Neuroimaging and genetics: Exploring, searching, and finding

This issue on the genetics of brain imaging phenotypes is a celebration of the happy marriage between two of science's highly interesting fields: neuroscience and genetics. The articles collected here are ample evidence that a good deal of synergy exists in this marriage. A wide selection of papers is presented that provide many different perspectives on how genes cause variation in brain structure and function, which in turn influence behavioral phenotypes (including psychopathology). They are examples of the many different methodologies in contemporary genetics and neuroscience research. Genetic methodology includes genome-wide association (GWA), candidate-gene association, and twin studies. Sources of data on brain phenotypes include cortical gray matter (GM) structural/volumetric measures from magnetic resonance imaging (MRI); white matter (WM) measures from diffusion tensor imaging (DTI), such as fractional anisotropy; functional- (activity-) based measures from electroencephalography (EEG), and functional MRI (fMRI). Together, they reflect a combination of scientific fields that have seen great technological advances, whether it is the single-nucleotide polymorphism (SNP) array in genetics, the increasingly high-resolution MRI imaging, or high angular resolution diffusion imaging technique for measuring WM connective properties.

Sexual harassment in the medical profession: Legal and ethical responsibilities

Sexual harassment of women in medicine in the Australian medical profession is a serious problem which presents substantial legal, ethical and cultural questions for the medical profession. Women have enforceable legal rights to gender equality and freedom from sexual harassment in the workplace. Both individual offenders and their employers face significant legal consequences for sexual harassment. Individual medical practitioners and employers need to understand their legal and ethical responsibilities in this context. This article analyses four areas of legal liability in every State and Territory which apply to individual offenders and employers: criminal law, discrimination law, civil law, and contract law. It also analyses ethical duties owed by doctors towards their colleagues under professional regulatory schemes. The analysis shows that individual doctors and their employers have clear legal and ethical obligations to prevent sexual harassment. On legal and ethical grounds, medical employers, professional colleges and associations, and regulators need to improve gender equality and professional culture in medicine. A five-step model for cultural change is proposed.

Miami heat: Patent law, informed consent and benefit-sharing

This article considers whether the granting of patents in respect of biomedical genetic research should be conditional upon the informed consent of research participants. It focuses upon several case studies. In Moore v the Regents of the University Of California, a patient sued his physician for breach of fiduciary duty and lack of informed consent, because the doctor had obtained a patent on the patient's cell line, without the patient's authorisation. In Greenberg v Miami Children's Hospital, the research participants, the Greenbergs, the National Tay Sachs and Allied Diseases Association, and Dor Yeshorim brought a legal action against the geneticist Reubon Matalon and the Miami Children's Hospital over a patent obtained on a gene related to the Canavan disease and accompany genetic diagnostic test. PXE International entered into a joint venture with Charles Boyd and the University of Hawaii, and obtained a patent together for ‘methods for diagnosing Pseudoxanthoma elasticum’. In light of such case studies, it is contended that there is a need to reform patent law, so as to recognise the bioethical principles of informed consent and benefit-sharing. The 2005 UNESCO Declaration on Bioethics and Human Rights provides a model for future case law and policy-making.

Let’s talk about lex: Narrative analysis as both research method and teaching technique in law

Law is narration: it is narrative, narrator and the narrated. As a narrative, the law is constituted by a constellation of texts – from official sources such as statutes, treaties and cases, to private arrangements such as commercial contracts, deeds and parenting plans. All are a collection of stories: cases are narrative contests of facts and rights; statutes are recitations of the substantive and procedural bases for social, economic and political interactions; private agreements are plots for future relationships, whether personal or professional. As a narrator, law speaks in the language of modern liberalism. It describes its world in abstractions rather than in concrete experience, universal principles rather than individual subjectivity. It casts people into ‘parties’ to legal relationships; structures human interactions into ‘issues’ or ‘problems’; and tells individual stories within larger narrative arcs such as ‘the rule of law’ and ‘the interests of justice’. As the narrated, the law is a character in its own story. The scholarship of law, for example, is a type of story-telling with law as its central character. For positivists, still the dominant group in the legal genre, law is a closed system of formal rules with an “immanent rationality” and its own “structure, substantive content, procedure and tradition,” dedicated to finality of judgment. For scholars inspired by the interpretative tradition in the humanities, law is a more ambivalent character, susceptible to influences from outside its realm and masking a hidden ideological agenda under its cloak of universality and neutrality. For social scientists, law is a protagonist on a wider social stage, impacting on society, the economy and the polity is often surprising ways.

