concentration after 12 months on the standard protocol.

The association of calcium supplementation and incident cardiovascular events in the Multi-ethnic Study of Atherosclerosis (MESA).

BACKGROUND AND AIMS: Many US adults use calcium supplements to address inadequate dietary intake and improve bone health. However, recent reports have suggested that use of calcium supplements may elevate cardiovascular disease (CVD) risk. In this study, we examined associations between baseline calcium supplement use and incident myocardial infarction (MI) (n = 208 events) and CVD events (n = 641 events) over 10.3 years in men and women from the Multi-Ethnic Study of Atherosclerosis (MESA) cohort (n = 6236), with dietary calcium intake at baseline also examined as a supplementary objective. METHODS AND RESULTS: Using Cox proportional hazards models, no compelling associations between calcium intake from supplements or diet and incident CVD events were observed upon multivariate adjustment for potential confounders. An association with lower MI risk was observed comparing those with low levels of calcium supplement use (1-499 mg) to those using no calcium supplements (hazard ratio 0.69, 95% CI 0.48, 0.98, p = 0.039). Relationships were homogeneous by gender, race/ethnicity, or chronic kidney disease. Results were also similar when the analysis was limited to postmenopausal women only. CONCLUSION: Analysis of incident MI and CVD events in the MESA cohort does not support a substantial association of calcium supplement use with negative cardiovascular outcomes.

Structure-function analysis of SAP97, a modular scaffolding protein that drives dendrite growth.

Activation of AMPA receptors assembled with the GluA1 subunit can promote dendrite growth in a manner that depends on its direct binding partner, SAP97. SAP97 is a modular scaffolding protein that has at least seven recognizable protein-protein interaction domains. Several complementary approaches were employed to show that the dendrite branching promoting action of full length SAP97 depends on ligand(s) that bind to the PDZ3 domain. Ligand(s) to PDZ1, PDZ2 and I3 domains also contribute to dendrite growth. The ability of PDZ3 ligand(s) to promote dendrite growth depends on localization at the plasma membrane along with GluA1 and SAP97. These results suggest that the assembly of a multi-protein complex at or near synapses is vital for the translation of AMPA-R activity into dendrite growth.

The association between vitamin K status and knee osteoarthritis features in older adults: the Health, Aging and Body Composition Study.

BACKGROUND: Vitamin K-dependent (VKD) proteins, including the mineralization inhibitor matrix-gla protein (MGP), are found in joint tissues including cartilage and bone. Previous studies suggest low vitamin K status is associated with higher osteoarthritis (OA) prevalence and incidence. OBJECTIVE: To clarify what joint tissues vitamin K is relevant to in OA, we investigated the cross-sectional and longitudinal association between vitamin K status and knee OA structural features measured using magnetic resonance imaging (MRI). METHODS: Plasma phylloquinone (PK, vitamin K1) and dephosphorylated-uncarboxylated MGP ((dp)ucMGP) were measured in 791 older community-dwelling adults who had bilateral knee MRIs (mean ± SD age = 74 ± 3 y; 67% female). The adjusted odds ratios (and 95% confidence intervals) [OR (95%CI)] for presence and progression of knee OA features according to vitamin K status were calculated using marginal models with generalized estimating equations (GEEs), adjusted for age, sex, body mass index (BMI), triglycerides and other pertinent confounders. RESULTS: Longitudinally, participants with very low plasma PK (<0.2 nM) were more likely to have articular cartilage and meniscus damage progression after 3 years [OR (95% CIs): 1.7(1.0-3.0), 2.6(1.3-5.2) respectively] compared to sufficient PK (≥ 1.0 nM). Higher plasma (dp)ucMGP (reflective of lower vitamin K status) was associated with higher odds of meniscus damage, osteophytes, bone marrow lesions, and subarticular cysts cross-sectionally [ORs (95% CIs) comparing highest to lowest quartile: 1.6(1.1-2.3); 1.7(1.1-2.5); 1.9(1.3-2.8); 1.5(1.0-2.1), respectively]. CONCLUSION: Community-dwelling men and women with very low plasma PK were more likely to have progression of articular cartilage and meniscus damage. Plasma (dp)ucMGP was associated with presence of knee OA features but not progression. Future studies are needed to clarify mechanisms underlying vitamin Ks role in OA.

