A transcription factor map as revealed by a genome-wide gene expression analysis of whole-blood mRNA transcriptome in multiple sclerosis

Background Several lines of evidence suggests that transcription factors are involved in the pathogenesis of Multiple Sclerosis (MS) but a complete mapping the whole network has been elusive. One of the reasons is that there are several clinical subtypes of MS and transcription factors which may be involved in one subtype may not be in others. We investigated the possibility that this network could be mapped using microarray technologies and modern bioinformatics methods on a dataset from whole blood in 99 untreated MS patients (36 Relapse Remitting MS, 43 Primary Progressive MS, and 20 Secondary Progressive MS) and 45 age-matched healthy controls, Methodology/Principal Findings We have used two different analytical methodologies: a differential expression analysis and a differential co-expression analysis, which have converged on a significant number of regulatory motifs that seem to be statistically overrepresented in genes which are either differentially expressed (or differentially co-expressed) in cases and controls (e.g. V$KROX_Q6, p-value < 3.31E-6; V$CREBP1_Q2, p-value < 9.93E-6, V$YY1_02, p-value < 1.65E-5). Conclusions/significance: Our analysis uncovered a network of transcription factors that potentially dysregulate several genes in MS or one or more of its disease subtypes. Analysing the published literature we have found that these transcription factors are involved in the early T-lymphocyte specification and commitment as well as in oligodendrocytes dedifferentiation and development. The most significant transcription factors motifs were for the Early Growth response EGR/KROX family, ATF2, YY1 (Yin and Yang 1), E2F-1/DP-1 and E2F-4/DP-2 heterodimers, SOX5, and CREB and ATF families.

Closing the case of APOE in multiple sclerosis : no association with disease risk in over 29,000 subjects

Background Single nucleotide polymorphisms (SNPs) rs429358 (ε4) and rs7412 (ε2), both invoking changes in the amino-acid sequence of the apolipoprotein E (APOE) gene, have previously been tested for association with multiple sclerosis (MS) risk. However, none of these studies was sufficiently powered to detect modest effect sizes at acceptable type-I error rates. As both SNPs are only imperfectly captured on commonly used microarray genotyping platforms, their evaluation in the context of genome-wide association studies has been hindered until recently. Methods We genotyped 12 740 subjects hitherto not studied for their APOE status, imputed raw genotype data from 8739 subjects from five independent genome wide association studies datasets using the most recent high-resolution reference panels, and extracted genotype data for 8265 subjects from previous candidate gene assessments. Results Despite sufficient power to detect associations at genome-wide significance thresholds across a range of ORs, our analyses did not support a role of rs429358 or rs7412 on MS susceptibility. This included meta-analyses of the combined data across 13 913 MS cases and 15 831 controls (OR=0.95, p=0.259, and OR 1.07, p=0.0569, for rs429358 and rs7412, respectively). Conclusion Given the large sample size of our analyses, it is unlikely that the two APOE missense SNPs studied here exert any relevant effects on MS susceptibility.

HLA-DRB1 associations with disease susceptibility and clinical course in Australians with multiple sclerosis

Human leucocyte antigen (HLA)-DRB1*1501 and other class II alleles influence susceptibility to multiple sclerosis (MS), but their contribution if any to the clinical course of MS remains uncertain. Here, we have investigated DRB1 alleles in a large sample of 1230 Australian MS cases, with some enrichment for subjects with primary progressive (PPMS) disease (n = 246) and 1210 healthy controls. Using logistic regression, we found that DRB1*1501 was strongly associated with risk (P = 7 x 10-45), as expected, and after adjusting for DRB1*1501, a predisposing effect was also observed for DRB1*03 (P = 5 x 10-7). Individuals homozygous for either DRB1*15 or DRB1*03 were considerably more at risk of MS than heterozygotes and non-carriers. Both the DRB1*04 and the DRB1*01/DRB1*15 genotype combination, respectively, protected against PPMS in comparison to subjects with relapsing disease. Together, these data provide further evidence of heterogeneity at the DRB1 locus and confirm the importance of HLA variants in the phenotypic expression of MS.

