Familial recurrence risks for multiple sclerosis in Australia

BACKGROUND: Genetic susceptibility to multiple sclerosis (MS) has been recognised for many years. Considerable data exist from the northern hemisphere regarding the familial recurrence risks for MS, but there are few data for the southern hemisphere and regions at lower latitude such as Australia. To investigate the interaction between environmental and genetic causative factors in MS, the authors undertook a familial recurrence risk study in three latitudinally distinct regions of Australia. METHODS: Immediate and extended family pedigrees have been collected for three cohorts of people with MS in Queensland, Victoria and Tasmania spanning 15° of latitude. Age of onset data from Queensland were utilised to estimate age-adjusted recurrence rates. RESULTS: Recurrence risks in Australia were significantly lower than in studies from northern hemisphere populations. The age-adjusted risk for siblings across Australia was 2.13% compared with 3.5% for the northern hemisphere. A similar pattern was seen for other relatives. The risks to relatives were proportional to the population risks for each site, and hence the sibling recurrence-risk ratio (λ(s)) was similar across all sites. DISCUSSION: The familial recurrence risk of MS in Australia is lower than in previously reported studies. This is directly related to the lower population prevalence of MS. The overall genetic susceptibility in Australia as measured by the λ(s) is similar to the northern hemisphere, suggesting that the difference in population risk is explained largely by environmental factors rather than by genetic admixture.

Talking the talk : therapeutic jurisprudence and oral competence

In Australian criminal justice systems, a wide range of pathways to sentencing and punishment exist alongside traditional court processes. In particular, therapeutic jurisprudence ('TJ') processes have emerged during the last quarter of a century and now occupy a key position in the criminal justice landscape. This article provides an introduction to TJ, highlighting in particular the emphasis it places on the active participation of offenders, before critically discussing offenders' capacity to engage with TJ processes. The article then summarises the research on the oral competence of offenders, and argues that offenders who lack oral competence may be disadvantaged in TJ processes. Finally, we provide an overview of the limited guidance that has been provided to TJ practitioners on how to maximise the participation of offenders with limited oral competence.

Human exposure to brominated flame retardants

Human polybrominated diphenyl ether (PBDE) exposure occurs through a range of pathways including: ingestion of dust including hand-to-mouth contact; inhalation (air/particulate matter); and ingestion via food including the unique nutrition sources of human milk and placental transfer. While inhalation has been deemed a minor source of exposure, ingestion of food and dust make greater contributions to overall PBDE body burden with intake via dust reported to be much higher in infants than in adults. PBDEs have been detected in samples of human milk, blood serum, cord blood, and adipose tissue worldwide. Concentrations have been found to be highest in populations from North America, followed by Australia, Europe, and Asia. While factors such as gender and parity may not affect concentrations, occupational exposure and age (infants and children) are associated with higher PBDE concentrations. In contrast to “traditional” persistent organic pollutants, there is an inverse relationship between PBDE body burden and age. Predicted body burden calculated using available information on intake and elimination rates of BFRs appears to underestimate measured human body burden data obtained through analysis of BFRs in blood or human milk. This may be due to unknown exposure or inaccurate elimination data. Further exposure studies should focus on younger age groups and an investigation of human PBDE half-lives.

Aberrant fibroblast growth factor receptor signaling in bladder and other cancers

