Health governance : law, regulation and policy

This special issue of Public Health is devoted to health governance, examining the role of law, regulation and policy in safeguarding the public's health. Each of us has devoted a career to thinking carefully about the role of law as a tool to prevent injury and disease and to promote the population's health and wellbeing. 1, 2, 3 and 4 In this Guest Editorial we first explain what we mean by the term ‘governance’, as well as the role of law in a well-regulated society. Next, we explore the increasingly important, and challenging, concept of what we call national and global federalism—the inter-relationships among the various levels of governance (local, national, supranational and transnational) and among various actors in national and global health. Third, we explain the origins of this journal symposium, which arises from three conferences on the topic in Hong Kong and Sydney. Finally, we offer a brief introduction to the articles that follow.

Registration of clinical trials: Challenges for global regulation

In 2004 the International Committee of Medical Journal Editors (ICMJE) issued a statement indicating that from 1 July 2005 registration in a publicly accessible trials registry would be a condition of publication in an ICMJE member journal. The World Health Organisation is coordinating the International Clinical Trials Registry Platform (ICTRP) as a means of providing a standardised framework for registration. This article considers the practical challenges and opportunities that arise from these developments and considers the relevance of trial registration for women and minorities and for developing countries.

Manoeuvring control of underactuated surface vessels using manifold regulation for Port-Hamiltonian systems

This paper considers the manoeuvring of underactuated surface vessels. The control objective is to steer the vessel to reach a manifold which encloses a waypoint. A transformation of configuration variables and a potential field are used in a Port-Hamiltonian framework to design an energy-based controller. With the proposed controller, the geometric task associated with the manoeuvring problem depends on the desired potential energy (closed-loop) and the dynamic task depends on the total energy and damping. Therefore, guidance and motion control are addressed jointly, leading to model-energy-based trajectory generation.

Genetic technologies and the regulation of reproductive decision-making in Australia

This article provides a critical analysis of the current Australian regulatory landscape at the interface between genetics and reproductive decision- making. The authors argue that a comparative analysis with other countries and international law and a contextual examination of the way law regulates concepts such as disease and health, abnormality and normality is necessary before we can develop appropriate policy and legislative responses in this area. Specific genetic testing technologies are considered including prenatal genetic testing, preimplantation genetic diagnosis and inheritable genetic modification. An increasing number of members of the Australian community are using genetic testing technologies when they decide to have a baby. The authors argue that as concepts of disease and health vary among members of the community and the potential to test for traits other than illness increases, a new tension arises between an ethic of individual choice and a role for government in regulating reproductive decision-making.

Epigenetic inactivation of chalcone synthase-A transgene transcription in petunia leads to a reversion of the post-transcriptional gene silencing phenotype

Petunia plants that exhibit a white-flowering phenotype as a consequence of chalcone synthase transgene-induced silencing occasionally give rise to revertant branches that produce flowers with wild-type pigmentation. Transcription run-on assays confirmed that the production of white flowers is caused by post-transcriptional gene silencing (PTGS), and indicated that transgene transcription is repressed in the revertant plants, providing evidence that induction of PTGS depends on the transcription rate. Transcriptional repression of the transgene was associated with cytosine methylation at CpG, CpNpG and CpNpN sites, and the expression was restored by treatment with either 5-azacytidine or trichostatin A. These results demonstrate that epigenetic changes occurred in the PTGS line, and these changes interfere with the initiation of transgene transcription, leading to a reversion of the PTGS phenotype.

Physical activity, self-regulation, and early academic achievement in preschool children

Research Findings The present study investigated whether active play during recess was associated with self-regulation and academic achievement in a prekindergarten sample. A total of 51 children in classes containing approximately half Head Start children were assessed on self-regulation, active play, and early academic achievement. Path analyses indicated that higher active play was associated with better self-regulation, which in turn was associated with higher scores on early reading and math assessments. Practice or Policy Results point to the benefits of active play for promoting self-regulation and offer insight into possible interventions designed to promote self-regulation and academic achievement.

