Zoledronic acid preserves bone structure and increases survival but does not limit tumour incidence in a prostate cancer bone metastasis model

Background The bisphosphonate, zoledronic acid (ZOL), can inhibit osteoclasts leading to decreased osteoclastogenesis and osteoclast activity in bone. Here, we used a mixed osteolytic/osteoblastic murine model of bone-metastatic prostate cancer, RM1(BM), to determine how inhibiting osteolysis with ZOL affects the ability of these cells to establish metastases in bone, the integrity of the tumour-bearing bones and the survival of the tumour-bearing mice. Methods The model involves intracardiac injection for arterial dissemination of the RM1(BM) cells in C57BL/6 mice. ZOL treatment was given via subcutaneous injections on days 0, 4, 8 and 12, at 20 and 100 µg/kg doses. Bone integrity was assessed by micro-computed tomography and histology with comparison to untreated mice. The osteoclast and osteoblast activity was determined by measuring serum tartrate-resistant acid phosphatase 5b (TRAP 5b) and osteocalcin, respectively. Mice were euthanased according to predetermined criteria and survival was assessed using Kaplan Meier plots. Findings Micro-CT and histological analysis showed that treatment of mice with ZOL from the day of intracardiac injection of RM1(BM) cells inhibited tumour-induced bone lysis, maintained bone volume and reduced the calcification of tumour-induced endochondral osteoid material. ZOL treatment also led to a decreased serum osteocalcin and TRAP 5b levels. Additionally, treated mice showed increased survival compared to vehicle treated controls. However, ZOL treatment did not inhibit the cells ability to metastasise to bone as the number of bone-metastases was similar in both treated and untreated mice. Conclusions ZOL treatment provided significant benefits for maintaining the integrity of tumour-bearing bones and increased the survival of tumour bearing mice, though it did not prevent establishment of bone-metastases in this model. From the mechanistic view, these observations confirm that tumour-induced bone lysis is not a requirement for establishment of these bone tumours.

The roles of the preproghrelin-derived peptides - ghrelin, desacyl ghrelin and obestatin - in prostate cancer

