A Single Injection of NTG-101 Reduces the Expression of Pain-Related Neurotrophins in a Canine Model of Degenerative Disc Disease

Background: Tissue sources of pain emanating from degenerative discs remains incompletely understood. Canine intervertebral discs (IVDs) were needle puncture injured, 4-weeks later injected with either phosphate-buffered saline (PBS) or NTG-101, harvested after an additional fourteen weeks and then histologically evaluated for the expression of NGFr, BDNF, TrkB and CALCRL proteins. Quantification was performed using the HALO automated cell-counting scoring platform. Immunohistochemical analysis was also performed on human IVD tissue samples obtained from spinal surgery. Immunohistochemical analysis and quantification of neurotrophins and neuropeptides was performed using an in vivo canine model of degenerative disc disease and human degenerative disc tissue sections. Discs injected with NTG-101 showed significantly lower levels of Nerve Growth Factor receptor (NGFr/TrkA, p = 0.0001), BDNF (p = 0.009), TrkB (p = 0.002) and CALCRL (p = 0.008) relative to PBS injections. Human IVD tissue obtained from spinal surgery due to painful DDD show robust expression of NGFr, BDNF, TrkB and CALCRL proteins. A single intradiscal injection of NTG-101 significantly inhibits the expression of NGFr, BDNF, TrkB and CALCRL proteins in degenerative canine IVDs. These results strongly suggest that NTG-101 inhibits the development of neurotrophins that are strongly associated with painful degenerative disc disease and may have profound effects upon the management of patients living with discogenic pain.     

Structural Abnormalities of the Optic Nerve and Retina in Huntington’s Disease Pre-Clinical and Clinical Settings

Huntington’s disease (HD) is a fatal neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein. HD-related pathological remodelling has been reported in HD mouse models and HD carriers. In this study, we studied structural abnormalities in the optic nerve by employing Spectral Domain Optical Coherence Tomography (SD-OCT) in pre-symptomatic HD carriers of Caucasian origin. Transmission Electron Microscopy (TEM) was used to investigate ultrastructural changes in the optic nerve of the well-established R6/2 mouse model at the symptomatic stage of the disease. We found that pre-symptomatic HD carriers displayed a significant reduction in the retinal nerve fibre layer (RNFL) thickness, including specific quadrants: superior, inferior and temporal, but not nasal. There were no other significant irregularities in the GCC layer, at the macula level and in the optic disc morphology. The ultrastructural analysis of the optic nerve in R6/2 mice revealed a significant thinning of the myelin sheaths, with a lamellar separation of the myelin, and a presence of myelonoid bodies. We also found a significant reduction in the thickness of myelin sheaths in peripheral nerves within the choroids area. Those ultrastructural abnormalities were also observed in HD photoreceptor cells that contained severely damaged membrane disks, with evident vacuolisation and swelling. Moreover, the outer segment of retinal layers showed a progressive disintegration. Our study explored structural changes of the optic nerve in pre- and clinical settings and opens new avenues for the potential development of biomarkers that would be of great interest in HD gene therapies.     

Fast electrical lysis of cells for capillary electrophoresis

In the past decade, capillary electrophoresis has demonstrated increasing utility for the quantitative analysis of single cells. New applications for the analysis of dynamic cellular properties demand sampling methods with sufficient temporal resolution to accurately measure these processes. In particular, intracellular signaling pathways involving many enzymes can be modulated on subsecond time scales. We have developed a technique to rapidly lyse an adherent mammalian cell using a single electrical pulse followed by efficient loading of the cellular contents into a capillary. Microfabricated electrodes were designed to create a maximum voltage drop across the flattened cell's plasma membrane at a minimum interelectrode voltage. The influence of the interelectrode distance, pulse duration, and pulse strength on the rate of cell lysis was determined. The ability to rapidly lyse a cell and collect and separate the cellular contents was demonstrated by loading cells with Oregon Green and two isomers of carboxyfluorescein. All three fluorophores were detected with a separation efficiency comparable to that of standards. Parallel comparison of electrical lysis to that produced by a laser-based lysis system revealed that the sampling efficiencies of the two techniques were comparable. Rapid cell lysis by an electrical pulse may increase the application of capillary electrophoresis to the study of cellular dynamics requiring fast sampling times.     

