375 resultados para Folkman Numbers


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Prostate cancer is a significant health problem faced by aging men. Currently, diagnostic strategies for the detection of prostate cancer are either unreliable, yielding high numbers of false positive results, or too invasive to be used widely as screening tests. Furthermore, the current therapeutic strategies for the treatment of the disease carry considerable side effects. Although organ confined prostate cancer can be curable, most detectable clinical symptoms occur in advanced disease when primary tumour cells have metastasised to distant sites - usually lymph nodes and bone. Many growth factors and steroids assist the continued growth and maintenance of prostatic tumour cells. Of these mitogens, androgens are important in the development of the normal prostate but are also required to sustain the growth of prostate cancer cells in the early stage of the disease. Not only are androgens required in the early stage of disease, but also many other growth factors and hormones interact to cause uncontrolled proliferation of malignant cells. The early, androgen sensitive phase of disease is followed by an androgen insensitive phase, whereby androgens are no longer required to stimulate the growth of the tumour cells. Growth factors such as transforming growth factor  and  (TGF/), epidermal growth factor (EGF), basic fibroblast growth factor (bFGF), insulin-like growth factors (IGFs), Vitamin D and thyroid hormone have been suggested to be important at this stage of disease. Interestingly, some of the kallikrein family of genes, including prostate specific antigen (PSA), the current serum diagnostic marker for prostate cancer, are regulated by androgens and many of the aforementioned growth factors. The kallikrein gene family is a group of serine proteases that are involved in a diverse range of physiological processes: regulation of local blood flow, angiogenesis, tissue invasion and mitogenesis. The earliest members of the kallikrein gene family (KLK1-KLK3) have been strongly associated with general disease states, such as hypertension, inflammation, pancreatitis and renal disease, but are also linked to various cancers. Recently, this family was extended to include 15 genes (KLK1-15). Several newer members of the kallikrein family have been implicated in the carcinogenesis and tumour metastasis of hormone-dependent cancers such as prostate, breast, endometrial and ovarian cancer. The aims of this project were to investigate the expression of the newly identified kallikrein, KLK4, in benign and malignant prostate tissues, and prostate cancer cell lines. This thesis has demonstrated the elevated expression of KLK4 mRNA transcripts in malignant prostate tissue compared to benign prostates. Additionally, expression of the full length KLK4 transcript was detected in the androgen dependent prostate cancer cell line, LNCaP. Based on the above finding, the LNCaP cell line was chosen to assess the potential regulation of full length KLK4 by androgen, thyroid hormone and epidermal growth factor. KLK4 mRNA and protein was found to be up-regulated by androgen and a combination of androgen and thyroid hormone. Thyroid hormone alone produced no significant change in KLK4 mRNA or protein over the control. Epidermal growth factor treatment also resulted in elevated expression levels of KLK4 mRNA and protein. To assess the potential functional role(s) of KLK4/hK4 in processes associated with tumour progression, full length KLK4 was transfected into PC-3 cells - a prostate cancer cell line originally derived from a secondary bone lesion. The KLK4/hK4 over-expressing cells were assessed for their proliferation, migration, invasion and attachment properties. The KLK4 over-expressing clones exhibited a marked change in morphology, indicative of a more aggressive phenotype. The KLK4 clones were irregularly shaped with compromised adhesion to the growth surface. In contrast, the control cell lines (parent PC-3 and empty vector clones) retained a rounded morphology with obvious cell to cell adhesion, as well as significant adhesion to their growth surface. The KLK4 clones exhibited significantly greater attachment to Collagen I and IV than native PC-3s and empty vector controls. Over a 12 hour period, in comparison to the control cells, the KLK4 clones displayed an increase in migration towards PC-3 native conditioned media, a 3 fold increase towards conditioned media from an osteoblastic cell line (Saos-2) and no change in migration towards conditioned media from neonatal foreskin fibroblast cells or 20% foetal bovine serum. Furthermore, the increase in migration exhibited by the KLK4 clones was partially blocked by the serine protease inhibitor, aprotinin. The data presented in this thesis suggests that KLK4/hK4 is important in prostate carcinogenesis due to its over-expression in malignant prostate tissues, its regulation by hormones and growth factors associated with prostate disease and the functional consequences of over-expression of KLK4/hK4 in the PC-3 cell line. These results indicate that KLK4/hK4 may play an important role in tumour invasion and bone metastasis via increased attachment to the bone matrix protein, Collagen I, and enhanced migration due to soluble factors produced by osteoblast cells. This suggestion is further supported by the morphological changes displayed by the KLK4 over-expressing cells. Overall, this data suggests that KLK4/hK4 should be further studied to more fully investigate the potential value of KLK4/hK4 as a diagnostic/prognostic biomarker or in therapeutic applications.

