The cytochrome P-450 isoenzyme CYP2E1 in the biological processing of industrial chemicals : consequences for occupational and environmental medicine

The importance of the isoform CYP2E1 of the human cytochrome P-450 superfamily of enzymes for occupational and environmental medicine is derived from its unique substrate spectrum that includes a number of highly important high-production chemicals, such as aliphatic and aromatic hydrocarbons, solvents and industrial monomers (i.a. alkanes, alkenes, aromatic and halogenated hydrocarbons). Many polymorphic genes, such as CYP2E1, show considerable differences in allelic distribution between different human populations. The polymorphic nature of the human CYP2E1 gene is significant for inter-individual differences in toxicity of its substrates. Since the substrate spectrum of CYP2E1 includes many compounds of basic relevance to industrial toxicology, a rationale for metabolic interactions of different CYP2E1 substrates is provided. In-depth research into the inter-individual phenotypic differences of human CYP2E1 enzyme activities was enabled by the recognition that the 6-hydroxylation of the drug chlorzoxazone is mediated by CYP2E1. Studies on CYP2E1 phenotyping have pointed to inter-individual variations in enzyme activities. There are consistent ethnic differences in CYP2E1 enzyme expression, mostly demonstrated between European and Japanese populations, which point to a major impact of genetic factors. The most frequently studied genetic polymorphisms are the restriction fragment length polymorphisms PstI/RsaI (mutant allele: CYP2E1*5B) located in the 5′-flanking region of the gene, as well as the DraI polymorphism (mutant allele: CYP2E1*6) located in intron 6. These polymorphisms are partly related, as they form the common allele designated CYP2E1*5A. Striking inter-ethnic differences between Europeans and Asians appear with respect to the frequencies of the CYP2E1*5A allele (only approximately 5% of Europeans are heterozygous, but 37% of Asians are, whilst 6% of Asians are homozygous). Available studies indicate a wide variation in human CYP2E1 expression, which are very likely based on complex gene-environment interactions. Major inter-ethnic differences are apparent on the genotyping and the phenotyping levels. Selected cases are presented where inter-ethnic variations of CYP2E1 may provide likely explanations for unexplained findings concerning industrial chemicals that are CYP2E1 substrates. Possible consequences of differential inter-individual and inter-ethnic susceptibilities are related to individual expressions of clinical symptoms of chemical toxicity, to results of biological monitoring of exposed workers, and to the interpretation of results of epidemiological or molecular-epidemiological studies.

Markers of genetic susceptibility in human environmental hygiene and toxicology : the role of selected CYP, NAT and GST genes