Relations between compliances of inhomogeneities having the same shape but different elastic constants

The contributions of inhomogeneities having the same shape but different elastic constants, to the overall elastic properties are interrelated. The utility of these relations lies, in particular, in the possibility to extend available results for pores or rigid inclusions to inhomogeneities of arbitrary elastic properties. The relations are exact for ellipsoids and approximate for non-ellipsoidal shapes. The constructed approximation also constitutes approximate connection between the first Eshelby’s problem (the eigenstrain problem) and the second one (the inhomogeneity problem), for non-ellipsoidal shapes. It also yields approximate formulas for the contribution of a non-ellipsoidal inhomogeneity to effective elastic properties.     

Evaluation of markov program models in virtual memory systems

A first order Markov model of program behaviour is developed from FORTRAN program instruction data. The program model is evaluated by using it to generate page references for input into a simple virtual memory operating system (VMOS) simulation model. The actual trace data are also used to drive the VMOS model. In both cases the fault probability is obtained for different replacement rules, memory sizes and page sizes. A comparison of fault probabilities is used to determine the effectiveness of the Markov program model.     

Iterative restoration of MR images corrupted with translational motion

Patient motion during the acquisition of magnetic resonance imaging data causes loss of resolution and ghost repetitions of the moving structures in the reconstructed image. In this paper the motion is modeled as being translational, and it is shown that this causes either the magnitude or the phase of the data to be corrupted, depending upon whether the motion is within or perpendicular to the imaging plane. The problem of restoring the image using only the corrupted data and no knowledge about the motion is addressed. The restoration problem is nonlinear in general, but is linear in two special cases. An iterative algorithm is developed that uses projections onto convex sets for magnitude retrieval and generalized projections for phase retrieval. In both cases constraint sets containing all a priori knowledge are used, and this is shown to be necessary for rapid convergence. The two algorithms may be combined to restore images corrupted by three-dimensional motion. The algorithms were verified using simulated data.     

Utilizing theory of mind for action selection applied in the domain of fighter pilot training

When developing intelligent agents, approaches that allow the anticipation of other agents is of utmost importance. For humans, this has also been shown to be crucial to establish good interactions. In this paper, a design for an agent that is equipped with theory of mind based reasoning capabilities is presented. The approach moves beyond the state of the art from several angles: first, it allows for the expression of certainties with respect to the predicted states of the other agents. Second, it allows the prediction during a substantial number of time steps in the future, thereby utilizing the theory of mind model multiple times. The approach has been applied to the domain of fighter pilots whereby intelligent opponents are developed to facilitate dedicated training for F16 fighter pilots.     

Modelling collective decision making in groups and crowds: Integrating social contagion and interacting emotions, beliefs and intentions

Collective decision making involves on the one hand individual mental states such as beliefs, emotions and intentions, and on the other hand interaction with others with possibly different mental states. Achieving a satisfactory common group decision on which all agree requires that such mental states are adapted to each other by social interaction. Recent developments in social neuroscience have revealed neural mechanisms by which such mutual adaptation can be realised. These mechanisms not only enable intentions to converge to an emerging common decision, but at the same time enable to achieve shared underlying individual beliefs and emotions. This paper presents a computational model for such processes. As an application of the model, an agent-based analysis was made of patterns in crowd behaviour, in particular to simulate a real-life incident that took place on May 4, 2010 in Amsterdam. From available video material and witness reports, useful empirical data were extracted. Similar patterns were achieved in simulations, whereby some of the parameters of the model were tuned to the case addressed, and most parameters were assigned default values. The results show the inclusion of contagion of belief, emotion, and intention states of agents results in better reproduction of the incident than non-inclusion.     

Factors facilitating or impeding older adults’ creative contributions in the collaborative design of a novel DTV-based application

This article describes some of the challenges of supporting older adults’ creative input to the design of an (as yet) undefined digital television application. Focusing on commonly used brainstorming and paper prototyping techniques, constructive insights are gathered from users with limited experience of interactive technology. Encouraging older participants to move beyond what they are familiar with, the research reports on how fragmented conceptual knowledge of familiar technologies can either facilitate or impede the creative development of new ideas. This includes bias or contradictory ideas that can emerge in the elicitation process. As reported, other factors, such as the self-perception of inadequate drawing skills, demonstrate further barriers for some older adults to articulate their visions and aspirations for suitably designed technology.     

Böhler Edelstahl

Böhler Edelstahl produces high performance tool and high speed steels via an optimised powder metallurgy/hot isostatic pressing route, as part of a high value special alloys portfolio.