Investigation of the coordinated functional activities of cytochrome P450 3A4 and P-glycoprotein in limiting the absorption of xenobiotics in Caco-2 cells

The coordination of the functional activities of intestinal CYP3A4 and P-gp in limiting the absorption of xenobiotics in Caco-2 cells was investigated. Growing Caco-2 cells were exposed to increasing concentrations of doxorubicin (1-2 μM) in plastic flasks to encourage a subpopulation of cells, that displayed an intrinsically higher multidrug resistance (mdr) phenotype than the parent cells, to survive and grow. Doxorubicin-exposed (hereinafter referred to as type I cells) and nonexposed Caco-2 cells (parent cells) on collagen-coated inserts were also treated with either 0 (control) or 0.25 μM 1α,25-dihydroxyvitamin D3 to promote cellular CYP3A4 expression. Increased P-gp protein expression, as detected by Western blotting, was noted in type I cells (213±54.35%) compared to that of parent cells (100±6.05%). Furthermore, they retained significantly less [3H]vincristine sulphate (p<0.05), a P-gp substrate, after efflux (272.89±11.86 fmol/mg protein) than the parent cells (381.39±61.82 fmol/mg protein). The expression of CYP3A4 in parental cells after 1α,25-dihydroxyvitamin D3 treatment was quantified to be 76.2±7.6 pmol/mg protein and comparable with that found in human jejunal enterocytes (70.0±20.0 pmol/mg protein). Type I cells, however, expressed a very low quantity of CYP3A4 both before and after the treatment that was beyond the minimum detection limit of Western blotting. Functionally, the rates of 1-hydroxylation of midazolam by CYP3A for both cell types ranged from 257.0±20.0 to 1057.0±46.0 pmol/min/mg protein. Type I cells, although having a higher P-gp expression and activity comparatively, metabolized midazolam less extensively than the parent cells. The results suggested that there were noncoordinated functional activities of intestinal CYP3A4 and P-gp in Caco-2 cells, although they both functioned independently to minimize intestinal epithelial absorption of xenobiotics. © 2002 Wiley-Liss, Inc. and the American Pharmaceutical Association.

Representations of voluntary childlessness in the UK Press, 1990-2008

Representations of voluntary childlessness — the declaration by an individual that he or she does not wish to bear or raise children — were studied in 116 articles published in British national newspapers in the period 1990—2008. Media framing analysis was used to examine broad patterns of framing of the topic, identifying four frames: voluntary childlessness as an individual rights issue, as a form of resistance, as a social trend, and as a personal decision. These frames, it is argued, may act as potential ‘scripts’ for newspaper readers who are debating the decision to start a family.

Development of a multicellular co-culture model of normal and cystic fibrosis human airways in vitro

Cystic fibrosis (CF) is the most common lethal inherited disease among Caucasians and arises due to mutations in a chloride channel, called cystic fibrosis transmembrane conductance regulator. A hallmark of this disease is the chronic bacterial infection of the airways, which is usually, associated with pathogens such as Pseudomonas aeruginosa, S. aureus and recently becoming more prominent, B. cepacia. The excessive inflammatory response, which leads to irreversible lung damage, will in the long term lead to mortality of the patient at around the age of 40 years. Understanding the pathogenesis of CF currently relies on animal models, such as those employing genetically-modified mice, and on single cell culture models, which are grown either as polarised or non-polarised epithelium in vitro. Whilst these approaches partially enable the study of disease progression in CF, both types of models have inherent limitations. The overall aim of this thesis was to establish a multicellular co-culture model of normal and CF human airways in vitro, which helps to partially overcome these limitations and permits analysis of cell-to-cell communication in the airways. These models could then be used to examine the co-ordinated response of the airways to infection with relevant pathogens in order to validate this approach over animals/single cell models. Therefore epithelial cell lines of non-CF and CF background were employed in a co-culture model together with human pulmonary fibroblasts. Co-cultures were grown on collagen-coated permeable supports at air-liquid interface to promote epithelial cell differentiation. The models were characterised and essential features for investigating CF infections and inflammatory responses were investigated and analysed. A pseudostratified like epithelial cell layer was established at air liquid interface (ALI) of mono-and co-cultures and cell layer integrity was verified by tight junction (TJ) staining and transepithelial resistance measurements (TER). Mono- and co-cultures were also found to secrete the airway mucin MUC5AC. Influence of bacterial infections was found to be most challenging when intact S. aureus, B. cepacia and P. aeruginosa were used. CF mono- and co-cultures were found to mimic the hyperinflammatory state found in CF, which was confirmed by analysing IL-8 secretions of these models. These co-culture models will help to elucidate the role fibroblasts play in the inflammatory response to bacteria and will provide a useful testing platform to further investigate the dysregulated airway responses seen in CF.

