Methodology for development of a physiological model incorporating CYP3A and P-glycoprotein for the prediction of intestinal drug absorption

The small intestine poses a major barrier to the efficient absorption of orally administered therapeutics. Intestinal epithelial cells are an extremely important site for extrahepatic clearance, primarily due to prominent P-glycoprotein-mediated active efflux and the presence of cytochrome P450s. We describe a physiologically based pharmacokinetic model which incorporates geometric variations, pH alterations and descriptions of the abundance and distribution of cytochrome 3A and P-glycoprotein along the length of the small intestine. Simulations using preclinical in vitro data for model drugs were performed to establish the influence of P-glycoprotein efflux, cytochrome 3A metabolism and passive permeability on drug available for absorption within the enterocytes. The fraction of drug escaping the enterocyte (F(G)) for 10 cytochrome 3A substrates with a range of intrinsic metabolic clearances were simulated. Following incorporation of P-glycoprotein in vitro efflux ratios all predicted F(G) values were within 20% of observed in vivo F(G). The presence of P-glycoprotein increased the level of cytochrome 3A drug metabolism by up to 12-fold in the distal intestine. F(G) was highly sensitive to changes in intrinsic metabolic clearance but less sensitive to changes in intestinal drug permeability. The model will be valuable for quantifying aspects of intestinal drug absorption and distribution.

Pragmatic development of service based real-time change data capture

This thesis makes a contribution to the Change Data Capture (CDC) field by providing an empirical evaluation on the performance of CDC architectures in the context of realtime data warehousing. CDC is a mechanism for providing data warehouse architectures with fresh data from Online Transaction Processing (OLTP) databases. There are two types of CDC architectures, pull architectures and push architectures. There is exiguous data on the performance of CDC architectures in a real-time environment. Performance data is required to determine the real-time viability of the two architectures. We propose that push CDC architectures are optimal for real-time CDC. However, push CDC architectures are seldom implemented because they are highly intrusive towards existing systems and arduous to maintain. As part of our contribution, we pragmatically develop a service based push CDC solution, which addresses the issues of intrusiveness and maintainability. Our solution uses Data Access Services (DAS) to decouple CDC logic from the applications. A requirement for the DAS is to place minimal overhead on a transaction in an OLTP environment. We synthesize DAS literature and pragmatically develop DAS that eciently execute transactions in an OLTP environment. Essentially we develop effeicient RESTful DAS, which expose Transactions As A Resource (TAAR). We evaluate the TAAR solution and three pull CDC mechanisms in a real-time environment, using the industry recognised TPC-C benchmark. The optimal CDC mechanism in a real-time environment, will capture change data with minimal latency and will have a negligible affect on the database's transactional throughput. Capture latency is the time it takes a CDC mechanism to capture a data change that has been applied to an OLTP database. A standard definition for capture latency and how to measure it does not exist in the field. We create this definition and extend the TPC-C benchmark to make the capture latency measurement. The results from our evaluation show that pull CDC is capable of real-time CDC at low levels of user concurrency. However, as the level of user concurrency scales upwards, pull CDC has a significant impact on the database's transaction rate, which affirms the theory that pull CDC architectures are not viable in a real-time architecture. TAAR CDC on the other hand is capable of real-time CDC, and places a minimal overhead on the transaction rate, although this performance is at the expense of CPU resources.

Development of a neurotoxicity test-system, using human post-mitotic, astrocytic and neuronal cell lines in co-culture

Astrocytes are essential for neuronal function and survival, so both cell types were included in a human neurotoxicity test-system to assess the protective effects of astrocytes on neurons, compared with a culture of neurons alone. The human NT2.D1 cell line was differentiated to form either a co-culture of post-mitotic NT2.N neuronal (TUJ1, NF68 and NSE positive) and NT2.A astrocytic (GFAP positive) cells (∼2:1 NT2.A:NT2.N), or an NT2.N mono-culture. Cultures were exposed to human toxins, for 4 h at sub-cytotoxic concentrations, in order to compare levels of compromised cell function and thus evidence of an astrocytic protective effect. Functional endpoints examined included assays for cellular energy (ATP) and glutathione (GSH) levels, generation of hydrogen peroxide (H2O2) and caspase-3 activation. Generally, the NT2.N/A co-culture was more resistant to toxicity, maintaining superior ATP and GSH levels and sustaining smaller significant increases in H2O2 levels compared with neurons alone. However, the pure neuronal culture showed a significantly lower level of caspase activation. These data suggest that besides their support for neurons through maintenance of ATP and GSH and control of H2O2 levels, following exposure to some substances, astrocytes may promote an apoptotic mode of cell death. Thus, it appears the use of astrocytes in an in vitro predictive neurotoxicity test-system may be more relevant to human CNS structure and function than neuronal cells alone. © 2007 Elsevier Ltd. All rights reserved.

