Relevance of the deletion polymorphisms of the glutathione S-transferases GSTT1 and GSTM1 in pharmacology and toxicology

Although cytosolic glutathione S-transferase (GST) enzymes occupy a key position in biological detoxification processes, two of the most relevant human isoenzymes, GSTT1-1 and GSTM1-1, are genetically deleted (non-functional alleles GSTT1*0 and GSTM1*0) in a high percentage of the human population, with major ethnic differences. The structures of the GSTT and GSTM gene areas explain the underlying genetic processes. GSTT1-1 is highly conserved during evolution and plays a major role in phase-II biotransformation of a number of drugs and industrial chemicals, e.g. cytostatic drugs, hydrocarbons and halogenated hydrocarbons. GSTM1-1 is particularly relevant in the deactivation of carcinogenic intermediates of polycyclic aromatic hydrocarbons. Several lines of evidence suggest that hGSTT1-1 and/or hGSTM1-1 play a role in the deactivation of reactive oxygen species that are likely to be involved in cellular processes of inflammation, ageing and degenerative diseases. There is cumulating evidence that combinations of the GSTM1*0 state with other genetic traits affecting the metabolism of carcinogens (CYP1A1, GSTP1) may predispose the aero-digestive tract and lung, especially in smokers, to a higher risk of cancer. The GSTM1*0 status appears also associated with a modest increase in the risk of bladder cancer, consistent with a GSTM1 interaction with carcinogenic tobacco smoke constituents. Both human GST deletions, although largely counterbalanced by overlapping substrate affinities within the GST superfamily, have consequences when the organism comes into contact with distinct man-made chemicals. This appears relevant in industrial toxicology and in drug metabolism.

Flupirtine enhances the anti-hyperalgesic effects of morphine in a rat model of prostate bone metastasis

Objective Current treatments for cancer pain are often inadequate, particularly when metastasis to bone is involved. The addition to the treatment regimen of another drug that has a complementary analgesic effect may increase the overall analgesia without the necessity to increase doses, thus avoiding dose-related side effects. This project investigated the synergistic effect of the addition of the potassium channel (KCNQ2–3) modulator flupirtine to morphine treatment in a rat model of prostate cancer-induced bone pain. Design Syngeneic prostate cancer cells were injected into the right tibia of male Wistar rats under anesthesia. This led to expanding tumor within the bone in 2 weeks, together with the concurrent development of hyperalgesia to noxious heat. Paw withdrawal thresholds from noxious heat were measured before and after the maximum non-sedating doses of morphine and flupirtine given alone and in combinations. Dose-response curves for morphine (0.13–5.0 mg/kg ip) and flupirtine (1.25–10.0 mg/kg ip) given alone and in fixed-dose combinations were plotted and subjected to an isobolographic analysis. Results Both morphine (ED50 = 0.74 mg/kg) and flupirtine (ED50 = 3.32 mg/kg) caused dose-related anti-hyperalgesia at doses that did not cause sedation. Isobolographic analysis revealed that there was a synergistic interaction between flupirtine and morphine. Addition of flupirtine to morphine treatment improved morphine anti-hyperalgesia, and resulted in the reversal of cancer-induced heat hyperalgesia. Conclusions These results suggest that flupirtine in combination with morphine may be useful clinically to provide better analgesia at lower morphine doses in the management of pain caused by tumors growing in bone.

Intravenous injection of leconotide, an omega conotoxin : synergistic antihyperalgesic effects with morphine in a rat model of bone cancer pain

