Effect of implant design and material on subsidence following dynamic loading of intervertebral devices

Introduction: Subsidence is not the consequence of a single loading event. More specifically, subsidence may be interpreted as the continuous sinking due to continuous loading. As such, a single static load may not be appropriate. Few studies involving cage subsidence have employed continuous cyclic loading. The goal of this study was to address the mechanical subsidence performance via prediction of the final subsidence depth and the rate of subsidence. It is hypothesized that those spacer designs, which engage the stronger vertebral body periphery, enable endplate stress distribution through increased contact area, and reduced stress concentrations would display more favorable performance characteristics with respect to subsidence. Materials and Methods: Three intervertebral spacer designs were evaluated; threaded titanium, endplate-sparing titanium, and Polyetheretherketone (PEEK). Devices were randomly but equally assigned to porcine L4 and L5 vertebral bodies with endplates prepared as per recommended surgical procedure. Specimens were loaded from –50 N to –350 N at 1 Hz for 600 cycles with continuous load versus deformation acquired at cycle 10 and at 25 cycle intervals thereafter. For each cycle interval, the net deformation between the maximum and minimal applied load (or subsidence) was computed. The deformation for all six samples of each design were averaged across each cycle interval and subjected to a nonlinear exponential analysis. More specifically, the subsidence is represented by the independent variable Y. Initial subsidence is calculated at the 10th loading cycle and was represented by the variable Y0. From the subsidence versus cycle data, the rate of subsidence (K) was determined as well as the plateau, or asymptotic limit, of the subsidence. All parameters were compared using a one way ANOVA with a Tukey posthoc test for determination of statistical difference (α \u3c 0.05) between designs. Results and Discussion: All implants displayed an exponential relationship with respect to the number of applied cycles. Significant differences among all three designs were determined for initial subsidence Y0 (P \u3c 0.001) and subsidence limit (plateau) (P \u3c 0.001). For both parameters, the endplate-sparing titanium device displayed the least subsidence when compared with the other designs. The subsidence rate K displayed a statistically reduced rate for the endplate-sparing titanium device when compared with the threaded or PEEK designs. (P \u3c 0.001). Clinically, such a condition results in a slow and gradual settling of the titanium implant upon the endplate surface. The PEEK implant displayed a more rapid and greater subsidence than either the endplate-sparing or threaded titanium designs. Conclusions: Under continuous loading, an endplate-sparing titanium device displayed significantly reduced initial and final subsidence and subsidence rate when compared with threaded and PEEK designs. The clinical implication of these results is that implant material modulus is not the sole determinant for subsidence. Acknowledgements: This work is the result of a sponsored research grant from Titan Spine LLC, 6140 Executive Drive, Mequon, WI 52092

Post-Transcriptional Dynamics is Involved in Rapid Adaptation to Hypergravity in Jurkat T Cells

The transcriptome of human immune cells rapidly reacts to altered gravity in a highly dynamic way. We could show in previous experiments that transcriptional patterns show profound adaption after seconds to minutes of altered gravity. To gain further insight into these transcriptional alteration and adaption dynamics, we conducted a highly standardized RNA-Seq experiment with human Jurkat T cells exposed to 9xg hypergravity for 3 and 15 min, respectively. We investigated the frequency with which individual exons were used during transcription and discovered that differential exon usage broadly appeared after 3 min and became less pronounced after 15 min. Additionally, we observed a shift in the transcript pool from coding towards non-coding transcripts. Thus, adaption of gravity-sensitive differentially expressed genes followed a dynamic transcriptional rebound effect. The general dynamics were compatible with previous studies on the transcriptional effects of short hypergravity on human immune cells and suggest that initial up-regulatory changes mostly result from increased elongation rates. The shift correlated with a general downregulation of the affected genes. All chromosome bands carried homogenous numbers of gravity-sensitive genes but showed a specific tendency towards up- or downregulation. Altered gravity affected transcriptional regulation throughout the entire genome, whereby the direction of differential expression was strongly dependent on the structural location in the genome. A correlation analysis with potential mediators of the early transcriptional response identified a link between initially upregulated genes with certain transcription factors. Based on these findings, we have been able to further develop our model of the transcriptional response to altered gravity