Design and development of logistics workflow systems for demand management with RFID

This paper discusses demand and supply chain management and examines how artificial intelligence techniques and RFID technology can enhance the responsiveness of the logistics workflow. This proposed system is expected to have a significant impact on the performance of logistics networks by virtue of its capabilities to adapt unexpected supply and demand changes in the volatile marketplace with the unique feature of responsiveness with the advanced technology, Radio Frequency Identification (RFID). Recent studies have found that RFID and artificial intelligence techniques drive the development of total solution in logistics industry. Apart from tracking the movement of the goods, RFID is able to play an important role to reflect the inventory level of various distribution areas. In today’s globalized industrial environment, the physical logistics operations and the associated flow of information are the essential elements for companies to realize an efficient logistics workflow scenario. Basically, a flexible logistics workflow, which is characterized by its fast responsiveness in dealing with customer requirements through the integration of various value chain activities, is fundamental to leverage business performance of enterprises. The significance of this research is the demonstration of the synergy of using a combination of advanced technologies to form an integrated system that helps achieve lean and agile logistics workflow.

Vulnerability of exporting nations to the development of a carbon label in the United Kingdom

Carbon labels inform consumers about the amount of greenhouse gases (GHGs) released during the production and consumption of goods, including food. In the future consumer and legislative responses to carbon labels may favour goods with lower emissions, and thereby change established supply chains. This may have unintended consequences. We present the carbon footprint of three horticultural goods of different origins supplied to the United Kingdom market: lettuce, broccoli and green beans. Analysis of these footprints enables the characterisation of three different classes of vulnerability which are related to: transport, national economy and supply chain specifics. There is no simple relationship between the characteristics of an exporting country and its vulnerability to the introduction of a carbon label. Geographically distant developing countries with a high level of substitutable exports to the UK are most vulnerable. However, many developing countries have low vulnerability as their main exports are tropical crops which would be hard to substitute with local produce. In the short term it is unlikely that consumers will respond to carbon labels in such a way that will have major impacts in the horticultural sector. Labels which require contractual reductions in GHG emissions may have greater impacts in the short term.

Does human capital endowment of foreign direct investment recipient countries really matter? evidence from cross-country firm level data

The stylized literature on foreign direct investment (FDI) suggests that developing countries should invest in the human capital of their labor force in order to attract FDI. However, if educational quality in developing country is uncertain such that formal education is a noisy signal of human capital, it might be rational for multinational enterprises to focus more on job-specific training than on formal education of the labor force. Using cross-country data from the textiles and garments industry, we demonstrate that training indeed has a greater impact on firm efficiency in developing countries than formal education of the workforce. © 2013 John Wiley & Sons Ltd.

Serum-free process development:improving the yield and consistency of human mesenchymal stromal cell production

Background aims: The cost-effective production of human mesenchymal stromal cells (hMSCs) for off-the-shelf and patient specific therapies will require an increasing focus on improving product yield and driving manufacturing consistency. Methods: Bone marrow-derived hMSCs (BM-hMSCs) from two donors were expanded for 36 days in monolayer with medium supplemented with either fetal bovine serum (FBS) or PRIME-XV serum-free medium (SFM). Cells were assessed throughout culture for proliferation, mean cell diameter, colony-forming potential, osteogenic potential, gene expression and metabolites. Results: Expansion of BM-hMSCs in PRIME-XV SFM resulted in a significantly higher growth rate (P < 0.001) and increased consistency between donors compared with FBS-based culture. FBS-based culture showed an inter-batch production range of 0.9 and 5 days per dose compared with 0.5 and 0.6 days in SFM for each BM-hMSC donor line. The consistency between donors was also improved by the use of PRIME-XV SFM, with a production range of 0.9 days compared with 19.4 days in FBS-based culture. Mean cell diameter has also been demonstrated as a process metric for BM-hMSC growth rate and senescence through a correlation (R² = 0.8705) across all conditions. PRIME-XV SFM has also shown increased consistency in BM-hMSC characteristics such as per cell metabolite utilization, in vitro colony-forming potential and osteogenic potential despite the higher number of population doublings. Conclusions: We have increased the yield and consistency of BM-hMSC expansion between donors, demonstrating a level of control over the product, which has the potential to increase the cost-effectiveness and reduce the risk in these manufacturing processes.