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This study, investigating 263 women undergoing trans-vaginal oocyte retrieval for in vitro fertilisation (IVF) found that microorganisms colonising follicular fluid contributed to adverse IVF (pre-implantation) and pregnancy (post-implantation) outcomes including poor quality embryos, failed pregnancy and early pregnancy loss (< 37 weeks gestation). Some microorganisms also showed in vitro growth patterns in liquid media that appeared to be enhanced by the hormonal stimulation protocol used for oocyte retrieval. Elaborated cytokines within follicular fluid were also associated with adverse IVF outcomes. This study is imperative because infertility affects 16% of the human population and the numbers of couples needing assistance continues to increase. Despite significant improvements in the technical aspects of assisted reproductive technologies (ART), the live birth rate has not increased proportionally. Overt genital tract infection has been associated with both infertility and adverse pregnancy outcomes (including miscarriage and preterm birth) as a direct result of the infection or the host response to it. Importantly, once inflammation had become established, medical treatment often failed to prevent these significant adverse outcomes. Current evaluations of fertility focus on the ovary as a site of steroid hormone production and ovulation. However, infertility as a result of subclinical colonisation of the ovary has not been reported. Furthermore, identification of the microorganisms present in follicular fluid and the local cytokine profile may provide clinicians with an early indication of the prognosis for IVF treatment in infertile couples, thus allowing antimicrobial treatment and/or counselling about possible IVF failure. During an IVF cycle, multiple oocytes undergo maturation in vivo in response to hormonal hyperstimulation. Oocytes for in vitro insemination are collected trans-vaginally. The follicular fluid that bathes the maturing oocyte in vivo, usually is discarded as part of the IVF procedure, but provides a unique opportunity to investigate microbial causes of adverse IVF outcomes. Some previous studies have identified follicular fluid markers that predict IVF pregnancy outcomes. However, there have not been any detailed microbiological studies of follicular fluid. For this current study, paired follicular fluid and vaginal secretion samples were collected from women undergoing IVF cycles to determine whether microorganisms in follicular fluid were associated with adverse IVF outcomes. Microorganisms in follicular fluid were regarded as either "colonisers" or "contaminants"; colonisers, if they were unique to the follicular fluid sample, and contaminants if the same microorganisms were detected in the vaginal and follicular fluid samples indicating that the follicular fluid was merely contaminated during the oocyte retrieval process. Quite unexpectedly, by these criteria, we found that follicular fluid from approximately 30% of all subjects was colonised with bacteria. Fertile and infertile women with colonised follicular fluid had decreased embryo transfer rates and decreased pregnancy rates compared to women with contaminated follicular fluids. The observation that follicular fluid was not always sterile, but contained a diverse range of microorganisms, is novel. Many of the microorganisms we detected in follicular fluid are known opportunistic pathogens that have been detected in upper genital tract infections and are associated with adverse pregnancy outcomes. Bacteria were able to survive for at least 28 weeks in vitro, in cultures of follicular fluid. Within 10 days of establishing these in vitro cultures, several species (Lactobacillus spp., Bifidobacterium spp., Propionibacterium spp., Streptococcus spp. and Salmonella entericus) had formed biofilms. Biofilms play a major role in microbial pathogenicity and persistence. The propensity of microbial species to form biofilms in follicular fluid suggests that successful treatment of these infections with antimicrobials may be difficult. Bifidobacterium spp. grew, in liquid media, only if concentrations of oestradiol and progesterone were similar to those achieved in vivo during an IVF cycle. In contrast, the growth of Streptococcus agalactiae and Escherichia coli was inhibited or abolished by the addition of these hormones to culture medium. These data suggest that the likelihood of microorganisms colonising follicular fluid and the species of bacteria involved is influenced by the stage of the menstrual cycle and, in the case of IVF, the nature and dose of steroid hormones administered for the maturation of multiple oocytes in vivo. Our findings indicate that the elevated levels of steroid hormones during an IVF cycle may influence the microbial growth within follicular fluid, suggesting that the treatment itself will impact on the microflora present in the female upper genital tract during pre-conception and early post-conception phases of the cycle. The effect of the host immune response on colonising bacteria and on the outcomes of IVF also was investigated. White blood cells reportedly compose between 5% and 15% of the cell population in follicular fluid. The follicular membrane is semi-permeable and cells are actively recruited as part of the normal menstrual cycle and in response to microorganisms. A previous study investigated follicular fluid cytokines from infertile women and fertile oocyte donors undergoing IVF, and concluded that there were no significant differences in the cytokine concentrations between the two groups. However, other studies have reported differences in the follicular fluid cytokine levels associated with infertile women with endometriosis or polycystic ovary syndrome. In this study, elevated levels of interleukin (IL)-1 á, IL-1 â and vascular endothelial growth factor (VEGF) in vaginal fluid were associated with successful fertilisation, which may be useful marker for successful fertilisation outcomes for women trying to conceive naturally or prior to oocyte retrieval for IVF. Elevated levels of IL-6, IL-12p40, granulocyte colony stimulating factor (GCSF) and interferon-gamma (IFN ã) in follicular fluid were associated with successful embryo transfer. Elevated levels of pro-inflammatory IL-18 and decreased levels of anti-inflammatory IL-10 were identified in follicular fluid from women with idiopathic infertility. Successful fertilisation and implantation is dependent on a controlled pro-inflammatory environment, involving active recruitment of pro-inflammatory mediators to the genital tract as part of the menstrual cycle and early pregnancy. However, ongoing pregnancy requires an enhanced anti-inflammatory environment to ensure that the maternal immune system does not reject the semi-allergenic foetus. The pro-inflammatory skew in the follicular fluid of women with idiopathic infertility, correlates with normal rates of fertilisation, embryo discard and embryo transfer, observed for this cohort, which were similar to the outcomes observed for fertile women. However, their pregnancy rate was reduced compared to fertile women. An altered local immune response in follicular fluid may provide a means of explaining infertility in this cohort, previously defined as 'idiopathic'. This study has found that microorganisms colonising follicular fluid may have contributed to adverse IVF and pregnancy outcomes. Follicular fluid bathes the cumulus oocyte complex during the in vivo maturation process, and microorganisms in the fluid, their metabolic products or the local immune response to these microorganisms may result in damage to the oocytes, degradation of the cumulus or contamination of the IVF culture system. Previous studies that have discounted bacterial contamination of follicular fluid as a cause of adverse IVF outcomes failed to distinguish between bacteria that were introduced into the follicular fluid at the time of trans-vaginal oocyte retrieval and those that colonised the follicular fluid. Those bacteria that had colonised the fluid may have had time to form biofilms and to elicit a local immune response. Failure to draw this distinction has previously prevented consideration of bacterial colonisation of follicular fluid as a cause of adverse IVF outcomes. Several observations arising from this study are of significance to IVF programs. Follicular fluid is not always sterile and colonisation of follicular fluid is a cause of adverse IVF and pregnancy outcomes. Hormonal stimulation associated with IVF may influence whether follicular fluid is colonised and enhance the growth of specific species of bacteria within follicular fluid. Bacteria in follicular fluid may form biofilms and literature has reported that this may influence their susceptibility to antibiotics. Monitoring the levels of selected cytokines within vaginal secretions may inform fertilisation outcomes. This study has identified novel factors contributing to adverse IVF outcomes and that are most likely to affect also natural conception outcomes. Early intervention, possibly using antimicrobial or immunological therapies may reduce the need for ART and improve reproductive health outcomes for all women.