Objective.  Leconotide (CVID, AM336, CNSB004) is an omega conopeptide similar to ziconotide, which blocks voltage sensitive calcium channels. However, unlike ziconotide, which must be administered intrathecally, leconotide can be given intravenously because it is less toxic. This study investigated the antihyperalgesic potency of leconotide given intravenously alone and in combinations with morphine-administered intraperitoneally, in a rat model of bone cancer pain. Design.  Syngeneic rat prostate cancer cells AT3B-1 were injected into one tibia of male Wistar rats. The tumor expanded within the bone causing hyperalgesia to heat applied to the ipsilateral hind paw. Measurements were made of the maximum dose (MD) of morphine and leconotide given alone and in combinations that caused no effect in an open-field activity monitor, rotarod, and blood pressure and heart rate measurements. Paw withdrawal thresholds from noxious heat were measured. Dose response curves for morphine (0.312–5.0 mg/kg intraperitoneal) and leconotide (0.002–200 µg/kg intravenous) given alone were plotted and responses compared with those caused by morphine and leconotide in combinations. Results.  Leconotide caused minimal antihyperalgesic effects when administered alone. Morphine given alone intraperitoneally caused dose-related antihyperalgesic effects (ED50 = 2.40 ± 1.24 mg/kg), which were increased by coadministration of leconotide 20 µg/kg (morphine ED50 = 0.16 ± 1.30 mg/kg); 0.2 µg/kg (morphine ED50 = 0.39 ± 1.27 mg/kg); and 0.02 µg/kg (morphine ED50 = 1.24 ± 1.30 mg/kg). Conclusions.  Leconotide caused a significant increase in reversal by morphine of the bone cancer-induced hyperalgesia without increasing the side effect profile of either drug. Clinical Implication.  Translation into clinical practice of the method of analgesia described here will improve the quantity and quality of analgesia in patients with bone metastases. The use of an ordinary parenteral route for administration of the calcium channel blocker (leconotide) at low dose opens up the technique to large numbers of patients who could not have an intrathecal catheter for drug administration. Furthermore, the potentiating synergistic effect with morphine on hyperalgesia without increased side effects will lead to greater analgesia with improved quality of life.

Diagnostic potential of saliva : current state and future applications

BACKGROUND: Over the past 10 years, the use of saliva as a diagnostic fluid has gained attention and has become a translational research success story. Some of the current nanotechnologies have been demonstrated to have the analytical sensitivity required for the use of saliva as a diagnostic medium to detect and predict disease progression. However, these technologies have not yet been integrated into current clinical practice and work flow. CONTENT: As a diagnostic fluid, saliva offers advantages over serum because it can be collected noninvasively by individuals with modest training, and it offers a cost-effective approach for the screening of large populations. Gland-specific saliva can also be used for diagnosis of pathology specific to one of the major salivary glands. There is minimal risk of contracting infections during saliva collection, and saliva can be used in clinically challenging situations, such as obtaining samples from children or handicapped or anxious patients, in whom blood sampling could be a difficult act to perform. In this review we highlight the production of and secretion of saliva, the salivary proteome, transportation of biomolecules from blood capillaries to salivary glands, and the diagnostic potential of saliva for use in detection of cardiovascular disease and oral and breast cancers. We also highlight the barriers to application of saliva testing and its advancement in clinical settings. SUMMARY: Saliva has the potential to become a first-line diagnostic sample of choice owing to the advancements in detection technologies coupled with combinations of biomolecules with clinical relevance. (C) 2011 American Association for Clinical Chemistry

Diagnostic potential of saliva : state of the art and future applications [Potenziale diagnostico della saliva: stato dell’arte e applicazioni future]

Over the past 10 years, the use of saliva as a diagnostic fluid has gained attention and has become a translational research success story. Some of the current nanotechnologies have been demonstrated to have the analytical sensitivity required for the use of saliva as a diagnostic medium to detect and predict disease progression. However, these technologies have not yet been integrated into current clinical practice and work flow. As a diagnostic fluid, saliva offers advantages over serum because it can be collected noninvasively by individuals with modest training, and it offers a cost-effective approach for the screening of large populations. Gland-specific saliva can also be used for diagnosis of pathology specific to one of the major salivary glands. There is minimal risk of contracting infections during saliva collection, and saliva can be used in clinically challenging situations, such as obtaining samples from children or handicapped or anxious patients, in whom blood sampling could be a difficult act to perform. In this review we highlight the production of and secretion of saliva, the salivary proteome, transportation of biomolecules from blood capillaries to salivary glands, and the diagnostic potential of saliva for use in detection of cardiovascular disease and oral and breast cancers. We also highlight the barriers to application of saliva testing and its advancement in clinical settings. Saliva has the potential to become a first-line diagnostic sample of choice owing to the advancements in detection technologies coupled with combinations of biomolecules with clinical relevance.