Inherited genetic traits co-determine the susceptibility of an individual to a toxic chemical. Special emphasis has been put on individual responses to environmental and industrial carcinogens, but other chronic diseases are of increasing interest. Polymorphisms of relevant xenobiotic metabolising enzymes may be used as toxicological susceptibility markers. A growing number of genes encoding enzymes involved in biotransformation of toxicants and in cellular defence against toxicant-induced damage to the cells has been identified and cloned, leading to increased knowledge of allelic variants of genes and genetic defects that may result in a differential susceptibility toward environmental toxicants. "Low penetrating" polymorphisms in metabolism genes tend to be much more common in the population than allelic variants of "high penetrating" cancer genes, and are therefore of considerable importance from a public health point of view. Positive associations between cancer and CYP1A1 alleles, in particular the *2C I462V allele, were found for tissues following the aerodigestive tract. Again, in most cases, the effect of the variant CYP1A1 allele becomes apparent or clearer in connection with the GSTM1 null allele. The CYP1B1 codon 432 polymorphism (CYP1B1*3) has been identified as a susceptibility factor in smoking-related head-and-neck squameous cell cancer. The impact of this polymorphic variant of CYP1B1 on cancer risk was also reflected by an association with the frequency of somatic mutations of the p53 gene. Combined genotype analysis of CYP1B1 and the glutathione transferases GSTM1 or GSTT1 has also pointed to interactive effects. Of particular interest for the industrial and environmental field is the isozyme CYP2E1. Several genotypes of this isozyme have been characterised which seem to be associated with different levels of expression of enzyme activity. The acetylator status for NAT2 can be determined by genotyping or by phenotyping. In the pathogenesis of human bladder cancer due to occupational exposure to "classical" aromatic amines (benzidine, 4-aminodiphenyl, 1-naphthylamine) acetylation by NAT2 is regarded as a detoxication step. Interestingly, the underlying European findings of a higher susceptibility of slow acetylators towards aromatic amines are in contrast to findings in Chinese workers occupationally exposed to aromatic amines which points to different mechanisms of susceptibility between European and Chinese populations. Regarding human bladder cancer, the hypothesis has been put forward that genetic polymorphism of GSTM1 might be linked with the occurrence of this tumour type. This supports the hypothesis that exposure to PAH might causally be involved in urothelial cancers. The human polymorphic GST catalysing conjugation of halomethanes, dihalomethanes, ethylene oxide and a number of other industrial compounds could be characterised as a class theta enzyme (GSTT1) by means of molecular biology. "Conjugator" and "non-conjugator" phenotypes are coincident with the presence and absence of the GSTT1 gene. There are wide variations in the frequencies of GSTT1 deletion (GSTT1 *0/0) among different ethnicities. Human phenotyping is facilitated by the GST activity towards methyl bromide or ethylene oxide in erythrocytes which is representative of the metabolic GSTT1 competence of the entire organism. Inter-individual variations in xenobiotic metabolism capacities may be due to polymorphisms of the genes coding for the enzymes themselves or of the genes coding for the receptors or transcription factors which regulate the expression of the enzymes. Also, polymorphisms in several regions of genes may cause altered ligand affinity, transactivation activity or expression levels of the receptor subsequently influencing the expression of the downstream target genes. Studies of individual susceptibility to toxicants and gene-environment interaction are now emerging as an important component of molecular epidemiology.

Genetic susceptibility to environmental toxicants : the interface between human and experimental studies in the development of new toxicological concepts

The growing knowledge of the genetic polymorphisms of enzymes metabolising xenobiotics in humans and their connections with individual susceptibility towards toxicants has created new and important interfaces between human epidemiology and experimental toxicology. The results of molecular epidemiological studies may provide new hypotheses and concepts, which call for experimental verification, and experimental concepts may obtain further proof by molecular epidemiological studies. If applied diligently, these possibilities may be combined to lead to new strategies of human-oriented toxicological research. This overview will present some outstanding examples for such strategies taken from the practically very important field of occupational toxicology. The main focus is placed on the effects of enzyme polymorphisms of the xenobiotic metabolism in association with the induction of bladder cancer and renal cell cancer after exposure to occupational chemicals. Also, smoking and induction of head and neck squamous cell cancer are considered.

