What Animal Models Have Taught Us About the Safety and Efficacy of Bisphosphonates in Chronic Kidney Disease

Purpose of Review Bisphosphonates (BPs) have long been the gold-standard anti-remodeling treatment for numerous metabolic bone diseases. Since these drugs are excreted unmetabolized through the kidney, they are not recommended for individuals with compromised kidney function due to concerns of kidney and bone toxicity. The goal of this paper is to summarize the preclinical BP work in models of kidney disease with particular focus on the bone, kidney, and vasculature. Recent Findings Summative data exists showing positive effects on bone and vascular calcifications with minimal evidence for bone or kidney toxicity in animal models. Summary Preclinical data suggest it may be worthwhile to take a step back and reconsider the use of bisphosphonates to lessen skeletal/vascular complications associated with compromised kidney function

Preparation, characterization and in vitro response of bioactive coatings on polyether ether ketone.

Polyether ether ketone (PEEK) is a highly heat-resistant thermoplastic with excellent strength and elastic modulus similar to human bone, making it an attractive material for orthopedic implants. However, the hydrophobic surface of PEEK implants induces fibrous encapsulation which is unfavorable for stable implant anchorage. In this study, PEEK was coated via ion-beam-assisted deposition (IBAD) using a two-layer design of yttria-stabilized zirconia (YSZ) as a heat-protection layer, and hydroxyapatite (HA) as a top layer to improve osseointegration. Microstructural analysis of the coatings showed a dense, uniform columnar grain structure in the YSZ layer and no delamination from the substrate. The HA layer was found to be amorphous and free of porosities in its as-deposited state. Subsequent heat treatment via microwave energy followed by autoclaving crystallized the HA layer, confirmed by SEM and XRD analysis. An in vitro study using MC3T3 preosteoblast cells showed improved bioactivity in heat-treated sample groups. Cell proliferation, differentiation, and mineralization were analyzed by MTT assay and DNA content, osteocalcin expression, and Alizarin Red S (AR-S) content, respectively. Initial cell growth was increased, and osteogenic maturation and mineralization were accelerated most on coatings that underwent a combined microwave and autoclave heat treatment process as compared to uncoated PEEK and amorphous HA surfaces. © 2015 Wiley Periodicals, Inc. J Biomed Mater Res Part B: Appl Biomater, 105B: 560-567, 2017.Funded by National Institute of Dental and Craniofacial Research of the National Institutes of Health. Grant Number: R21DE022925This is the author accepted manuscript. The final version is available from Wiley via http://dx.doi.org/10.1002/jbm.b.3357

Assessment of regional bone tissue perfusion in rats using fluorescent microspheres

Disturbances in bone blood flow have been shown to have deleterious effects on bone properties yet there remain many unanswered questions about skeletal perfusion in health and disease, partially due to the complexity of measurement methodologies. The goal of this study was use fluorescent microspheres in rats to assess regional bone perfusion by adapting mouse-specific fluorescent microsphere protocol. Ten fifteen-week old Sprague Dawley rats were injected with fluorescent microspheres either via cardiac injection (n = 5) or via tail vein injection (n = 5). Femora and tibiae were harvested and processed to determine tissue fluorescence density (TFD) which is proportional to the number of spheres trapped in the tissue capillaries. Right and left total femoral TFD (2.77 ± 0.38 and 2.70 ± 0.24, respectively) and right and left tibial TFD (1.11 ± 0.26 and 1.08 ± 0.34, respectively) displayed bilateral symmetry in flow when assessed in cardiac injected animals. Partitioning of the bone perfusion into three segments along the length of the bone showed the distal femur and proximal tibia received the greatest amount of perfusion within their respective bones. Tail vein injection resulted in unacceptably low TFD levels in the tibia from 4 of the 5 animals. In conclusion this report demonstrates the viability of cardiac injection of fluorescent microspheres to assess bone tissue perfusion in rats

Automated Classification of Starch Granules Using Supervised Pattern Recognition of Morphological Properties

Image analysis techniques have been used to investigate the likelihood of being able to classify and assign a probability regarding the plant origin of individual starch granules in a collection of granules. Quantifiable variables were used to characterize the granules, and the assignments and probabilities were calculated objectively. We consider the classification of images containing granules of a single species and of mixed species and the possibility of assigning a class to granules of unknown species in an image of a slide obtained from the dental calculus of chimpanzees.AnthropologyHuman Evolutionary Biolog

Zoledronate treatment has different effects in mouse strains with contrasting baseline bone mechanical phenotypes