Prostate cancer is the second most common cause of cancer related deaths in Western men. Despite the significant improvements in current treatment techniques, there is no cure for advanced metastatic, castrate-resistant disease. Early detection and prevention of progression to a castrate-resistant state may provide new strategies to improve survival. A number of growth factors have been shown to act in an autocrine/paracrine manner to modulate prostate cancer tumour growth. Our laboratory has previously shown that ghrelin and its receptors (the functional GHS-R1a and the non-functional GHS-R1b) are expressed in prostate cancer specimens and cell lines. We have shown that ghrelin increases cell proliferation in the PC3 and LNCaP prostate cancer cell lines through activation of ERK1/2, suggesting that ghrelin could regulate prostate cancer cell growth and play a role in the progression of the disease. Ghrelin is a 28 amino-acid peptide hormone, identified to be the natural ligand of the growth hormone secretagogue receptor (GHS-R1a). It is well characterised as a growth hormone releasing and as an orexigenic peptide that stimulates appetite and feeding and regulates energy expenditure and bodyweight. In addition to its orexigenic properties, ghrelin has been shown to play a regulatory role in a number of systems, including the reproductive, immune and cardiovascular systems and may play a role in a number of pathological conditions such as chronic heart failure, anorexia, cachexia, obesity, diabetes and cancer. In cancer, ghrelin and its receptor are expressed in a range of tumours and cancer cell lines and ghrelin has been demonstrated to modulate cell proliferation, apoptosis, migration and invasion in some cell types. The ghrelin gene (GHRL) encodes preproghrelin peptide, which is processed to produce three currently known functional peptides - ghrelin, desacyl ghrelin and obestatin. Prohormone convertases (PCs) have been shown to cleave the preproghrelin peptide into two primary products - the 28 amino acid peptide, ghrelin, and the remaining 117 amino acid C-terminal peptide, C-ghrelin. C-ghrelin can then be further processed to produce the 23 amino acid peptide, obestatin. Ghrelin circulates in two different forms - an octanoylated form (known as ghrelin) and a non-octanoylated form, desacyl ghrelin. The unique post-translational addition of octanoic acid to the serine 3 residue of the propeptide chain to form acylated ghrelin is catalysed by ghrelin O-acyltransferase (GOAT). This modification is necessary for binding of ghrelin to its only known functional receptor, the GHS-R1a. As desacyl ghrelin cannot bind and activate the GHS-R1a, it was initially thought to be an inactive peptide, despite the fact that it circulates at much higher levels than ghrelin. Further research has demonstrated that desacyl ghrelin is biologically active and shares some of the actions of ghrelin, as well as having some opposing and distinct roles. Interestingly, both ghrelin and desacyl ghrelin have been shown to modulate apoptosis, cell differentiation and proliferation in some cell types, and to stimulate cell proliferation through activation of ERK1/2 and PI3K/Akt pathways. The third known peptide product of the ghrelin preprohormone, obestatin, was initially thought to oppose the actions of ghrelin in appetite regulation and food intake and to mediate its effects through the G protein-coupled receptor 39 (GPR39). Subsequent research failed to reproduce the initial findings, however, and the possible anorexigenic effects of obestatin, as well as the identity of its receptor, remain unclear. Obestatin plays some important physiological roles, including roles in improving memory, the inhibition of thirst and anxiety, increased secretion of pancreatic juice, and regulation of cell proliferation, survival, apoptosis and differentiation. Preliminary studies have also shown that obestatin stimulates cell proliferation in some cell types through activation of ERK1/2, Akt and PKC pathways. Overall, however, at the commencement of this PhD project, relatively little was known regarding the functions and mechanisms of action of the preproghrelin-derived functional peptides in modulating prostate cancer cell proliferation. The roles of obestatin, and desacyl ghrelin as potential growth factors had not previously been investigated, and the potential expression and regulation of the preproghrelin processing enzymes, GOAT and prohormone convertases was unknown in prostate cancer cell lines. Therefore, the overall objectives of this study were to: 1. investigate the effects of obestatin on cell proliferation and signaling in prostate cancer cell lines 2. compare the effects of desacyl ghrelin and ghrelin on cell proliferation and signaling in prostate cancer cell lines 3. investigate whether prostate cancer cell lines possess the necessary enzymatic machinery to produce ghrelin and desacyl ghrelin and if these peptides can regulate GOAT expression Our laboratory has previously shown that ghrelin stimulates cell proliferation in the PC3 and LNCaP prostate cancer cell line through activation of the ERK1/2 pathway. In this study it has been demonstrated that treatments with either ghrelin, desacyl ghrelin or obestatin over 72 hours significantly increased cell proliferation in the PC3 prostate cancer cell line but had no significant effect in the RWPE-1 transformed normal prostate cell line. Ghrelin (1000nM) stimulated cell proliferation in the PC3 prostate cancer cell line by 31.66 6.68% (p<0.01) with the WST-1 method, and 13.55 5.68% (p<0.05) with the CyQUANT assay. Desacyl ghrelin (1000nM) increased cell proliferation in PC3 cells by 21.73 2.62% (p<0.01) (WST-1), and 15.46 7.05% (p<0.05) (CyQUANT) above untreated control. Obestatin (1000nM) induced a 28.37 7.47% (p<0.01) (WST-1) and 12.14 7.47% (p<0.05) (CyQUANT) significant increase in cell proliferation in the PC3 prostate cancer cell line. Ghrelin and desacyl ghrelin treatments stimulated Akt and ERK phosphorylation across a range of concentrations (p<0.01). Obestatin treatment significantly stimulated Akt, ERK and PKC phosphorylation (p<0.05). Through the use of specific inhibitors, the MAPK inhibitor U0126 and the Akt1/2 kinase inhibitor, it was demonstrated that ghrelin- and obestatin-induced cell proliferation in the PC3 prostate cancer cell line is mediated through activation of ERK1/2 and Akt pathways. Although desacyl ghrelin significantly stimulated Akt and ERK phosphorylation, U0126 failed to prevent desacyl ghrelin-induced cell proliferation suggesting ghrelin and desacyl ghrelin might act through different mechanisms to increase cell proliferation. Ghrelin and desacyl ghrelin have shown a proliferative effect in osteoblasts, pancreatic -cells and cardiomyocytes through activation of ERK1/2 and PI3K/Akt pathways. Here it has been shown that ghrelin and its non-acylated form exert the same function and stimulate cell proliferation in the PC3 prostate cancer cell line through activation of the Akt pathway. Ghrelin-induced proliferation was also mediated through activation of the ERK1/2 pathway, however, desacyl ghrelin seems to stimulate cell proliferation in an ERK1/2-independent manner. As desacyl ghrelin does not bind and activate GHSR1a, the only known functional ghrelin receptor, the finding that both ghrelin and desacyl ghrelin stimulate cell proliferation in the PC3 cell line suggests that these peptides could be acting through the yet unidentified alternative ghrelin receptor in this cell type. Obestatin treatment also stimulated PKC phosphorylation, however, a direct role for this pathway in stimulating cell proliferation could not be proven using available PKC pathway inhibitors, as they caused significant cell death over the extended timeframe of the cell proliferation assays. Obestatin has been shown to stimulate cell proliferation through activation of PKC isoforms in human retinal epithelial cells and in the human gastric cancer cell line KATO-III. We have demonstrated that all of the prostate-derived cell lines examined (PC3, LNCaP, DU145, 22Rv1, RWPE-1 and RWPE-2) expressed GOAT and at least one of the prohormone convertases, which are known to cleave the proghrelin peptide, PC1/3, PC2 and furin, at the mRNA level. These cells, therefore, are likely to possess the necessary machinery to cleave the preproghrelin protein and to produce the mature ghrelin and desacyl ghrelin peptides. In addition to prohormone convertases, the presence of octanoic acid is essential for acylated ghrelin production. In this study octanoic acid supplementation significantly increased cell proliferation in the PC3 prostate cancer cell line by over 20% compared to untreated controls (p<0.01), but surprisingly, not in the DU145, LNCaP or 22Rv1 prostate cancer cell lines or in the RWPE-1 and RWPE-2 prostate-derived cell lines. In addition, we demonstrated that exogenous ghrelin induced a statistically significant two-fold decrease in GOAT mRNA expression in the PC3 cell line (p<0.05), suggesting that ghrelin could pontentially downregulate its own acylation and, therefore, regulate the balance between ghrelin and desacyl ghrelin. This was not observed, however, in the DU145 and LNCaP prostate cancer cell lines. The GOAT-ghrelin system represents a direct link between ingested nutrients and regulation of ghrelin production and the ghrelin/desacyl ghrelin ratio. Regulation of ghrelin acylation is a potentially attractive and desirable tool for the development of better therapies for a number of pathological conditions where ghrelin has been shown to play a key role. The finding that desacyl ghrelin stimulates cell proliferation in the PC3 prostate cancer cell line, and responds to ghrelin in the same way, suggests that this cell line expresses an alternative ghrelin receptor. Although all the cell lines examined expressed both GHS-R1a and GHS-R1b mRNA, it remains uncertain whether these cell lines express the unidentified alternative ghrelin receptor. It is possible that the varied responses seen could be due to the expression of different ghrelin receptors in different cell lines. In addition to GOAT, prohormone convertases and octanoic acid availability may regulate the production of different peptides from the ghrelin preprohormone. The studies presented in this thesis provide significant new information regarding the roles and mechanisms of action of the preproghrelin-derived peptides, ghrelin, desacyl ghrelin and obestatin, in modulating prostate cancer cell line proliferation. A number of key questions remain to be resolved, however, including the identification of the alternative ghrelin/desacyl ghrelin receptor, the identification of the obestatin receptor, a clarification of the signaling mechanisms which mediate cell proliferation in response to obestatin treatment and a better understanding of the regulation at both the gene and post-translational levels of functional peptide generation. Further studies investigating the role of the ghrelin axis using in vivo prostate cancer models may be warranted. Until these issues are determined, the potential for the ghrelin axis, to be recognised as a novel useful target for therapy for cancer or other pathologies will be uncertain.

