The retrograde delivery of adenovirus vector carrying the gene for brain-derived neurotrophic factor protects neurons and oligodendrocytes from apoptosis in the chronically compressed spinal cord of twy/twy mice

STUDY DESIGN: The twy/twy mouse undergoes spontaneous chronic mechanical compression of the spinal cord; this in vivo model system was used to examine the effects of retrograde adenovirus (adenoviral vector [AdV])-mediated brain-derived neurotrophic factor (BDNF) gene delivery to spinal neural cells. OBJECTIVE: To investigate the targeting and potential neuroprotective effect of retrograde AdV-mediated BDNF gene transfection in the chronically compressed spinal cord in terms of prevention of apoptosis of neurons and oligodendrocytes. SUMMARY OF BACKGROUND DATA: Several studies have investigated the neuroprotective effects of neurotrophins, including BDNF, in spinal cord injury. However, no report has described the effects of retrograde neurotrophic factor gene delivery in compressed spinal cords, including gene targeting and the potential to prevent neural cell apoptosis. METHODS: AdV-BDNF or AdV-LacZ (as a control gene) was injected into the bilateral sternomastoid muscles of 18-week old twy/twy mice for retrograde gene delivery via the spinal accessory motor neurons. Heterozygous Institute of Cancer Research mice (+/twy), which do not undergo spontaneous spinal compression, were used as a control for the effects of such compression on gene delivery. The localization and cell specificity of ß-galactosidase expression (produced by LacZ gene transfection) and BDNF expression in the spinal cord were examined by coimmunofluorescence staining for neural cell markers (NeuN, neurons; reactive immunology protein, oligodendrocytes; glial fibrillary acidic protein, astrocytes; OX-42, microglia) 4 weeks after gene injection. The possible neuroprotection afforded by retrograde AdV-BDNF gene delivery versus AdV-LacZ-transfected control mice was assessed by scoring the prevalence of apoptotic cells (terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling-positive cells) and immunoreactivity to active caspases -3, -8, and -9, p75, neurofilament 200 kD (NF), and for the oligodendroglial progenitor marker, NG2. RESULTS.: Four weeks after injection, the retrograde delivery of the LacZ marker gene was identified in cervical spinal neurons and some glial cells, including oligodendrocytes in the white matter of the spinal cord, in both the twy/twy mouse and the heterozygous Institute of Cancer Research mouse (+/twy). In the compressed spinal cord of twy/twy mouse, AdV-BDNF gene transfection resulted in a significant decrease in the number of terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling-positive cells present in the spinal cord and a downregulation in the caspase apoptotic pathway compared with AdV-LacZ (control) gene transfection. There was a marked and significant increase in the areas of the spinal cord of AdV-BDNF-injected mice that were NF- and NG2-immunopositive compared with AdV-LacZ-injected mice, indicating the increased presence of neurons and oligodendrocytes in response to BDNF transfection. CONCLUSION: Our results demonstrate that targeted retrograde BDNF gene delivery suppresses apoptosis in neurons and oligodendrocytes in the chronically compressed spinal cord of twy/twy mouse. Further work is required to establish whether this method of gene delivery may provide neuroprotective effects in other situations of compressive spinal cord injury.

Modular system design and control for flexible assembly

Flexible Assembly Systems (FASs) are normally associated with the automatic, or robotic, assembly of products, supported by automated material handling systems. However, manual assembly operations are still prevalent within many industries, where the complexity and variety of products prohibit the development of suitable automated assembly equipment. This article presents a generic model for incorporating flexibility into the design and control of assembly operations concerned with high variety/low volume manufacture, drawing on the principles for Flexible Manufacturing Systems (FMS) and Just-in-Time (JIT) delivery. It is based on work being undertaken in an electronics company where the assembly operations have been overhauled and restructured in response to a need for greater flexibility, shorter cycle times and reduced inventory levels. The principles employed are in themselves not original. However, the way they have been combined and tailored has created a total manufacturing control system which represents a new concept for responding to demands placed on market driven firms operating in an uncertain environment.