Multiple sclerosis and continence issues : an exploratory study

The study described in this article aimed to identify issues relating to incontinence and assess the impact of referral to a continence adviser on the lives of people with multiple sclerosis (MS). The study design used an in-depth, two-phase anonymous mail survey within a general community as nominated by the participants. Fifty-six people participated in phase 1 and eleven people completed phase 2. The results indicated that incontinence is a problem for the vast majority of participants — people with MS. One-third of the eligible participants took up the option of a consultation, assessment and treatment from a continence nurse. Reasons for not taking up the visit from the continence nurse included ‘managing OK’, ‘didn’t think it would help’, ‘embarrassed’ and ‘too busy’. Increasing awareness of urinary incontinence in the community is important and education needs to focus on at-risk groups in presenting the range of options available to assist people experiencing incontinence.

Environments For Healthy Living (EFHL) Griffith birth cohort study : characteristics of sample and profile of antenatal exposures

Background The Environments for Healthy Living (EFHL) study is a repeated sample, longitudinal birth cohort in South East Queensland, Australia. We describe the sample characteristics and profile of maternal, household, and antenatal exposures. Variation and data stability over recruitment years were examined. Methods Four months each year from 2006, pregnant women were recruited to EFHL at routine antenatal visits on or after 24 weeks gestation, from three public maternity hospitals. Participating mothers completed a baseline questionnaire on individual, familial, social and community exposure factors. Perinatal data were extracted from hospital birth records. Descriptive statistics and measures of association were calculated comparing the EFHL birth sample with regional and national reference populations. Data stability of antenatal exposure factors was assessed across five recruitment years (2006–2010 inclusive) using the Gamma statistic for ordinal data and chi-squared for nominal data. Results Across five recruitment years 2,879 pregnant women were recruited which resulted in 2904 live births with 29 sets of twins. EFHL has a lower representation of early gestational babies, fewer still births and a lower percentage of low birth weight babies, when compared to regional data. The majority of women (65%) took a multivitamin supplement during pregnancy, 47% consumed alcohol, and 26% reported having smoked cigarettes. There were no differences in rates of a range of antenatal exposures across five years of recruitment, with the exception of increasing maternal pre-pregnancy weight (p=0.0349), decreasing rates of high maternal distress (p=0.0191) and decreasing alcohol consumption (p<0.0001). Conclusions The study sample is broadly representative of births in the region and almost all factors showed data stability over time. This study, with repeated sampling of birth cohorts over multiple years, has the potential to make important contributions to population health through evaluating longitudinal follow-up and within cohort temporal effects.

Enabling open access to and re-use of publicly funded research data in Malaysian public universities : a legal and policy analysis

Numerous statements and declarations have been made over recent decades in support of open access to research data. The growing recognition of the importance of open access to research data has been accompanied by calls on public research funding agencies and universities to facilitate better access to publicly funded research data so that it can be re-used and redistributed as public goods. International and inter-governmental bodies such as the ICSU/CODATA, the OECD and the European Union are strong supporters of open access to and re-use of publicly funded research data. This thesis focuses on the research data created by university researchers in Malaysian public universities whose research activities are funded by the Federal Government of Malaysia. Malaysia, like many countries, has not yet formulated a policy on open access to and re-use of publicly funded research data. Therefore, the aim of this thesis is to develop a policy to support the objective of enabling open access to and re-use of publicly funded research data in Malaysian public universities. Policy development is very important if the objective of enabling open access to and re-use of publicly funded research data is to be successfully achieved. In developing the policy, this thesis identifies a myriad of legal impediments arising from intellectual property rights, confidentiality, privacy and national security laws, novelty requirements in patent law and lack of a legal duty to ensure data quality. Legal impediments such as these have the effect of restricting, obstructing, hindering or slowing down the objective of enabling open access to and re-use of publicly funded research data. A key focus in the formulation of the policy was the need to resolve the various legal impediments that have been identified. This thesis analyses the existing policies and guidelines of Malaysian public universities to ascertain to what extent the legal impediments have been resolved. An international perspective is adopted by making a comparative analysis of the policies of public research funding agencies and universities in the United Kingdom, the United States and Australia to understand how they have dealt with the identified legal impediments. These countries have led the way in introducing policies which support open access to and re-use of publicly funded research data. As well as proposing a policy supporting open access to and re-use of publicly funded research data in Malaysian public universities, this thesis provides procedures for the implementation of the policy and guidelines for addressing the legal impediments to open access and re-use.