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Reports of increasing numbers of obese Australian children and adolescents have raised the alarm to be proactive in reducing this so called epidemic. It has evoked a call for greater emphasis on teaching physical education in schools, as a measure for attaining fitness not only with obese students but for all students. This paper emphasises how preservice teachers need to be a key target for implementing physical education (PE) reform in schools, as many primary teachers will be generalists and may not be confident enough to implement PE effectively. Through a review of existing literature, teaching practices essential for the effective promotion and implementation of PE were identified under six broad categories: personal-professional skills development, addressing system requirements, pedagogical practices, managing student behaviour, providing feedback to students, and reflecting on practice. Subsequently, the development of these practices in preservice teachers is considered in the context of a university-school collaboration where preservice teachers taught physical education to primary school students for one day per week over a four week period. These authentic teaching experiences provided the preservice teachers with vital opportunities to put theory into practice and interact with “real-world” students. Self-evaluative data from 38 of these preservice teachers, in the form of a five-part Likert scale survey and extended response survey, demonstrated that they were able to develop the majority of the essential teaching practices identified by literature. In particular, the preservice teachers developed self efficacy, enthusiasm, and motivation for teaching PE, facets which are often found to be lacking in generalist primary teachers and yet are essential if children’s perceptions and habits regarding physical activity are to be changed.