Spatial inequalities in colorectal and breast cancer survival : premature deaths and associated factors

This study examines the influence of cancer stage, distance to treatment facilities and area disadvantage on breast and colorectal cancer spatial survival inequalities. We also estimate the number of premature deaths after adjusting for cancer stage to quantify the impact of spatial survival inequalities. Population-based descriptive study of residents aged <90 years in Queensland, Australia diagnosed with primary invasive breast (25,202 females) or colorectal (14,690 males, 11,700 females) cancers during 1996-2007. Bayesian hierarchical models explored relative survival inequalities across 478 regions. Cancer stage and disadvantage explained the spatial inequalities in breast cancer survival, however spatial inequalities in colorectal cancer survival persisted after adjustment. Of the 6,019 colorectal cancer deaths within 5 years of diagnosis, 470 (8%) were associated with spatial inequalities in non-diagnostic factors, i.e. factors beyond cancer stage at diagnosis. For breast cancers, of 2,412 deaths, 170 (7%) were related to spatial inequalities in non-diagnostic factors. Quantifying premature deaths can increase incentive for action to reduce these spatial inequalities.

Performance evaluation of onsite sewage treatment : Evaluation of current research

Efficient management of domestic wastewater is a primary requirement for human well being. Failure to adequately address issues of wastewater collection, treatment and disposal can lead to adverse public health and environmental impacts. The increasing spread of urbanisation has led to the conversion of previously rural land into urban developments and the more intensive development of semi urban areas. However the provision of reticulated sewerage facilities has not kept pace with this expansion in urbanisation. This has resulted in a growing dependency on onsite sewage treatment. Though considered only as a temporary measure in the past, these systems are now considered as the most cost effective option and have become a permanent feature in some urban areas. This report is the first of a series of reports to be produced and is the outcome of a research project initiated by the Brisbane City Council. The primary objective of the research undertaken was to relate the treatment performance of onsite sewage treatment systems with soil conditions at site, with the emphasis being on septic tanks. This report consists of a ‘state of the art’ review of research undertaken in the arena of onsite sewage treatment. The evaluation of research brings together significant work undertaken locally and overseas. It focuses mainly on septic tanks in keeping with the primary objectives of the project. This report has acted as the springboard for the later field investigations and analysis undertaken as part of the project. Septic tanks still continue to be used widely due to their simplicity and low cost. Generally the treatment performance of septic tanks can be highly variable due to numerous factors, but a properly designed, operated and maintained septic tank can produce effluent of satisfactory quality. The reduction of hydraulic surges from washing machines and dishwashers, regular removal of accumulated septage and the elimination of harmful chemicals are some of the practices that can improve system performance considerably. The relative advantages of multi chamber over single chamber septic tanks is an issue that needs to be resolved in view of the conflicting research outcomes. In recent years, aerobic wastewater treatment systems (AWTS) have been gaining in popularity. This can be mainly attributed to the desire to avoid subsurface effluent disposal, which is the main cause of septic tank failure. The use of aerobic processes for treatment of wastewater and the disinfection of effluent prior to disposal is capable of producing effluent of a quality suitable for surface disposal. However the field performance of these has been disappointing. A significant number of these systems do not perform to stipulated standards and quality can be highly variable. This is primarily due to houseowner neglect or ignorance of correct operational and maintenance procedures. The other problems include greater susceptibility to shock loadings and sludge bulking. As identified in literature a number of design features can also contribute to this wide variation in quality. The other treatment processes in common use are the various types of filter systems. These include intermittent and recirculating sand filters. These systems too have their inherent advantages and disadvantages. Furthermore as in the case of aerobic systems, their performance is very much dependent on individual houseowner operation and maintenance practices. In recent years the use of biofilters has attracted research interest and particularly the use of peat. High removal rates of various wastewater pollutants have been reported in research literature. Despite these satisfactory results, leachate from peat has been reported in various studies. This is an issue that needs further investigations and as such biofilters can still be considered to be in the experimental stage. The use of other filter media such as absorbent plastic and bark has also been reported in literature. The safe and hygienic disposal of treated effluent is a matter of concern in the case of onsite sewage treatment. Subsurface