Proof of concept : A bioinformatic and serological screening method for identifying new peptide antigens for Chlamydia trachomatis related sequelae in women

This study aimed to identify new peptide antigens from Chlamydia (C.) trachomatis in a proof of concept approach which could be used to develop an epitope-based serological diagnostic for C. trachomatis related infertility in women. A bioinformatics analysis was conducted examining several immunodominant proteins from C. trachomatis to identify predicted immunoglobulin epitopes unique to C. trachomatis. A peptide array of these epitopes was screened against participant sera. The participants (all female) were categorized into the following cohorts based on their infection and gynecological history; acute (single treated infection with C. trachomatis), multiple (more than one C. trachomatis infection, all treated), sequelae (PID or tubal infertility with a history of C. trachomatis infection), and infertile (no history of C. trachomatis infection and no detected tubal damage). The bioinformatics strategy identified several promising epitopes. Participants who reacted positively in the peptide 11 ELISA were found to have an increased likelihood of being in the sequelae cohort compared to the infertile cohort with an odds ratio of 16.3 (95% c.i. 1.65 – 160), with 95% specificity and 46% sensitivity (0.19-0.74). The peptide 11 ELISA has the potential to be further developed as a screening tool for use during the early IVF work up and provides proof of concept that there may be further peptide antigens which could be identified using bioinformatics and screening approaches.

Analysis of kinase gene expression in the frontal cortex of suicide victims: Implications of fear and stress

Suicide is a serious public health issue that results from an interaction between multiple risk factors including individual vulnerabilities to complex feelings of hopelessness, fear, and stress. Although kinase genes have been implicated in fear and stress, including the consolidation and extinction of fearful memories, expression profiles of those genes in the brain of suicide victims are less clear. Using gene expression microarray data from the Online Stanley Genomics Database 1 and a quantitative PCR, we investigated the expression profiles of multiple kinase genes including the calcium calmodulin-dependent kinase (CAMK), the cyclin-dependent kinase, the mitogen-activated protein kinase (MAPK), and the protein kinase C (PKC) in the prefrontal cortex (PFC) of mood disorder patients died with suicide (N = 45) and without suicide (N = 38). We also investigated the expression pattern of the same genes in the PFC of developing humans ranging in age from birth to 49 year (N = 46). The expression levels of CAMK2B, CDK5, MAPK9, and PRKCI were increased in the PFC of suicide victims as compared to non-suicide controls (false discovery rate, FDR-adjusted p < 0.05, fold change >1.1). Those genes also showed changes in expression pattern during the postnatal development (FDR-adjusted p < 0.05). These results suggest that multiple kinase genes undergo age-dependent changes in normal brains as well as pathological changes in suicide brains. These findings may provide an important link to protein kinases known to be important for the development of fear memory, stress associated neural plasticity, and up-regulation in the PFC of suicide victims. More research is needed to better understand the functional role of these kinase genes that may be associated with the pathophysiology of suicide

The health outcomes and costs of people attending an interdisciplinary chronic disease service in regional Australia : protocol for a longitudinal cohort investigation

Background Rates of chronic disease are escalating around the world. To date health service evaluations have focused on interventions for single chronic diseases. However, evaluations of the effectiveness of new intervention strategies that target single chronic diseases as well as multimorbidity are required, particularly in areas outside major metropolitan centres where access to services, such as specialist care, is difficult and where the retention and recruitment of health professionals affects service provision. Methods This study is a longitudinal investigation with a baseline and three follow-up assessments comparing the health and health costs of people with chronic disease before and after intervention at a chronic disease clinic, in regional Australia. The clinic is led by students under the supervision of health professionals. The study will provide preliminary evidence regarding the effectiveness of the intervention, and evaluate the influence of a range of factors on the health outcomes and costs of the patients attending the clinic. Patients will be evaluated at baseline (intake to the service), and at 3-, 6-, and 12-months after intake to the service. Health will be measured using the SF-36 and health costs will be measured using government and medical record sources. The intervention involves students and health professionals from multiple professions working together to treat patients with programs that include education and exercise therapy programs for back pain, and Healthy Lifestyle programs; as well as individual consultations involving single professions. Discussion Understanding the effect of a range of factors on the health state and health costs of people attending an interdisciplinary clinic will inform health service provision for this clinical group and will determine which factors need to be controlled for in future observational studies. Preliminary evidence regarding changes in health and health costs associated with the intervention will be a platform for future clinical trials of intervention effectiveness. The results will be of interest to teams investigating new chronic disease programs particularly for people with multimorbidity, and in areas outside major metropolitan centres.

