Controlled Fabrication of Quality ZnO NWs/CNTs and ZnO NWs/Gr Heterostructures via Direct Two-Step CVD Method.

A novel and advanced approach of growing zinc oxide nanowires (ZnO NWs) directly on single-walled carbon nanotubes (SWCNTs) and graphene (Gr) surfaces has been demonstrated through the successful formation of 1D-1D and 1D-2D heterostructure interfaces. The direct two-step chemical vapor deposition (CVD) method was utilized to ensure high-quality materials' synthesis and scalable production of different architectures. Iron-based universal compound molecular ink was used as a catalyst in both processes (a) to form a monolayer of horizontally defined networks of SWCNTs interfaced with vertically oriented ZnO NWs and (b) to grow densely packed ZnO NWs directly on a graphene surface. We show here that our universal compound molecular ink is efficient and selective in the direct synthesis of ZnO NWs/CNTs and ZnO NWs/Gr heterostructures. Heterostructures were also selectively patterned through different fabrication techniques and grown in predefined locations, demonstrating an ability to control materials' placement and morphology. Several characterization tools were employed to interrogate the prepared heterostructures. ZnO NWs were shown to grow uniformly over the network of SWCNTs, and much denser packed vertically oriented ZnO NWs were produced on graphene thin films. Such heterostructures can be used widely in many potential applications, such as photocatalysts, supercapacitors, solar cells, piezoelectric or thermal actuators, as well as chemical or biological sensors.

The cardioprotective effect of dexrazoxane (Cardioxane) is consistent with sequestration of poly(ADP-ribose) by self-assembly and not depletion of topoisomerase 2B.

Following systematic scrutiny of the evidence in support of the hypothesis that the cardioprotective mechanism of action of dexrazoxane is mediated by a 'depletion' or 'downregulation' of Top2ß protein levels in heart tissue, the author concludes that this hypothesis is untenable. In seeking to understand how dexrazoxane protects the heart, the outcomes of a customised association rule learning algorithm incorporating the use of antecedent surrogate variables (CEME, 2017 McCormack Pharma) reveal a previously unknown relationship between dexrazoxane and poly(ADP-ribose) (PAR) polymer. The author shows how this previously unknown relationship explains both acute and long-term cardioprotection in patients receiving anthracyclines. In addition, as a direct inhibitor of PAR dexrazoxane has access to the epigenome and this offers a new insight into protection by dexrazoxane against doxorubicin-induced late-onset damage [McCormack K, manuscript in preparation]. Notably, through this review article, the author illustrates the practical application of probing natural language text using an association rule learning algorithm for the discovery of new and interesting associations that, otherwise, would remain lost. Historically, the use of CEME enabled the first report of the capacity of a small molecule to catalyse the hybrid self-assembly of a nucleic acid biopolymer via canonical and non-canonical, non-covalent interactions analogous to Watson Crick and Hoogsteen base pairing, respectively.

A framework for different levels of integration of computational models into web-based virtual patients.

BACKGROUND: Virtual patients are increasingly common tools used in health care education to foster learning of clinical reasoning skills. One potential way to expand their functionality is to augment virtual patients' interactivity by enriching them with computational models of physiological and pathological processes. OBJECTIVE: The primary goal of this paper was to propose a conceptual framework for the integration of computational models within virtual patients, with particular focus on (1) characteristics to be addressed while preparing the integration, (2) the extent of the integration, (3) strategies to achieve integration, and (4) methods for evaluating the feasibility of integration. An additional goal was to pilot the first investigation of changing framework variables on altering perceptions of integration. METHODS: The framework was constructed using an iterative process informed by Soft System Methodology. The Virtual Physiological Human (VPH) initiative has been used as a source of new computational models. The technical challenges associated with development of virtual patients enhanced by computational models are discussed from the perspectives of a number of different stakeholders. Concrete design and evaluation steps are discussed in the context of an exemplar virtual patient employing the results of the VPH ARCH project, as well as improvements for future iterations. RESULTS: The proposed framework consists of four main elements. The first element is a list of feasibility features characterizing the integration process from three perspectives: the computational modelling researcher, the health care educationalist, and the virtual patient system developer. The second element included three integration levels: basic, where a single set of simulation outcomes is generated for specific nodes in the activity graph; intermediate, involving pre-generation of simulation datasets over a range of input parameters; advanced, including dynamic solution of the model. The third element is the description of four integration strategies, and the last element consisted of evaluation profiles specifying the relevant feasibility features and acceptance thresholds for specific purposes. The group of experts who evaluated the virtual patient exemplar found higher integration more interesting, but at the same time they were more concerned with the validity of the result. The observed differences were not statistically significant. CONCLUSIONS: This paper outlines a framework for the integration of computational models into virtual patients. The opportunities and challenges of model exploitation are discussed from a number of user perspectives, considering different levels of model integration. The long-term aim for future research is to isolate the most crucial factors in the framework and to determine their influence on the integration outcome.