disposal is the most common and the only option in the case of septic tank treatment. Soil is an excellent treatment medium if suitable conditions are present. The processes of sorption, filtration and oxidation can remove the various wastewater pollutants. The subsurface characteristics of the disposal area are among the most important parameters governing process performance. Therefore it is important that the soil and topographic conditions are taken into consideration in the design of the soil absorption system. Seepage trenches and beds are the common systems in use. Seepage pits or chambers can be used where subsurface conditions warrant, whilst above grade mounds have been recommended for a variety of difficult site conditions. All these systems have their inherent advantages and disadvantages and the preferable soil absorption system should be selected based on site characteristics. The use of gravel as in-fill for beds and trenches is open to question. It does not contribute to effluent treatment and has been shown to reduce the effective infiltrative surface area. This is due to physical obstruction and the migration of fines entrained in the gravel, into the soil matrix. The surface application of effluent is coming into increasing use with the advent of aerobic treatment systems. This has the advantage that treatment is undertaken on the upper soil horizons, which is chemically and biologically the most effective in effluent renovation. Numerous research studies have demonstrated the feasibility of this practice. However the overriding criteria is the quality of the effluent. It has to be of exceptionally good quality in order to ensure that there are no resulting public health impacts due to aerosol drift. This essentially is the main issue of concern, due to the unreliability of the effluent quality from aerobic systems. Secondly, it has also been found that most householders do not take adequate care in the operation of spray irrigation systems or in the maintenance of the irrigation area. Under these circumstances surface disposal of effluent should be approached with caution and would require appropriate householder education and stringent compliance requirements. However despite all this, the efficiency with which the process is undertaken will ultimately rest with the individual householder and this is where most concern rests. Greywater too should require similar considerations. Surface irrigation of greywater is currently being permitted in a number of local authority jurisdictions in Queensland. Considering the fact that greywater constitutes the largest fraction of the total wastewater generated in a household, it could be considered to be a potential resource. Unfortunately in most circumstances the only pretreatment that is required to be undertaken prior to reuse is the removal of oil and grease. This is an issue of concern as greywater can considered to be a weak to medium sewage as it contains primary pollutants such as BOD material and nutrients and may also include microbial contamination. Therefore its use for surface irrigation can pose a potential health risk. This is further compounded by the fact that most householders are unaware of the potential adverse impacts of indiscriminate greywater reuse. As in the case of blackwater effluent reuse, there have been suggestions that greywater should also be subjected to stringent guidelines. Under these circumstances the surface application of any wastewater requires careful consideration. The other option available for the disposal effluent is the use of evaporation systems. The use of evapotranspiration systems has been covered in this report. Research has shown that these systems are susceptible to a number of factors and in particular to climatic conditions. As such their applicability is location specific. Also the design of systems based solely on evapotranspiration is questionable. In order to ensure more reliability, the systems should be designed to include soil absorption. The successful use of these systems for intermittent usage has been noted in literature. Taking into consideration the issues discussed above, subsurface disposal of effluent is the safest under most conditions. This is provided the facility has been designed to accommodate site conditions. The main problem associated with subsurface disposal is the formation of a clogging mat on the infiltrative surfaces. Due to the formation of the clogging mat, the capacity of the soil to handle effluent is no longer governed by the soil’s hydraulic conductivity as measured by the percolation test, but rather by the infiltration rate through the clogged zone. The characteristics of the clogging mat have been shown to be influenced by various soil and effluent characteristics. Secondly, the mechanisms of clogging mat formation have been found to be influenced by various physical, chemical and biological processes. Biological clogging is the most common process taking place and occurs due to bacterial growth or its by-products reducing the soil pore diameters. Biological clogging is generally associated with anaerobic conditions. The formation of the clogging mat provides significant benefits. It acts as an efficient filter for the removal of microorganisms. Also as the clogging mat increases the hydraulic impedance to flow, unsaturated flow conditions will occur below the mat. This permits greater contact between effluent and soil particles thereby