Drug bioactivation, covalent binding to target proteins and toxicity relevance

A number of therapeutic drugs with different structures and mechanisms of action have been reported to undergo metabolic activation by Phase I or Phase II drug-metabolizing enzymes. The bioactivation gives rise to reactive metabolites/intermediates, which readily confer covalent binding to various target proteins by nucleophilic substitution and/or Schiff's base mechanism. These drugs include analgesics (e.g., acetaminophen), antibacterial agents (e.g., sulfonamides and macrolide antibiotics), anticancer drugs (e.g., irinotecan), antiepileptic drugs (e.g., carbamazepine), anti-HIV agents (e.g., ritonavir), antipsychotics (e.g., clozapine), cardiovascular drugs (e.g., procainamide and hydralazine), immunosupressants (e.g., cyclosporine A), inhalational anesthetics (e.g., halothane), nonsteroidal anti-inflammatory drugs (NSAIDSs) (e.g., diclofenac), and steroids and their receptor modulators (e.g., estrogens and tamoxifen). Some herbal and dietary constituents are also bioactivated to reactive metabolites capable of binding covalently and inactivating cytochrome P450s (CYPs). A number of important target proteins of drugs have been identified by mass spectrometric techniques and proteomic approaches. The covalent binding and formation of drug-protein adducts are generally considered to be related to drug toxicity, and selective protein covalent binding by drug metabolites may lead to selective organ toxicity. However, the mechanisms involved in the protein adduct-induced toxicity are largely undefined, although it has been suggested that drug-protein adducts may cause toxicity either through impairing physiological functions of the modified proteins or through immune-mediated mechanisms. In addition, mechanism-based inhibition of CYPs may result in toxic drug-drug interactions. The clinical consequences of drug bioactivation and covalent binding to proteins are unpredictable, depending on many factors that are associated with the administered drugs and patients. Further studies using proteomic and genomic approaches with high throughput capacity are needed to identify the protein targetsof reactive drug metabolites, and to elucidate the structure-activity relationships of drug's covalent binding to proteins and their clinical outcomes.

Defining quality of life for Chinese elderly stroke survivors

Purpose: This study aimed to identify the constituents and conceptual characteristics of the quality of life (QOL) of Chinese elderly stroke survivors, living in the community in Hong Kong.

Method: A triangulated approach was used to identify the QOL components for this population. This process involved a comparison of QOL components gathered from three different methods, namely, focus group interviews, review of the literature and the contents of the generic Hong Kong Chinese version of the World Health Organization Quality of Life Scale (CWHOQOL-HK). Five health professionals were involved in the comparison process. A percentage of inter-judge agreement was used to determine the reliability of the comparisons made between the judges.

Results: This study identified 36 components considered to contribute to the QOL of Chinese elderly stroke survivors in Hong Kong. The conceptual characteristics of their QOL generally concurred with those identified in the literature.

Conclusion: Both similarities and differences were found in the QOL components identified in this study when compared to those identified in studies of Western populations who are elderly and had a stroke. The contents of the CWHOQOL-HK scale were found to lack adequacy in representing the QOL of Chinese elderly stroke survivors in Hong Kong. Recommendations are given, based on the findings of this study, to overcome this limitation for its application as a QOL measure for this population.

Correlation between optical and SEM measurements of wool cortical cell size

Wool fibres consist of micro to nano scale protein constituents that could be used for innovative applications. While techniques for extracting these constituents or making wool fibres into organic powders have been developed, effectively dispersing the particles and accurately determining their size has been difficult in practice. In this study, an ultrasonic method was employed to disperse cortical cells extracted from wool fibres into an
immersion oil or ethanol. Specimens of the cortical cells were then observed under optical microscopy and scanning electron microscopy, respectively. Cell length and maximum cell diameter were measured to quantify the cell size. The results suggest significant discrepancies exist in the cortical cell size obtained from the two different measurement techniques. The maximum diameter of wool cortical cells obtained from the optical microscope was much larger than that from the scanning electron microscope, while the length was much shorter. A correction factor is given so that cortical cell size obtained from the two measurement techniques can be compared.