Hepatitis C, mental health and equity of access to antiviral therapy : a systematic narrative review

Introduction Access to hepatitis C (hereafter HCV) antiviral therapy has commonly excluded populations with mental health and substance use disorders because they were considered as having contraindications to treatment, particularly due to the neuropsychiatric effects of interferon that can occur in some patients. In this review we examined access to HCV interferon antiviral therapy by populations with mental health and substance use problems to identify the evidence and reasons for exclusion. Methods We searched the following major electronic databases for relevant articles: PsycINFO, Medline, CINAHL, Scopus, Google Scholar. The inclusion criteria comprised studies of adults aged 18 years and older, peer-reviewed articles, date range of (2002--2012) to include articles since the introduction of pegylated interferon with ribarvirin, and English language. The exclusion criteria included articles about HCV populations with medical co-morbidities, such as hepatitis B (hereafter HBV) and human immunodeficiency virus (hereafter HIV), because the clinical treatment, pathways and psychosocial morbidity differ from populations with only HCV. We identified 182 articles, and of these 13 met the eligibility criteria. Using an approach of systematic narrative review we identified major themes in the literature. Results Three main themes were identified including: (1) pre-treatment and preparation for antiviral therapy, (2) adherence and treatment completion, and (3) clinical outcomes. Each of these themes was critically discussed in terms of access by patients with mental health and substance use co-morbidities demonstrating that current research evidence clearly demonstrates that people with HCV, mental health and substance use co-morbidities have similar clinical outcomes to those without these co-morbidities. Conclusions While research evidence is largely supportive of increased access to interferon by people with HCV, mental health and substance use co-morbidities, there is substantial further work required to translate evidence into clinical practice. Further to this, we conclude that a reconsideration of the appropriateness of the tertiary health service model of care for interferon management is required and exploration of the potential for increased HCV care in primary health care settings.

Intrusion detection in distributed systems, an approach based on taint marking

This paper presents a new framework for distributed intrusion detection based on taint marking. Our system tracks information flows between applications of multiple hosts gathered in groups (i.e., sets of hosts sharing the same distributed information flow policy) by attaching taint labels to system objects such as files, sockets, Inter Process Communication (IPC) abstractions, and memory mappings. Labels are carried over the network by tainting network packets. A distributed information flow policy is defined for each group at the host level by labeling information and defining how users and applications can legally access, alter or transfer information towards other trusted or untrusted hosts. As opposed to existing approaches, where information is most often represented by two security levels (low/high, public/private, etc.), our model identifies each piece of information within a distributed system, and defines their legal interaction in a fine-grained manner. Hosts store and exchange security labels in a peer to peer fashion, and there is no central monitor. Our IDS is implemented in the Linux kernel as a Linux Security Module (LSM) and runs standard software on commodity hardware with no required modification. The only trusted code is our modified operating system kernel. We finally present a scenario of intrusion in a web service running on multiple hosts, and show how our distributed IDS is able to report security violations at each host level.

Induction of multiple reinstatements of ethanol- and sucrose-seeking behavior in Long–Evans rats by the α-2 adrenoreceptor antagonist yohimbine

Rationale Developing models to efficiently explore the mechanisms by which stress can mediate reinstatement of drug-seeking behavior is crucial to the development of new pharmacotherapies for alcohol use disorders. Objectives We examined the effects of multiple reinstatement sessions using the pharmacological stressor, yohimbine, in ethanol- and sucrose-seeking rats in order to develop a more efficient model of stress-induced reinstatement. Methods Long–Evans rats were trained to self-administer 10% ethanol with a sucrose-fading procedure, 20% ethanol without a sucrose-fading procedure, or 5% sucrose in 30-min operant self-administration sessions, followed by extinction training. After reaching extinction criteria, the animals were tested once per week with yohimbine vehicle and yohimbine (2 mg/kg), respectively, 30 min prior to the reinstatement sessions or blood collection. Levels of reinstatement and plasma corticosterone (CORT) were determined each week for four consecutive weeks. Results Yohimbine induced reinstatement of ethanol- and sucrose-seeking in each of the 4 weeks. Interestingly, the magnitude of the reinstatement decreased for the 10% ethanol group after the first reinstatement session but remained stable for the 20% ethanol group trained without sucrose. Plasma CORT levels in response to injection of both vehicle and yohimbine were significantly higher in the ethanol-trained animals compared to sucrose controls. Conclusions The stable reinstatement in the 20% ethanol group supports the use of this training procedure in studies using within-subject designs with multiple yohimbine reinstatement test sessions. Additionally, these results indicate that the hormonal response to stressors can be altered following extinction from self-administration of relatively modest amounts of ethanol.