Detecting signals in pharmacogenomic genome-wide association studies.

In a common pharmacogenomic scenario, outcome measures are compared for treated and untreated subjects across genotype-defined subgroups. The key question is whether treatment benefit (or harm) is particularly strong in certain subgroups, and therefore the statistical analysis focuses on the interaction between treatment and genotype. However, genome-wide analysis in such scenarios requires careful statistical thought as, in addition to the usual problems of multiple testing, the marker-defined sample sizes, and therefore power, vary across the individual genotypes being evaluated. The variability in power means that the usual practice of using a common P-value threshold across tests has difficulties. The reason is that the use of a fixed threshold, with variable power, implies that the costs of type I and type II errors vary across tests in a manner that is implicit rather than dictated by the analyst. In this paper we discuss this problem and describe an easily implementable solution based on Bayes factors. We pay particular attention to the specification of priors, which is not a straightforward task. The methods are illustrated using data from a randomized controlled clinical trial in which homocysteine levels are compared in individuals receiving low and high doses of folate supplements and across marker subgroups. The method we describe is implemented in the R computing environment with code available from http://faculty.washington.edu/jonno/cv.html.

Effects of Curcumin C3 Complex® on Physical Function in Moderately Functioning Older Adults with Low-Grade Inflammation - A Pilot Trial.

BACKGROUND: Natural dietary compounds that can modulate the inflammation process have the potential to improve physical function through a number of biological pathways, and thus may represent an alternative approach to avert functional decline compared to more time-burdening lifestyle interventions. In this pilot trial, we tested the feasibility and explored the effect of a nutritional compound, Curcumin C3 Complex® for improving physical function and muscle strength in moderately functioning older adults with low-grade inflammation. METHODS: Moderately functioning (short physical performance battery, SPPB <10) and sedentary older adults (>65 years) with low-grade systemic inflammation (c-reactive protein >1mg/dL) were randomized to receive Curcumin C3 Complex® (n=9) (1000mg/day) or placebo (n=8) groups for 12 weeks. All participants (age range: 66-94 years, 8 females and 9 males) underwent functional testing (SPPB and walking speed by the 400-meter walk test) and lower-limb strength (knee flexion and extension peak torque by the Biodex test) at baseline and 12 weeks. Venous blood was collected at baseline, 4, 8 and 12 weeks for safety blood chemistry analyses and biomarkers of inflammation. RESULTS: A total of 17 participants were randomized and completed the study. Adherence was high (> 90%) and there were no adverse events reported or abnormal blood chemistries reported. Based on effect sizes, participants in the Curcumin C3 Complex® group demonstrated large effect sizes in the SPPB (Cohen's effect size d=0.75) and measures of knee extension (d=0.69) and flexion peak torque (d=0.82). Effect sizes for galectin-3 (d=-0.31) (larger decrease) and interleukin-6 (d=0.38) (smaller increase) were small in the Curcumin C3 Complex® group compared to placebo. CONCLUSION: This pilot trial suggests that there were no difficulties with recruitment, adherence and safety specific to the study protocol. Preliminary findings warrant a Phase IIb clinical trial to test the effect of Curcumin C3 Complex® on physical function and muscle strength in older adults at risk for mobility disability.

Pericardial fat is associated with carotid stiffness in the Multi-Ethnic Study of Atherosclerosis.