Improving “last mile” delivery performance to retailers in hub and spoke distribution systems

Purpose – The purpose of this paper is to investigate the “last mile” delivery link between a hub and spoke distribution system and its customers. The proportion of retail, as opposed to non-retail (trade) customers using this type of distribution system has been growing in the UK. The paper shows the applicability of simulation to demonstrate changes in overall delivery policy to these customers. Design/methodology/approach – A case-based research method was chosen with the aim to provide an exemplar of practice and test the proposition that simulation can be used as a tool to investigate changes in delivery policy. Findings – The results indicate the potential improvement in delivery performance, specifically in meeting timed delivery performance, that could be made by having separate retail and non-retail delivery runs from the spoke terminal to the customer. Research limitations/implications – The simulation study does not attempt to generate a vehicle routing schedule but demonstrates the effects of a change on delivery performance when comparing delivery policies. Practical implications – Scheduling and spreadsheet software are widely used and provide useful assistance in the design of delivery runs and the allocation of staff to those delivery runs. This paper demonstrates to managers the usefulness of investigating the efficacy of current design rules and presents simulation as a suitable tool for this analysis. Originality/value – A simulation model is used in a novel application to test a change in delivery policy in response to a changing delivery profile of increased retail deliveries.

Investigating local delivery by road to retail and non-retail customers in the UK logistics sector

Over recent years, hub-and-spoke distribution techniques have attracted widespread research attention. Despite there being a growing body of literature in this area there is less focus on the spoke-terminal element of the hub-and-spoke system as being a key component in the overall service received by the end-user. Current literature is highly geared towards discussing bulk optimization of freight units rather than to the more discrete and individualistic profile characteristics of shared-user Less-than-truckload (LTL) freight. In this paper, a literature review is presented to review the role hub-and-spoke systems play in meeting multi-profile customer demands, particularly in developing sectors with more sophisticated needs, such as retail. The paper also looks at the use of simulation technology as a suitable tool for analyzing spoke-terminal operations within developing hub-and spoke systems.

Consideration of the efficacy of non-ionic vesicles in the targeted delivery of oral vaccines

The fundamentals of this research were to exploit non-ionic surfactant technology for delivery and administration of vaccine antigens across the oral route and to gain a better understanding of vaccine trafficking. Using a newly developed method for manufacture of non-ionic surfactant vesicles (niosomes and bilosomes) lower process temperatures were adopted thus reducing antigen exposure to potentially damaging conditions. Vesicles prepared by this method offered high protection to enzymatic degradation, with only ~10 % antigen loss measured when vesicles incorporating antigen were exposed to enzyme digestion. Interestingly, when formulated using this new production method, the addition of bile salt to the vesicles offered no advantage in terms of stability within simulated gastro-intestinal conditions. Considering their ability to deliver antigen to their target site, results demonstrated that incorporation of antigen within vesicles enhanced delivery and targeting of the antigen to the Peyer's Patch, again with niosomes and bilosomes offering similar efficiency. Delivery to both the Peyer's patches and mesentery lymphatics was shown to be dose dependent at lower concentrations, with saturation kinetics applying at higher concentrations. This demonstrates that in the formulation of vaccine delivery systems, the lipid/antigen dose ratio is not only a key factor in production cost, but is equally a key factor in the kinetics of delivery and targeting of a vaccine system. © 2013 Controlled Release Society.

Consideration of the efficacy of non-ionic vesicles in the targeted delivery of oral vaccines