Self-regulation from birth to age seven : associations with maternal mental health, parenting, and social, emotional and behavioural outcomes for children

Self-regulation refers to our individual capacities to regulate our behaviours, emotions, and thoughts, with these skills developing rapidly across early childhood. This thesis examined sleep, emotional, and cognitive regulation development, and related parental influences, for children participating in the Longitudinal Study of Australian Children. Important longitudinal associations among children's self-regulation, maternal mental health, parenting, and later behaviour problems for children were also investigated. A unique contribution of this research was a prevalence estimate of early childhood self-regulation problems in Australian children that was documented for the first time.

A rapid transcriptional activation is induced by the dormancy-breaking chemical hydrogen cyanamide in kiwifruit (Actinidia deliciosa) buds

Budbreak in kiwifruit (Actinidia deliciosa) can be poor in locations that have warm winters with insufficient winter chilling. Kiwifruit vines are often treated with the dormancy-breaking chemical hydrogen cyanamide (HC) to increase and synchronize budbreak. This treatment also offers a tool to understand the processes involved in budbreak. A genomics approach is presented here to increase our understanding of budbreak in kiwifruit. Most genes identified following HC application appear to be associated with responses to stress, but a number of genes appear to be associated with the reactivation of growth. Three patterns of gene expression were identified: Profile 1, an HC-induced transient activation; Profile 2, an HC-induced transient activation followed by a growth-related activation; and Profile 3, HC- and growth-repressed. One group of genes that was rapidly up-regulated in response to HC was the glutathione S-transferase (GST) class of genes, which have been associated with stress and signalling. Previous budbreak studies, in three other species, also report up-regulated GST expression. Phylogenetic analysis of these GSTs showed that they clustered into two sub-clades, suggesting a strong correlation between their expression and budbreak across species.

Regulation of ROCK1 via Notch1 during breast cancer cell migration into dense matrices

Background The behaviour of tumour cells depends on factors such as genetics and the tumour microenvironment. The latter plays a crucial role in normal mammary gland development and also in breast cancer initiation and progression. Breast cancer tissues tend to be highly desmoplastic and dense matrix as a pre-existing condition poses one of the highest risk factors for cancer development. However, matrix influence on tumour cell gene expression and behaviour such as cell migration is not fully elucidated. Results We generated high-density (HD) matrices that mimicked tumour collagen content of 20 mg/cm3 that were ~14-fold stiffer than low-density (LD) matrix of 1 mg/cm3. Live-cell imaging showed breast cancer cells utilizing cytoplasmic streaming and cell body contractility for migration within HD matrix. Cell migration was blocked in the presence of both the ROCK inhibitor, Y-27632, and the MMP inhibitor, GM6001, but not by the drugs individually. This suggests roles for ROCK1 and MMP in cell migration are complicated by compensatory mechanisms. ROCK1 expression and protein activity, were significantly upregulated in HD matrix but these were blocked by treatment with a histone deacetylase (HDAC) inhibitor, MS-275. In HD matrix, the inhibition of ROCK1 by MS-275 was indirect and relied upon protein synthesis and Notch1. Inhibition of Notch1 using pooled siRNA or DAPT abrogated the inhibition of ROCK1 by MS-275. Conclusion Increased matrix density elevates ROCK1 activity, which aids in cell migration via cell contractility. The upregulation of ROCK1 is epigenetically regulated in an indirect manner involving the repression of Notch1. This is demonstrated from inhibition of HDACs by MS-275, which caused an upregulation of Notch1 levels leading to blockade of ROCK1 expression.

Epithelial to mesenchymal transition and breast cancer

Epithelial-mesenchymal plasticity in breast carcinoma encompasses the phenotypic spectrum whereby epithelial carcinoma cells within a primary tumor acquire mesenchymal features and re-epithelialize to form a cohesive secondary mass at a metastatic site. Such plasticity has implications in progression of breast carcinoma to metastasis, and will likely influence response to therapy. The transcriptional and epigenetic regulation of molecular and cellular processes that underlie breast cancer and result in characteristic changes in cell behavior can be monitored using an increasing array of marker proteins. Amongst these markers exists the potential for emergent prognostic, predictive and therapeutic targeting.