BACKGROUND AND AIMS: Arterial stiffness is a prominent feature of vascular aging and a risk factor for cardiovascular disease (CVD). Fat around the heart and blood vessels (i.e. pericardial fat, Pfat) may contribute to arterial stiffness via a local paracrine effect of adipose tissue on the surrounding vasculature. Thus, we determined the association between Pfat and carotid stiffness in 5770 participants (mean age 62 years, 53% female, 25% African American, 24% Hispanic, and 13% Chinese) from the Multi-Ethnic Study of Atherosclerosis. METHODS AND RESULTS: Pfat was measured by computed tomography, and ultrasonography of the common carotid artery was used to calculate the distensibility coefficient (DC) and Young's modulus (YM). Lower DC and higher YM values indicate stiffer arteries. Pfat quartile was highly associated with demographic, behavioral, anthropometric, hemodynamic, metabolic, and disease variables in both men and women. After adjusting for height, clinical site, CVD risk factors, and medications, a 1 standard deviation (41.91 cm(3)) increment in Pfat was associated with a 0.00007±0.00002 1/mm Hg lower DC (p=0.0002) in men and a 48.1±15.1 mm Hg/mm higher YM in women (p=0.002). Additional adjustment for C-reactive protein, coronary artery calcification, and carotid intima-media thickness had only modest effects. More importantly, adjusting for body mass index and waist circumference did not significantly change the overall results. CONCLUSION: Higher Pfat is associated with higher carotid stiffness, independent of traditional CVD risk factors and obesity.

Evaluation of a novel electropositive filter for the concentration of viruses from diverse water matrices.

Human enteric viruses are important agents of waterborne illness. They are diffusely distributed in environmental waters, necessitating concentration of tens to hundreds of litres for effective detection. This study evaluates the novel ViroCap disposable capsule filter for concentration of coliphage MS2 and poliovirus (PV1) from deionised (DI) water and artificial seawater, as well as natural ground, surface, and seawater. Retention and recoveries for the ViroCap were compared with two well-characterised filters: the 1MDS for DI water, and the OptiCap XL for artificial seawater. The mean adsorption for MS2 by the ViroCap was 88%. Recovery of MS2 was significantly greater (p< or=0.01) than alternative filters tested: 65% from DI water and 63% from artificial seawater, compared to 30% for the 1MDS and 15% for the OptiCap for the respective matrices. Recovery of PV1 from DI water (37%) was similar to that of the 1MDS (51%). PV1 recoveries from artificial seawater were significantly greater (p< or =0.01) for the ViroCap (44%) than the OptiCap (11%). Recovery of MS2 from seeded environmental samples yielded 44% from groundwater, 53% from surface water, and 51% from seawater. ViroCap disposable filter is efficient for concentrating MS2 and PV1 from diverse matrices and is robust across a range of ionic concentrations.

High pressure superconductivity in iron-based layered compounds studied using designer diamonds.

High pressure superconductivity in iron-based superconductor FeSe(0.5)Te(0.5) has been studied up to 15 GPa and 10 K using an eight probe designer diamond anvil in a diamond anvil cell device. Four probe electrical resistance measurements show the onset of superconductivity (T(c)) at 14 K at ambient pressure with T(c) increasing with increasing pressure to 19 K at a pressure of 3.6 GPa. At higher pressures beyond 3.6 GPa, T(c) decreases and extrapolation suggests non-superconducting behavior above 10 GPa. The loss of superconductivity coincides with the pressure induced disordering of the Fe(SeTe)(4) tetrahedra reported at 11 GPa in x-ray diffraction studies at ambient temperature.

Psoas and Paraspinous Muscle Measurements on Computed Tomography Predict Mortality in European Americans with Type 2 Diabetes Mellitus.

BACKGROUND: Appendicular skeletal muscle mass index and muscle attenuation (density) are negatively associated with mortality in European-derived populations. OBJECTIVES: The present analyses assessed association between axial skeletal muscle density and muscle index with mortality in European Americans with type 2 diabetes mellitus (T2D). DESIGN: Single-center observational study. SETTING: Diabetes Heart Study. PARTICIPANTS: 839 European Americans with T2D. METHODS: Computed tomography-measured psoas and paraspinous muscle mass index (cross sectional area/height2) and radiographic density (Hounsfield Units) were assessed in all participants. A Cox proportional hazards model was computed. The fully-adjusted model included covariates age, sex, body mass index, smoking, alcohol use, diabetes duration, insulin use, hormone replacement therapy (women), prevalent cardiovascular disease (CVD), hypertension, and coronary artery calcified atherosclerotic plaque mass score. Deaths were recorded in the National Death Index data through December 31, 2015. RESULTS: Participants included 428 women and 411 men with median (25th, 75th quartile) age 62.8 (56.1, 69.1) years and diabetes duration 8.0 (5.0, 14.0) years. After 11.9 (9.4, 13.3) years of follow-up, 314 (37.4%) of participants were deceased. In the fully-adjusted model, psoas muscle density (hazard ratio [HR] 0.81, p<0.001), psoas muscle index (HR 0.82, p=0.008), and paraspinous muscle density (HR 0.85, p=0.003) were inversely associated with mortality. Paraspinous muscle index was not significantly associated with mortality (HR 0.90, p=0.08). Results did not differ significantly between men and women. CONCLUSIONS: In addition to established risk factors for mortality and CVD, higher psoas muscle index, psoas muscle density, and paraspinous muscle density were significantly associated with lower all-cause mortality in European Americans with T2D.

