Kinematic Demands of Nucleus Arthroplasty Technology

Recent advancements in biomaterial technologies have fostered growth in alternative surgical procedures to fusion surgery for treatment of early stages of degenerative disc disease. One application of immediate interest is that of nucleus arthroplasty (NA). Novel materials are being developed to better match the nonlinear biomechanical properties of the native tissue. The effects of changing the motion segment unit (MSU) properties via surgery (nucleotomy) or placement of a nucleus arthroplasty material, changes the effort or work required to move the altered spine condition through a prescribed kinematic path relative to the intact spine condition. The closer the loading mechanics of the altered spine are to the intact spine condition, the better the likelihood the device will restore the native properties. The objective of this research was to use a new testing protocol to evaluate different designs used in nucleus replacement devices and compare their restorative characteristics to the native tissue. Seven human lumbar MSUs were tested in the harvested, nucleotomy, compliant implanted, and non-compliant implanted spine conditions. The spinal segments were mounted in a spine robot and tested in flexion and extension about six fixed points of rotation located along the centerline of the disc and 5 mm below the endplate. The spinal MSUs were rotated about the designated fixed points of rotation until a target bending moment of 8Nm of flexion or extension was reached, or the compressive or shear forces exceeded 500N. Measurements for all test conditions included the MSU axial force normal to the plane of the disc, shear force along the plane of the disc, sagittal rotation, and sagittal bending moment. During flexion testing, greater MSU rotation occurred for the nucleotomy condition compared to the harvested and implanted spine conditions for all points of rotation. There were no differences between the harvested and compliant implanted spine condition in the MSU rotations, compressive load, or shear load for all points of rotation. The non-compliant implanted spine condition caused greater compressive and shear forces at the posterior points of rotation. Compared to the other three spine conditions, the nucleotomy spine condition had significantly greater rotation in flexion. In extension testing, greater shear and compressive forces acted on the MSU for the nucleotomy spine condition compared to harvested and implanted spine conditions at central and posterior points. Denucleating the MSU led to a more destabilized spine condition with greater MSU rotation in flexion and greater disk compression in extension. After implantation of a compliant implant, variation was reduced and the response profile moved towards the harvested state for all test points. Implantation of a non-compliant implant caused an increase in the shear and compressive forces acting across the joint. Since spinal discs and compliant nucleus replacement technologies do not have a prescribed axis of rotation, evaluating the kinematic response at multiple locations of rotation may more effectively characterize the restorative effect of these technologies compared to more traditional in vitro test methods. Overall, this method offers new insight into thoroughly understanding the kinematics response of all types of nucleus arthroplasty technologies

Adiposity, Cardiometabolic Risk, and Vitamin D Status: The Framingham Heart Study

OBJECTIVE: Because vitamin D deficiency is associated with a variety of chronic diseases, understanding the characteristics that promote vitamin D deficiency in otherwise healthy adults could have important clinical implications. Few studies relating vitamin D deficiency to obesity have included direct measures of adiposity. Furthermore, the degree to which vitamin D is associated with metabolic traits after adjusting for adiposity measures is unclear. RESEARCH DESIGN AND METHODS: We investigated the relations of serum 25-hydroxyvitamin D (25[OH]D) concentrations with indexes of cardiometabolic risk in 3,890 nondiabetic individuals; 1,882 had subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) volumes measured by multidetector computed tomography (CT). RESULTS: In multivariable-adjusted regression models, 25(OH)D was inversely associated with winter season, waist circumference, and serum insulin (P < 0.005 for all). In models further adjusted for CT measures, 25(OH)D was inversely related to SAT (−1.1 ng/ml per SD increment in SAT, P = 0.016) and VAT (−2.3 ng/ml per SD, P < 0.0001). The association of 25(OH)D with insulin resistance measures became nonsignificant after adjustment for VAT. Higher adiposity volumes were correlated with lower 25(OH)D across different categories of BMI, including in lean individuals (BMI <25 kg/m2). The prevalence of vitamin D deficiency (25[OH]D <20 ng/ml) was threefold higher in those with high SAT and high VAT than in those with low SAT and low VAT (P < 0.0001). CONCLUSIONS: Vitamin D status is strongly associated with variation in subcutaneous and especially visceral adiposity. The mechanisms by which adiposity promotes vitamin D deficiency warrant further study.National Institutes of Health's National Heart, Lung, and Blood Institute (N01-HC-25195, R01-DK-80739): American Heart Associatio

