Epigenetic mechanisms mediating vulnerability and resilience to psychiatric disorders

The impact that stressful encounters have upon long-lasting behavioural phenotypes is varied. Whereas a significant proportion of the population will develop "stress-related" conditions such as post-traumatic stress disorder or depression in later life, the majority are considered "resilient" and are able to cope with stress and avoid such psychopathologies. The reason for this heterogeneity is undoubtedly multi-factorial, involving a complex interplay between genetic and environmental factors. Both genes and environment are of critical importance when it comes to developmental processes, and it appears that subtle differences in either of these may be responsible for altering developmental trajectories that confer vulnerability or resilience. At the molecular level, developmental processes are regulated by epigenetic mechanisms, with recent clinical and pre-clinical data obtained by ourselves and others suggesting that epigenetic differences in various regions of the brain are associated with a range of psychiatric disorders, including many that are stress-related. Here we provide an overview of how these epigenetic differences, and hence susceptibility to psychiatric disorders, might arise through exposure to stress-related factors during critical periods of development.

Genome-wide analysis in a murine Dnmt1 knockdown model identifies epigenetically silenced genes in primary human pituitary tumors

DNA methylation at promoter CpG islands (CGI) is an epigenetic modification associated with inappropriate gene silencing in multiple tumor types. In the absence of a human pituitary tumor cell line, small interfering RNA-mediated knockdown of the maintenance methyltransferase DNA methyltransferase (cytosine 5)-1 (Dnmt1) was used in the murine pituitary adenoma cell line AtT-20. Sustained knockdown induced reexpression of the fully methylated and normally imprinted gene neuronatin (Nnat) in a time-dependent manner. Combined bisulfite restriction analysis (COBRA) revealed that reexpression of Nnat was associated with partial CGI demethylation, which was also observed at the H19 differentially methylated region. Subsequent genome-wide microarray analysis identified 91 genes that were significantly differentially expressed in Dnmt1 knockdown cells (10% false discovery rate). The analysis showed that genes associated with the induction of apoptosis, signal transduction, and developmental processes were significantly overrepresented in this list (P < 0.05). Following validation by reverse transcription-PCR and detection of inappropriate CGI methylation by COBRA, four genes (ICAM1, NNAT, RUNX1, and S100A10) were analyzed in primary human pituitary tumors, each displaying significantly reduced mRNA levels relative to normal pituitary (P < 0.05). For two of these genes, NNAT and S100A10, decreased expression was associated with increased promoter CGI methylation. Induced expression of Nnat in stable transfected AtT-20 cells inhibited cell proliferation. To our knowledge, this is the first report of array-based "epigenetic unmasking" in combination with Dnmt1 knockdown and reveals the potential of this strategy toward identifying genes silenced by epigenetic mechanisms across species boundaries.

Price linkages in the copper futures, primary, and scrap markets

This study investigates how markets for different levels of copper purity are interrelated by testing the long-run price linkage and causalities among the copper futures, primary, copper scrap, and brass scrap markets. It is expected that copper markets that deal with high purity levels, such as the futures, primary, and copper scrap markets, have a long-run relationship. However, brass scrap markets where copper with a lower purity is traded may not have a price linkage with other copper markets. The results reveal that a long-run relationship holds between the futures, primary, and copper scrap markets but the brass scrap market does not have a long-run relationship with the other markets. From the short-run and long-run causality tests, we determine that the futures market plays an important role in transmitting price information to other copper markets while such information flow is not found for the brass scrap market.

Conceptions of learning held by Aboriginal students in a tertiary program in Indigenous primary health care

This paper is a description of a pilot investigation into conceptions of learning held by a sample of 10 Aboriginal students in a Bachelors degree courses. Results from this study suggest that this group of students view and approach learning in much the same way as other university students. They mostly hold quantitative conceptions of learning and use repetitive strategies which are potentially at odds with the objectives and procedures of the problems based program in which they are studying.