Cerebral Ketones Detected by 3T MR Spectroscopy in Patients with High-Grade Glioma on an Atkins-Based Diet.

BACKGROUND AND PURPOSE: Ketogenic diets are being explored as a possible treatment for several neurological diseases, but the physiologic impact on the brain is unknown. The objective of this study was to evaluate the feasibility of 3T MR spectroscopy to monitor brain ketone levels in patients with high-grade gliomas who were on a ketogenic diet (a modified Atkins diet) for 8 weeks. MATERIALS AND METHODS: Paired pre- and post-ketogenic diet MR spectroscopy data from both the lesion and contralateral hemisphere were analyzed using LCModel software in 10 patients. RESULTS: At baseline, the ketone bodies acetone and ß-hydroxybutyrate were nearly undetectable, but by week 8, they increased in the lesion for both acetone (0.06 ± 0.03 ≥ 0.27 ± 0.06 IU, P = .005) and ß-hydroxybutyrate (0.07 ± 0.07 ≥ 0.79 ± 0.32 IU, P = .046). In the contralateral brain, acetone was also significantly increased (0.041 ± 0.01 ≥ 0.16 ± 0.04 IU, P = .004), but not ß-hydroxybutyrate. Acetone was detected in 9/10 patients at week 8, and ß-hydroxybutyrate, in 5/10. Acetone concentrations in the contralateral brain correlated strongly with higher urine ketones (r = 0.87, P = .001) and lower fasting glucose (r = -0.67, P = .03). Acetoacetate was largely undetectable. Small-but-statistically significant decreases in NAA were also observed in the contralateral hemisphere at 8 weeks. CONCLUSIONS: This study suggests that 3T MR spectroscopy is feasible for detecting small cerebral metabolic changes associated with a ketogenic diet, provided that appropriate methodology is used.

Monocyte chemotactic protein-1 in the migration of differentiated leukaemic cells toward alveolar epithelial cells.

All-trans retinoic acid (ATRA) can induce acute respiratory distress syndrome in patients with acute promyelocytic leukaemia (APL). The current study investigated the role of monocyte chemotactic protein (MCP)-1 in the chemotactic transmigration of ATRA-treated NB4 (ATRA-NB4) APL cells toward A549 alveolar epithelial cells. NB4 and A549 cells were separately cultured with ATRA and/or dexamethasone (DEX). ATRA-NB4 cells were then placed in an upper insert and co-incubated with A549 cells or their conditioned medium (CM) located in a lower plate to test their transmigration activity. ATRA stimulated NB4 cells to transmigrate toward the A549 cells. The secretion of MCP-1 was enhanced by ATRA treatment in both A549 and NB4 cells. The binding assay demonstrated that ATRA-NB4 cells bound MCP-1. Pre-treatment of both CM-A549 cells with antibodies against MCP-1 and of ATRA-NB4 cells with antibodies against MCP-1 receptors reduced ATRA-NB4 cell transmigration. DEX did not suppress MCP-1 secretion and transmigration in ATRA-NB4 cells, although when applied to A549 cells, MCP-1 secretion was suppressed and ATRA-NB4 cell transmigration was attenuated. Monocyte chemotactic protein-1 secreted from alveolar epithelial cells plays an important role in the cell-cell interaction involved in the chemotactic transmigration of all-trans retinoic acid-treated acute promyelocytic leukaemia cells toward alveolar epithelial cells.

Detection of naturally occurring enteroviruses in waters using direct RT-PCR and integrated cell culture-RT-PCR.