A vision and strategy for the virtual physiological human: 2012 update.

European funding under Framework 7 (FP7) for the virtual physiological human (VPH) project has been in place now for 5 years. The VPH Network of Excellence (NoE) has been set up to help develop common standards, open source software, freely accessible data and model repositories, and various training and dissemination activities for the project. It is also working to coordinate the many clinically targeted projects that have been funded under the FP7 calls. An initial vision for the VPH was defined by the FP6 STEP project in 2006. In 2010, we wrote an assessment of the accomplishments of the first two years of the VPH in which we considered the biomedical science, healthcare and information and communications technology challenges facing the project (Hunter et al. 2010 Phil. Trans. R. Soc. A 368, 2595-2614 (doi:10.1098/rsta.2010.0048)). We proposed that a not-for-profit professional umbrella organization, the VPH Institute, should be established as a means of sustaining the VPH vision beyond the time-frame of the NoE. Here, we update and extend this assessment and in particular address the following issues raised in response to Hunter et al.: (i) a vision for the VPH updated in the light of progress made so far, (ii) biomedical science and healthcare challenges that the VPH initiative can address while also providing innovation opportunities for the European industry, and (iii) external changes needed in regulatory policy and business models to realize the full potential that the VPH has to offer to industry, clinics and society generally.

The Virtual Physiological Human ToolKit.

The Virtual Physiological Human (VPH) is a major European e-Science initiative intended to support the development of patient-specific computer models and their application in personalized and predictive healthcare. The VPH Network of Excellence (VPH-NoE) project is tasked with facilitating interaction between the various VPH projects and addressing issues of common concern. A key deliverable is the 'VPH ToolKit'--a collection of tools, methodologies and services to support and enable VPH research, integrating and extending existing work across Europe towards greater interoperability and sustainability. Owing to the diverse nature of the field, a single monolithic 'toolkit' is incapable of addressing the needs of the VPH. Rather, the VPH ToolKit should be considered more as a 'toolbox' of relevant technologies, interacting around a common set of standards. The latter apply to the information used by tools, including any data and the VPH models themselves, and also to the naming and categorizing of entities and concepts involved. Furthermore, the technologies and methodologies available need to be widely disseminated, and relevant tools and services easily found by researchers. The VPH-NoE has thus created an online resource for the VPH community to meet this need. It consists of a database of tools, methods and services for VPH research, with a Web front-end. This has facilities for searching the database, for adding or updating entries, and for providing user feedback on entries. Anyone is welcome to contribute.

A vision and strategy for the virtual physiological human in 2010 and beyond.

European funding under framework 7 (FP7) for the virtual physiological human (VPH) project has been in place now for nearly 2 years. The VPH network of excellence (NoE) is helping in the development of common standards, open-source software, freely accessible data and model repositories, and various training and dissemination activities for the project. It is also helping to coordinate the many clinically targeted projects that have been funded under the FP7 calls. An initial vision for the VPH was defined by framework 6 strategy for a European physiome (STEP) project in 2006. It is now time to assess the accomplishments of the last 2 years and update the STEP vision for the VPH. We consider the biomedical science, healthcare and information and communications technology challenges facing the project and we propose the VPH Institute as a means of sustaining the vision of VPH beyond the time frame of the NoE.