Fibroblast growth factors (FGFs) are potent mitogens, morphogens, and inducers of angiogenesis, and FGF signaling governs the genesis of diverse tissues and organs from the earliest stages. With such fundamental embryonic and homeostatic roles, it follows that aberrant FGF signaling underlies a variety of diseases. Pathological modifications to FGF expression are known to cause salivary gland aplasia and autosomal dominant hypophosphatemic rickets, while mutations in FGF receptors (FGFRs) result in a range of skeletal dysplasias. Anomalous FGF signaling is also associated with cancer development and progression. Examples include the overexpression of FGF2 and FGF6 in prostate cancer, and FGF8 overexpression in breast and prostate cancers. Alterations in FGF signaling regulators also impact tumorigenesis, which is exemplified by the down-regulation of Sprouty 1, a negative regulator of FGF signaling, in prostate cancer. In addition, several FGFRs are mutated in human cancers (including FGFR2 in gastric cancer and FGFR3 in bladder cancer). We recently identified intriguing alterations in the FGF pathway in a novel model of bladder carcinoma that consists of a parental cell line (TSU-Pr1/T24) and two sublines with increasing metastatic potential (TSU-Pr1-B1 and TSU-Pr1-B2), which were derived successively through in vivo cycling. It was found that the increasingly metastatic sublines (TSU-Pr1-B1 and TSU-Pr1-B2) had undergone a mesenchymal to epithelial transition. FGFR2IIIc expression, which is normally expressed in mesenchymal cells, was increased in the epithelial-like TSU-Pr1-B1 and TSU-Pr1-B2 sublines and FGFR2 knock-down was associated with the reversion of cells from an epithelial to a mesenchymal phenotype. These observations suggest that modified FGF pathway signaling should be considered when studying other cancer types.

Carcinoma ex pleomorphic adenoma : a comprehensive review of clinical, pathological and molecular data

Carcinoma ex pleomorphic adenoma (Ca ex PA) is a carcinoma arising from a primary or recurrent benign pleomorphic adenoma. It often poses a diagnostic challenge to clinicians and pathologists. This study intends to review the literature and highlight the current clinical and molecular perspectives about this entity. The most common clinical presentation of CA ex PA is of a firm mass in the parotid gland. The proportion of adenoma and carcinoma components determines the macroscopic features of this neoplasm. The entity is difficult to diagnose pre-operatively. Pathologic assessment is the gold standard for making the diagnosis. Treatment for Ca ex PA often involves an ablative surgical procedure which may be followed by radiotherapy. Overall, patients with Ca ex PA have a poor prognosis. Accurate diagnosis and aggressive surgical management of patients presenting with Ca ex PA can increase their survival rates. Molecular studies have revealed that the development of Ca ex PA follows a multi-step model of carcinogenesis, with the progressive loss of heterozygosity at chromosomal arms 8q, then 12q and finally 17p. There are specific candidate genes in these regions that are associated with particular stages in the progression of Ca ex PA. In addition, many genes which regulate tumour suppression, cell cycle control, growth factors and cell-cell adhesion play a role in the development and progression of Ca ex PA. It is hopeful that these molecular data can give clues for the diagnosis and management of the disease.

Analysis of the extreme diversity of salivary alpha-amylase isoforms generated by physiological proteolysis using liquid chromatography-tandem mass spectrometry

Saliva is a crucial biofluid for oral health and is also of increasing importance as a non-invasive source of disease biomarkers. Salivary alpha-amylase is an abundant protein in saliva, and changes in amylase expression have been previously associated with a variety of diseases and conditions. Salivary alpha-amylase is subject to a high diversity of post-translational modifications, including physiological proteolysis in the oral cavity. Here we developed methodology for rapid sample preparation and non-targeted LC-ESI-MS/MS analysis of saliva from healthy subjects and observed an extreme diversity of alpha-amylase proteolytic isoforms. Our results emphasize the importance of consideration of post-translational events such as proteolysis in proteomic studies, biomarker discovery and validation, particularly in saliva. (C) 2012 Elsevier B.V. All rights reserved.