Viruses detected by rapid molecular assays are not always infectious. In this study we compared enterovirus levels in natural waters using culture and reverse transcription-polymerase chain reaction (RT-PCR) techniques to determine whether molecular units of naturally occurring enteroviruses can be utilized to predict viral infectivity. Viruses were concentrated from 12 river water and effluent samples using 1 MDS filter-filtration and beef extract-elution. An integrated cell culture-RT-PCR (ICC-RT-PCR) was applied to the concentrates; and these waters contained up to 1.9 MPN of culturable (on BGM cells) viruses per litre (0.57 MPN/300 ml). Sample concentrates were also subjected to a direct 'molecular' approach using solvent-extraction, PEG-precipitation, and RNA-extraction before RT-PCR detection. The detection sensitivity of the direct RT-PCR was equivalent to 0.46 estimated (culturable) MPN/reaction, per 300 ml water. Two-thirds of the samples demonstrated consistent presence or absence of viruses by ICC-RT-PCR and direct RT-PCR. The direct RT-PCR approach resulted in over-estimation of naturally occurring infectious viruses as high as 91-fold in waters. Increased RT-PCR units may not reflect higher levels of culturable viruses in natural waters. The differences in virus levels detected by molecular and culture assays could be attributed to factors of volume of sample analyzed, different concentration schemes utilized that may affect the presence of residual inhibitors, and different stability exhibited by enterovirus strains/groups.

A method to measure predictive ability of an injury risk curve using an observation-adjusted area under the receiver operating characteristic curve.

Area under the receiver operating characteristic curve (AROC) is commonly used to choose a biomechanical metric from which to construct an injury risk curve (IRC). However, AROC may not handle censored datasets adequately. Survival analysis creates robust estimates of IRCs which accommodate censored data. We present an observation-adjusted ROC (oaROC) which uses the survival-based IRC to estimate the AROC. We verified and evaluated this method using simulated datasets of different censoring statuses and sample sizes. For a dataset with 1000 left and right censored observations, the median AROC closely approached the oaROCTrue, or the oaROC calculated using an assumed "true" IRC, differing by a fraction of a percent, 0.1%. Using simulated datasets with various censoring, we found that oaROC converged onto oaROCTrue in all cases. For datasets with right and non-censored observations, AROC did not converge onto oaROCTrue. oaROC for datasets with only non-censored observations converged the fastest, and for a dataset with 10 observations, the median oaROC differed from oaROCTrue by 2.74% while the corresponding median AROC with left and right censored data differed from oaROCTrue by 9.74%. We also calculated the AROC and oaROC for a published side impact dataset, and differences between the two methods ranged between -24.08% and 24.55% depending on metric. Overall, when compared with AROC, we found oaROC performs equivalently for doubly censored data, better for non-censored data, and can accommodate more types of data than AROC. While more validation is needed, the results indicate that oaROC is a viable alternative which can be incorporated into the metric selection process for IRCs.

miRNA-34c-5p inhibits amphiregulin-induced ovarian cancer stemness and drug resistance via downregulation of the AREG-EGFR-ERK pathway.

Epithelial ovarian cancer is the most lethal gynecological cancer mainly due to late diagnosis, easy spreading and rapid development of chemoresistance. Cancer stem cells are considered to be one of the main mechanisms for chemoresistance, as well as metastasis and recurrent disease. To explore the stemness characteristics of ovarian cancer stem cells, we successfully enriched ovarian cancer stem-like cells from an established ovarian cancer cell line (SKOV-I6) and a fresh ovarian tumor-derived cell line (OVS1). These ovarian cancer stem-like cells possess important cancer stemness characteristics including sphere-forming and self-renewing abilities, expressing important ovarian cancer stem cell and epithelial-mesenchymal transition markers, as well as increased drug resistance and potent tumorigenicity. Microarray analysis of OVS1-derived sphere cells revealed increased expression of amphiregulin (AREG) and decreased expression of its conserved regulatory microRNA, miR-34c-5p, when compared with the OVS1 parental cells. Overexpression of AREG and decreased miR-34c-5p expression in SKOV-I6 and OVS1 sphere cells were confirmed by quantitative real-time PCR analysis. Luciferase reporter assay and mutant analysis confirmed that AREG is a direct target of miR-34c-5p. Furthermore, AREG-mediated increase of sphere formation, drug resistance toward docetaxel and carboplatin, as well as tumorigenicity of SKOV-I6 and OVS1 cells could be abrogated by miR-34c-5p. We further demonstrated that miR-34c-5p inhibited ovarian cancer stemness through downregulation of the AREG-EGFR-ERK pathway. Overexpression of AREG was found to be correlated with advanced ovarian cancer stages and poor prognosis. Taken together, our data suggest that AREG promotes ovarian cancer stemness and drug resistance via the AREG-EGFR-ERK pathway and this is inhibited by miR-34c-5p. Targeting AREG, miR-34c-5p could be a potential strategy for anti-cancer-stem cell therapy in ovarian cancer.