Mechanical properties and bioactive surface modification via alkali-heat treatment of a porous ti-18Nb-4Sn alloy for biomedical applications

A porous Ti–18 at.%Nb–4 at.%Sn (hereafter, Ti–18Nb–4Sn) alloy was prepared by powder metallurgy. The porous structures were examined by scanning electron microscopy and the phase constituents were analysed by X-ray diffraction. Mechanical properties of the porous alloy were investigated using a compressive test. To enhance the bioactivity of the alloy surface, alkali-heat treatment was used to modify the surface. The bioactivity of the pre-treated alloy sample was investigated using a biomimetic process by soaking the sample into simulated body fluid (SBF). Results indicate that the elastic modulus and plateau stress of the porous Ti–18Nb–4Sn alloy decrease with decreasing relative density. The mechanical properties of the porous alloy can be tailored to match those of human bone. After soaking in SBF for 7 days, a hydroxyapatite layer formed on the surface of the pre-treated porous Ti–18Nb–4Sn alloy. The pre-treated porous Ti–18Nb–4Sn alloy therefore has the potential to be a bioactive implant material.

Faith, tradition, and dynamic order : Michael Polanyi's liberal thought from 1941 to 1951

In his writings between 1941 and 1951, Michael Polanyi developed a distinctive view of liberal social and political life. Planned organizations are a part of all modern societies, according to Polanyi, but in liberal modernity he highlighted dynamic social orders whose agents freely adjust their efforts in light of the initiatives and accomplishments of their peers. Liberal society itself is the most extensive of dynamic orders, with the market economy, and cultural orders of scientific research, Protestant religious inquiry, and common law among its constituents. Liberal society and its dynamic orders of culture are, Polanyi explained, directed at transcendent ideals (truth, beauty, and justice). He saw knowledge, rules of practice, and standards of value in these orders as being preserved in traditions that inform and constrain the initiatives of their members. Investing faith in a cultural enterprise, Polanyi's agents choose to act   responsibly, dedicating their freedom to an ideal end. They are custodians and cultivators of the heritage of their dynamic order.

Influence of porosity on shape memory behavior of porous TiNi shape memory alloy

Porous Ti-50.5at.%Ni shape memory alloy (SMA) samples with a range of  porosities were prepared by spacer sintering. The porous structure of the alloy was examined using scanning electron microscopy (SEM). The phase constituents of the porous TiNi alloy were determined by X-ray diffraction (XRD). The shape memory behavior of the porous TiNi alloy was investigated using loading–unloading compression tests. Results indicate that the porous TiNi alloy exhibits superelasticity and the recoverable strain by the superelasticity decreases with the increase of porosity. After a prestrain of 7%, the superelastically recovered strains for the porous TiNi alloy samples with porosities of 46%, 59%, 69% and 77% are 2.0%, 1.8%, 1.5% and 1.3%, respectively. The pores in the TiNi alloy samples cause stress/strain concentration, as well as crack initiation, which adversely affect the shape memory behavior of the porous TiNi alloy.

Antidiabetic properties of polysaccharide- and polyphenolic-enriched fractions from the brown seaweed Ascophyllum nodosum

We screened seaweed species from Atlantic Canada for antidiabetic activity by testing extracts for α-glucosidase inhibitory effect and glucose uptake stimulatory activity. An aqueous ethanolic extract of Ascophyllum nodosum was found to be active in both assays, inhibiting rat intestinal α-glucosidase (IC50 = 77 μg/mL) and stimulating basal glucose uptake into 3T3-L1 adipocytes during a 20-minute incubation by about 3-fold (at 400 μg/mL extract). Bioassay-guided fractionation of the A. nodosum extract showed that α-glucosidase inhibition was associated with polyphenolic components in the extract. These polyphenolics, along with other constituents appeared to be responsible for the stimulatory activity on glucose uptake. However, attempts to further concentrate this activity through fractionation techniques were unsuccessful. A crude polyphenol extract (PPE), an enriched polyphenolic fraction (PPE-F1) and a polysaccharide extract (PSE) were prepared from commercial A. nodosum powder and administered to streptozotocin-diabetic mice for up to 4-weeks by daily gavage at 200 mg/kg body mass. PPE and PPE-F1 improved fasting serum glucose level in diabetic mice; however, the effect was only statistically significant at day 14. In addition, PPE-F1 was shown to blunt the rise in blood glucose after an oral sucrose tolerance test in diabetic mice. Mice treated with PPE and PPE-F1 had decreased blood total cholesterol and glycated serum protein levels compared with untreated diabetic mice, whereas PPE also normalized the reduction in liver glycogen level that occurred in diabetic animals. All 3 A. nodosum preparations improved blood antioxidant capacity.