Understanding causal relationships between the built and social environment, health and associated behaviours and risk factors

Introduction: Built environment interventions designed to reduce non-communicable diseases and health inequity, complement urban planning agendas focused on creating more ‘liveable’, compact, pedestrian-friendly, less automobile dependent and more socially inclusive cities.However, what constitutes a ‘liveable’ community is not well defined. Moreover, there appears to be a gap between the concept and delivery of ‘liveable’ communities. The recently funded NHMRC Centre of Research Excellence (CRE) in Healthy Liveable Communities established in early 2014, has defined ‘liveability’ from a social determinants of health perspective. Using purpose-designed multilevel longitudinal data sets, it addresses five themes that address key evidence-base gaps for building healthy and liveable communities. The CRE in Healthy Liveable Communities seeks to generate and exchange new knowledge about: 1) measurement of policy-relevant built environment features associated with leading non-communicable disease risk factors (physical activity, obesity) and health outcomes (cardiovascular disease, diabetes) and mental health; 2) causal relationships and thresholds for built environment interventions using data from longitudinal studies and natural experiments; 3) thresholds for built environment interventions; 4) economic benefits of built environment interventions designed to influence health and wellbeing outcomes; and 5) factors, tools, and interventions that facilitate the translation of research into policy and practice. This evidence is critical to inform future policy and practice in health, land use, and transport planning. Moreover, to ensure policy-relevance and facilitate research translation, the CRE in Healthy Liveable Communities builds upon ongoing, and has established new, multi-sector collaborations with national and state policy-makers and practitioners. The symposium will commence with a brief introduction to embed the research within an Australian health and urban planning context, as well as providing an overall outline of the CRE in Healthy Liveable Communities, its structure and team. Next, an overview of the five research themes will be presented. Following these presentations, the Discussant will consider the implications of the research and opportunities for translation and knowledge exchange. Theme 2 will establish whether and to what extent the neighbourhood environment (built and social) is causally related to physical and mental health and associated behaviours and risk factors. In particular, research conducted as part of this theme will use data from large-scale, longitudinal-multilevel studies (HABITAT, RESIDE, AusDiab) to examine relationships that meet causality criteria via statistical methods such as longitudinal mixed-effect and fixed-effect models, multilevel and structural equation models; analyse data on residential preferences to investigate confounding due to neighbourhood self-selection and to use measurement and analysis tools such as propensity score matching and ‘within-person’ change modelling to address confounding; analyse data about individual-level factors that might confound, mediate or modify relationships between the neighbourhood environment and health and well-being (e.g., psychosocial factors, knowledge, perceptions, attitudes, functional status), and; analyse data on both objective neighbourhood characteristics and residents’ perceptions of these objective features to more accurately assess the relative contribution of objective and perceptual factors to outcomes such as health and well-being, physical activity, active transport, obesity, and sedentary behaviour. At the completion of the Theme 2, we will have demonstrated and applied statistical methods appropriate for determining causality and generated evidence about causal relationships between the neighbourhood environment, health, and related outcomes. This will provide planners and policy makers with a more robust (valid and reliable) basis on which to design healthy communities.

Theorizing the use of multiple conceptual models in combination

Conceptual modelling continues to be an important means for graphically capturing the requirements of an information system. Observations of modelling practice suggest that modellers often use multiple conceptual models in combination, because they articulate different aspects of real-world domains. Yet, the available empirical as well as theoretical research in this area has largely studied the use of single models, or single modelling grammars. We develop a Theory of Combined Ontological Coverage by extending an existing theory of ontological expressiveness of conceptual modelling grammars. Our new theory posits that multiple conceptual models are used to increase the maximum coverage of the real-world domain being modelled, whilst trying to minimize the ontological overlap between the models. We illustrate how the theory can be applied to analyse sets of conceptual models. We develop three propositions of the theory about evaluations of model combinations in terms of users’ selection, understandability and usefulness of conceptual models.