Ergonomic DHM systems - limitations and trends – a systematic literature review focused on the ‘future of ergonomics’

Digital Human Models (DHM) have been used for over 25 years. They have evolved from simple drawing templates, which are nowadays still used in architecture, to complex and Computer Aided Engineering (CAE) integrated design and analysis tools for various ergonomic tasks. DHM are most frequently used for applications in product design and production planning, with many successful implementations documented. DHM from other domains, as for example computer user interfaces, artificial intelligence, training and education, or the entertainment industry show that there is also an ongoing development towards a comprehensive understanding and holistic modeling of human behavior. While the development of DHM for the game sector has seen significant progress in recent years, advances of DHM in the area of ergonomics have been comparatively modest. As a consequence, we need to question if current DHM systems are fit for the design of future mobile work systems. So far it appears that DHM in Ergonomics are rather limited to some traditional applications. According to Dul et al. (2012), future characteristics of Human Factors and Ergonomics (HFE) can be assigned to six main trends: (1) global change of work systems, (2) cultural diversity, (3) ageing, (4) information and communication technology (ICT), (5) enhanced competiveness and the need for innovation, and; (6) sustainability and corporate social responsibility. Based on a literature review, we systematically investigate the capabilities of current ergonomic DHM systems versus the ‘Future of Ergonomics’ requirements. It is found that DHMs already provide broad functionality in support of trends (1) and (2), and more limited options in regards to trend (3). Today’s DHM provide access to a broad range of national and international databases for correct differentiation and characterization of anthropometry for global populations. Some DHM explicitly address social and cultural modeling of groups of people. In comparison, the trends of growing importance of ICT (4), the need for innovation (5) and sustainability (6) are addressed primarily from a hardware-oriented and engineering perspective and not reflected in DHM. This reflects a persistent separation between hardware design (engineering) and software design (information technology) in the view of DHM – a disconnection which needs to be urgently overcome in the era of software defined user interfaces and mobile devices. The design of a mobile ICT-device is discussed to exemplify the need for a comprehensive future DHM solution. Designing such mobile devices requires an approach that includes organizational aspects as well as technical and cognitive ergonomics. Multiple interrelationships between the different aspects result in a challenging setting for future DHM. In conclusion, the ‘Future of Ergonomics’ pose particular challenges for DHM in regards to the design of mobile work systems, and moreover mobile information access.

The multi-platform user engagement and data visualisation tool

The ability to identify and assess user engagement with transmedia productions is vital to the success of individual projects and the sustainability of this mode of media production as a whole. It is essential that industry players have access to tools and methodologies that offer the most complete and accurate picture of how audiences/users engage with their productions and which assets generate the most valuable returns of investment. Drawing upon research conducted with Hoodlum Entertainment, a Brisbane-based transmedia producer, this project involved an initial assessment of the way engagement tends to be understood, why standard web analytics tools are ill-suited to measuring it, how a customised tool could offer solutions, and why this question of measuring engagement is so vital to the future of transmedia as a sustainable industry. Working with data provided by Hoodlum Entertainment and Foxtel Marketing, the outcome of the study was a prototype for a custom data visualisation tool that allowed access, manipulation and presentation of user engagement data, both historic and predictive. The prototyped interfaces demonstrate how the visualization tool would collect and organise data specific to multiplatform projects by aggregating data across a number of platform reporting tools. Such a tool is designed to encompass not only platforms developed by the transmedia producer but also sites developed by fans. This visualisation tool accounted for multiplatform experience projects whose top level is comprised of people, platforms and content. People include characters, actors, audience, distributors and creators. Platforms include television, Facebook and other relevant social networks, literature, cinema and other media that might be included in the multiplatform experience. Content refers to discreet media texts employed within the platform, such as tweet, a You Tube video, a Facebook post, an email, a television episode, etc. Core content is produced by the creators’ multiplatform experiences to advance the narrative, while complimentary content generated by audience members offers further contributions to the experience. Equally important is the timing with which the components of the experience are introduced and how they interact with and impact upon each other. Being able to combine, filter and sort these elements in multiple ways we can better understand the value of certain components of a project. It also offers insights into the relationship between the timing of the release of components and user activity associated with them, which further highlights the efficacy (or, indeed, failure) of assets as catalysts for engagement. In collaboration with Hoodlum we have developed a number of design scenarios experimenting with the ways in which data can be visualised and manipulated to tell a more refined story about the value of user engagement with certain project components and activities. This experimentation will serve as the basis for future research.