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This research addresses whether educators should consider measuring if students have learned what was intended, as recommended by education researchers. Students in an Introductory Marketing subject were asked to complete a voluntary survey rating their own progress on the intended learning outcomes for the course. One hundred and one surveys were completed by students in the second-last teaching week of the semester. Student identification numbers were used to link student perceptions with their grade outcomes. Regression analysis was used to ascertain whether student perceptions of their progress on the intended learning outcomes for the course could be used to predict their grades. While the results were significant, student perceptions of their progress on learning outcomes were a poor predictor of grade outcomes. The results of this study suggest that student perceptions may not mirror the reality. These results are somewhat surprising and future research examining the degree of change in the learning outcomes perceived by students is warranted. This will further contribute to decisions surrounding whether educators should measure if students have learned what was intended.

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Significant numbers of children are severely abused and neglected by parents and caregivers. Infants and very young children are the most vulnerable and are unable to seek help. To identify these situations and enable child protection and the provision of appropriate assistance, many jurisdictions have enacted ‘mandatory reporting laws’ requiring designated professionals such as doctors, nurses, police and teachers to report suspected cases of severe child abuse and neglect. Other jurisdictions have not adopted this legislative approach, at least partly motivated by a concern that the laws produce dramatic increases in unwarranted reports, which, it is argued, lead to investigations which infringe on people’s privacy, cause trauma to innocent parents and families, and divert scarce government resources from deserving cases. The primary purpose of this paper is to explore the extent to which opposition to mandatory reporting laws is valid based on the claim that the laws produce ‘overreporting’. The first part of this paper revisits the original mandatory reporting laws, discusses their development into various current forms, explains their relationship with policy and common law reporting obligations, and situates them in the context of their place in modern child protection systems. This part of the paper shows that in general, contemporary reporting laws have expanded far beyond their original conceptualisation, but that there is also now a deeper understanding of the nature, incidence, timing and effects of different types of severe maltreatment, an awareness that the real incidence of maltreatment is far higher than that officially recorded, and that there is strong evidence showing the majority of identified cases of severe maltreatment are the result of reports by mandated reporters. The second part of this paper discusses the apparent effect of mandatory reporting laws on ‘overreporting’ by referring to Australian government data about reporting patterns and outcomes, with a particular focus on New South Wales. It will be seen that raw descriptive data about report numbers and outcomes appear to show that reporting laws produce both desirable consequences (identification of severe cases) and problematic consequences (increased numbers of unsubstantiated reports). Yet, to explore the extent to which the data supports the overreporting claim, and because numbers of unsubstantiated reports alone cannot demonstrate overreporting, this part of the paper asks further questions of the data. Who makes reports, about which maltreatment types, and what are the outcomes of those reports? What is the nature of these reports; for example, to what extent are multiple numbers of reports made about the same child? What meaning can be attached to an ‘unsubstantiated’ report, and can such reports be used to show flaws in reporting effectiveness and problems in reporting laws? It will be suggested that available evidence from Australia is not sufficiently detailed or strong to demonstrate the overreporting claim. However, it is also apparent that, whether adopting an approach based on public health and or other principles, much better evidence about reporting needs to be collected and analyzed. As well, more nuanced research needs to be conducted to identify what can reasonably be said to constitute ‘overreports’, and efforts must be made to minimize unsatisfactory reporting practice, informed by the relevant jurisdiction’s context and aims. It is also concluded that, depending on the jurisdiction, the available data may provide useful indicators of positive, negative and unanticipated effects of specific components of the laws, and of the strengths, weaknesses and needs of the child protection system.