Virtual physiological human: training challenges.

The virtual physiological human (VPH) initiative encompasses a wide range of activities, including structural and functional imaging, data mining, knowledge discovery tool and database development, biomedical modelling, simulation and visualization. The VPH community is developing from a multitude of relatively focused, but disparate, research endeavours into an integrated effort to bring together, develop and translate emerging technologies for application, from academia to industry and medicine. This process initially builds on the evolution of multi-disciplinary interactions and abilities, but addressing the challenges associated with the implementation of the VPH will require, in the very near future, a translation of quantitative changes into a new quality of highly trained multi-disciplinary personnel. Current strategies for undergraduate and on-the-job training may soon prove insufficient for this. The European Commission seventh framework VPH network of excellence is exploring this emerging need, and is developing a framework of novel training initiatives to address the predicted shortfall in suitably skilled VPH-aware professionals. This paper reports first steps in the implementation of a coherent VPH training portfolio.

The role of computational fluid dynamics in the management of unruptured intracranial aneurysms: a clinicians' view.

OBJECTIVE: The importance of hemodynamics in the etiopathogenesis of intracranial aneurysms (IAs) is widely accepted. Computational fluid dynamics (CFD) is being used increasingly for hemodynamic predictions. However, alogn with the continuing development and validation of these tools, it is imperative to collect the opinion of the clinicians. METHODS: A workshop on CFD was conducted during the European Society of Minimally Invasive Neurological Therapy (ESMINT) Teaching Course, Lisbon, Portugal. 36 delegates, mostly clinicians, performed supervised CFD analysis for an IA, using the @neuFuse software developed within the European project @neurIST. Feedback on the workshop was collected and analyzed. The performance was assessed on a scale of 1 to 4 and, compared with experts' performance. RESULTS: Current dilemmas in the management of unruptured IAs remained the most important motivating factor to attend the workshop and majority of participants showed interest in participating in a multicentric trial. The participants achieved an average score of 2.52 (range 0-4) which was 63% (range 0-100%) of an expert user. CONCLUSIONS: Although participants showed a manifest interest in CFD, there was a clear lack of awareness concerning the role of hemodynamics in the etiopathogenesis of IAs and the use of CFD in this context. More efforts therefore are required to enhance understanding of the clinicians in the subject.

Some new insights into the effects of opioids in phasic and tonic nociceptive tests.

In this review we critically appraise the value of some phasic and tonic nociceptive tests as models for differentiating the antinociceptive effects of opioid agonists. Using heat-evoked withdrawal of the hind paw or tail of a rodent, several early studies have assessed the effects of stimulus intensity upon antinociceptive potency of opioid agonists. After intrathecal (i.t.) administration of either morphine or sufentanil, for example, for any incremental change in stimulus intensity, the degree of right shift in the dose-response relationship was greater for morphine than for sufentanil. At first glance, such data appear to provide robust support for the pharmacological model of fractional receptor occupancy (FRO), which, according to the historical tenets of classical receptor theory, describes the relationship between intrinsic efficacy and the total receptor concentration. However, new data which elegantly characterize the relative contribution of small calibre unmyelinated and myelinated nociceptive afferents in mediating thermal-evoked responses challenge the exclusivity of such explanations with origins in classical theory. Within our review we report the results of experiments which provide direct electrophysiological evidence that noxious skin heating at a low rate activates C-polymodal nociceptors, but does not effectively activate A-delta mechanothermal nociceptors. In contrast, a high rate of skin heating activates both nociceptor classes, but produces a more intense activation of A-delta nociceptors that occurs after a shorter onset latency compared with the activation of C-fibre nociceptors. Thus, in direct challenge to the traditional model of FRO, a shift in the dose-response relationship of morphine to the right with a reduction in efficacy, may reflect the limited effectiveness of morphine to attenuate the A-delta-mediated component which assumes increasing dominance at high intensity heating. In our appraisal of other nociceptive models we provide an in-depth characterization of afferent processing in the early neonate rat, in which opioids have been tested in both phasic (tail flick and hot-plate) and tonic (formalin) tests. Afferent processing in this model is typified by several behavioural, anatomical and functional features which, although not pathological, are characteristic of those observed in models of nerve injury using the adult rat. Notably, these features include a lack of segmental inhibition ('disinhibition') and afferent input in large diameter myelinated fibres which make synaptic contacts within superficial laminae of the dorsal horn that in the adult are predominantly nociceptive. Paradoxically, because this paradigm demonstrates increased sensitivity to the antinociceptive effects of opioids it may have special merit as a model of tonic pain. It was recently announced that the i.t. administration of pertussis toxin (PTX) caused hyperalgesia and allodynia that appears similar to the symptoms reported by patients suffering from neuropathic pain. Unlike the effects of other opioids so far tested, buprenorphine-induced antinociception is not blocked in this model. This is an exciting finding and provides new optimism that some opioids, notably buprenorphine, may have a special role in managing some types of neuropathic pain.