Sphingosine-1-phosphate, a novel second messenger involved in cell growth regulation and signal transduction, affects growth and invasiveness of human breast cancer cells

This review will focus on the role of sphingosine and its phosphorylated derivative sphingosine-1-phosphate (SPP) in cell growth regulation and signal transduction. We will show that many of the effects attributed to sphingosine in quiescent Swiss 3T3 fibroblasts are mediated via its conversion to SPP. We propose that SPP has appropriate properties to function as an intracellular second messenger based on the following: it elicits diverse cellular responses; it is rapidly produced from sphingosine by a specific kinase and rapidly degraded by a specific lyase; its concentration is low in quiescent cells but increases rapidly and transiently in response to the growth factors, fetal calf serum (FCS) and platelet derived growth factor (PDGF); it releases Ca2+ from internal sources in an InsP3-independent manner; and finally, it may link sphingolipid signaling pathways to cellular ras-mediated signaling pathways by elevating phosphatidic acid levels. The effects of this novel second messenger on growth, differentiation and invasion of human breast cancer cells will be discussed. © 1994 Kluwer Academic Publishers.

Taxation determinations as de facto regulation : private equity exits in Australia

The Australian Taxation Office (AT)) attempted to challenge both the private equity fund reliance on double tax agreements and the assertion that profits were capital in nature in its dispute with private equity group TPG. Failure to resolve the dispute resulted in the ATO issuing two taxation determinations: TD 2010/20 which states that the general anti-avoidance provisions can apply to arrangements designed to alter the intended effect of Australia's international tax agreements net; and TD 2010/21 which states that the profits on the sale of shares in a company group acquired in a leveraged buyout is assessable income. The purpose of this article is to determine the effectiveness of the administrative rulings regime as a regulatory strategy. This article, by using the TPG-Myer scenario and subsequent tax determinations as a case study, collects qualitative data which is then analysed (and triangulated) using tonal and thematic analysis. Contemporaneous commentary of private equity stakeholders, tax professionals, and media observations are analysed and evaluated within a framework of responsive regulation and utilising the current ATO compliance model. Contrary to the stated purpose of the ATO rulings regime to alleviate complexities in Australian taxation law and provide certainty to taxpayers, and despite the de facto law status afforded these rulings, this study found that the majority of private equity stakeholders and their advisors perceived that greater uncertainty was created by the two determinations. Thus, this study found that in the context of private equity fund investors, a responsive regulation measure in the form of taxation determinations was not effective.

Differential regulation of growth and invasiveness of MCF-7 breast cancer cells by antiestrogens

Estrogen increases the ability of the estrogen-dependent MCF-7 human breast cancer cell line to both proliferate and invade through an artificial basement membrane. In studying the response of MCF-7 cells to various antiestrogens, we found that 4-hydroxytamoxifen and tamoxifen inhibited cell proliferation but increased their invasiveness. In contrast, the structurally unrelated benzothiophene antiestrogens, LY117018 and LY156758, were potent antiproliferative agents which did not stimulate invasiveness. The differential effects of these antiestrogenic agents on invasion correlated with changes in production of collagenase IV, while no significant change was seen in the chemotactic activity of the cells. Invasiveness was increased by 17β-estradiol or 4-hydroxytamoxifen after a few hours of treatment and was rapidly lost when 17β-estradiol was withdrawn. Stimulation of invasiveness with 17β-estradiol was blocked by the antiestrogen, LY117018. Cells from the MDA-MB-231 line which lacks estrogen receptors were not affected by estrogen or antiestrogen in terms of proliferation or invasion. These studies indicate that the invasiveness of MCF-7 cells is regulated by antiestrogens through the estrogen receptor and may be mediated by collagenase IV activity. Antiestrogens which reduce both the proliferation and invasiveness of these cells may be interesting new candidates for clinical application.