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Insect monitoring and sampling programmes are used in the stored grains industry for the detection and estimation of insect pests. At the low pest densities dictated by economic and commercial requirements, the accuracy of both detection and abundance estimates can be influenced by variations in the spatial structure of pest populations over short distances. Geostatistical analysis of Rhyzopertha dominica populations in 2 dimensions showed that, in both the horizontal and vertical directions and at all temperatures examined, insect numbers were positively correlated over short (0-5cm) distances, and negatively correlated over longer (≥10cm) distances. Analysis in 3 dimensions showed a similar pattern, with positive correlations over short distances and negative correlations at longer distances. At 35°C, insects were located significantly further from the grain surface than at 25 and 30°C. Dispersion metrics showed statistically significant aggregation in all cases. This is the first research using small sample units, high sampling intensities, and a range of temperatures, to show spatial structuring of R. dominica populations over short distances. This research will have significant implications for sampling in the stored grains industry.

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In the past fifteen years, increasing attention has been given to the role of Vocational Education and Training (VET) in attracting large numbers of international students and its contribution to the economic development of Australia. This trend has given rise to many challenges in vocational education, especially with regard to providing quality education that ensures international students’ stay in Australia is a satisfactory experience. Teachers are key stakeholders in international education and share responsibility for ensuring international students gain quality learning experiences and positive outcomes. However, the challenges and needs of these teachers are generally not well understood. Therefore, this paper draws on the dilemmas faced by teachers of international students associated with professional, personal, ethical and educational aspects. This paper reports on a Masters Research project that is designed to investigate the dilemmas that teachers of international students face in VET in Australia, particularly in Brisbane. This study uses a qualitative approach within the interpretive constructivist paradigm to gain real-life insights through responsive interviewing and inductive data analysis. While the data collection has been done, the analysis of data is in progress. Responsive interviews with teachers of VET with different academic and national backgrounds, ages, industry experience have identified particular understandings, ideologies and representations of what it means to be a teacher in today's multicultural VET environment; provoking both resistances and new pedagogical understanding of teacher dilemmas and their work environment through the eyes of teachers of international students. The paper considers the challenges for the VET practitioners within the VET system while reflecting on the theme for the 2011 AVETRA conference, “Research in VET: Janus- Reflecting Back, Projecting Forward” by focusing particularly on “Rethinking pedagogies and pathways in VET work through the voice of VET workers”.

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Here we present a sequential Monte Carlo (SMC) algorithm that can be used for any one-at-a-time Bayesian sequential design problem in the presence of model uncertainty where discrete data are encountered. Our focus is on adaptive design for model discrimination but the methodology is applicable if one has a different design objective such as parameter estimation or prediction. An SMC algorithm is run in parallel for each model and the algorithm relies on a convenient estimator of the evidence of each model which is essentially a function of importance sampling weights. Other methods for this task such as quadrature, often used in design, suffer from the curse of dimensionality. Approximating posterior model probabilities in this way allows us to use model discrimination utility functions derived from information theory that were previously difficult to compute except for conjugate models. A major benefit of the algorithm is that it requires very little problem specific tuning. We demonstrate the methodology on three applications, including discriminating between models for decline in motor neuron numbers in patients suffering from neurological diseases such as Motor Neuron disease.

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‘Sustainability’ is a policy mantra of modern governments particularly in relation to natural resources. The traditional connection between land ownership and access to natural resources, such as forestry, flora, fauna, minerals, water and energy, has given rise to an unprecedented number of restrictions and obligations on land owners in their use of the land and resources. The growing numbers of statutory exceptions and restrictions on rights of ownership and use of a fee simple holder presents serious challenges for the utility of the Torrens register, which was originally designed to record private interests in land or affecting title to land. Advocates proposing uniform Torrens legislation should give consideration to an alignment of government policies emphasising sustainability as a core requirement of effective land use and management, and the core Torrens concepts of indefeasibility and security of title. This article examines the challenges for a uniform Torrens system created by increases statutory regulation of land ownership and makes recommendations about how an effective alignment of sustainability objectives and Torrens principles may be achieved.