enhancing the purification process. This is particularly important in the case of highly permeable soils. However the adverse impacts of the clogging mat formation cannot be ignored as they can lead to significant reduction in the infiltration rate. This in fact is the most common cause of soil absorption systems failure. As the formation of the clogging mat is inevitable, it is important to ensure that it does not impede effluent infiltration beyond tolerable limits. Various strategies have been investigated to either control clogging mat formation or to remediate its severity. Intermittent dosing of effluent is one such strategy that has attracted considerable attention. Research conclusions with regard to short duration time intervals are contradictory. It has been claimed that the intermittent rest periods would result in the aerobic decomposition of the clogging mat leading to a subsequent increase in the infiltration rate. Contrary to this, it has also been claimed that short duration rest periods are insufficient to completely decompose the clogging mat, and the intermediate by-products that form as a result of aerobic processes would in fact lead to even more severe clogging. It has been further recommended that the rest periods should be much longer and should be in the range of about six months. This entails the provision of a second and alternating seepage bed. The other concepts that have been investigated are the design of the bed to meet the equilibrium infiltration rate that would eventuate after clogging mat formation; improved geometry such as the use of seepage trenches instead of beds; serial instead of parallel effluent distribution and low pressure dosing of effluent. The use of physical measures such as oxidation with hydrogen peroxide and replacement of the infiltration surface have been shown to be only of short-term benefit. Another issue of importance is the degree of pretreatment that should be provided to the effluent prior to subsurface application and the influence exerted by pollutant loadings on the clogging mat formation. Laboratory studies have shown that the total mass loadings of BOD and suspended solids are important factors in the formation of the clogging mat. It has also been found that the nature of the suspended solids is also an important factor. The finer particles from extended aeration systems when compared to those from septic tanks will penetrate deeper into the soil and hence will ultimately cause a more dense clogging mat. However the importance of improved pretreatment in clogging mat formation may need to be qualified in view of other research studies. It has also shown that effluent quality may be a factor in the case of highly permeable soils but this may not be the case with fine structured soils. The ultimate test of onsite sewage treatment system efficiency rests with the final disposal of effluent. The implication of system failure as evidenced from the surface ponding of effluent or the seepage of contaminants into the groundwater can be very serious as it can lead to environmental and public health impacts. Significant microbial contamination of surface and groundwater has been attributed to septic tank effluent. There are a number of documented instances of septic tank related waterborne disease outbreaks affecting large numbers of people. In a recent incident, the local authority was found liable for an outbreak of viral hepatitis A and not the individual septic tank owners as no action had been taken to remedy septic tank failure. This illustrates the responsibility placed on local authorities in terms of ensuring the proper operation of onsite sewage treatment systems. Even a properly functioning soil absorption system is only capable of removing phosphorus and microorganisms. The nitrogen remaining after plant uptake will not be retained in the soil column, but will instead gradually seep into the groundwater as nitrate. Conditions for nitrogen removal by denitrification are not generally present in a soil absorption bed. Dilution by groundwater is the only treatment available for reducing the nitrogen concentration to specified levels. Therefore based on subsurface conditions, this essentially entails a maximum allowable concentration of septic tanks in a given area. Unfortunately nitrogen is not the only wastewater pollutant of concern. Relatively long survival times and travel distances have been noted for microorganisms originating from soil absorption systems. This is likely to happen if saturated conditions persist under the soil absorption bed or due to surface runoff of effluent as a result of system failure. Soils have a finite capacity for the removal of phosphorus. Once this capacity is exceeded, phosphorus too will seep into the groundwater. The relatively high mobility of phosphorus in sandy soils have been noted in the literature. These issues have serious implications in the design and siting of soil absorption systems. It is not only important to ensure that the system design is based on subsurface conditions but also the density of these systems in given areas is a critical issue. This essentially involves the adoption of a land capability approach to determine the limitations of an individual site for onsite sewage disposal. The most limiting factor at a particular site would determine the overall capability classification for that site which would also dictate the type of effluent disposal method to be adopted.