The fundamentals of this research were to exploit non-ionic surfactant technology for delivery and administration of vaccine antigens across the oral route and to gain a better understanding of vaccine trafficking. Using a newly developed method for manufacture of non-ionic surfactant vesicles (niosomes and bilosomes) lower process temperatures were adopted thus reducing antigen exposure to potentially damaging conditions. Vesicles prepared by this method offered high protection to enzymatic degradation, with only ~10 % antigen loss measured when vesicles incorporating antigen were exposed to enzyme digestion. Interestingly, when formulated using this new production method, the addition of bile salt to the vesicles offered no advantage in terms of stability within simulated gastro-intestinal conditions. Considering their ability to deliver antigen to their target site, results demonstrated that incorporation of antigen within vesicles enhanced delivery and targeting of the antigen to the Peyer's Patch, again with niosomes and bilosomes offering similar efficiency. Delivery to both the Peyer's patches and mesentery lymphatics was shown to be dose dependent at lower concentrations, with saturation kinetics applying at higher concentrations. This demonstrates that in the formulation of vaccine delivery systems, the lipid/antigen dose ratio is not only a key factor in production cost, but is equally a key factor in the kinetics of delivery and targeting of a vaccine system. © 2013 Controlled Release Society.

Personalized Question-Answering Mobile System

Mobile messaging is an integral and vital part of the mobile industry and contributes significantly to worldwide total mobile service revenues. In today’s competitive world, differentiation is a significant factor in the success of the business communication. SMS (Short Message Service) provides a powerful vehicle for service differentiation. What is missing, however, is the availability of personalized SMS messages. In particular, the exploitation of user profile information allows a selection and content delivery that meets preferences and interests for the individual. Personalization of mobile messages is important in today’s service-oriented society, and has proven to be crucial for the acceptance of services provided by the mobile telecommunication networks. In this paper we focus on user profile description and the mechanism for delivering the relevant information to the mobile user in accordance with his/her profile.

Agent-Oriented Middleware Supporting Delivery of Mobile Elearning Services

Within project Distributed eLearning Center (DeLC) we are developing a system for distance and eLearning, which offers fixed and mobile access to electronic content and services. Mobile access is based on InfoStation architecture, which provides Bluetooth and WiFi connectivity. On InfoStation network we are developing multi-agent middleware that provides context-aware, adaptive and personalized access to the mobile services to the users. For more convenient testing and optimization of the middleware a simulation environment, called CA3 SiEnv, is being created.

Adaptive E-learning Content Design and Delivery Based on Learning Styles and Knowledge Level

ACM Computing Classification System (1998): K.3.1, K.3.2.

Structural design of contact lens-based drug delivery systems; in vitro and in vivo studies of ocular triggering mechanisms

This study identifies and investigates the potential use of in-eye trigger mechanisms to supplement the widely available information on release of ophthalmic drugs from contact lenses under passive release conditions. Ophthalmic dyes and surrogates have been successfully employed to investigate how these factors can be drawn together to make a successful system. The storage of a drug-containing lens in a pH lower than that of the ocular environment can be used to establish an equilibrium that favours retention of the drug in the lens prior to ocular insertion. Although release under passive conditions does not result in complete dye elution, the use of mechanical agitation techniques which mimic the eyelid blink action in conjunction with ocular tear chemistry promotes further release. In this way differentiation between passive and triggered in vitro release characteristics can be established. Investigation of the role of individual tear proteins revealed significant differences in their ability to alter the equilibrium between matrix-held and eluate-held dye or drug. These individual experiments were then investigated in vivo using ophthalmic dyes. Complete elution was found to be achievable in-eye; this demonstrated the importance of that fraction of the drug retained under passive conditions and the triggering effect of in-eye conditions on the release process. Understanding both the structure-property relationship between drug and material and in-eye trigger mechanisms, using ophthalmic dyes as a surrogate, provides the basis of knowledge necessary to design ocular drug delivery vehicles for in-eye release in a controllable manner.

Implementing a knowledge management system within an NHS hospital:a case study exploring the roll-out of an Electronic Patient Record (EPR)

This research aims to contribute to understanding the implementation of knowledge management systems (KMS) in the field of health through a case study, leading to theory building and theory extension. We use the concept of the business process approach to knowledge management as a theoretical lens to analyse and explore how a large teaching hospital developed, executed and practically implemented a KMS. A qualitative study was conducted over a 2.5 year period with data collected from semi-structured interviews with eight members of the strategic management team, 12 clinical users and 20 patients in addition to non-participant observation of meetings and documents. The theoretical propositions strategy was used as the overarching approach for data analysis. Our case study provides evidence that true patient centred approaches to supporting care delivery with a KMS benefit from process thinking at both the planning and implementation stages, and an emphasis on the knowledge demands resulting from: the activities along the care pathways; where cross-overs in care occur; and knowledge sharing for the integration of care. The findings also suggest that despite the theoretical awareness of KMS implementation methodologies, the actual execution of such systems requires practice and learning. Flexible, fluid approaches through rehearsal are important and communications strategies should focus heavily on transparency incorporating both structured and unstructured communication methods.