Prevalence of retinopathy among adults with self-reported diabetes mellitus: the Sri Lanka diabetes and Cardiovascular Study

Background: At present there are no large scale nationally-representative studies from Sri Lanka on the prevalence and associations of Diabetic Retinopathy (DR). The present study aims to evaluate the prevalence and risk factors for DR in a community-based nationally-representative sample of adults with self-reported diabetes mellitus from Sri Lanka. Methods: A cross-sectional community-based national study among 5,000 adults (≥18 years) was conducted in Sri Lanka, using a multi-stage stratified cluster sampling technique. An interviewer-administered questionnaire was used to collect data. Ophthalmological evaluation of patients with ‘known’ diabetes (previously diagnosed at a government hospital or by a registered medical practitioner) was done using indirect ophthalmoscopy. A binary-logistic regression analysis was performed with ‘presence of DR’ as the dichotomous dependent variable and other independent covariates. Results: Crude prevalence of diabetes was 12.0%(n=536),of which 344 were patients with ‘known’ diabetes.Mean age was 56.4 ± 10.9 years and 37.3% were males. Prevalence of any degree of DR was 27.4% (Males-30.5%, Females-25.6%; p = 0.41). In patients with DR, majority had NPDR (93.4%), while 5.3% had maculopathy. Patients with DR had a significantly longer duration of diabetes than those without. In the binary-logistic regression analysis in all adults duration of diabetes (OR:1.07), current smoking (OR:1.67) and peripheral neuropathy (OR:1.72)all were significantly associated with DR. Conclusions: Nearly 1/3rd of Sri Lankan adults with self-reported diabetes are having retinopathy. DR was associated with diabetes duration, cigarette smoking and peripheral neuropathy. However, further prospective follow up studies are required to establish causality for identified risk factors

Characteristics of microbial drug resistance and its correlates in chronic diabetic foot ulcer infections

While virulence factors and the biofilm-forming capabilities of microbes are the key regulators of the wound healing process, the host immune response may also contribute in the events following wound closure or exacerbation of non-closure. We examined samples from diabetic and non-diabetic foot ulcers/wounds for microbial association and tested the microbes for their antibiotic susceptibility and ability to produce biofilms. A total of 1074 bacterial strains were obtained with staphylococci, Pseudomonas, Citrobacter and enterococci as major colonizers in diabetic samples. Though non-diabetic samples had a similar assemblage, the frequency of occurrence of different groups of bacteria was different. Gram-negative bacteria were found to be more prevalent in the diabetic wound environment while Gram-positive bacteria were predominant in non-diabetic ulcers. A higher frequency of monomicrobial infection was observed in samples from non-diabetic individuals when compared to samples from diabetic patients. The prevalence of different groups of bacteria varied when the samples were stratified according to age and sex of the individuals. Several multidrug-resistant strains were observed among the samples tested and most of these strains produced moderate to high levels of biofilms. The weakened immune response in diabetic individuals and synergism among pathogenic micro-organisms may be the critical factors that determine the delicate balance of the wound healing process.

Exploring the nexus between tourism and output in Cook Islands: An ARDL bounds approach

Tourism plays an important role in the development of Cook Islands. In this paper we examine the nexus between tourism and growth using quarterly data over the period 2009Q1–2014Q2 using the recently upgraded ARDL bounds test to cointegration tool, Microfit 5.01, which provides sample adjusted bounds and hence is more reliable for small sample size studies. We perform the cointegration using the ARDL bounds test and examine the direction of causality. Using visitor arrival and output in per capita terms as respective proxy for tourism development and growth, we examine the long-run association and report the elasticity coefficient of tourism and causality nexus, accordingly. Using unit root break tests, we note that 2011Q1 and 2011Q2 are two structural break periods in the output series. However, we note that this period is not statistically significant in the ARDL model and hence excluded from the estimation. Subsequently, the regression results show the two series are cointegrated. The long-run elasticity coefficient of tourism is estimated to be 0.83 and the short-run is 0.73. A bidirectional causality between tourism and income is noted for Cook Islands which indicates that tourism development and income mutually reinforce each other. In light of this, socio-economic policies need to focus on broad-based, inclusive and income-generating tourism development projects which are expected to have feedback effect.

Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants

We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.

Influence of LRP5 polymorphisms on normal variation in BMD

Genetic studies based on cohorts with rare and extreme bone phenotypes have shown that the LRP5 gene is an important genetic modulator of BMD. Using family-based and case-control approaches, this study examines the role of the LRP5 gene in determining normal population variation of BMD and describes significant association and suggestive linkage between LRP5 gene polymorphisms and BMD in >900 individuals with a broad range of BMD. Introduction: Osteoporosis is a common, highly heritable condition determined by complex interactions of genetic and environmental etiologies. Genetic factors alone can account for 50-80% of the interindividual variation in BMD. Mutations in the LRP5 gene on chromosome 11q12-13 have been associated with rare syndromes characterized by extremely low or high BMD, but little is known about the contribution of this gene to the development of osteoporosis and determination of BMD in a normal population. Materials and Methods: To examine the entire spectrum of low to high BMD, 152 osteoporotic probands, their families (597 individuals), and 160 women with elevated BMD (T score > 2.5) were recruited. BMD at the lumbar spine, femoral neck, and hip were measured in each subject using DXA. Results: PAGE sequencing of the LRP5 gene revealed 10 single nucleotide polymorphisms (SNPs), 8 of which had allele frequencies of >5%, in exons 8, 9, 10, 15, and 18 and in introns 6, 7, and 21. Within families, a strong association was observed between an SNP at nucleotide C171346A in intron 21 and total hip BMD (p < 1 × 10-5 in men only, p = 0.0019 in both men and women). This association was also observed in comparisons of osteoporotic probands and unrelated elevated BMD in women (p = 0.03), along with associations with markers in exons 8 (C135242T, p = 0.007) and 9 (C141759T, p = 0.02). Haplotypes composed of two to three of the SNPs G121513A, C135242T, G138351A, and C141759T were strongly associated with BMD when comparing osteoporotic probands and high BMD cases (p < 0.003). An SNP at nucleotide C165215T in exon 18 was linked to BMD at the lumbar spine, femoral neck, and total hip (parametric LOD scores = 2.8, 2.5, and 2.2 and nonparametric LOD scores = 0.3, 1.1, and 2.2, respectively) but was not genetically associated with BMD variation. Conclusion: These results show that common LRP5 polymorphisms contribute to the determination of BMD in the general population.

Phoenix activity: Regulatory challenges and the law

Remedying the mischief of phoenix activity is of practical importance. The benefits include continued confidence in our economy, law that inspires best practice among directors, and law that is articulated in a manner such that penalties act as a sufficient deterrent and the regulatory system is able to detect offenders and bring them to account. Any further reforms must accommodate and tolerate legal phoenix activity. Phoenix activity pushes tolerance of entrepreneurial activity to its absolute limits. The wisest approach would be to front end the reforms so as to alleviate the considerable detection and enforcement burden upon regulatory bodies. There is little doubt that breach of the existing law is difficult and expensive to detect; and this is a significant burden when regulators have shrinking budgets and are rapidly losing feet on the ground. This front end approach may need to include restrictions on access to limited liability. The more limited liability is misused, the stronger the argument to limit access to limited liability. This paper proposes that such an approach is a legitimate next step for a robust and mature capitalist economy.

The conundrum of phoenix activity in Australia: Is further reform necessary?

Corporate phoenixing activity is estimated to cost the Australian economy $1-3 billion dollars annually. Significant questions arise as to whether existing legal frameworks are adequate to deal with phoenix activity, and whether further reform is necessary. Bills proposing reform appear to be languishing amid doubts as to their potential effectiveness. This paper will examine the conundrum presented by phoenix activity, the importance of further reform and the impact of the lack of a statutory definition of ‘phoenix activity’ on a regulatory environment that not only uses the term, but punishes offenders accused of it.