Comparison of intraspecific genetic structure among related chironomids (Diptera) from New Zealand and Patagonia : disparity between potential and realized dispersal

Population genetic studies of freshwater invertebrate taxa in New Zealand and South America are currently few despite the geologically and climatically dynamic histories of these regions. The focus of our study was a comparison of the influence on realized dispersal of 2 closely related nonbiting midges (Chironomidae) of population fragmentation on these separated austral land masses. We used a 734-base pair (bp) fragment of cytochrome c oxidase subunit I (COI) to investigate intraspecific genetic structure in Naonella forsythi Boothroyd in New Zealand and Ferringtonia patagonica Edwards in Patagonia. We proposed hypotheses about their potential dispersal and, hence, expected patterns of genetic structure in these 2 species based on published patterns for the closely related Australian taxon Echinocladius martini Cranston. Genetic structure revealed for both N. forsythi and F. patagonica was characterized by several highly divergent (2.0–10.5%) lineages of late Miocene–Pliocene age within each taxon that were not geographically localized. Many were distributed widely. This pattern differed greatly from population structure in E. martini, which was typified by much greater endemicity of divergent genetic lineages. Nevertheless, diversification of lineages in all 3 taxa appeared to be temporally congruent with the onset of late Miocene glaciations in the southern hemisphere that may have driven fragmentation of suitable habitat, promoting isolation of populations and divergence in allopatry. We argue that differences in realized dispersal post-isolation may be the result of differing availability of suitable habitat in interglacial periods.

Extinction risk analysis of exploited green turtle stocks in the Indo-Pacific

In parts of the Indo-Pacific, large-scale exploitation of the green turtle Chelonia mydas continues to pose a serious threat to the persistence of this species; yet very few studies have assessed the pattern and extent of the impact of such harvests. We used demographic and genetic data in an age-based model to investigate the viability of an exploited green turtle stock from Aru, south-east Indonesia. We found that populations are decreasing under current exploitation pressures. The effects of increasingly severe exploitation activities at foraging and nesting habitat varied depending on the migratory patterns of the stock. Our model predicted a rapid decline of the Aru stock in Indonesia under local exploitation pressure and a shift in the genetic composition of the stock. We used the model to investigate the influence of different types of conservation actions on the persistence of the Aru stock. The results show that local management actions such as nest protection and reducing harvests of adult nesting and foraging turtles can have considerable conservation outcomes and result in the long-term persistence of genetically distinct management units. © 2010 The Authors. Animal Conservation © 2010 The Zoological Society of London.

Epigenetic modelling

The field of epigenetics looks at changes in the chromosomal structure that affect gene expression without altering DNA sequence. A large-scale modelling project to better understand these mechanisms is gaining momentum. Early advances in genetics led to the all-genetic paradigm: phenotype (an organism's characteristics/behaviour) is determined by genotype (its genetic make-up). This was later amended and expressed by the well-known formula P = G + E, encompassing the notion that the visible characteristics of a living organism (the phenotype, P) is a combination of hereditary genetic factors (the genotype, G) and environmental factors (E). However, this method fails to explain why in diseases such as schizophrenia we still observe differences between identical twins. Furthermore, the identification of environmental factors (such as smoking and air quality for lung cancer) is relatively rare. The formula also fails to explain cell differentiation from a single fertilized cell. In the wake of early work by Waddington, more recent results have emphasized that the expression of the genotype can be altered without any change in the DNA sequence. This phenomenon has been tagged as epigenetics. To form the chromosome, DNA strands roll over nucleosomes, which are a cluster of nine proteins (histones), as detailed in Figure 1. Epigenetic mechanisms involve inherited alterations in these two structures, eg through attachment of a functional group to the amino acids (methyl, acetyl and phosphate). These 'stable alterations' arise during development and cell proliferation and persist through cell division. While information within the genetic material is not changed, instructions for its assembly and interpretation may be. Modelling this new paradigm, P = G + E + EpiG, is the object of our study.

Leaf and inflorescence structure and phylogenetics of Tripogon and affiliated genera (Poaceae: Chloridoideae)

This thesis provides new knowledge on an understudied group of grasses, some of which are resurrection grasses (i.e. able to withstand extreme drought). The sole Australian species (Tripogon loliiformis) is morphologically diverse and could be more than one species. This study sought to determine how many species of Tripogon occur in Australia, their relationships to other species in the genus and to two other genera of resurrection grasses (Eragrostiella and Oropetium). Results of the research indicate there is not enough evidence, from DNA sequence data, to warrant splitting up T. loliiformis into multiple species. The extensive morphological diversity seems to be influenced by environmental conditions. The three genera are so closely related that they could be grouped into a single genus. This new knowledge opens up pathways for future investigations, including studying genes responsible for desiccation tolerance and the conservation of native grasses that occur in rocky habitats.