The relationship between firm survival and innovation : an introduction to the literature

The rapid growth in use of the Internet as a business tool provides a new perspective in the study of the organizational challenges of new technologies. The innovation literature has grown vastly since its establishment in the 1920s, covering a broad range of disciplines (Foxall 1984) and measures a wide variety of variables (Rogers 1995). At first glance, studies that look at the relationship between innovation and firm survival appear contradictory. However, the results appear compatible when additional factors, such as industry type, organizational age, company size or the duration of the study are taken into account.

Universal access to ambulance does not increase overall demand for ambulance services in Queensland, Australia

Objective. To determine the impact of the introduction of universal access to ambulance services via the implementation of the Community Ambulance Cover (CAC) program in Queensland in 2003–04. Method. The study involved a 10-year (2000–01 to 2009–10) retrospective analysis of routinely collected data reported by the Queensland Ambulance Service (QAS) and by the Council of Ambulance Authorities. The data were analysed for the impact of policy changes that resulted in universal access to ambulance services in Queensland. Results. QASis a statewide, publically funded ambulance service. In Queensland, ambulance utilisation rate (AUR)per 1000 persons grew by 41% over the decade or 3.9% per annum (10-year mean = 149.8, 95% CI: 137.3–162.3). The AUR mean after CAC was significantly higher for urgent incidents than for non-urgent ones. However projection modelling demonstrates that URs after the introduction of CAC were significantly lower than the projected utilisation for the same period. Conclusions. The introduction of universal access under the Community Ambulance Cover program in Queensland has not had any significant independent long-term impact on demand overall. There has been a reduction in the long-term growth rate, which may have been contributed to by an ‘appropriate use’ public awareness program.

Psychosocial experience of cancer : surpassing mere survival and recognising the potential for posttraumatic growth as well as distress.

The publication of the fourth edition of the Diagnostic and Statistical Manual of Mental Disorders (DSM-IV; American Psychiatric Association, 1994) introduced the notion that a life-threatening illness can be a stressor and catalyst for Posttraumatic Stress Disorder (PTSD). Since then a solid body of research has been established investigating the post-diagnosis experience of cancer. These studies have identified a number of short and long-term life changes resulting from a diagnosis of cancer and associated treatments. In this chapter, we discuss the psychosocial response to the cancer experience and the potential for cancer-related distress. Cancer can represent a life-threatening diagnosis that may be associated with aggressive treatments and result in physical and psychological changes. The potential for future trauma through the lasting effects of the disease and treatment, and the possibility of recurrence, can be a source of continued psychological distress. In addition to the documented adverse repercussions of cancer, we also outline the recent shift that has occurred in the psycho-oncology literature regarding positive life change or posttraumatic growth that is commonly reported after a diagnosis of cancer. Adopting a salutogenic framework acknowledges that the cancer experience is a dynamic psychosocial process with both negative and positive repercussions. Next, we describe the situational and individual factors that are associated with posttraumatic growth and the types of positive life change that are prevalent in this context. Finally, we discuss the implications of this research in a therapeutic context and the directions of future posttraumatic growth research with cancer survivors. This chapter will present both quantitative and qualitative research that indicates the potential for personal growth from adversity rather than just mere survival and return to pre-diagnosis functioning. It is important to emphasise however, that the presence of growth and prevalence of resilience does not negate the extremely distressing nature of a cancer diagnosis for the patient and their families and the suffering that can accompany treatment regimes. Indeed, it will be explained that for growth to occur, the experience must be one that quite literally shatters previously held schemas in order to act as a catalyst for change.

A novel winding structure in planar inductors to decrease overall capacitive couplings

This paper analyses effects of winding structure on capacitive coupling reduction appearing in the planar magnetic elements at high frequencies. Capacitive coupling appears between the conductive layers of the planar transformers resulting in high current spikes and consequently high power dissipation. With finite element analysis, the equivalent capacitive coupling of magnetic elements is calculated for different structures of planar windings. Finally, a new winding structure with minimum capacitive coupling is introduced for the planar magnetic elements, which is verified by simulation and experiments.