HYBRID TCP/UDP video transport for H.264/AVC content delivery in burst loss networks

In this paper we propose a hybrid TCP/UDP transport, specifically for H.264/AVC encoded video, as a compromise between the delay-prone TCP and the loss-prone UDP. When implementing the hybrid approach, we argue that the playback at the receiver often need not be 100% perfect, provided that a certain level of quality is assured. Reliable TCP is used to transmit and guarantee delivery of the most important packets. This allows use of additional features in the H.264/AVC standard which simultaneously provide an enhanced playback quality, in addition to a reduction in throughput. These benefits are demonstrated through experimental results using a test-bed to emulate the hybrid proposal. We compare the proposed system with other protection methods, such as FEC, and in one case show that for the same bandwidth overhead, FEC is unable to match the performance of the hybrid system in terms of playback quality. Furthermore, we measure the delay associated with our approach, and examine its potential for use as an alternative to the conventional methods of transporting video by either TCP or UDP alone. © 2011 IEEE.

Permanent magnet synchronous generator based wind power generation system fault protection schemes

The PMSG-based wind power generation system protection is presented in this paper. For large-scale systems, a voltagesource converter rectifier is included. Protection circuits for this topology are studied with simulation results for cable permanent fault conditions. These electrical protection methods are all in terms of dumping redundant energy resulting from disrupted path of power delivery. Pitch control of large-scale wind turbines are considered for effectively reducing rotor shaft overspeed. Detailed analysis and calculation of damping power and resistances are presented. Simulation results including fault overcurrent, DC-link overvoltage and wind turbine overspeed are shown to illustrate the system responses under different protection schemes to compare their application and effectiveness.

Using discrete event simulation to investigate road delivery policies to UK retailers

Retail customers provide a number of significant challenges to the efficiency and effectiveness of distribution systems. These challengers include shorter delivery windows, fluctuating volumes and a wider product mix. This paper demonstrates the use of discrete-event simulation to investigate policy issues regarding the incorporation of retail customers in a road delivery network from the spoke terminal of a hub and spoke distribution system. In particular a comparison of a mixed (retail and non-retail) delivery policy with a dedicated retail delivery run is made.

The use of sodium carboxymethylcellulose in the preparation of spray-dried proteins for pulmonary drug delivery

The use of sodium carboxymethylcellulose (NaCMC) as a spray-drying excipient in the preparation of inhalable formulations of proteins was investigated, using alkaline phosphatase as a model functional protein. Two spray-dried powders were investigated: a control powder comprising 100% (w/w) alkaline phosphatase and a test powder comprising 67% (w/w) NaCMC and 33% (w/w) alkaline phosphatase. Following physicochemical characterisation, the powders were prepared as both dry powder inhaler (DPI) and pressurised metered dose inhaler (pMDI) formulations. The aerosolisation performance of the formulations was assessed using a Multi-Stage Liquid Impinger, both immediately after preparation and over a 16-week storage period. Formulating the control powder as a DPI resulted in a poor fine particle fraction (FPF: 10%), whereas the FPF of the NaCMC-modified DPI formulation was significantly greater (47%). When the powders were formulated as pMDI systems, the control and NaCMC-modified powders demonstrated FPFs of 52% and 55%, respectively. Following storage, reduced FPF was observed for all formulations except the NaCMC-modified pMDI system; the performance of this formulation following storage was statistically equivalent to that immediately following preparation. Co-spray-drying proteins and peptides with NaCMC may therefore offer an alternative method for the preparation of stable and respirable pMDI formulations for pulmonary delivery. © 2010 Elsevier B.V.