Human immunodeficiency virus type 1 viral background plays a major role in development of resistance to protease inhibitors.

The observed in vitro and in vivo benefit of combination treatment with anti-human immunodeficiency virus (HIV) agents prompted us to examine the potential of resistance development when two protease inhibitors are used concurrently. Recombinant HIV-1 (NL4-3) proteases containing combined resistance mutations associated with BMS-186318 and A-77003 (or saquinavir) were either inactive or had impaired enzyme activity. Subsequent construction of HIV-1 (NL4-3) proviral clones containing the same mutations yielded viruses that were severely impaired in growth or nonviable, confirming that combination therapy may be advantageous. However, passage of BMS-186318-resistant HIV-1 (RF) in the presence of either saquinavir or SC52151, which represented sequential drug treatment, produced viable viruses resistant to both BMS-186318 and the second compound. The predominant breakthrough virus contained the G48V/A71T/V82A protease mutations. The clone-purified RF (G48V/A71T/V82A) virus, unlike the corresponding defective NL4-3 triple mutant, grew well and displayed cross-resistance to four distinct protease inhibitors. Chimeric virus and in vitro mutagenesis studies indicated that the RF-specific protease sequence, specifically the Ile at residue 10, enabled the NL4-3 strain with the triple mutant to grow. Our results clearly indicate that viral genetic background will play a key role in determining whether cross-resistance variants will arise.

The conceptual table: a strategy for the development of a theoretical framework of a field research or knowledge

This is a guide to develop a theoretical framework for any field of knowledge. It is a rational and organized to put everything that is known or has been written about an issue or a problem way.

On the development of a theory of traveler attitude-behavior interrelationships: volume II: theoretical and empirical findings. Final report.

Transportation Systems Center, Cambridge, Mass.

The development of a public assistance recipient perception inventory (p.a.r.p.i.)

"FSS 73-12-1."

Stepping Stones Triple P: A pilot study to evaluate acceptability of the program by parents of a child diagnosed with an Autism Spectrum Disorder

The experience of parents of children with Autism Spectrum Disorder (ASD) in standard parenting programs has not been researched, although anecdotal evidence suggests that they do not find them acceptable. Forty-two parents of children with ASD were asked to view a DVD explaining individual parenting strategies from Stepping Stones, a new branch of the Triple P program targeted specifically at parents of children with disabilities. Parents were asked to rate each strategy for acceptability, usability and behavioural intention, i.e., their intention to use the strategy. Additionally, parental attributions and parental perceived control were explored as possible barriers to positive evaluations of Stepping Stones parenting strategies. A focus group of parents was used to gather more detailed parent response to the program. Parent responses to the program were generally positive and attribution of the child's behaviour to uncontrollable factors was found to predict higher ratings of usability. The results were interpreted within the context of Weiner's attributional theory and the theory of reasoned action. The limitations of this study and suggestions for future research are discussed. (c) 2005 Elsevier Ltd. All rights reserved.

Theoretical foundations of neural networks

Neural networks have often been motivated by superficial analogy with biological nervous systems. Recently, however, it has become widely recognised that the effective application of neural networks requires instead a deeper understanding of the theoretical foundations of these models. Insight into neural networks comes from a number of fields including statistical pattern recognition, computational learning theory, statistics, information geometry and statistical mechanics. As an illustration of the importance of understanding the theoretical basis for neural network models, we consider their application to the solution of multi-valued inverse problems. We show how a naive application of the standard least-squares approach can lead to very poor results, and how an appreciation of the underlying statistical goals of the modelling process allows the development of a more general and more powerful formalism which can tackle the problem of multi-modality.

The impact of brand owner on consumers' brand perceptions : a development of Heider's Balance Theory

Studies have shown that the brand “owner” is very influential in positioning the brand and when the brand “owner” ceases his or her active role the brand will be perceived differently by the consumers. Balance Theory (HBT), a cognitive psychological theory, studies the triadic relationships between two persons and an entity and predicts that when a person’s original perception of the relationship is disturbed, the person restructures to a new balanced perception. Consequently, this research was undertaken to: conceptualize the brand owner’s impact on consumer’s brand perception; test the applicability of both the static and dynamic predictions of the Heider’s Balance Theory in brand owner-consumer-brand relation (OCB); construct and test a model of brand owner-consumer-brand relation; and examine if personality has an influence on OCB. A discovery-oriented approach was taken to understand the selected market segment, the ready-to-wear and diffusion lines of international designer labels. Chinese Brand Personality Scale, fashion proneness and hedonic and utilitarian shopping scales were developed, and validated. 51 customers were surveyed. Both traditional and extended methods used in the Balance Theory were employed in this study. Responses to liked brand have been used to test and develop the model, while those for disliked brand were used for test and confirmation. A “what if’ experimental approach was employed to test the applicability of dynamic HBT theory in OCB Model. The hypothesized OCB Model has been tested and validated. Consumers have been found to have separate views on the brand and the brand owner; and their responses to contrasting ethical and non-ethical news of the brand owner are different. Personality has been found to have an influence and two personality adapted models have been tested and validated. The actual results go beyond the prediction of the Balance Theory. Dominant triple positive balance mode, dominant negative balance mode, and mode of extreme antipathy have been found. It has been found that not all balanced modes are good for the brand. Contrary to Heider’s findings, simply liking may not necessarily lead to unit relation in the OCB Model.

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.

Development of an enantiomer selective microsampling assay for the quantification of ketorolac suitable for paediatric pharmacokinetic studies

Background: Ketorolac, a potent nonsteroidal anti-inflammatory drug used for pain control in children, exists as a racemate of inactive R (+) and active S (-) enantiomers. Aim: To develop a microsampling assay for the enantioselective analysis of ketorolac in children. Methods: Ketorolac enantiomers were extracted from 50 µl of plasma by liquid–liquid extraction and separated on a ChiralPak AD-RH. Detection was by a TSQ quantum triple quadrupole mass spectrometer with an electrospray ionisation source operating in a positive ion mode. Five children (age 13.8 (1.6) years, weight 52.7 (7.2) kg), were administered intravenous ketorolac 0.5 mg/kg (maximum 10 mg) and blood samples were taken at 0, 0.25, 0.5, 1, 2, 4, 6, 8 and 12 h post administration. CL, VD and t1/2 were calculated based on non-compartmental methods. Results: The standard curves for R (+) and S (-) ketorolac were linear in the range 0–2000 ng/ml. The LLOQs of the method were 0.15 ng on column and 0.31 ng on column for R (+) and S (-) ketorolac, respectively. The median (range) VD and CL of R (+) and S (-) ketorolac were 0.12 l/kg (0.07–0.17), 0.017 l/h/kg (0.12–0.29) and 0.17 (0.09–0.31) l/kg, 0.049 (0.02–0.1) l/h/kg, p = 0.043), respectively. The median (range) elimination half-life (t1/2) of the R (+) and S (-) ketorolac was 5.0 h (2.5–5.8) and 3.1 h (1.8–4.4), p = 0.043), respectively. Conclusion: The development of a simple, rapid and reliable ketorolac assay suitable for paediatric PK studies is reported. Copyright © 2013 John Wiley & Sons, Ltd.