The empire of cancer: Gene patents and cancer voices

In his book, The Emperor of All Maladies, Siddhartha Mukherjee writes a history of cancer — "It is a chronicle of an ancient disease — once a clandestine, 'whispered-about' illness — that has metamorphosed into a lethal shape-shifting entity imbued with such penetrating metaphorical, medical, scientific, and political potency that cancer is often described as the defining plague of our generation." Increasingly, an important theme in the history of cancer is the role of law, particularly in the field of intellectual property law. It is striking that a number of contemporary policy debates over intellectual property and public health have concerned cancer research, diagnosis, and treatment. In the area of access to essential medicines, there has been much debate over Novartis’ patent application in respect of Glivec, a treatment for leukaemia. India’s Supreme Court held that the Swiss company’s patent application violated a safeguard provision in India’s patent law designed to stop evergreening. In the field of tobacco control, the Australian Government introduced plain packaging for tobacco products in order to address the health burdens associated with the tobacco epidemic. This regime was successfully defended in the High Court of Australia. In the area of intellectual property and biotechnology, there have been significant disputes over the Utah biotechnology company Myriad Genetics and its patents in respect of genetic testing for BRCA1 and BRCA2, which are related to breast cancer and ovarian cancer. The Federal Court of Australia handed down a decision on the validity of Myriad Genetics’ patent in respect of genetic testing for BRCA1 in February 2013. The Supreme Court of the United States heard a challenge to the validity of Myriad Genetics’ patents in this area in April 2013, and handed down a judgment in July 2013. Such disputes have involved tensions between intellectual property rights, and public health. This article focuses upon one of these important test cases involving intellectual property, public health, and cancer research. In June 2010, Cancer Voices Australia and Yvonne D’Arcy brought an action in the Federal Court of Australia against the validity of a BRCA1 patent — held by Myriad Genetics Inc, the Centre de Recherche du Chul, the Cancer Institute of Japan and Genetic Technologies Limited. Yvonne D’Arcy — a Brisbane woman who has had treatment for breast cancer — maintained: "I believe that what they are doing is morally and ethically corrupt and that big companies should not control any parts of the human body." She observed: "For my daughter, I've had her have [sic] mammograms, etc, because of me but I would still like her to be able to have the test to see if the mutation gene is in there from me." The applicants made the following arguments: "Genes and the information represented by human gene sequences are products of nature universally present in each individual, and the information content of a human gene sequence is fixed. Genetic variations or mutations are products of nature. The isolation of the BRCA1 gene mutation from the human body constitutes no more than a medical or scientific discovery of a naturally occurring phenomenon and does not give rise to a patentable invention." The applicants also argued that "the alleged invention is not a patentable invention in that, so far as claimed in claims 1–3, it is not a manner of manufacture within the meaning of s 6 of the Statute of Monopolies". The applicants suggested that "the alleged invention is a mere discovery". Moreover, the applicants contended that "the alleged invention of each of claims 1-3 is not a patentable invention because they are claims for biological processes for the generation of human beings". The applicants, though, later dropped the argument that the patent claims related to biological processes for the generation of human beings. In February 2013, Nicholas J of the Federal Court of Australia considered the case brought by Cancer Voices Australia and Yvonne D’Arcy against Myriad Genetics. The judge presented the issues in the case, as follows: "The issue that arises in this case is of considerable importance. It