Rarefaction and extrapolation with Hill numbers: A framework for sampling and estimation in species diversity studies

Quantifying and assessing changes in biological diversity are central aspects of many ecological studies, yet accurate methods of estimating biological diversity from sampling data have been elusive. Hill numbers, or the effective number of species, are increasingly used to characterize the taxonomic, phylogenetic, or functional diversity of an assemblage. However, empirical estimates of Hill numbers, including species richness, tend to be an increasing function of sampling effort and, thus, tend to increase with sample completeness. Integrated curves based on sampling theory that smoothly link rarefaction (interpolation) and prediction (extrapolation) standardize samples on the basis of sample size or sample completeness and facilitate the comparison of biodiversity data. Here we extended previous rarefaction and extrapolation models for species richness (Hill number qD, where q = 0) to measures of taxon diversity incorporating relative abundance (i.e., for any Hill number qD, q \u3e 0) and present a unified approach for both individual-based (abundance) data and samplebased (incidence) data. Using this unified sampling framework, we derive both theoretical formulas and analytic estimators for seamless rarefaction and extrapolation based on Hill numbers. Detailed examples are provided for the first three Hill numbers: q = 0 (species richness), q = 1 (the exponential of Shannon\u27s entropy index), and q = 2 (the inverse of Simpson\u27s concentration index). We developed a bootstrap method for constructing confidence intervals around Hill numbers, facilitating the comparison of multiple assemblages of both rarefied and extrapolated samples. The proposed estimators are accurate for both rarefaction and short-range extrapolation. For long-range extrapolation, the performance of the estimators depends on both the value of q and on the extrapolation range. We tested our methods on simulated data generated from species abundance models and on data from large species inventories. We also illustrate the formulas and estimators using empirical data sets from biodiversity surveys of temperate forest spiders and tropical ants. © 2014 by the Ecological Society of America

Predicting success of oligomerized pool engineering (OPEN) for zinc finger target site sequences

<p>Abstract</p> <p>Background</p> <p>Precise and efficient methods for gene targeting are critical for detailed functional analysis of genomes and regulatory networks and for potentially improving the efficacy and safety of gene therapies. Oligomerized Pool ENgineering (OPEN) is a recently developed method for engineering C2H2 zinc finger proteins (ZFPs) designed to bind specific DNA sequences with high affinity and specificity <it>in vivo</it>. Because generation of ZFPs using OPEN requires considerable effort, a computational method for identifying the sites in any given gene that are most likely to be successfully targeted by this method is desirable.</p> <p>Results</p> <p>Analysis of the base composition of experimentally validated ZFP target sites identified important constraints on the DNA sequence space that can be effectively targeted using OPEN. Using alternate encodings to represent ZFP target sites, we implemented Naïve Bayes and Support Vector Machine classifiers capable of distinguishing "active" targets, i.e., ZFP binding sites that can be targeted with a high rate of success, from those that are "inactive" or poor targets for ZFPs generated using current OPEN technologies. When evaluated using leave-one-out cross-validation on a dataset of 135 experimentally validated ZFP target sites, the best Naïve Bayes classifier, designated ZiFOpT, achieved overall accuracy of 87% and specificity⁺of 90%, with an ROC AUC of 0.89. When challenged with a completely independent test set of 140 newly validated ZFP target sites, ZiFOpT performance was comparable in terms of overall accuracy (88%) and specificity⁺(92%), but with reduced ROC AUC (0.77). Users can rank potentially active ZFP target sites using a confidence score derived from the posterior probability returned by ZiFOpT.</p> <p>Conclusion</p> <p>ZiFOpT, a machine learning classifier trained to identify DNA sequences amenable for targeting by OPEN-generated zinc finger arrays, can guide users to target sites that are most likely to function successfully <it>in vivo</it>, substantially reducing the experimental effort required. ZiFOpT is freely available and incorporated in the Zinc Finger Targeter web server (<url>http://bindr.gdcb.iastate.edu/ZiFiT</url>).</p