Focused antithrombotic therapy: Novel anti-platelet salicylates with reduced ulcerogenic potential and higher first-pass detoxification than aspirin in rats

The use of aspirin as an anti-platelet drug is limited by its propensity to induce gastric injury and by its adverse effect on vascular prostacyclin formation. Two phenolic non-steroidal anti-inflammatory drugs (salicyclic acid and diflunisal) were modified by esterification with a series of O-acyl moieties. The short-term ulcerogenic in vitro and in vivo anti-platelet properties, pharmacodynamic profiles, and extent of hepatic extraction of these phenolic esters were compared with aspirin (acetylsalicylic acid). The more lipophilic esters (longer carbon chain length in O-acyl group) show significantly less gastrotoxicity in stressed rats than does aspirin after a single oral dose. The in vitro and in vivo anti-platelet studies show that these phenolic esters inhibited (1) arachidonate-triggered human platelet aggregation and (2) thrombin-stimulated rat serum thromboxane Ag production by platelets in the clotting process almost as effectively as aspirin. The hepatic extractions of these O-acyl derivatives are significantly higher than those of aspirin. The pharmacodynamic studies show that these O-acyl derivatives of salicylic acid and diflunisal probably bind to, or combine with, the same site on the platelet cyclooxygenase as aspirin. Replacing the O-acetyl group with longer chain O-acyl moiety in this series of phenolic esters markedly reduced the potential of these agents to induce short-term gastric injury but did not lessen their activity as inhibitors of platelet aggregation. These non-acetyl salicylates may therefore represent a novel class of anti-platelet drugs with less ulcerogenic potential.

Insect peptides with improved protease-resistance protect mice against bacterial infection

At a time of the emergence of drug-resistant bacterial strains, the development of antimicrobial compounds with novel mechanisms of action is of considerable interest. Perhaps the most promising among these is a family of antibacterial peptides originally isolated from insects. These were shown to act in a stereospecific manner on an as-yet unidentified target bacterial protein. One of these peptides, drosocin, is inactive in vivo due to the rapid decomposition in mammalian sera. However, another family member, pyrrhocoricin, is significantly more stable, has increased in vitro efficacy against Gram-negative bacterial strains, and if administered alone, as we show here, is devoid of in vitro or in vivo toxicity. At low doses, pyrrhocoricin protected mice against Escherichia call infection, but at a higher dose augmented the infection of compromised animals. Analogs of pyrrhocoricin were, therefore, synthesized to further improve protease resistance and reduce toxicity. A linear derivative containing unnatural amino acids at both termini showed high potency and lack of toxicity in vivo and an expanded cyclic analog displayed broad activity spectrum in vitro. The bioactive conformation of native pyrrhocoricin was determined by nuclear magnetic resonance spectroscopy, and similar to drosocin, reverse turns were identified as pharmacologically important elements at the termini, bridged by an extended peptide domain. Knowledge of the primary and secondary structural requirements for in vivo activity of these peptides allows the design of novel antibacterial drug leads.

In Australia are people born in other countries at higher risk of road trauma than locally born people?

This study examined whether people born in other countries had higher rates of death and hospitalization due to road crashes than people born in Australia. Data on deaths that occurred in the whole of Australia between 1994 and 1997 and hospitalizations that occurred in the state of New South Wales, Australia, between I July 1995 and 30 June 1997 due to road crashes were analyzed. The rates of death and hospitalization, adjusted for age and area of residence, were calculated using population data from the 1996 Australian census. The study categorized people born in other countries according to the language (English speaking, non-English speaking) and the road convention (left-hand side, right-hand side) of their country of birth. Australia has the left-hand side driving convention. The study found that drivers born in other countries had rates of death or hospitalization due to road trauma equal to or below those of Australian born drivers. In contrast, pedestrians born in other countries, especially older pedestrians had higher rates of death and hospitalization due to road crashes. Pedestrians aged 60 years or more born in non-English speaking countries where traffic travels on the right-hand side of the road had risks about twice those of Australian born pedestrians in the same age group. (C) 2003 Elsevier Ltd. All rights reserved.

Enamel matrix derivative induces matrix synthesis by cultured human periodontal fibroblast cells