Integration of semantically annotated data by the KnoFuss architecture

Most of the existing work on information integration in the Semantic Web concentrates on resolving schema-level problems. Specific issues of data-level integration (instance coreferencing, conflict resolution, handling uncertainty) are usually tackled by applying the same techniques as for ontology schema matching or by reusing the solutions produced in the database domain. However, data structured according to OWL ontologies has its specific features: e.g., the classes are organized into a hierarchy, the properties are inherited, data constraints differ from those defined by database schema. This paper describes how these features are exploited in our architecture KnoFuss, designed to support data-level integration of semantic annotations.

Interactive exploration of image collections on mobile devices

Image collections are ever growing and hence visual information is becoming more and more important. Moreover, the classical paradigm of taking pictures has changed, first with the spread of digital cameras and, more recently, with mobile devices equipped with integrated cameras. Clearly, these image repositories need to be managed, and tools for effectively and efficiently searching image databases are highly sought after, especially on mobile devices where more and more images are being stored. In this paper, we present an image browsing system for interactive exploration of image collections on mobile devices. Images are arranged so that visually similar images are grouped together while large image repositories become accessible through a hierarchical, browsable tree structure, arranged on a hexagonal lattice. The developed system provides an intuitive and fast interface for navigating through image databases using a variety of touch gestures. © 2012 Springer-Verlag.

Reliability estimation of second life battery system power electronic topologies for grid frequency response applications

This paper is part of a project which aims to research the opportunities for the re-use of batteries after their primary use in low and ultra low carbon vehicles on the electricity grid system. One potential revenue stream is to provide primary/secondary/high frequency response to National Grid through market mechanisms via DNO's or Energy service providers. Some commercial battery energy storage systems (BESS) already exist on the grid system, but these tend to use costly new or high performance batteries. Second life batteries should be available at lower cost than new batteries but reliability becomes an important issue as individual batteries may suffer from degraded performance or failure. Therefore converter topology design could be used to influence the overall system reliability. A detailed reliability calculation of different single phase battery-to-grid converter interfacing schemes is presented. A suitable converter topology for robust and reliable BESS is recommended.

Use of medications with anticholinergic activity and self-reported injurious falls in older community-dwelling adults

Objectives: To assess the association between the use of medications with anticholinergic activity and the subsequent risk of injurious falls in older adults. Design: Prospective, population-based study using data from The Irish Longitudinal Study on Ageing. Setting: Irish population. Participants: Community-dwelling men and women without dementia aged 65 and older (N = 2,696). Measurements: Self-reported injurious falls reported once approximately 2 years after baseline interview. Self-reported regular medication use at baseline interview. Pharmacy dispensing records from the Irish Health Service Executive Primary Care Reimbursement Service in a subset (n = 1,553). Results: Nine percent of men and 17% of women reported injurious falls. In men, the use of medications with definite anticholinergic activity was associated with greater risk of subsequent injurious falls (adjusted relative risk (aRR) = 2.55, 95% confidence interval (CI) = 1.33-4.88), but the risk of having any fall and the number of falls reported were not significantly greater. Greater anticholinergic burden was associated with greater injurious falls risk. No associations were observed for women. Findings were similar using pharmacy dispensing records. The aRR for medications with definite anticholinergic activity dispensed in the month before baseline and subsequent injurious falls in men was 2.53 (95% CI = 1.15-5.54). Conclusion: The regular use of medications with anticholinergic activity is associated with subsequent injurious falls in older men, although falls were self-reported after a 2-year recall and so may have been underreported. Further research is required to validate this finding in men and to consider the effect of duration and dose of anticholinergic medications.

A matter of professionalism? Reflection and reflexivity in continuing engineering education and practice

The argument that this paper sets out to critique is that in order to promote professionalism in Engineering Education and Practice, graduate level engineering programmes need to introduce the concepts of reflection and reflexivity into the curriculum right from the onset. By focusing upon the delivery of a newly developed „Work Based‟ Master’s level programme in Professional Engineering, this paper provides an overview of the first part of an empirical study which sets out to investigate the challenges associated with embedding reflection and reflexivity into Engineering Education. The paper concludes by noting that whilst student engineers may struggle with the concepts of reflection and reflexivity, with support and encouragement such difficulties can be overcome. Moreover, by encouraging students to reflect upon their Professional Practice, the programme not only enables students to consider how they may apply what they have learnt to their Professional Practice, but also encourages them to think about how they can link their experiences as Professional Engineers to what and how they learn both whilst on the programme but also as lifelong learners.