On a établit une recherche d’un produit anti-diabétique, parmi les algues locales de la région Atlantique du Canada, en examinant la capacité d’un effet inhibiteur de l’enzyme α-glucosidase et une stimulation de l’incorporation cellulaire du glucose. Un extrait éthanol-aqueux de Ascophyllum nodosum nous a donné une activité positive chez les deux essais, une inhibition de l’α-glucosidase provenant de l’intestin du rat (IC50 = 77 μg/mL) et puis une stimulation triple, à une concentration de 400 μg/mL, de l’incorporation du glucose dans les adipocytes 3T3-L1 durant une période de 20 minutes. L’extrait de A. nodosum a été divisé, guidé par les résultats biologiques, et a ainsi démontré la présence d’éléments polyphénoliques associé à l’inhibition de l’α-glucosidase. Ces éléments polyphénoliques ainsi que d’autres semblent être responsables de l’incorporation stimulée du glucose. Il a été impossible de raffiner cette activité lors d’une division des composants. Un extrait brut polyphénolique (PPE), un extrait enrichi polyphénolique (PPE-F1) et puis un extrait polysaccharide (PSE) furent préparés d’une poudre commerciale de A. nodosum et utilisés dans une étude utilisant des souris, rendues diabétiques par injections de streptozotocin, traitées par un gavage journalier de l’extrait 200 mg/kg du poids corporel durant une période de 4 semaines. Le taux du glucose sanguin à jeun des souris fut moins élevé en présence des extraits qu’en leurs absence. Cependant, l’effet était seulement significatif au jour 14. Les résultats étant toutefois variables. En plus, lors d’un essai oral de la tolérance au sucrose chez la souris diabétique, l’extrait PPE-F1 a empêché l’augmentation du taux du glucose sanguin. Les extraits PPE et PPE-F1 ont réduit le taux de cholestérol sanguin et les niveaux de glycation des protéines en comparaison de ces niveaux en absence des extraits tandis que l’extrait PPE a présenté une réduction du niveau de glycogène du foie chez les souris diabétiques. Les trois extraits de A. nodosum ont tous amélioré la capacité antioxidante du sang.

Development of a salmon protein hydrolysate that lowers blood pressure

A salmon protein hydrolysate (SPH) was developed containing several angiotensin I-converting enzyme (ACE) inhibitory tripeptides the most abundant of which were Val-Leu-Trp, Val-Phe-Tyr, and Leu-Ala-Phe. Simulated digestion experiments showed that active constituents of SPH would survive in the digestive tract and be available for absorption into the bloodstream. In fact, ACE inhibitory activity was improved following simulated digestion suggesting that there were larger peptides in SPH that might contribute to bioactivity in vivo. A single oral dose (1,500 mg/kg body mass) of SPH significantly lowered blood pressure in spontaneously hypertensive rats (SHR). The treatment of SHR with either SPH fraction (<3,000 Da) or SPH fraction (>3,000 Da) reduced blood pressure. We conclude that the ability of SPH to lower blood pressure is due to a combination of ACE inhibitory tripeptides as identified, as well as additional unknown, peptide species that are generated during digestion of SPH in the gastrointestinal tract.

Consideration of corporate social orientation in managing sport organisations' internal stakeholders