relates to the patentability of genes, or gene sequences, and the practice of 'gene patenting'. Briefly stated, the issue to be decided is whether under the Patents Act 1990 (Cth) a valid patent may be granted for a claim that covers naturally occurring nucleic acid — either deoxyribonucleic acid (DNA) or ribonucleic acid (RNA) — that has been 'isolated'". In this context, the word "isolated" implies that naturally occurring nucleic acid found in the cells of the human body, whether it be DNA or RNA, has been removed from the cellular environment in which it naturally exists and separated from other cellular components also found there. The genes found in the human body are made of nucleic acid. The particular gene with which the patent in suit is concerned (BRCA1) is a human breast and ovarian cancer disposing gene. Various mutations that may be present in this gene have been linked to various forms of cancer including breast cancer and ovarian cancer.' The judge held in this particular case that Myriad Genetics’ patent claims were a "manner of manufacture" under s 6 of the Statute of Monopolies and s 18(1)(a) of the Patents Act 1990 (Cth). The matter is currently under appeal in the Full Court of the Federal Court of Australia. This article interprets the dispute over Myriad Genetics in light of the scholarly work of Nobel Laureate Professor Joseph Stiglitz on inequality. Such work has significant explanatory power in the context of intellectual property and biotechnology. First, Stiglitz has contended that "societal inequality was a result not just of the laws of economics, but also of how we shape the economy — through politics, including through almost every aspect of our legal system". Stiglitz is concerned that "our intellectual property regime … contributes needlessly to the gravest form of inequality." He maintains: "The right to life should not be contingent on the ability to pay." Second, Stiglitz worries that "some of the most iniquitous aspects of inequality creation within our economic system are a result of 'rent-seeking': profits, and inequality, generated by manipulating social or political conditions to get a larger share of the economic pie, rather than increasing the size of that pie". He observes that "the most iniquitous aspect of this wealth appropriation arises when the wealth that goes to the top comes at the expense of the bottom." Third, Stiglitz comments: "When the legal regime governing intellectual property rights is designed poorly, it facilitates rent-seeking" and "the result is that there is actually less innovation and more inequality." He is concerned that intellectual property regimes "create monopoly rents that impede access to health both create inequality and hamper growth more generally." Finally, Stiglitz has recommended: "Government-financed research, foundations, and the prize system … are alternatives, with major advantages, and without the inequality-increasing disadvantages of the current intellectual property rights system.’" This article provides a critical analysis of the Australian litigation and debate surrounding Myriad Genetics’ patents in respect of genetic testing for BRCA1. First, it considers the ruling of Nicholas J in the Federal Court of Australia that Myriad Genetics’ patent was a manner of manufacture as it related to an artificially created state of affairs, and not mere products of nature. Second, it examines the policy debate over gene patents in Australia, and its relevance to the litigation involving Myriad Genetics. Third, it examines comparative law, and contrasts the ruling by Nicholas J in the Federal Court of Australia with developments in the United States, Canada, and the European Union. Fourth, this piece considers the reaction to the decision of Nicholas at first instance in Australia. Fifth, the article assesses the prospects of an appeal to the Full Federal Court of Australia over the Myriad Genetics’ patents. Finally, this article observes that, whatever happens in respect of litigation against Myriad Genetics, there remains controversy over Genetic Technologies Limited. The Melbourne firm has been aggressively licensing and enforcing its related patents on non-coding DNA and genomic mapping.