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Geelong, Victoria’s second city, has an AFL football club whose culture and identity is closely tied to the city itself. An analysis of its playing group for the colonial period demonstrates that this local tribalism began early. As football became professionalised towards the end of the nineteenth century, country Victoria lost power in relative terms to metropolitan Melbourne: for example, Ballarat’s three main clubs lost their senior status. But Geelong, with its one remaining senior club, prospered and was admitted to the VFL ranks in 1897. The Geelong players were the sons and nephews of the Western District squattocracy and so had access to networks of power and influence. Many attended the prestigious Geelong Grammar School and the worthy Geelong College (in surprisingly equal numbers). They pursued careers both on the land and in professional roles, and maintained the social connections they had built through the club and other local institutions. Despite their elite standing, however, they continued to be regarded by the supporter base as an embodiment of the city and a defence against the city’s Melbourne critics that Geelong was a mere ‘sleepy hollow’.

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Natural convection in a triangular enclosure subject to non-uniformly cooling at the inclined surfaces and uniformly heating at the base is investigated numerically. The numerical simulations of the unsteady flows over a range of Rayleigh numbers and aspect ratios are carried out using Finite Volume Method. Since the upper surface is cooled and the bottom surface is heated, the air flow in the enclosure is potentially unstable to Rayleigh Benard instability. It is revealed that the transient flow development in the enclosure can be classified into three distinct stages; an early stage, a transitional stage and a steady stage. It is also found that the flow inside the enclosure strongly depends on the governing parameters; Rayleigh number and aspect ratio. The asymmetric behaviour of the flow about the geometric centre line is discussed in detailed. The heat transfer through the roof and the ceiling as a form of Nusselt number is also reported in this study.

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This paper will focus on the group of people who were born between 1946 and 1962 immediately after the Second World War when servicemen and women returned from the forces and started families. They have been named the baby boomers because of their numbers. In Australia it is estimated that there are four million baby boomers who are approaching retirement age. The paper raises the question of whether the attitudes we have about older workers need to change and mature. Evidence for questioning entrenched myths about older staff in the work force will be discussed.

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Objective: To (1) search the English-language literature for original research addressing the effect of cryotherapy on joint position sense (JPS) and (2) make recommendations regarding how soon healthy athletes can safely return to participation after cryotherapy. Data Sources: We performed an exhaustive search for original research using the AMED, CINAHL, MEDLINE, and SportDiscus databases from 1973 to 2009 to gather information on cryotherapy and JPS. Key words used were cryotherapy and proprioception, cryotherapy and joint position sense, cryotherapy, and proprioception. Study Selection: The inclusion criteria were (1) the literature was written in English, (2) participants were human, (3) an outcome measure included JPS, (4) participants were healthy, and (5) participants were tested immediately after a cryotherapy application to a joint. Data Extraction: The means and SDs of the JPS outcome measures were extracted and used to estimate the effect size (Cohen d) and associated 95% confidence intervals for comparisons of JPS before and after a cryotherapy treatment. The numbers, ages, and sexes of participants in all 7 selected studies were also extracted. Data Synthesis: The JPS was assessed in 3 joints: ankle (n 5 2), knee (n 5 3), and shoulder (n 5 2). The average effect size for the 7 included studies was modest, with effect sizes ranging from 20.08 to 1.17, with a positive number representing an increase in JPS error. The average methodologic score of the included studies was 5.4/10 (range, 5–6) on the Physiotherapy Evidence Database scale. Conclusions: Limited and equivocal evidence is available to address the effect of cryotherapy on proprioception in the form of JPS. Until further evidence is provided, clinicians should be cautious when returning individuals to tasks requiring components of proprioceptive input immediately after a cryotherapy treatment.

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In the late twentieth and early twenty-first centuries, Australia’s relationship with its Asian neighbours has been the subject of ongoing aesthetic, cultural and political contestations. As Alison Richards has noted, Australia’s colonial legacy, its Asia-Pacific location, and its ‘white’ self-perception have always made Australia’s relations with Asia fraught. In the latter part of the twentieth century, the paradoxes inherent in Australia’s relationships with and within the Asian region became a dominant theme in debates about nation, nationhood and identity, and prompted a shift in the construction of ‘Asianness’ on Australian stages. On the one hand, anxiety about the multicultural policy of the 1970s and 1980s, and then Prime Minister Paul Keating’s push for greater economic, cultural and artistic exchange with Asia via policies such as the Creative Nation Cultural Policy (1994), saw large numbers of Australians latch on to the reactionary, racist politics of Pauline Hanson’s One Nation Party. As Jacqueline Lo has argued, in this period Asian-Australians were frequently represented as an unassimilable Other, a threat to Australia’s ‘white’ identity, and to individual Australians’ jobs and opportunities. On the other hand, during the same period, a desire to counter the racism in Australian culture, and develop a ‘voice’ that would distinguish Australian cultural products from European theatrical traditions, combined with the new opportunities for cross-cultural exchange that came with the Creative Nation Cultural Policy to produce what Helen Gilbert and Jacqueline Lo have characterised as an Asian turn in Australian theatre...