Increasing pressure from the public has raised the expectations on corporations to be better citizens of their communities and society as a whole (Bennet 2002; Carroll 1999; Epstein 1989; Van Marrewijk 2003; Wood 1991). As a result, corporations have engaged in corporate social responsibility efforts with most of the subsequent research focused on its impact on consumer response (e.g., attitudes, behaviours, etc.) (Bhattacharya & Sen 2001, 2004; Porter & Kramer 2002). Similarly, research interest on corporate social responsibility in the sport industry has risen, yet no research studies have explored the influence and perceptions about corporate social responsibility of important internal constituents (employees and volunteers) of sport organisations. Particular interest would be in uncovering what employees and volunteers specifically believe are important among CSR elements (ethical, discretionary, legal, economic) and what impact a sense of 'shared CSR values' with the respective sport organisation would have on employee and volunteer response. Will understanding how shared social values influence organisational commitment provide insight on recruitment, retention and/or development strategies of employees and volunteers? Further, assessing any difference in sensemaking between these two groups would be of additional value to this line of enquiry, as the perceptions of the organisation are understood as "tantamount to reality, since organisations are social constructions made up of and acting in accordance with shared perceptions," (Brickson 2007, p. 865) particularly those of employees and volunteers of sport organisations. With increasing academic and industry interest of corporate social responsibility in sport and to address the obvious gap on CSR and employees and volunteers in the literature, the present study will explore how CSR impacts internal constituents (employees and volunteers) of sport organisations. Specifically, the main purpose of the present study is to assess the level of perceived shared values as they related to CSR (measured as corporate social orientation) between employees- organisation and volunteers- organisation. Further, the influence of the level of perceived shared corporate social orientation (CSO) on organisational identification will be evaluated in the context of a proposed model, which includes the relationship of perceived shared corporate social orientation>organisational identification> attitudinal and behavioural outcomes (i.e., commitment, satisfaction, and organisational behaviour). Using a sample of employees and volunteers of a sport organisation, the respondents will be asked to complete an online survey composed of demographic items, the corporate social orientation scale, and items that measure organisational identification, value commitment, job/ volunteer satisfaction, and organisational citizenship behaviours. Discussion of how other stakeholder (e.g., sponsors, consumers, etc.) perceptions on CSR potentially impacts the model and outcomes (e.g., corporate reputation, consumer behaviour) will be addressed. Analyses and results will support discussion and conclusions made to provide evidence for practitioner and researcher implications.

Building commitment through integrating employees

Corporate collapses of past decade have affected all stakeholders through a loss of public confidence, loss of jobs and loss of shareholders' funds. We have seen poor business decisions, extravagant business acquisitions, lack of attention to detail, exorbitant directors fees, lack of board scrutiny and inadequate disclosure internationally and in Australia in cases such as Enron, WorldCom, HIH, the Australian Wheat Board, and numerous state banks. This paper analyzes annual reports, web sites and CSR/ Sustainability and Governance reports of twenty selected companies to highlight the position of human resources and labour in their governance frameworks, and by linking the data to Stum's (2001) performance pyramid, evaluates the extent of organizational commitment. It concludes that despite all the rhetoric around employees being stakeholders, employees continue to be viewed as 'outsiders' with governance primarily focused on shareholder concerns. Employees are primarily seen as constituents of legal and regulatory frameworks and employee codes of conduct and lack a position in strategy and effective decisionmaking structures, thereby conveying to employees that they are perceived only as workers, and not as a person (Stum, 2001). Naturally, the organizations fail to win the commitment of their employees.

From what we know to how we use it : five principles for turning entrepreneurship research and practitioner action guidelines

This and the companion paper that follows owe their existence to a paper presented by Kevin Hindle at the AGSE Regional Entrepreneurship and Innovation Research Exchange in February 2004. In his paper, Hindle (2004) argued passionately that entrepreneurship researchers must ensure that the best of their hardwon wisdom does not find its beginning motivation and final resting place in the pages of arcane journals that practitioners never read. He suggested that if every entrepreneurship researcher committed, say once every two years, to write a "how to" article it would significantly enhance the status of the research community in the eyes of practising entrepreneurs and those who provide support and services to them.

The argument was well-received, particularly by two people in the audience, Robert Anderson, the managing editor of the Journal of Small Business and Entrepreneurship, the journal of the Canadian Council for Small Business and Entrepreneurship/Conseil Canadien des PME et de l'entrepreneuriat (CCSBE/ CCPME), and Brian Gibson, the editor of Small Enterprise Research, the journal of the Small Enterprise Association of Australia and New Zealand (SEAANZ). For both editors, Hindle's argument was a familiar one. The membership of CCSBE/CCPME and SEAANZ consists of academic researchers, educators, government employees in both policy and program areas, and those offering support and services to entrepreneurs and the managers of small enterprises. In both organizations, there is a general consensus that the needs of "academics" are well met, but not so the needs of the non-academic constituents.

Back to basics : breakthrough proposals for the Australian environment

In this book Dr Geoff Wescott proposes a new approach to environmental decision making. He suggests we move forward from relying solely on individual virtuous action to improve our environment. He argues that the time has come to get ʻback to basicsʼ: for governments to be decisive and courageous and make positive environmental decisions in the interests of their current and future constituents rather than continue to be locked into short term decision making at the beck and call of corporations and large political donors.