Multilevel determinants of breast cancer survival : association with geographic remoteness and area-level socioeconomic disadvantage

A major priority for cancer control agencies is to reduce geographical inequalities in cancer outcomes. While the poorer breast cancer survival among socioeconomically disadvantaged women is well established, few studies have looked at the independent contribution that area- and individual-level factors make to breast cancer survival. Here we examine relationships between geographic remoteness, area-level socioeconomic disadvantage and breast cancer survival after adjustment for patients’ socio- demographic characteristics and stage at diagnosis. Multilevel logistic regression and Markov chain Monte Carlo simulation were used to analyze 18 568 breast cancer cases extracted from the Queensland Cancer Registry for women aged 30 to 70 years diagnosed between 1997 and 2006 from 478 Statistical Local Areas in Queensland, Australia. Independent of individual-level factors, area-level disadvantage was associated with breast-cancer survival (p=0.032). Compared to women in the least disadvantaged quintile (Quintile 5), women diagnosed while resident in one of the remaining four quintiles had significantly worse survival (OR 1.23, 1.27, 1.30, 1.37 for Quintiles 4, 3, 2 and 1 respectively).) Geographic remoteness was not related to lower survival after multivariable adjustment. There was no evidence that the impact of area-level disadvantage varied by geographic remoteness. At the individual level, Indigenous status, blue collar occupations and advanced disease were important predictors of poorer survival. A woman’s survival after a diagnosis of breast cancer depends on the socio-economic characteristics of the area where she lives, independently of her individual-level characteristics. It is crucial that the underlying reasons for these inequalities be identified to appropriately target policies, resources and effective intervention strategies.

Survival, sublethal injury and recovery of environmental Burkholderia pseudomallei in soil subjected to desiccation

Environmental Burkholderia pseudomallei isolated from sandy soil at Castle Hill, Townsville, in the dry tropic region of Queensland, Australia, was inoculated into sterile-soil laboratory microcosms subjected to variable soil moisture. Survival and sublethal injury of the B. pseudomallei strain were monitored by recovery using culture-based methods. Soil extraction buffer yielded higher recoveries as an extraction agent than sterile distilled water. B. pseudomallei was not recoverable when inoculated into desiccated soil but remained recoverable from moist soil subjected to 91 days desiccation and showed a growth response to increased soil moisture over at least 113 days. Results indicate that endemic dry tropic soil may act as a reservoir during the dry season, with an increase in cell number and potential for mobilization from soil into water in the wet season.

SECIS-binding protein 2 promotes cell survival by protecting against oxidative stress

Reactive oxygen species (ROS) are a primary cause of cellular damage that leads to cell death. In cells, protection from ROS-induced damage and maintenance of the redox balance is mediated to a large extent by selenoproteins, a distinct family of proteins that contain selenium in form of selenocysteine (Sec) within their active site. Incorporation of Sec requires the Sec-insertion sequence element (SECIS) in the 3'-untranslated region of selenoproteins mRNAs and the SECIS-binding protein 2 (SBP2). Previous studies have shown that SBP2 is required for the Sec-incorporation mechanism; however, additional roles of SBP2 in the cell have remained undefined. We herein show that depletion of SBP2 by using antisense oligonucleotides (ASOs) causes oxidative stress and induction of caspase- and cytochrome c-dependent apoptosis. Cells depleted of SBP2 have increased levels of ROS, which lead to cellular stress manifested as 8-oxo-7,8-dihydroguanine (8-oxo-dG) DNA lesions, stress granules, and lipid peroxidation. Small-molecule antioxidants N-acetylcysteine, glutathione, and α-tocopherol only marginally reduced ROS and were unable to rescue cells fully from apoptosis, indicating that apoptosis might be directly mediated by selenoproteins. Our results demonstrate that SBP2 is required for protection against ROS-induced cellular damage and cell survival. Antioxid. Redox Signal. 12, 797–808.