Knowledge management challenges in small-and medium-sized enterprises

Background & Research Focus Managing knowledge for innovation and organisational benefit has been extensively investigated in studies of large firms (Smith, Collins & Clark, 2005; Zucker, et al., 2007) and to a large extent there is limited research into studies of small- and medium- sized enterprises (SMEs). There are some investigations in knowledge management research on SMEs, but what remains to be seen in particular is the question of where are the potential challenges for managing knowledge more effectively within these firms? Effective knowledge management (KM) processes and systems lead to improved performance in pursuing distinct capabilities that contribute to firm-level innovation (Nassim 2009; Zucker et al. 2007; Verona and Ravasi 2003). Managing internal and external knowledge in a way that links it closely to the innovation process can assist the creation and implementation of new products and services. KM is particularly important in knowledge intensive firms where the knowledge requirements are highly specialized, diverse and often emergent. However, to a large extent the KM processes of small firms that are often the source of new knowledge and an important element of the value networks of larger companies have not been closely studied. To address this gap which is of increasing importance with the growing number of small firms, we need to further investigate knowledge management processes and the ways that firms find, capture, apply and integrate knowledge from multiple sources for their innovation process. This study builds on the previous literature and applies existing frameworks and takes the process and activity view of knowledge management as a starting point of departure (see among others Kraaijenbrink, Wijnhoven & Groen, 2007; Enberg, Lindkvist, & Tell, 2006; Lu, Wang & Mao, 2007). In this paper, it is attempted to develop a better understanding of the challenges of knowledge management within the innovation process in small knowledge-oriented firms. The paper aims to explore knowledge management processes and practices in firms that are engaged in the new product/service development programs. Consistent with the exploratory character of the study, the research question is: How is knowledge integrated, sourced and recombined from internal and external sources for innovation and new product development? Research Method The research took an exploratory case study approach and developed a theoretical framework to investigate the knowledge situation of knowledge-intensive firms. Equipped with the conceptual foundation, the research adopted a multiple case study method investigating four diverse Australian knowledge-intensive firms from IT, biotechnology, nanotechnology and biochemistry industries. The multiple case study method allowed us to document in some depth the knowledge management experience of the theses firms. Case study data were collected through a review of company published data and semi-structured interviews with managers using an interview guide to ensure uniform coverage of the research themes. This interview guide was developed following development of the framework and a review of the methodologies and issues covered by similar studies in other countries and used some questions common to these studies. It was framed to gather data around knowledge management activity within the business, focusing on the identification, acquisition and utilisation of knowledge, but collecting a range of information about subject as well. The focus of the case studies was on the use of external and internal knowledge to support their knowledge intensive products and services. Key Findings Firstly a conceptual and strategic knowledge management framework has been developed. The knowledge determinants are related to the nature of knowledge, organisational context, and mechanism of the linkages between internal and external knowledge. Overall, a number of key observations derived from this study, which demonstrated the challenges of managing knowledge and how important KM is as a management tool for innovation process in knowledge-oriented firms. To summarise, findings suggest that knowledge management process in these firms is very much project focused and not embedded within the overall organisational routines and mainly based on ad hoc and informal processes. Our findings highlighted lack of formal knowledge management process within our sampled firms. This point to the need for more specialised capabilities in knowledge management for these firms. We observed a need for an effective knowledge transfer support system which is required to facilitate knowledge sharing and particularly capturing and transferring tacit knowledge from one team members to another. In sum, our findings indicate that building effective and adaptive IT systems to manage and share knowledge in the firm is one of the biggest challenges for these small firms. Also, there is little explicit strategy in small knowledge-intensive firms that is targeted at systematic KM either at the strategic or operational level. Therefore, a strategic approach to managing knowledge for innovation as well as leadership and management are essential to achieving effective KM. In particular, research findings demonstrate that gathering tacit knowledge, internal and external to the organization, and applying processes to ensure the availability of knowledge for innovation teams, drives down the risks and cost of innovation. KM activities and tools, such as KM systems, environmental scanning, benchmarking, intranets, firm-wide databases and communities of practice to acquire knowledge and to make it accessible, were elements of KM. Practical Implications The case study method that used in this study provides practical insight into the knowledge management process within Australian knowledge-intensive firms. It also provides useful lessons which can be used by other firms in managing the knowledge more effectively in the innovation process. The findings would be helpful for small firms that may be searching for a practical method for managing and integrating their specialised knowledge. Using the results of this exploratory study and to address the challenges of knowledge management, this study proposes five practices that are discussed in the paper for managing knowledge more efficiently to improve innovation: (1) Knowledge-based firms must be strategic in knowledge management processes for innovation, (2) Leadership and management should encourage various practices for knowledge management, (3) Capturing and sharing tacit knowledge is critical and should be managed, (4)Team knowledge integration practices should be developed, (5) Knowledge management and integration through communication networks, and technology systems should be encouraged and strengthen. In sum, the main managerial contribution of the paper is the recognition of knowledge determinants and processes, and their effects on the effective knowledge management within firm. This may serve as a useful benchmark in the strategic planning of the firm as it utilises new and specialised knowledge.

From styling to strategy : transforming an Australian manufacturing SME's perception of design

This thesis explores the shift in perception of design from a styling and product-focused tool, towards a holistic strategic approach within a small to medium sized manufacturing company. This research is significant because it demonstrates how design tools and approaches can be used within business to translate theory into operational, strategic and cultural outcomes. The outcomes of this research will encourage other businesses to take on similar design-led projects with the ultimate goal of employing design as a means to create a sustainable competitive advantage.