Translational neurophysiology in sheep:Measuring sleep and neurological dysfunction in CLN5 affected Batten disease sheep

This is the final published version of a paper originally published in BRAIN 2015: 138; 862?874, DOI: http://dx.doi.org/10.1093/brain/awv026Creating valid mouse models of slowly progressing human neurological diseases is challenging, not least because the short lifespan of rodents confounds realistic modelling of disease time course. With their large brains and long lives, sheep offer significant advantages for translational studies of human disease. Here we used normal and CLN5 Batten disease affected sheep to demonstrate the use of the species for studying neurological function in a model of human disease. We show that electroencephalography can be used in sheep, and that longitudinal recordings spanning many months are possible. This is the first time such an electroencephalography study has been performed in sheep. We characterized sleep in sheep, quantifying characteristic vigilance states and neurophysiological hallmarks such as sleep spindles. Mild sleep abnormalities and abnormal epileptiform waveforms were found in the electroencephalographies of Batten disease affected sheep. These abnormalities resemble the epileptiform activity seen in children with Batten disease and demonstrate the translational relevance of both the technique and the model. Given that both spontaneous and engineered sheep models of human neurodegenerative diseases already exist, sheep constitute a powerful species in which longitudinal in vivo studies can be conducted. This will advance our understanding of normal brain function and improve our capacity for translational research into neurological disorders.This work was funded by CHDI Inc. (AJM). Founding the\ud sheep flock, and costs in NZ relating to the rearing and\ud genotyping of the animals were funded by a series of grants\ud from the Neurological Foundation of NZ and the Batten\ud Disease Support and Research Association (DNP, NLM)

Cytoskeletal stability and metabolic alterations in primary human macrophages in long-term microgravity

The immune system is one of the most affected systems of the human body during space flight. The cells of the immune system are exceptionally sensitive to microgravity. Thus, serious concerns arise, whether space flight associated weakening of the immune system ultimately precludes the expansion of human presence beyond the Earth's orbit. For human space flight, it is an urgent need to understand the cellular and molecular mechanisms by which altered gravity influences and changes the functions of immune cells. The CELLBOX-PRIME (= CellBox-Primary Human Macrophages in Microgravity Environment) experiment investigated for the first time microgravity-associated long-term alterations in primary human macrophages, one of the most important effector cells of the immune system. The experiment was conducted in the U.S. National Laboratory on board of the International Space Station ISS using the NanoRacks laboratory and Biorack type I standard CELLBOX EUE type IV containers. Upload and download were performed with the SpaceX CRS-3 and the Dragon spaceship on April 18th, 2014 / May 18th, 2014. Surprisingly, primary human macrophages exhibited neither quantitative nor structural changes of the actin and vimentin cytoskeleton after 11 days in microgravity when compared to 1g controls. Neither CD18 or CD14 surface expression were altered in microgravity, however ICAM-1 expression was reduced. The analysis of 74 metabolites in the cell culture supernatant by GC-TOF-MS, revealed eight metabolites with significantly different quantities when compared to 1g controls. In particular, the significant increase of free fucose in the cell culture supernatant was associated with a significant decrease of cell surface-bound fucose. The reduced ICAM-1 expression and the loss of cell surface-bound fucose may contribute to functional impairments, e.g. the activation of T cells, migration and activation of the innate immune response. We assume that the surprisingly small and non-significant cytoskeletal alterations represent a stable "steady state" after adaptive processes are initiated in the new microgravity environment. Due to the utmost importance of the human macrophage system for the elimination of pathogens and the clearance of apoptotic cells, its apparent robustness to a low gravity environment is crucial for human health and performance during long-term space missions

Rapid Downregulation of H3K4me3 Binding to Immunoregulatory Genes in Altered Gravity in Primary Human M1 Macrophages