Background: Periodontal wound healing and regeneration require that new matrix be synthesized, creating an environment into which cells can migrate. One agent which has been described as promoting periodontal regeneration is an enamel matrix protein derivative (EMD). Since no specific growth factors have been identified in EMD preparations, it is postulated that EMD acts as a matrix enhancement factor. This study was designed to investigate the effect of EMD in vitro on matrix synthesis by cultured periodontal fibroblasts. Methods: The matrix response of the cells was evaluated by determination of the total proteoglycan synthesis, glycosaminoglycan profile, and hyaluronan synthesis by the uptake of radiolabeled precursors. The response of the individual proteoglycans, versican, decorin, and biglycan were examined at the mRNA level by Northern blot analysis. Hyaluronan synthesis was probed by identifying the isotypes of hyaluronan synthase (HAS) expressed in periodontal fibroblasts as HAS-2 and HAS-3 and the effect of EMD on the levels of mRNA for each enzyme was monitored by reverse transcription polymerase chain reaction (RTPCR). Comparisons were made between gingival fibroblast (GF) cells and periodontal ligament (PDLF) cells. Results: EMD was found to significantly affect the synthesis of the mRNAs for the matrix proteoglycans versican, biglycan, and decorin, producing a response similar to, but potentially greater than, mitogenic cytokines. EMD also stimulated hyaluronan synthesis in both GF and PDLF cells. Although mRNA for HAS-2 was elevated in GF after exposure to EMD, the PDLF did not show a similar response. Therefore, the point at which the stimulation of hyaluronan becomes effective may not be at the level of stimulation of the mRNA for hyaluronan synthase, but, rather, at a later point in the pathway of regulation of hyaluronan synthesis. In all cases, GF cells appeared to be more responsive to EMD than PDLF cells in vitro. Conclusions: EMD has the potential to significantly modulate matrix synthesis in a manner consistent with early regenerative events.

A framework for valuing derivative securities

This paper develops a general framework for valuing a wide range of derivative securities. Rather than focusing on the stochastic process of the underlying security and developing an instantaneously-riskless hedge portfolio, we focus on the terminal distribution of the underlying security. This enables the derivative security to be valued as the weighted sum of a number of component pieces. The component pieces are simply the different payoffs that the security generates in different states of the world, and they are weighted by the probability of the particular state of the world occurring. A full set of derivations is provided. To illustrate its use, the valuation framework is applied to plain-vanilla call and put options, as well as a range of derivatives including caps, floors, collars, supershares, and digital options.

The social construction of PETE in higher education: Toward a research agenda

The focus of this paper is the social construction of physical education teacher education (PETE) and its fate within the broader process of curriculum change in the physical activity field. Our task is to map the dimensions of a research program centered on the social construction of the physical activity field and PETE in higher education. Debates in the pages of Quest and elsewhere over the past two decades have highlighted not only the contentious nature of PETE practices and structures but also that PETE is changing. This paper offers one way of making sense of the ongoing process of contestation and struggle through the presentation of a theoretical framework. This framework, primarily drawing upon the work of Lave and Wenger (1991) and Bernstein (1990, 1996), is described before it is used to study the social construction of PETE in Australia. We assess the progress that has been made in developing this research program, and the questions already evident for further developments of a program of study of the physical activity field in higher education.

Globalization and women in southeast Asian higher education management

This paper draws on data from a group case study of women in higher education management in Hong Kong, Singapore, Malaysia, and Thailand. I investigate culture-specific dimensions of what the Western literature has conceptualized as glass ceiling impediments to women's career advancement in higher education. I frame my argument within recent debates about globalization and glocalization to show how the push-pull and disjunctive dynamics of globalization are experienced in local sites by social actors who traverse global flows and yet remain tethered to local discourses, values, and practices. All of the women in this study were trained in Western universities and are fluent English speakers, world-class experts in their fields, well versed with equity discourses, and globally connected on international nongovernment organization (NGO) and academic circuits. They are indeed global cosmopolitans. And yet their testimonies indicate that so-called Asian values and religious-cultural ideologies demand the enactment of a specific construct of Asian femininity that militates against meritocratic equality and academic career aspirations to senior management levels. Despite the global nature of the University and increasing global flows of academics, students, and knowledge, the politics of academic glass ceilings are not universal but always locally inflected with cultural values and norms. As such, the politics of disadvantage for women in higher education require local and situated analyses in the context of global patterns of the educational status Of women and the changing nature of higher education.

Conspicuous males suffer higher predation risk: visual modelling and experimental evidence from lizards

Colour pattern variation is a striking and widespread phenomenon. Differential predation risk between individuals is often invoked to explain colour variation, but empirical support for this hypothesis is equivocal. We investigated differential conspicuousness and predation risk in two species of Australian rock dragons, Ctenophorus decresii and C. vadnappa. To humans, the coloration of males of these species varies between 'bright' and 'dull'. Visual modelling based on objective colour measurements and the spectral sensitivities of avian visual pigments showed that dragon colour variants are differentially conspicuous to the visual system of avian predators when viewed against the natural background. We conducted field experiments to test for differential predation risk, using plaster models of 'bright' and 'dull' males. 'Bright' models were attacked significantly more often than 'dull' models suggesting that differential conspicuousness translates to differential predation risk in the wild. We also examined the influence of natural geographical range on predation risk. Results from 22 localities suggest that predation rates vary according to whether predators are familiar with the prey species. This study is among the first to demonstrate both differential conspicuousness and differential predation risk in the wild using an experimental protocol. (C) 2003 Published by Elsevier Ltd on behalf of The Association for the Study of Animal Behaviour.