Development of a technological innovation capability assessment model:a case study of manufacturing SMEs in Sialkot, Pakistan

Small and Medium Enterprises (SMEs) play an important part in the economy of any country. Initially, a flat management hierarchy, quick response to market changes and cost competitiveness were seen as the competitive characteristics of an SME. Recently, in developed economies, technological capabilities (TCs) management- managing existing and developing or assimilating new technological capabilities for continuous process and product innovations, has become important for both large organisations and SMEs to achieve sustained competitiveness. Therefore, various technological innovation capability (TIC) models have been developed at firm level to assess firms‘ innovation capability level. These models output help policy makers and firm managers to devise policies for deepening a firm‘s technical knowledge generation, acquisition and exploitation capabilities for sustained technological competitive edge. However, in developing countries TCs management is more of TCs upgrading: acquisitions of TCs from abroad, and then assimilating, innovating and exploiting them. Most of the TIC models for developing countries delineate the level of TIC required as firms move from the acquisition to innovative level. However, these models do not provide tools for assessing the existing level of TIC of a firm and various factors affecting TIC, to help practical interventions for TCs upgrading of firms for improved or new processes and products. Recently, the Government of Pakistan (GOP) has realised the importance of TCs upgrading in SMEs-especially export-oriented, for their sustained competitiveness. The GOP has launched various initiatives with local and foreign assistance to identify ways and means of upgrading local SMEs capabilities. This research targets this gap and developed a TICs assessment model for identifying the existing level of TIC of manufacturing SMEs existing in clusters in Sialkot, Pakistan. SME executives in three different export-oriented clusters at Sialkot were interviewed to analyse technological capabilities development initiatives (CDIs) taken by them to develop and upgrade their firms‘ TCs. Data analysed at CDI, firm, cluster and cross-cluster level first helped classify interviewed firms as leader, follower and reactor, with leader firms claiming to introduce mostly new CDIs to their cluster. Second, the data analysis displayed that mostly interviewed leader firms exhibited ‗learning by interacting‘ and ‗learning by training‘ capabilities for expertise acquisition from customers and international consultants. However, these leader firms did not show much evidence of learning by using, reverse engineering and R&D capabilities, which according to the extant literature are necessary for upgrading existing TIC level and thus TCs of firm for better value-added processes and products. The research results are supported by extant literature on Sialkot clusters. Thus, in sum, a TIC assessment model was developed in this research which qualitatively identified interviewed firms‘ TIC levels, the factors affecting them, and is validated by existing literature on interviewed Sialkot clusters. Further, the research gives policy level recommendations for TIC and thus TCs upgrading at firm and cluster level for targeting better value-added markets.

The development of attenuation compensation models of fluorescence spectroscopy signals

This study examines the effect of blood absorption on the endogenous fluorescence signal intensity of biological tissues. Experimental studies were conducted to identify these effects. To register the fluorescence intensity, the fluorescence spectroscopy method was employed. The intensity of the blood flow was measured by laser Doppler flowmetry. We proposed one possible implementation of the Monte Carlo method for the theoretical analysis of the effect of blood on the fluorescence signals. The simulation is constructed as a four-layer skin optical model based on the known optical parameters of the skin with different levels of blood supply. With the help of the simulation, we demonstrate how the level of blood supply can affect the appearance of the fluorescence spectra. In addition, to describe the properties of biological tissue, which may affect the fluorescence spectra, we turned to the method of diffuse reflectance spectroscopy (DRS). Using the spectral data provided by the DRS, the tissue attenuation effect can be extracted and used to correct the fluorescence spectra.