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The opening phrase of the title is from Charles Darwin’s notebooks (Schweber 1977). It is a double reminder, firstly that mainstream evolutionary theory is not just about describing nature but is particularly looking for mechanisms or ‘causes’, and secondly, that there will usually be several causes affecting any particular outcome. The second part of the title is our concern at the almost universal rejection of the idea that biological mechanisms are sufficient for macroevolutionary changes, thus rejecting a cornerstone of Darwinian evolutionary theory. Our primary aim here is to consider ways of making it easier to develop and to test hypotheses about evolution. Formalizing hypotheses can help generate tests. In an absolute sense, some of the discussion by scientists about evolution is little better than the lack of reasoning used by those advocating intelligent design. Our discussion here is in a Popperian framework where science is defined by that area of study where it is possible, in principle, to find evidence against hypotheses – they are in principle falsifiable. However, with time, the boundaries of science keep expanding. In the past, some aspects of evolution were outside the current boundaries of falsifiable science, but increasingly new techniques and ideas are expanding the boundaries of science and it is appropriate to re-examine some topics. It often appears that over the last few decades there has been an increasingly strong assumption to look first (and only) for a physical cause. This decision is virtually never formally discussed, just an assumption is made that some physical factor ‘drives’ evolution. It is necessary to examine our assumptions much more carefully. What is meant by physical factors ‘driving’ evolution, or what is an ‘explosive radiation’. Our discussion focuses on two of the six mass extinctions, the fifth being events in the Late Cretaceous, and the sixth starting at least 50,000 years ago (and is ongoing). Cretaceous/Tertiary boundary; the rise of birds and mammals. We have had a long-term interest (Cooper and Penny 1997) in designing tests to help evaluate whether the processes of microevolution are sufficient to explain macroevolution. The real challenge is to formulate hypotheses in a testable way. For example the numbers of lineages of birds and mammals that survive from the Cretaceous to the present is one test. Our first estimate was 22 for birds, and current work is tending to increase this value. This still does not consider lineages that survived into the Tertiary, and then went extinct later. Our initial suggestion was probably too narrow in that it lumped four models from Penny and Phillips (2004) into one model. This reduction is too simplistic in that we need to know about survival and ecological and morphological divergences during the Late Cretaceous, and whether Crown groups of avian or mammalian orders may have existed back into the Cretaceous. More recently (Penny and Phillips 2004) we have formalized hypotheses about dinosaurs and pterosaurs, with the prediction that interactions between mammals (and groundfeeding birds) and dinosaurs would be most likely to affect the smallest dinosaurs, and similarly interactions between birds and pterosaurs would particularly affect the smaller pterosaurs. There is now evidence for both classes of interactions, with the smallest dinosaurs and pterosaurs declining first, as predicted. Thus, testable models are now possible. Mass extinction number six: human impacts. On a broad scale, there is a good correlation between time of human arrival, and increased extinctions (Hurles et al. 2003; Martin 2005; Figure 1). However, it is necessary to distinguish different time scales (Penny 2005) and on a finer scale there are still large numbers of possibilities. In Hurles et al. (2003) we mentioned habitat modification (including the use of Geogenes III July 2006 31 fire), introduced plants and animals (including kiore) in addition to direct predation (the ‘overkill’ hypothesis). We need also to consider prey switching that occurs in early human societies, as evidenced by the results of Wragg (1995) on the middens of different ages on Henderson Island in the Pitcairn group. In addition, the presence of human-wary or humanadapted animals will affect the distribution in the subfossil record. A better understanding of human impacts world-wide, in conjunction with pre-scientific knowledge will make it easier to discuss the issues by removing ‘blame’. While continued spontaneous generation was accepted universally, there was the expectation that animals continued to reappear. New Zealand is one of the very best locations in the world to study many of these issues. Apart from the marine fossil record, some human impact events are extremely recent and the remains less disrupted by time.