Economic theory informing approaches to phoenix activity in small business: A neo-Schumpeterian analysis

The adequacy and efficiency of existing legal and regulatory frameworks dealing with corporate phoenix activity have been repeatedly called into question over the past two decades through various reviews, inquiries, targeted regulatory operations and the implementation of piecemeal legislative reform. Despite these efforts, phoenix activity does not appear to have abated. While there is no law in Australia that declares ‘phoenix activity’ to be illegal, the behaviour that tends to manifest in phoenix activity can be capable of transgressing a vast array of law, including for example, corporate law, tax law, and employment law. This paper explores the notion that the persistence of phoenix activity despite the sheer extent of this law suggests that the law is not acting as powerfully as it might as a deterrent. Economic theories of entrepreneurship and innovation can to some extent explain why this is the case and also offer a sound basis for the evaluation and reconsideration of the existing law. The challenges facing key regulators are significant. Phoenix activity is not limited to particular corporate demographic: it occurs in SMEs, large companies and in corporate groups. The range of behaviour that can amount to phoenix activity is so broad, that not all phoenix activity is illegal. This paper will consider regulatory approaches to these challenges via analysis of approaches to detection and enforcement of the underlying law capturing illegal phoenix activity. Remedying the mischief of phoenix activity is of practical importance. The benefits include continued confidence in our economy, law that inspires best practice among directors, and law that is articulated in a manner such that penalties act as a sufficient deterrent and the regulatory system is able to detect offenders and bring them to account. Any further reforms must accommodate and tolerate legal phoenix activity, at least to some extent. Even then, phoenix activity pushes tolerance of repeated entrepreneurial failure to its absolute limit. The more limited liability is misused and abused, the stronger the argument to place some restrictions on access to limited liability. This paper proposes that such an approach is a legitimate next step for a robust and mature capitalist economy.

More equal than others?: Meeting the professional development needs of rural primary and secondary science teachers

It is often assumed that teachers in rural and remote schools are at a disadvantage when it comes to accessing professional development. But is there sufficient evidence to support this assumption? This paper reports findings from two national surveys comparing the professional development priorities of primary and secondary science teachers from metropolitan, provincial and remote schools. The research found that while teachers' unmet needs for some PD opportunities increased significantly with school remoteness, this was not the case for all opportunities. In teasing out the different PD priorities of primary and secondary science teachers, the paper provides evidence to help education authorities and professional organisations address the specific needs of teachers in different locations.

Is corporate rescue a realistic ideal? Business as usual in Australia and the United Kingdom

This paper seeks to review the operation of Australian corporate law rescue regimes in the context of those originally contemplated by Sir Kenneth Cork and more latterly in Australia, primarily in the hands of Ron Harmer. In doing so, it draws upon some of the observations made by Professor Fletcher in the second wave of 20th century corporate rescue reform in the United Kingdom.

Engineered protease inhibitors based on sunflower trypsin inhibitor-1 (SFTI-1) provide insights into the role of sequence and conformation in Laskowski mechanism inhibition

Laskowski inhibitors regulate serine proteases by an intriguing mode of action that involves deceiving the protease into synthesizing a peptide bond. Studies exploring naturally occurring Laskowski inhibitors have uncovered several structural features that convey the inhibitor's resistance to hydrolysis and exceptional binding affinity. However, in the context of Laskowski inhibitor engineering, the way that various modifications intended to fine-tune an inhibitor's potency and selectivity impact on its association and dissociation rates remains unclear. This information is important as Laskowski inhibitors are becoming increasingly used as design templates to develop new protease inhibitors for pharmaceutical applications. In this study, we used the cyclic peptide, sunflower trypsin inhibitor-1 (SFTI-1), as a model system to explore how the inhibitor's sequence and structure relate to its binding kinetics and function. Using enzyme assays, MD simulations and NMR spectroscopy to study SFTI variants with diverse sequence and backbone modifications, we show that the geometry of the binding loop mainly influences the inhibitor's potency by modulating the association rate, such that variants lacking a favourable conformation show dramatic losses in activity. Additionally, we show that the inhibitor's sequence (including both the binding loop and its scaffolding) influences its potency and selectivity by modulating both the association and the dissociation rates. These findings provide new insights into protease inhibitor function and design that we apply by engineering novel inhibitors for classical serine proteases, trypsin and chymotrypsin and two kallikrein-related peptidases (KLK5 and KLK14) that are implicated in various cancers and skin diseases.