The sensitivity of human immune system cells to gravity changes has been investigated in numerous studies. Human macrophages mediate innate and thus rapid immune defense on the one hand and activate T- and B-cell-based adaptive immune response on the other hand. In this process they finally act as immunoeffector cells, and are essential for tissue regeneration and remodeling. Recently, we demonstrated in the human Jurkat T cell line that genes are differentially regulated in cluster structures under altered gravity. In order to study an in vivo near system of immunologically relevant human cells under physically real microgravity, we performed parabolic flight experiments with primary human M1 macrophages under highly standardized conditions and performed chromatin immunoprecipitation DNA sequencing (ChIP-Seq) for whole-genome epigenetic detection of the DNA-binding loci of the main transcription complex RNA polymerase II and the transcription-associated epigenetic chromatin modification H3K4me3. We identified an overall downregulation of H3K4me3 binding loci in altered gravity, which were unequally distributed inter- and intrachromosomally throughout the genome. Three-quarters of all affected loci were located on the p arm of the chromosomes chr5, chr6, chr9, and chr19. The genomic distribution of the downregulated H3K4me3 loci corresponds to a substantial extent to immunoregulatory genes. In microgravity, analysis of RNA polymerase II binding showed increased binding to multiple loci at coding sequences but decreased binding to central noncoding regions. Detection of altered DNA binding of RNA polymerase II provided direct evidence that gravity changes can lead to altered transcription. Based on this study, we hypothesize that the rapid transcriptional response to changing gravitational forces is specifically encoded in the epigenetic organization of chromatin

Serotonin 5-HT2A receptors underlie increased motor behaviors induced in dopamine-depleted rats by intrastriatal 5-HT2A/2C agonism

ABSTRACT Gene expression studies have suggested that dopamine (DA) depletion increases the sensitivity of striatal direct pathway neurons to the effects of serotonin (5-HT) via the 5-HT 2 receptor. The present study examined the possible influence(s) of 5-HT 2A or 5-HT 2C receptor-mediated signaling locally within the striatum on motor behavior triggered by 5-HT 2 receptor agonism in the neonatal DA-depleted rat. Male Sprague-Dawley rats were treated with 6-hydroxydopamine (6-OHDA; 60 g in 5 l per lateral ventricle) on postnatal day 3 to achieve near-total DA depletion bilaterally. Sixty days later, sham-operated (saline-injected) or 6-OHDA-treated rats were challenged with the 5-HT 2A/2C agonist DOI [(Ϯ)-1-(4-iodo-2,5-dimethoxyphenyl)-2-aminopropane] or saline either by systemic treatment or bilateral intrastriatal infusion. Motor behavior was quantified for 60 min after agonist injection using computerized activity monitors. Systemic DOI treatment (0.2 or 2.0 mg/kg i.p.) was more effective in inducing motor activity in the DA-depleted group compared with intact controls. Intrastriatal DOI infusion (1.0 or 10.0 g/side) also produced a significant rise in motor activity in the DA-depleted group during the 30-to 60-min period of behavioral analysis but did not influence behavior in intact animals. The effects of intrastriatal DOI infusion were blocked by intrastriatal coinfusion of the 5-HT 2 antagonist ketanserin (1. A loss of dopamine (DA) transmission to the rodent striatum during early postnatal development results in a compensatory increase in serotonin (5-HT) innervation to the dorsal striatum Several studies indicate that 5-HT 2A receptors are positioned to mediate the influences of enhanced 5-HT signaling in the DA-depleted striatum. First, 5-HT release agents and 5-HT 2 receptor agonists gain potency in inducing striatal preprotachykinin (PPT; encodes substance P and neurokini

Tierwohlorientierte Bestandsführung: Milchrind: Erarbeitung der fachlichen Grundlagen zur Erfassung und Bewertung von Tierhygiene, Tiergerechtheit und Tiergesundheit für eine tierwohlorientierte Bestandsführung von Milchrindern

Die in dieser Studie erarbeiteten Kennzahlen für die Tierwohlorientierte Bestandsführung beim Milchrind bilden die Grundlage um eine IT-basierte Lösung zu schaffen. Die IT-basierte Lösung soll es den Milchkuhhalterinnen und Milchkuhhaltern ermöglicht, den gesetzlichen Verpflichtungen effizient nachzukommen und das Wohlbefinden ihrer Tiere selbstständig und kontinuierlich nach dem HACCP-Konzept zu optimieren. Redaktionsschluss: 05.06.202