Multivariate variance-components analysis in DTI

Twin studies are a major research direction in imaging genetics, a new field, which combines algorithms from quantitative genetics and neuroimaging to assess genetic effects on the brain. In twin imaging studies, it is common to estimate the intraclass correlation (ICC), which measures the resemblance between twin pairs for a given phenotype. In this paper, we extend the commonly used Pearson correlation to a more appropriate definition, which uses restricted maximum likelihood methods (REML). We computed proportion of phenotypic variance due to additive (A) genetic factors, common (C) and unique (E) environmental factors using a new definition of the variance components in the diffusion tensor-valued signals. We applied our analysis to a dataset of Diffusion Tensor Images (DTI) from 25 identical and 25 fraternal twin pairs. Differences between the REML and Pearson estimators were plotted for different sample sizes, showing that the REML approach avoids severe biases when samples are smaller. Measures of genetic effects were computed for scalar and multivariate diffusion tensor derived measures including the geodesic anisotropy (tGA) and the full diffusion tensors (DT), revealing voxel-wise genetic contributions to brain fiber microstructure.

Polymorphisms in the receptor tyrosine kinase MERTK gene are associated with Multiple Sclerosis susceptibility

Multiple sclerosis (MS) is a debilitating, chronic demyelinating disease of the central nervous system affecting over 2 million people worldwide. The TAM family of receptor tyrosine kinases (TYRO3, AXL and MERTK) have been implicated as important players during demyelination in both animal models of MS and in the human disease. We therefore conducted an association study to identify single nucleotide polymorphisms (SNPs) within genes encoding the TAM receptors and their ligands associated with MS. Analysis of genotype data from a genome-wide association study which consisted of 1618 MS cases and 3413 healthy controls conducted by the Australia and New Zealand Multiple Sclerosis Genetics Consortium (ANZgene) revealed several SNPs within the MERTK gene (Chromosome 2q14.1, Accession Number NG_011607.1) that showed suggestive association with MS. We therefore interrogated 28 SNPs in MERTK in an independent replication cohort of 1140 MS cases and 1140 healthy controls. We found 12 SNPs that replicated, with 7 SNPs showing p-values of less than 10-5 when the discovery and replication cohorts were combined. All 12 replicated SNPs were in strong linkage disequilibrium with each other. In combination, these data suggest the MERTK gene is a novel risk gene for MS susceptibility. © 2011 Ma et al.

Whole blood transcriptional profiling in ankylosing spondylitis identifies novel candidate genes that might contribute to the inflammatory and tissue-destructive disease aspects

Introduction: A number of genetic-association studies have identified genes contributing to ankylosing spondylitis (AS) susceptibility but such approaches provide little information as to the gene activity changes occurring during the disease process. Transcriptional profiling generates a 'snapshot' of the sampled cells' activity and thus can provide insights into the molecular processes driving the disease process. We undertook a whole-genome microarray approach to identify candidate genes associated with AS and validated these gene-expression changes in a larger sample cohort. Methods: A total of 18 active AS patients, classified according to the New York criteria, and 18 gender- and age-matched controls were profiled using Illumina HT-12 whole-genome expression BeadChips which carry cDNAs for 48,000 genes and transcripts. Class comparison analysis identified a number of differentially expressed candidate genes. These candidate genes were then validated in a larger cohort using qPCR-based TaqMan low density arrays (TLDAs). Results: A total of 239 probes corresponding to 221 genes were identified as being significantly different between patients and controls with a P-value <0.0005 (80% confidence level of false discovery rate). Forty-seven genes were then selected for validation studies, using the TLDAs. Thirteen of these genes were validated in the second patient cohort with 12 downregulated 1.3- to 2-fold and only 1 upregulated (1.6-fold). Among a number of identified genes with well-documented inflammatory roles we also validated genes that might be of great interest to the understanding of AS progression such as SPOCK2 (osteonectin) and EP300, which modulate cartilage and bone metabolism. Conclusions: We have validated a gene expression signature for AS from whole blood and identified strong candidate genes that may play roles in both the inflammatory and joint destruction aspects of the disease.

Genetic susceptibility to ankylosing spondylitis

Ankylosing spondylitis is a highly heritable, common rheumatic condition, primarily affecting the axial skeleton. The association with HLA-B27 has been demonstrated worldwide, and evidence for a role of HLA-B27 in disease comes from linkage and association studies in humans, and transgenic animal models. However, twin studies indicate that HLA-B27 contributes only 16% of the total genetic risk for disease. Furthermore, there is compelling evidence that non-B27 genes, both within and outwith the major histocompatability complex, are involved in disease aetiology. In this post-genomic era we have the tools to help elicit the genetic basis of disease. This review describes methods for genetic investigation of ankylosing spondylitis, and summarises the status of current research in this exciting area.