The enigma of potassium ion in the management of dentine hypersensitivity: is nitric oxide the elusive second messenger?

We report the development of a 'second-messenger' model in an attempt to re-evaluate the role of K+ as a desensitising agent. Despite unequivocal validation of the effectiveness of potassium-based dentifrices in the management of dentine hypersensitivity, the mechanism(s) of action of K+ remains unclear. Although experimental paradigms of the Nernst equation demonstrate a direct inhibitory effect of K+ ion upon nerve conduction, in vivo considerable constraints can be argued to preclude this mechanism of action. Indeed, measurements of solution velocity within individual dentinal tubules obtained by scanning electrochemical microscopy indicate that outward movement of tubular fluid may represent a far greater barrier to the inward diffusion of K+ ions than previously estimated from measurements of hydraulic conductance across bulk dentine. Despite such probable limited penetration of dentine tubules, K+ ions may desensitise deeply-located nerve terminals through activation of a second-messenger transduction pathway that is capable of controlling the gain of K+-evoked effects which remain physically restricted to the more superficial aspects of the tubule. In addition to a direct effect upon transmembrane potential K+ can also indirectly attenuate neural activity through effects upon levels of the endogenously-synthesised free radical, nitric oxide (NO). Stimulation of the release of NO by K+ has been observed using a variety of cell preparations, which include endothelium, smooth muscle, adrenal medulla, hypothalamus and cerebellum. Importantly, a growing number of studies now report that an increase in the production of NO is associated with analgesia through a modulation of nociceptive input and a downregulation of sensitised nociceptors, most likely achieved through an increase in intraneural content of cGMP. The clinical role of a K+-evoked liberation of NO as a principal mechanism in the management of dentine hypersensitivity is supported by recent findings which include: (1) the localisation of NADPH-diaphorase activity and inducible nitric oxide synthase (iNOS) immunoreactivity within odontoblasts, their processes in dentine, and the subodontoblast layer of the pulp; (2) iNOS causes a sustained release of large (nanomolar) amounts of NO; (3) NO is freely diffusible and capable of displaying remarkably potent effector actions at distant target cells; (4) the actions of NO may be enhanced by endogenous carrier molecules such as S-nitrosothiols; (5) the synthesis of NO can be evoked by concentrations of K+ ion far less (i.e. <1 mM) than those required for direct inhibitory effects upon neural activity.

Non-steroidal anti-inflammatory drugs and spinal nociceptive processing.

Non-steroidal anti-inflammatory drugs have a direct action on spinal nociceptive processing in vivo with a relative order of potency which correlates with their capacity as inhibitors of cyclooxygenase activity. However, recent clinical surveys and new in vivo evidence strongly suggest that for some of these agents, centrally mediated analgesia may also be achieved by additional mechanisms, which are independent of prostaglandin synthesis inhibition. In this review we explore the likelihood for such mechanisms following an extensive survey of existing data. The implications of these mechanisms are discussed in the light of our current understanding of spinal nociceptive processing.