A staining protocol for identifying secondary compounds in Myrtaceae

• Premise of the study: Here we propose a staining protocol using TBO and Ruthenium red in order to reliably identify secondary compounds in the leaves of some species of Myrtaceae. • Methods and results: Leaves of 10 species representing 10 different genera of Myrtaceae were processed and stained using five different combinations of Ruthenium red and TBO. Optimal staining conditions were determined as 1 min of Ruthenium red (0.05% aqueous) and 45 sec of TBO (0.1% aqueous). Secondary compounds clearly identified under this treatment include mucilage in mesophyll, polyphenols in cuticle, lignin in fibers and xylem, tannins and carboxylated polysaccharides in epidermis and pectic substances in primary cell walls. • Conclusions: Potential applications of this protocol include systematic, phytochemical and ecological investigations in Myrtaceae. It might be applicable to other plant families rich in secondary compounds and could be used as preliminary screening method for extraction of these elements.

A frontier functions approach to optimal scales of sustainable production

This paper translates the concepts of sustainable production to three dimensions of economic, environmental and ecological sustainability to analyze optimal production scales by solving optimizing problems. Economic optimization seeks input-output combinations to maximize profits. Environmental optimization searches for input-output combinations that minimize the polluting effects of materials balance on the surrounding environment. Ecological optimization looks for input-output combinations that minimize the cumulative destruction of the entire ecosystem. Using an aggregate space, the framework illustrates that these optimal scales are often not identical because markets fail to account for all negative externalities. Profit-maximizing firms normally operate at the scales which are larger than optimal scales from the viewpoints of environmental and ecological sustainability; hence policy interventions are favoured. The framework offers a useful tool for efficiency studies and policy implication analysis. The paper provides an empirical investigation using a data set of rice farms in South Korea.

Development of a new regulatory model for occupational health and safety in the New South Wales coal industry: an issues paper for the New South Wales Department of Mineral Resources

This paper addresses the regulatory issues arising in developing a new regulatory model for the New South Wales Coal Industry. As such, it identifies the relevant literature on this subject, the options available for reform, and the experience of Australian and key international bodies responsible for the development of regulatory standards in this area. In particular it: Identifies the main shortcomings in the existing regulatory approach; Identifies the potential roles/main strengths and weaknesses of different types of standards (eg specification, performance, process and systems-based rules) and potential “best practice’ combinations of standards; Examines the appropriateness of the current regulatory regime whereby the general OHS legislation (including the general duty provisions) applies to mining in addition to the large body of regulation which is specific to mining; Identifies the importance of, and possible means of addressing, issues of worker participation within the coal mining industry; Draws on the literature on what motivates companies and individuals for the purpose of recommending key provisions for inclusion in new legislation to provide appropriate personal and organisational incentives; Draws on the literature on major hazards facilities to suggest the appropriate roles for OHS management systems and safety reports or comparable approaches (eg mine safety management plans); Draws on the United Kingdom (UK) and United States of America (USA) experience of coal mine safety and its regulation for comparative purposes, and for insights as to what sort of regulation most effectively reduces work related injury and disease in coal mining; Examines the relevant roles of International Labour Organisation (ILO) Conventions; Examines the extent to which different regulatory regimes would be appropriate to open cut and underground coal mining; and Examines options for reform. This paper is focussed specifically on the issues identified above.

Integrating PV systems into distribution networks with battery energy storage systems

Integrating Photovoltaic (PV) systems with battery energy storage in the distribution network will be essential to allow for continued uptake of domestic PV system installations. With increasing concerns regarding environmental and climate change issues, incorporating sources of renewable energy into power networks across the world will be key for a sustainable future. Australia is well placed to utilise solar energy as a significant component of its future energy generation and within the last 5 years there has been a rapid growth in the penetration levels seen by the grid. This growth of PV systems is causing a number of issues including intermittency of supply, negative power flow and voltage rises. Using the simulator tool GridLAB-D with a model of a typical South-East Queensland (SEQ) 11 kV distribution feeder, the effect of various configurations of PV systems have been offset with Battery Energy Storage Systems (BESS). From this, combinations of PV and storage that are most effective at mitigating the issues were explored.

