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.

Organisational learning - a critical systems thinking discipline

Original Paper European Journal of Information Systems (2001) 10, 135–146; doi:10.1057/palgrave.ejis.3000394 Organisational learning—a critical systems thinking discipline P Panagiotidis1,3 and J S Edwards2,4 1Deloitte and Touche, Athens, Greece 2Aston Business School, Aston University, Aston Triangle, Birmingham, B4 7ET, UK Correspondence: Dr J S Edwards, Aston Business School, Aston University, Aston Triangle, Birmingham, B4 7ET, UK. E-mail: j.s.edwards@aston.ac.uk 3Petros Panagiotidis is Manager responsible for the Process and Systems Integrity Services of Deloitte and Touche in Athens, Greece. He has a BSc in Business Administration and an MSc in Management Information Systems from Western International University, Phoenix, Arizona, USA; an MSc in Business Systems Analysis and Design from City University, London, UK; and a PhD degree from Aston University, Birmingham, UK. His doctorate was in Business Systems Analysis and Design. His principal interests now are in the ERP/DSS field, where he serves as project leader and project risk managment leader in the implementation of SAP and JD Edwards/Cognos in various major clients in the telecommunications and manufacturing sectors. In addition, he is responsible for the development and application of knowledge management systems and activity-based costing systems. 4John S Edwards is Senior Lecturer in Operational Research and Systems at Aston Business School, Birmingham, UK. He holds MA and PhD degrees (in mathematics and operational research respectively) from Cambridge University. His principal research interests are in knowledge management and decision support, especially methods and processes for system development. He has written more than 30 research papers on these topics, and two books, Building Knowledge-based Systems and Decision Making with Computers, both published by Pitman. Current research work includes the effect of scale of operations on knowledge management, interfacing expert systems with simulation models, process modelling in law and legal services, and a study of the use of artifical intelligence techniques in management accounting. Top of pageAbstract This paper deals with the application of critical systems thinking in the domain of organisational learning and knowledge management. Its viewpoint is that deep organisational learning only takes place when the business systems' stakeholders reflect on their actions and thus inquire about their purpose(s) in relation to the business system and the other stakeholders they perceive to exist. This is done by reflecting both on the sources of motivation and/or deception that are contained in their purpose, and also on the sources of collective motivation and/or deception that are contained in the business system's purpose. The development of an organisational information system that captures, manages and institutionalises meaningful information—a knowledge management system—cannot be separated from organisational learning practices, since it should be the result of these very practices. Although Senge's five disciplines provide a useful starting-point in looking at organisational learning, we argue for a critical systems approach, instead of an uncritical Systems Dynamics one that concentrates only on the organisational learning practices. We proceed to outline a methodology called Business Systems Purpose Analysis (BSPA) that offers a participatory structure for team and organisational learning, upon which the stakeholders can take legitimate action that is based on the force of the better argument. In addition, the organisational learning process in BSPA leads to the development of an intrinsically motivated information organisational system that allows for the institutionalisation of the learning process itself in the form of an organisational knowledge management system. This could be a specific application, or something as wide-ranging as an Enterprise Resource Planning (ERP) implementation. Examples of the use of BSPA in two ERP implementations are presented.

Human sensitivity to phase perturbations in natural images:A statistical framework

Fourier-phase information is important in determining the appearance of natural scenes, but the structure of natural-image phase spectra is highly complex and difficult to relate directly to human perceptual processes. This problem is addressed by extending previous investigations of human visual sensitivity to the randomisation and quantisation of Fourier phase in natural images. The salience of the image changes induced by these physical processes is shown to depend critically on the nature of the original phase spectrum of each image, and the processes of randomisation and quantisation are shown to be perceptually equivalent provided that they shift image phase components by the same average amount. These results are explained by assuming that the visual system is sensitive to those phase-domain image changes which also alter certain global higher-order image statistics. This assumption may be used to place constraints on the likely nature of cortical processing: mechanisms which correlate the outputs of a bank of relative-phase-sensitive units are found to be consistent with the patterns of sensitivity reported here.

Predicting adult occupational environments from childhood personality traits

To test aspects of a theory of the role of personality and gender on the development of vocational interests and their subsequent effects on adult occupational choices, the authors of this study examined associations among childhood personality traits, gender, and occupational environments more than 40 years later. Participants (N = 587) were assessed on the Big Five by their teachers when the participants were between 6 and 12 years old. In middle-age (late 40s), the participants reported their occupation. Holland's (1997) RIASEC vocational types (Realistic, Investigative, Artistic, Social, Enterprising, Conventional) were used to characterize the job environments of reported occupations. Childhood Openness/Intellect and Conscientiousness, but no other Big Five traits, were associated with occupational environments. For the most strongly sex-typed work environments, associations with Openness/Intellect were moderated by gender. These findings suggest that the roots of the strongest gender-stereotyping effects in occupations may be found not only in the social factors associated with gender but also in the individual differences of children related to Openness/Intellect.

Nanopatterned UV curable hydrogels for biomedical applications

With an increasing use of emerging patterning technologies such as UV-NIL in biotechnological applications there is at the same time a raising demand for new material for such applications. Here we present a PEG based precursor mixed with a photoinitiator to make it UV sensitive as a new material aimed at biotechnological applications. Using HSQ patterned quartz stamps we observed excellent pattern replication indicating good flow properties of the resist. We were able to obtain imprints with <20 nm residual layer. The PEG based resist has hydrogel properties and it swelling in water was observed by AFM.

Bromocriptine:old drug, new formulation and new indication

Bromocriptine is an ergot alkaloid dopamine D receptor agonist that has been used extensively in the past to treat hyperprolactinaemia, galactorrhoea and Parkinsonism. It is known that hypothalamic hypodopaminergic states and disturbed circadian rhythm are associated with the development of insulin resistance, obesity and diabetes in animals and humans. When administered in the early morning at the start of the light phase, a new quick release (QR) formulation of bromocriptine appears to act centrally to reset circadian rhythms of hypothalamic dopamine and serotonin and improve insulin resistance and other metabolic abnormalities. Phase II and III clinical studies show that QR-bromocriptine lowers glycated haemoglobin by 0.6-1.2% (7-13 mmol/mol) either as monotherapy or in combination with other antidiabetes medications. Apart from nausea, the drug is well tolerated. The doses used to treat diabetes (up to 4.8 mg daily) are much lower than those used to treat Parkinson's disease and have not been associated with retroperitoneal fibrosis or heart valve abnormalities. QR-bromocriptine (Cycloset™) has recently been approved in the USA for the treatment of type 2 diabetes mellitus (T2DM). Thus, a QR formulation of bromocriptine timed for peak delivery in the early morning may provide a novel neurally mediated approach to the control of hyperglycaemia in T2DM. © 2010 Blackwell Publishing Ltd.

Demonstrating doubly-differential quadrature phase shift keying in the optical domain

We report for the first time the experimental demonstration of doubly differential quadrature phase shift keying (DDQPSK) using optical coherent detection. This method is more robust against high frequency offsets (FO) than conventional single differential quadrature phase shift keying (SDQPSK) with offset compensation. DDQPSK is shown to be able to compensate large FOs (up to the baud rate) and has lower computational requirements than other FO compensation methods. DDQPSK is a simple algorithm to implement in a real-time decoder for optical burst switched network scenarios. Simulation results are also provided, which show good agreement with the experimental results for both SDQPSK and DDQPSK transmissions. © 1989-2012 IEEE.