Aref, M. W., McNerny, E. M. B., Brown, D., Jepsen, K. J., & Allen, M. R. (2016). Zoledronate treatment has different effects in mouse strains with contrasting baseline bone mechanical phenotypes. Osteoporosis International : A Journal Established as Result of Cooperation between the European Foundation for Osteoporosis and the National Osteoporosis Foundation of the USA, 27(12), 3637–3643. https://doi.org/10.1007/s00198-016-3701-

Raloxifene neutralizes bone brittleness induced by anti-remodeling treatment and increases fatigue life through non-cell mediated mechanisms

Pre-clinical data have shown that tissue level effects stemming from bisphosphonateinduced suppression of bone remodeling can result in bone that is stronger yet more brittle. Raloxifene has been shown to reduce bone brittleness through non-cellular mechanisms. The goal of this work was to test the hypothesis that raloxifene can reverse the bone brittleness resulting from bisphosphonate treatment. Dog and mouse bone from multiple bisphosphonate dosing experiments were soaked in raloxifene and then assessed for mechanical properties. Mice treated with zoledronate in vivo had lower post-yield mechanical properties compared to controls. Raloxifene soaking had significant positive effects on select mechanical properties of bones from both vehicle and zoledronate treated mice. Although the effects were blunted in zoledronate bones relative to vehicle, the soaking was sufficient to normalize properties to control levels. Additional studies showed that raloxifene-soaked bones had a significant positive effect on cycles to failure (+114%) compared to control-soaked mouse bone. Finally, raloxifene soaking significantly improved select properties of ribs from dogs treated for 3 years with alendronate. These data show that ex vivo soaking in raloxifene can act through non-cellular mechanisms to enhance mechanical properties of bone previously treated with bisphosphonate. We also document that the positive effects of raloxifene soaking extend to enhancing fatigue properties of bone

Troponin Elevations After Electroconvulsive Therapy: The Need for Caution

BACKGROUND: Electroconvulsive therapy is used to treat patients with severe or resistant depression. Troponin elevations are associated with an adverse prognosis, and it is well known that central nervous system insults can cause biochemical evidence of cardiac injury. No study previously has studied this with electroconvulsive therapy. METHODS: Patients scheduled for electroconvulsive therapy were enrolled. Clinical information, an electrocardiogram, and a baseline sample for cardiac troponin I and T (cTnI and cTnT) were obtained. Electroconvulsive therapy was done with standard techniques. Subsequently, electrocardiograms and additional samples were obtained. cTnT was measured with the Roche assay and cTnI with the Dade Stratus equipment. Values above the 99th percentile were considered abnormal. RESULTS: Seventy patients completed the study. Four patients had elevated levels of cTn before treatment. In 3 patients, the elevations persisted. Four additional patients developed elevated cTn levels during electroconvulsive therapy. Two of the patients with cTn elevations died. No other events occurred during follow-up. CONCLUSIONS: Elevations of cTn occurred in 11.5% of patients treated with electroconvulsive therapy. Some of the elevations preceded therapy and some occurred during treatment. Given the adverse prognostic importance of cTn elevations in general, in addition to additional studies, an increased degree of medical scrutiny may be appropriate for this group of patients and for those receiving electroconvulsive therapy

STITCHER: Dynamic assembly of likely amyloid and prion β-structures from secondary structure predictions

The supersecondary structure of amyloids and prions, proteins of intense clinical and biological interest, are difficult to determine by standard experimental or computational means. In addition, significant conformational heterogeneity is known or suspected to exist in many amyloid fibrils. Previous work has demonstrated that probability-based prediction of discrete β-strand pairs can offer insight into these structures. Here, we devise a system of energetic rules that can be used to dynamically assemble these discrete β-strand pairs into complete amyloid β-structures. The STITCHER algorithm progressively ‘stitches’ strand-pairs into full β-sheets based on a novel free-energy model, incorporating experimentally observed amino-acid side-chain stacking contributions, entropic estimates, and steric restrictions for amyloidal parallel β-sheet construction. A dynamic program computes the top 50 structures and returns both the highest scoring structure and a consensus structure taken by polling this list for common discrete elements. Putative structural heterogeneity can be inferred from sequence regions that compose poorly. Predictions show agreement with experimental models of Alzheimer's amyloid beta peptide and the Podospora anserina Het-s prion. Predictions of the HET-s homolog HET-S also reflect experimental observations of poor amyloid formation. We put forward predicted structures for the yeast prion Sup35, suggesting N-terminal structural stability enabled by tyrosine ladders, and C-terminal heterogeneity. Predictions for the Rnq1 prion and alpha-synuclein are also given, identifying a similar mix of homogenous and heterogeneous secondary structure elements. STITCHER provides novel insight into the energetic basis of amyloid structure, provides accurate structure predictions, and can help guide future experimental studies. Proteins 2011