Theory and practice of automotive modal lock-in – an Indonesian case

This thesis examines the question why the automotive mode and the large technological system it creates, continues to dominate urban transport systems despite the availability of more cost-efficient alternatives. A number of theoretical insights are developed into the way these losses evolve from path dependent growth, and lead to market failure and lock-in. The important role of asymmetries of influence is highlighted. A survey of commuters in Jakarta Indonesia is used to provide a measure of transport modal lock-in (TML) in a developing country conurbation. A discrete choice experiment is used to provide evidence for the thesis central hypothesis that in such conurbations there is a high level of commuter awareness of the negative externalities generated by TML which can produce a strong level of support for its reversal. Why TML nevertheless remains a strong and durable feature of the transport system is examined with reference to the role of asymmetries of influence.

Graduated driver licensing : an international review

Graduated driver licensing (GDL) aims to gradually increase the exposure of new drivers to more complex driving situations and typically consists of learner, provisional and open licence phases. The first phase, the learner licence, is designed to allow novice drivers to obtain practical driving experience in lower risk situations. The learner licence can delay licensure, encourage novice drivers to learn under supervision, mandate the number of hours of practice required to progress to the next phase and encourage parental involvement. The second phase, the provisional licence, establishes various driving restrictions and thereby reduces exposure to situations of higher risk, such as driving at night, with passengers or after drinking alcohol. Parental involvement with a GDL system appears essential in helping novices obtain sufficient practice and in enforcing compliance with restrictions once the new driver obtains a provisional licence. Given the significant number of young drivers involved in crashes within Oman, GDL is one countermeasure that may be beneficial in reducing crash risk and involvement for this group.

The potential for new understandings of normal and abnormal cognition by integration of neuroimaging and behavioral data : Not an exercise in carrying coals to Newcastle

Discovering the means to prevent and cure schizophrenia is a vision that motivates many scientists. But in order to achieve this goal, we need to understand its neurobiological basis. The emergent metadiscipline of cognitive neuroscience fields an impressive array of tools that can be marshaled towards achieving this goal, including powerful new methods of imaging the brain (both structural and functional) as well as assessments of perceptual and cognitive capacities based on psychophysical procedures, experimental tasks and models developed by cognitive science. We believe that the integration of data from this array of tools offers the greatest possibilities and potential for advancing understanding of the neural basis of not only normal cognition but also the cognitive impairments that are fundamental to schizophrenia. Since sufficient expertise in the application of these tools and methods rarely reside in a single individual, or even a single laboratory, collaboration is a key element in this endeavor. Here, we review some of the products of our integrative efforts in collaboration with our colleagues on the East Coast of Australia and Pacific Rim. This research focuses on the neural basis of executive function deficits and impairments in early auditory processing in patients using various combinations of performance indices (from perceptual and cognitive paradigms), ERPs, fMRI and sMRI. In each case, integration of two or more sources of information provides more information than any one source alone by revealing new insights into structure-function relationships. Furthermore, the addition of other imaging methodologies (such as DTI) and approaches (such as computational models of cognition) offers new horizons in human brain imaging research and in understanding human behavior.

Language change in socially structured populations

Language contact is a significant external social factor that impacts on the change in natural languages over time. In some circumstances this corresponds to language competition, in which individuals in a population choose one language over another based on their social interactions. We investigated the dynamics of language change in two initially separate populations of agents that were then mixed with levels of influence determined by the social classes of the two populations, with 16 different combinations tested. As expected, the study found that how the communities interact with each other impacts on the communal language developed. However, it was also found that the acquisition of new words was substantial even with limited interaction between populations and low levels of influence, and that comprehension could be well established across language groups even when production of words from the other language group was low.