Integrated chronic disease management in primary-secondary care : a systematic literature review of the evidence

Introduction: Diabetes has traditionally been managed as a single chronic disease state, but it exists with co-morbidities such as depression and metabolic syndrome. Treatment is multifaceted, requiring both primary and secondary care, however, the delivery of diabetes care is often fragmented. Integrated chronic disease management is a growing model of interest, and is underpinned by the chronic care model (CCM), devised as a guide for primary care management of patients with chronic conditions. The model identifies six key elements for effective care, and has shown promise in improving the management of diabetes. Aim: To find empirical evidence of integrated care interventions targeted at co-morbidities including diabetes, across primary/secondary care. Method: A systematic review of peer reviewed literature from PubMed, CINAHL, Embase, Cochrane Library and Joanna Briggs was performed. Studies were reviewed according to inclusion criteria- studies published in English, between 2004-2014, empirical studies, studies with evidence of primary/secondary implementation, and those dealing with chronic co-morbid disease states. Results: 51 studies met the inclusion criteria. Included studies were mostly from the US (38), with five from Australia, UK (2), Canada (2), Netherlands (1), Norway (1), Ireland (1), and one multi-country study. It was found that all interventions adopted at least one (average 3-4) of the chronic care model, with the majority implementing delivery system redesign activities within the primary care practice/s. We found evidence of interventions which significantly reduced emergency department and hospital admissions, improved processes of care, patient health outcomes such as HbA1c, improved patient satisfaction, and reduced costs. Conclusion/Implications for practice: Diabetes exists as a co-morbid disease, requiring both primary and secondary care. We found that integrated care interventions adopting elements of the chronic care model positively impacted on patient outcomes, service utilisation, as well as costs. This review has highlighted that it may not be necessary to adopt all CCM elements to improve clinical outcomes, patient satisfaction and costs.

Age, physical inactivity, obesity, health conditions, and health-related quality of life among patients receiving conservative management for musculoskeletal disorders

Background Musculoskeletal conditions and insufficient physical activity have substantial personal and economic costs among contemporary aging societies. This study examined the age distribution, comorbid health conditions, body mass index (BMI), self-reported physical activity levels, and health-related quality of life of patients accessing ambulatory hospital clinics for musculoskeletal disorders. The study also investigated whether comorbidity, BMI, and self-reported physical activity were associated with patients’ health-related quality of life after adjusting for age as a potential confounder. Methods A cross-sectional survey was undertaken in three ambulatory hospital clinics for musculoskeletal disorders. Participants (n=224) reported their reason for referral, age, comorbid health conditions, BMI, physical activity levels (Active Australia Survey), and health-related quality of life (EQ-5D). Descriptive statistics and linear modeling were used to examine the associations between age, comorbidity, BMI, intensity and duration of physical activity, and health-related quality of life. Results The majority of patients (n=115, 51.3%) reported two or more comorbidities. In addition to other musculoskeletal conditions, common comorbidities included depression (n=41, 18.3%), hypertension (n=40, 17.9%), and diabetes (n=39, 17.4%). Approximately one-half of participants (n=110, 49.1%) self-reported insufficient physical activity to meet minimum recommended guidelines and 150 (67.0%) were overweight (n=56, 23.2%), obese (n=64, 28.6%), severely obese (n=16, 7.1%), or very severely obese (n=14, 6.3%), with a higher proportion of older patients affected. A generalized linear model indicated that, after adjusting for age, self-reported physical activity was positively associated (z=4.22, P<0.001), and comorbidities were negatively associated (z=-2.67, P<0.01) with patients’ health-related quality of life. Conclusion Older patients were more frequently affected by undesirable clinical attributes of comorbidity, obesity, and physical inactivity. However, findings from this investigation are compelling for the care of patients of all ages. Potential integration of physical activity behavior change or other effective lifestyle interventions into models of care for patients with musculoskeletal disorders is worthy of further investigation.

Q-RARA : a rapid and rigorous method for researching small, primary health care organisations

Understanding the organisational processes driving quality primary care is crucial to the maintaining and improving practice. Qualitative methods are increasingly popular in health services research, but this area is dominated by interview studies. Multiple qualitative methods are rarely used in a systematically integrated fashion. We developed a method to study small primary health care organizations using rapid appraisal and qualitative mixed methods: Q-RARA – Qualitative Rapid Appraisal, Rigorous Analysis