Available evidence does not support serosorting as an HIV risk reduction strategy

Recent data highlighted the association between penetration of antiretrovirals in the central nervous system (CNS) and neurocognitive impairment in HIVpositive patients. Existing antiretrovirals have been ranked according to a score of neuropenetration, which was shown to be a predictor of anti-HIVactivity in the CNS and improvement of neurocognitive disorders [1]. Main factors affecting drug penetration are known to be protein binding, lipophilicity and molecular weight [2]. Moreover, active translation by membrane transporters (such as p-glycoprotein) could be a key mechanism of passage [3]. The use of raltegravir (RGV), a novel antiretroviral drug targeted to inhibit the HIV preintegrase complex, is increasing worldwide due to its efficacy and tolerability. However, penetration of RGV in the CNS has not been yet elucidated. In fact, prediction of RGV neuropenetration according to molecular characteristics is controversial. Intermediate protein binding (83%) and large volume of distribution (273 l) could suggest a high distribution beyond extracellular spaces [4]. On the contrary, low lipophilicity (oil/water partition coefficient at pH 7.4 of 2.80) and intermediate molecular weight (482.51 Da) suggest a limited diffusion. Furthermore, in-vitro studies suggest that RGV is substrate of p-glycoprotein, although this efflux pump has not been identified to significantly affect plasma pharmacokinetics [5]. In any case, no data concerning RGV passage into cerebrospinal fluid of animals or humans have yet been published.

Developing a transdisciplinary approach to improve urban traffic congestion based on Product Ecosystem theory

Product Ecosystem theory is an emerging theory that shows that disruptive “game changing” innovation is only possible when the entire ecosystem is considered. When environmental variables change faster than products or services can adapt, disruptive innovation is required to keep pace. This has many parallels with natural ecosystems where species that cannot keep up with changes to the environment will struggle or become extinct. In this case the environment is the city, the environmental pressures are pollution and congestion, the product is the car and the product ecosystem is comprised of roads, bridges, traffic lights, legislation, refuelling facilities etc. Each one of these components is the responsibility of a different organisation and so any change that affects the whole ecosystem requires a transdisciplinary approach. As a simple example, cars that communicate wirelessly with traffic lights are only of value if wireless-enabled traffic lights exist and vice versa. Cars that drive themselves are technically possible but legislation in most places doesn’t allow their use. According to innovation theory, incremental innovation tends to chase ever diminishing returns and becomes increasingly unable to tackle the “big issues.” Eventually “game changing” disruptive innovation comes along and solves the “big issues” and/or provides new opportunities. Seen through this lens, the environmental pressures of urban traffic congestion and pollution are the “big issues.” It can be argued that the design of cars and the other components of the product ecosystem follow an incremental innovation approach. That is why the “big issues” remain unresolved. This paper explores the problems of pollution and congestion in urban environments from a Product Ecosystem perspective. From this a strategy will be proposed for a transdisciplinary approach to develop and implement solutions.

A responsive sanction to promote systematic compliance? Enforceable undertakings in occupational health and safety regulation

This article examines the use of enforceable undertakings in Australian occupational health and safety (OHS) regulation. Enforceable undertakings are promises by persons alleged to have breached their regulatory obligations to do something, which if not done, is enforceable in court. Enforceable undertakings potentially have an important responsive and restorative role to play in a regulatory enforcement strategy to ensure compliance with OHS statutes, and have been used in other areas of business regulation, including trade practices, financial, prudential, consumer, civil aviation, environmental and communications and media regulation. The article then reports on a study of the operation of enforceable undertakings in Queensland to enforce compliance with OHS obligations. We conclude that this early experience of enforceable undertakings in Queensland provides useful guidance as to how the enforceable undertaking provisions might best be implemented elsewhere, and preliminary evidence of the complexities of their likely effectiveness in OHS regulation.