The Effect of Chronic Kidney Disease on a Physical Activity Intervention: Impact on Physical Function, Adherence, and Safety.

BACKGROUND: Because chronic kidney disease (CKD) is associated with muscle wasting, older adults with CKD are likely to have physical function deficits. Physical activity can improve these deficits, but whether CKD attenuates the benefits is unknown. Our objective was to determine if CKD modified the effect of a physical activity intervention in older adults. METHODS: This is an exploratory analysis of the LIFE-P study, which compared a 12-month physical activity program (PA) to a successful aging education program (SA) in older adults. CKD was defined as a baseline eGFR < 60 mL/min/1.73 m2. We examined the Short Physical Performance Battery (SPPB) at baseline, 6 and 12 months. Secondary outcomes included serious adverse events (SAE) and adherence to intervention frequency. Linear mixed models were adjusted for age, sex, diabetes, hypertension, CKD, intervention, site, visit, baseline SPPB, and interactions of intervention and visit and of intervention, visit, and baseline CKD. RESULTS: The sample included 368 participants. CKD was present in 105 (28.5%) participants with a mean eGFR of 49.2 ± 8.1 mL/min/1.73 m2. Mean SPPB was 7.38 ± 1.41 in CKD participants; 7.59 ± 1.44 in those without CKD (p = 0.20). For CKD participants in PA, 12-month SPPBs increased to 8.90 (95% CI 8.32, 9.47), while PA participants without CKD increased to 8.40 (95% CI 8.01, 8.79, p = 0.43). For CKD participants in SA, 12-month SPPBs increased to 7.67 (95% CI 7.07, 8.27), while participants without CKD increased to 8.12 (95% CI 7.72, 8.52, p = 0.86). Interaction between CKD and intervention was non-significant (p = 0.88). Number and type of SAEs were not different between CKD and non-CKD participants (all p > 0.05). In PA, adherence for CKD participants was 65.5 ± 25.4%, while for those without CKD was 74.0 ± 22.2% (p = 0.12). CONCLUSION: Despite lower adherence, older adults with CKD likely derive clinically meaningful benefits from physical activity with no apparent impact on safety, compared to those without CKD.

Type 2 diabetes is not independently associated with spinal trabecular volumetric bone mineral density measured by QCT in the Diabetes Heart Study.

The purpose of this study was to investigate the association between type 2 diabetes mellitus (DM2) and trabecular volumetric bone mineral density (vBMD) of the thoracic and lumbar spine measured by quantitative computed tomography (QCT) in 483 female (410 with DM2) and 398 male (365 with DM2) adults (age 36-86 years, BMI 16-58, 88% with DM2) in the Diabetes Heart Study. After accounting for familial correlation using generalized estimating equations (GEE), lumbar spine vBMD was positively associated with BMI (r = 0.24, P < 0.0001) and inversely associated with age (r = -0.51, P < 0.0001). In women, age-adjusted thoracic spinal vBMD (mg/ml, mean +/- SE) was higher in diabetics (147.6 +/- 2.3) compared to unaffected individuals (138.6 +/- 3.4) (P = 0.02), with age-adjusted lumbar spinal vBMD showing a similar but non-significant trend (132.9 +/- 2.1 in diabetics vs. 127.2 +/- 3.6 in unaffected individuals, P = 0.15). In contrast, in men, age-adjusted lumbar and thoracic vBMD were not different between diabetics and unaffected controls (lumbar vBMD = 125.0 +/- 1.8 in diabetics and 125.8 +/- 5.6 in unaffected individuals, P = 0.89; thoracic vBMD = 137.4 +/- 2.1 in diabetics vs. 134.2 +/- 5.5 in controls, P = 0.56). After multivariate analysis adjusting for age, sex, race, BMI, physical activity, dietary intake, smoking, and alcohol use, interaction between diabetes status and trabecular vBMD of the spine was no longer observed. In women only, age-adjusted areal BMD (determined by dual X-ray absorptiometry (DXA)) of the spine and hip were significantly higher in diabetics than non-diabetic (all P < 0.05), although the differences disappeared after additional adjustment for BMI. These data suggest that areal BMD measured by DXA and trabecular volumetric BMD measured by QCT are not associated with type 2 diabetes independently from BMI.