The global financial crisis and the centro properties group earnings revision and refinancing announcements : an event study

This study analyses the impact of the global financial crisis using Centro Properties Group's earnings revision and refinancing announcements on December 17th 2007 as the event date to investigate the change in risk profile for A-REITs that were included in the S&P/ASX 300. The study finds that nine of the 25 A-REIT constituents on the S&P/ASX 300 recorded statistically significant negative abnormal returns on 17th December 2007 and that the systematic risk for many A-REITs moved significantly higher after this date. This increased systematic risk has major implications for the cost of capital to the sector.

Internet and competitive advantage in Australian professional sport organisations

The electronic revolution has proven to be a powerful stimulus for change in business practice. As a business tool however, the Internet must endure the same scrutiny under which other business activities are placed. If the use of the Internet in business is a sound strategy, then it must contribute toward competitive advantage. The sport business industry has not been isolated from the vagaries of Internet applications. Moreover, as the industry has become more competitive, forcing sporting organisations towards unprecedented levels of accountability and business practice, the Internet has been increasingly seen as a potential 'holy grail' for sport organisations struggling for revenue (Stewart & Smith, 1999). This research is a response to these pressures. It seeks to identify Internet based opportunities for competitive advantage, and to provide strategies and recommendations for the successful use of the Internet in Australian professional sport organisations. In realising this objective, a newly developed and integrated Business Activity Model has been constructed. The model assists in the identification of specific Internet based competitive advantage strategies, and provides a theoretical framework for this research. The Business Activity Model conceptualises, for the first time, the relationships between the value chain, constituents of electronically enabled competitive advantage, and the Internet. With Australia's limited group of fully professional sports capable of sustaining the human resources and budgets necessary to implement comprehensive e-commerce strategies, the organisations selected to participate in this research represent the pinnacle of Australian professional sport clubs. Specifically, the 55 clubs competing in the Australian Football League (A.F.L.), National Basketball League (N.B.L.), National Rugby League (N.R.L.), and National Soccer League (N.S.L.) constituted the research sample and population. In concert with the 87% participation rate, sampling approached a census. A telephone-administered survey, based primarily on the rigorously tested instrument developed by Sethi and King (1994), was employed for data collection. This research employs a comprehensive set of descriptive statistics, and is bolstered by a confirmatory and an exploratory factor analysis, undertaken on one component of the data. The outcome of this research was the identification of seven practical recommendations for Australian professional sport organisations seeking to improve competitive advantage via the Internet. These recommendations were based on an inventory of the 'gaps' between the strategies proposed by the literature, and the practices of the sample, and relate to both overall Internet strategy, and specific web site applications. The development of the new Business Activity Model and the identification of key online strategy themes support and complement these recommendations. An examination of variations in the practices of participating organisations, and some comparisons against United States sporting organisations, also provides depth and context to the findings. This research provides a platform for sport managers to effectively harness the potential of the Internet, through their web sites in particular, and realise significant competitive advantages. The Business Activity Model provides managers in all industries with a tool for the detection and understanding of potential elements of competitive advantage, and incorporates all activities critical to business in the new digital economy. Seven practical recommendations for improved online performance based on identified competitive advantage and strategies fulfils the primary objective of this research. E-commerce continues to grow at astronomical rates, and with the Internet poised to become the life-blood of 21st century sporting organisations, these recommendations will assist managers in their ongoing search for competitive advantage.

Tariff protection and politics : Castlemaine 1870-1901

This study, set within the contextual background of Victorian politics, ‘seeks to identify the economic, political and social implications of tariff protection for the Castlemaine region from 1870-1901. The introduction of the Victorian tariff in 1865 precipitated a reversal of earlier attitudes towards protection by politicians and their constituents. Reasons are sought for changes in the perceptions of the Castlemaine electorate and its political representatives towards the tariff between 1870 and Federation. An examination has been made of the role of the tariff in the creation of employment in the region’s primary and secondary industries together with its influence on politicians, primary and secondary industry leaders and workers. Also explored is the relative impact of the tariff on the economic performance of Castlemaine industries, whether producing for export or domestic markets.