Environmental, personal, and genetic determinants of response to vitamin D supplementation in older adults

CONTEXT AND OBJECTIVE: Suboptimal vitamin D status can be corrected by vitamin D supplementation, but individual responses to supplementation vary. We aimed to examine genetic and nongenetic determinants of change in serum 25-hydroxyvitamin D (25(OH)D) after supplementation. DESIGN AND PARTICIPANTS: We used data from a pilot randomized controlled trial in which 644 adults aged 60 to 84 years were randomly assigned to monthly doses of placebo, 30 000 IU, or 60 000 IU vitamin D3 for 12 months. Baseline characteristics were obtained from a self-administered questionnaire. Eighty-eight single-nucleotide polymorphisms (SNPs) in 41 candidate genes were genotyped using Sequenom MassArray technology. Serum 25(OH)D levels before and after the intervention were measured using the Diasorin Liaison platform immunoassay. We used linear regression models to examine associations between genetic and nongenetic factors and change in serum 25(OH)D levels. RESULTS: Supplement dose and baseline 25(OH)D level explained 24% of the variability in response to supplementation. Body mass index, self-reported health status, and ambient UV radiation made a small additional contribution. SNPs in CYP2R1, IRF4, MC1R, CYP27B1, VDR, TYRP1, MCM6, and HERC2 were associated with change in 25(OH)D level, although only CYP2R1 was significant after adjustment for multiple testing. Models including SNPs explained a similar proportion of variability in response to supplementation as models that included personal and environmental factors. CONCLUSION: Stepwise regression analyses suggest that genetic variability may be associated with response to supplementation, perhaps suggesting that some people might need higher doses to reach optimal 25(OH)D levels or that there is variability in the physiologically normal level of 25(OH)D.

Douglas Shire Water Quality Monitoring Strategy: Final Report: a Report to Douglas Shire Council and the Department of the Environment and Heritage

This report describes results and conclusions from the monitoring component of the Douglas Shire Council (DSC) water quality project. The components of this project that this report addresses are: • Site selection and installation of in-stream and off-paddock automatic water quality monitoring equipment in the Douglas Shire. • Design of appropriate sampling strategies for automatic stations. • Estimation of loads of suspended sediment, total nitrogen and total phosphorus in rivers and also estimation of the changes in nutrient loads from sugar cane under different fertilizer application rates. • Development of a community-based water quality sampling program to complement the automatic sampling efforts. • Design of an optimised, long-term water quality monitoring strategy.

Electrochemical current rectification – a novel signal amplification strategy for highly sensitive and selective aptamer-based biosensor

Electrochemical aptamer-based (E-AB) sensors represent an emerging class of recently developed sensors. However, numerous of these sensors are limited by a low surface density of electrode-bound redox-oligonucleotides which are used as probe. Here we propose to use the concept of electrochemical current rectification (ECR) for the enhancement of the redox signal of E-AB sensors. Commonly, the probe-DNA performs a change in conformation during target binding and enables a nonrecurring charge transfer between redox-tag and electrode. In our system, the redox-tag of the probe-DNA is continuously replenished by solution-phase redox molecules. A unidirectional electron transfer from electrode via surface-linked redox-tag to the solution-phase redox molecules arises that efficiently amplifies the current response. Using this robust and straight-forward strategy, the developed sensor showed a substantial signal amplification and consequently improved sensitivity with a calculated detection limit of 114 nM for ATP, which was improved by one order of magnitude compared with the amplification-free detection and superior to other previous detection results using enzymes or nanomaterials-based signal amplification. To the best of our knowledge, this is the first demonstration of an aptamer-based electrochemical biosensor involving electrochemical rectification, which can be presumably transferred to other biomedical sensor systems.

An interpretative structural modeling based network reconfiguration strategy for power systems

The network reconfiguration is an important stage of restoring a power system after a complete blackout or a local outage. Reasonable planning of the network reconfiguration procedure is essential for rapidly restoring the power system concerned. An approach for evaluating the importance of a line is first proposed based on the line contraction concept. Then, the interpretative structural modeling (ISM) is employed to analyze the relationship among the factors having impacts on the network reconfiguration. The security and speediness of restoring generating units are considered with priority, and a method is next proposed to select the generating unit to be restored by maximizing the restoration benefit with both the generation capacity of the restored generating unit and the importance of the line in the restoration path considered. Both the start-up sequence of generating units and the related restoration paths are optimized together in the proposed method, and in this way the shortcomings of separately solving these two issues in the existing methods are avoided. Finally, the New England 10-unit 39-bus power system and the Guangdong power system in South China are employed to demonstrate the basic features of the proposed method.