Genetic Moderators of the Impact of Physical Activity on Depressive Symptoms.

BACKGROUND: Converging evidence suggests that physical activity is an effective intervention for both clinical depression and sub-threshold depressive symptoms; however, findings are not always consistent. These mixed results might reflect heterogeneity in response to physical activity, with some subgroups of individuals responding positively, but not others. OBJECTIVES: 1) To examine the impact of genetic variation and sex on changes in depressive symptoms in older adults after a physical activity (PA) intervention, and 2) to determine if PA differentially improves particular symptom dimensions of depression. DESIGN: Randomized controlled trial. SETTING: Four field centers (Cooper Institute, Stanford University, University of Pittsburgh, and Wake Forest University). PARTICIPANTS: 396 community-dwelling adults aged 70-89 years who participated in the Lifestyle Interventions and Independence for Elders Pilot Study (LIFE-P). INTERVENTION: 12-month PA intervention compared to an education control. MEASUREMENTS: Polymorphisms in the serotonin transporter (5-HTT), brain-derived neurotrophic factor (BDNF), and apolipoprotein E (APOE) genes; 12-month change in the Center for Epidemiologic Studies Depression Scale total score, as well as scores on the depressed affect, somatic symptoms, and lack of positive affect subscales. RESULTS: Men randomized to the PA arm showed the greatest decreases in somatic symptoms, with a preferential benefit in male carriers of the BDNF Met allele. Symptoms of lack of positive affect decreased more in men compared to women, particularly in those possessing the 5-HTT L allele, but the effect did not differ by intervention arm. APOE status did not affect change in depressive symptoms. CONCLUSIONS: Results of this study suggest that the impact of PA on depressive symptoms varies by genotype and sex, and that PA may mitigate somatic symptoms of depression more than other symptoms. The results suggest that a targeted approach to recommending PA therapy for treatment of depression is viable.

Molecular characterization of a family of tandemly repeated DNA sequences, TR-1, in heterochromatic knobs of maize and its relatives.

Two families of tandem repeats, 180-bp and TR-1, have been found in the knobs of maize. In this study, we isolated 59 clones belonging to the TR-1 family from maize and teosinte. Southern hybridization and sequence analysis revealed that members of this family are composed of three basic sequences, A (67 bp); B (184 bp) or its variants B' (184 bp), 2/3B (115 bp), 2/3B' (115 bp); and C (108 bp), which are arranged in various combinations to produce repeat units that are multiples of approximately 180 bp. The molecular structure of TR-1 elements suggests that: (1) the B component may evolve from the 180-bp knob repeat as a result of mutations during evolution; (2) B' may originate from B through lateral amplification accompanied by base-pair changes; (3) C plus A may be a single sequence that is added to B and B', probably via nonhomologous recombination; and (4) 69 bp at the 3' end of B or B', and the entire sequence of C can be removed from the elements by an unknown mechanism. Sequence comparisons showed partial homologies between TR-1 elements and two centromeric sequences (B repeats) of the supernumerary B chromosome. This result, together with the finding of other investigators that the B repeat is also fragmentarily homologous to the 180-bp repeat, suggests that the B repeat is derived from knob repeats in A chromosomes, which subsequently become structurally modified. Fluorescence in situ hybridization localized the B repeat to the B centromere and the 180-bp and TR-1 repeats to the proximal heterochromatin knob on the B chromosome.